Understanding the Journey: A Parent's Guide to DIPG

Understanding the Journey: A Parent’s Guide to DIPG

Edited by Ruth I. Homan, MPH

(ACCO)

Printed in the United States of America

Published by American Childhood Cancer Organization

Cover and Interior Design: Ruth I. Homan MPH

Interior Layout: Ruth I. Homan, MPH, Devon Harp

Printing History: May 2012

ISBN 978-0-9854593-0-7

Library of Congress Control Number: 2012908135

e American Childhood Cancer Organization’s® name and logo are registered trademarks

of the national oce of the American Childhood Cancer Organization

. Visit us on the

web at: http://www.acco.org.

is book is written to provide information about childhood cancer and should not be

used as an alternative to receiving professional advice. Every eort has been made to ensure

that the information in this book is accurate at the time of printing, however, there is no

guarantee that the information will remain current over time. Always seek the advice of a

trained professional.

ACCO.ORG

Dedicated to all of the children who have battled or will battle

DIPG, and to Andrew Smith—for the impact you left on my life.

“It is only in the darkness, we can see the brightest stars.”

Martin Luther King Jr.

With the support of

Table of Contents

Preface vii

Part I. Understanding the Diagnosis

1. Brain Tumors 101 1

Violette Renard Recinos, MD, George I. Jallo, MD

2. Typical History of DIPG 17

Eric H. Raabe, MD, PhD, Kenneth Cohen, MD, MBA

3. Pontine Anatomy and Function 27

Sven Hochheimer, MD, Javad Nazarian, PhD, Suresh N. Magge, MD

4. Imaging DIPG 43

Jonathan Finlay, MD, Girish Dhall, MD, John Grimm, MD,

Stefan Bluml, PhD

Part II. Treatment

5. Clinical Trials for DIPG 71

Adam Cohen, MS, MD, Howard Colman, MD, PhD

6. Surgery: What it Can and Cannot Oer DIPG 89

Michael H. Handler, MD

7. Radiation erapy 101

Arthur Liu, MD, PhD

8. Radiosensitizers for DIPG 111

Roger J. Packer, MD

9. Chemotherapy and Biologics 123

David N. Korones, MD

10. e Use of Steroids in Patients with DIPG 139

Eric Bouet, MD, Ute Bartels, MD

Part III. Other Care Issues

11. Caring For Your Child At Home 153

Deborah Lafond, DNP, PNP-BC, CPON, CHPPN

12. Communication: When a Child Can No Longer Speak 193

Brownstone, MSW, RSW, Caelyn Kaise, MHSc, SLP (C), Reg. CASLPO,

Ceilidh Eaton Russell, CCLS, MSc (candidate)

Part IV. Research

13. Overcoming Research Hurdles in DIPG 223

Patricia Baxter, MD, Susan Blaney, MD

14. e Future of Genomics and Proteomics in DIPG 231

Mark W. Kieran, MD, PhD

15. Animal Models for DIPGs 239

Oren J. Becher, MD

16. Neural Stem Cells and DIPG 245

Michelle Monje, MD, PhD

17. Convection-Enhanced Delivery in DIPG 249

Zhiping Zhou, MD, PhD, Mark M. Souweidane, MD

18. Vaccine Treatment Strategies 269

Christopher Moertel, MD

Part V. End of Life Decisions

19. DIPG and Tissue Donation 273

Cynthia Hawkins, MD, PhD, Eric Bouet, MD, Ute Bartels, MD

20. Organ and Tissue Donation 285

Angela Punnett, MD, FRCPC

21. Integrating Palliative Care and Dicult Decisions 293

Justin N. Baker, MD, FAAP, FAAHPM, Adam J. Tyson, MD,

Javier R. Kane, MD

22. Journey of Sadness and Hopes: A Letter to Parents 319

Tammy I. Kang, MD, MSCE, Chris Feudtner, MD, PhD, MPH

Part VI. Appendices

A. Sample Medications Form 333

B. Glossary of Terms 335

C. Resources 343

D. Research Articles 355

VII

Preface

e American Childhood Cancer Organization’s (ACCO) mission is to provide

information and support for children and adolescents with cancer and their

families; to provide grassroots leadership through advocacy and awareness;

and to support research leading to a cure for all children diagnosed with this

life-threatening disease.

Since ACCO's founding in 1970, clinical research has increased the ve-year

survival rate of childhood cancer in the U.S. to approximately 80 percent. is

improvement in survival brings hope to tens of thousands of families whose

children are treated for cancer each year. In spite of the progress, however, too

many families still endure the loss of their precious son or daughter to cancer.

In the U.S. cancer continues to be the primary cause of death by disease in

childhood. As a result, families whose children are currently ghting this disease

need access to information to help them with the many treatment decisions

they must make; and there is an acute need for an increase in pediatric oncology

research funding that will lead to the development of new treatments for children

diagnosed with cancer in the future.

Among the many devastating childhood cancers, children who are diagnosed

with diuse intrinsic pontine glioma (DIPG) desperately need access to new

treatments. Regarded as the most aggressive of all pediatric brain tumors, all of

these children face a dismal prognosis. Currently, radiation therapy oers a short

reprieve from a ravaging disease. e tragedy of this disease is best expressed

in the following words from one parent's writing about her precious daughter.

"Imagine that you had a cherubic, mischievous, energetic and moody

two year old with ashing blue eyes, a brilliant smile and curly red

hair. Imagine that each morning she got you up at 5:15 a.m. by

standing up in her crib and shouting, "Maaamaaa, I'm awaaaake!

Maaamaaa, where are you?" Imagine if when you went into her

room she threw both her arms up towards you in a great big hug

and chattered her way into the living room, telling you she wanted

Cheerios for breakfast…with banana…and milk…and can we paint

now…and watch Caillou. Imagine if when you tried to get her dressed

Preface

VIII

Preface

in the morning, she ran away from you laughing, no matter how

exasperated you got. Imagine if she insisted on picking out her own

clothes, and you let her, rather than ght about it. Imagine if she

could sing the entire theme song to "Golden Girls," could go down

the slide on her own, could pee on the potty, catch a ball, dance and

chase her friends. Imagine when you step o the subway after work

and walk into her daycare room, all the kids turn to look at who has

entered the room, and when she sees you she ashes the most brilliant

smile and comes running with her arms up, saying "Mama! Mama!

Mama!" Imagine if no matter how many times she had a tantrum

and demanded things from you and exhausted you, she ended each

night with a snuggle and a kiss and you breathed in the smell of her

curls and felt warm happiness all over. Imagine if you could never

love anything as much as you loved your rst born child, your dream

come true, your daughter.

Now imagine it is 9 months later. Imagine she is lying next to you in

your bed. She can't walk. She can't use her arms or hands. She can't

hold her head up. She can't see the television. She can't tell you she

loves you. She can't hug you. She is lying in the bed sound asleep,

but coughing on her own saliva, which she is starting to choke on

because she can barely swallow. Imagine she was dying and there was

nothing you could do to change it. Imagine if you knew that one

day soon you would never get to see her again. Never see her smile,

feel her hand slip into yours, kiss her warm cheek, feel her sigh into

your chest.

at is the simple reality of what we are living with. And it's hard. No

matter how many good things happen to us, no matter how much

we believe in a bright future for ourselves and a time of healing, we

are being tortured. No matter how well or easily we manage to get

through the days, to talk with our friends, to laugh and joke and

even ght sometimes, we are broken inside. It's a very strange way

to live. We need to not focus only on what we are losing, but on all

we have gained, but despair creeps in nonetheless.

What is keeping us moving forward right now, even when our hearts

are completely broken, is watching how our daughter has chosen to

live her short life. How she treats each day as a new adventure; pushes

herself both physically and mentally to ensure that she accomplishes

what she wants on that particular day. Sometimes it's something

big—painting with her mouth and visiting the pigs at the farm. And

sometimes it's just being able to mouth the words "ice cream," and

then napping most of the day. But she is always true to herself, and

even though things are hard for her, she ignores the barriers of DIPG

and chooses to forge her own path. Most importantly, she believes

that when life gives you a hundred reasons to cry, you need to nd a

thousand reasons to smile…And in my own smiles, I have become

familiar with the bittersweet taste of getting to parent my precious

daughter—the best experience in the world, but like a spring day

that is much, much, too short."

As this parent so eloquently states, having a child diagnosed with DIPG is the

most dicult journey that any parent will ever endure. is book was written to

help parents understand that journey so that they are better equipped to make

decisions regarding their child’s diagnosis, treatment, entry into clinical trials,

palliative care and quality of life during this critical time. It was also written to

provide hope for a future when children diagnosed with DIPG will be cured

of their disease and able to live long and healthy lives.

e Contributors

In November 2009, I was introduced to Andrew Smith—a magical young boy

who was battling DIPG. He was hospitalized at the National Institutes of Health

(NIH) in Bethesda, Maryland, where he and his family were making a decision

regarding his participation in a clinical trial. It was anksgiving, and through

Andrew's determination to communicate and the communication skills of his

parents with the "yes/no" questioning technique, we learned that the hospital

menu did not include pumpkin pie—a "must have" item during the holiday

season. We also learned that Andrew (who was a "foodie") would love not just

a piece of pumpkin pie, but an entire pie! I was blessed with making that for

Andrew, and also blessed with his life and the personal introduction to DIPG.

Around the same time, Loice Swisher—a friend and fellow childhood cancer

advocate—informed me of the need for a book that parents could turn to that

would assist them with their understanding of the disease and the treatment

decisions they needed to make on behalf of their children. We worked up a draft

of potential chapters and authors and thus began the "journey" of this book.

Our hope was to provide essential information from the diagnosis of DIPG

through to the end of life. Clinicians and scientists who were researching and/

or treating children with DIPG were asked to volunteer their time and expertise

Preface

in the writing of this much needed resource. Every expert who was asked agreed

to participate—each contributing a chapter that detailed their DIPG research

and/or their clinical specialty.

To add a perspective from the 'trenches,' each chapter (with the exception of

the research chapters), is followed by personal stories written by parents. ese

sections entitled “Parent Perspectives” illustrate the despair and the hope that

accompany the DIPG experience. As with all hardships, those individuals

who have endured life's burdens become experts in their personal journeys.

Like the professionals who are researching and treating our nation's children

with brainstem glioma, parents of children with DIPG also became experts in

knowing how to provide the best of care for their children.

I am deeply indebted to the following professionals who gave of their time and

expertise to author comprehensive chapters for this book. My deepest gratitude

is extended to: Violette Renard Recinos, MD, George I. Jallo, MD, Eric H.

Raabe, MD, PhD, Kenneth Cohen, MD, MBA, Sven Hochheimer, MD, Javad

Nazarian, PhD, Suresh N. Magge, MD, Jonathan Finlay, MD, Girish Dhall,

MD, John Grimm, MD, Stefan Bluml, PhD, Adam Cohen, MS, MD, Howard

Colman, MD, PhD, Michael H. Handler, MD, Arthur Liu, MD, PhD, Roger

J. Packer, MD, David N. Korones, MD, Eric Bouet, MD, Ute Bartels, MD,

Deborah Lafond, DNP, PNP-BC, CPON, CHPPN, David Brownstone, MSW,

RSW, Caelyn Kaise, MHSc, SLP (C), Reg. CASLPO, Ceilidh Eaton Russell,

CCLS, MSc (candidate), Patricia Baxter, MD, Susan Blaney, MD, Mark W.

Kieran, MD, PhD, Oren J. Becher, MD, Michelle Monje, MD, PhD, Zhiping

Zhou, MD, PhD, Mark M. Souweidane, MD, Christopher Moertel, MD,

Cynthia Hawkins, MD, PhD, Angela Punnett, MD, FRCPC, Justin N. Baker,

MD, FAAP, AAHPM, Adam J. Tyson, MD, Javier R. Kane, MD, Tammy I.

Kang, MD, MSCE, and Chris Feudtner, MD, PhD, MPH.

My thanks would not be complete without expressing my deepest appreciation

to all of the parents who took their time to write and share their children's

personal stories. ere are 164 writings by parents in this book. ese stories give

credibility and passion to the book and emphasize why the book is so critically

needed. ese stories also serve as a reminder that these are the precious lives of

children who just want to grow up.

e words "ank you," cannot adequately express my gratitude for the time

that Sandy Smith spent pulling together the parent stories. Sandy is a woman

who has turned her own grief, from losing her son to DIPG, into generously

giving of herself to help DIPG families navigate their journeys. She makes herself

available—whether it's to assist a family as they are starting down this path, or to

facilitate tissue donation at the end of life. She makes herself available as a trusted

patient navigator and friend. As a result of working together on this book, I too

am proud to be able to call Sandy a very dear friend. I also want to personally

thank Kim Spady, Jonathan Agin and Nettie Boivin for the time they spent

reviewing parent stories, providing personal insight into the DIPG journey, and

for answering my emails day or night during the nal production phase of this

book. Your generosity of time and wisdom are appreciated more than you will

ever know.

My heartfelt appreciation is extended to Dr. Andrew von Eschenbach for the

thoughtful and compassionate words that he provided for the back cover copy

of this book. I am forever grateful for his commitment to childhood cancer

research and the role that he played during his term as Director of the NCI to

provide funding for TARGET—an initiative that utilizes genomic technologies

to identify therapeutic targets in childhood cancers (http://target.cancer.gov).

His belief that increasing eorts to target and control cancer by modulating and

altering the behavior of the disease on a molecular level directly resulted in the

funding of this innovative childhood cancer research project.

I am personally grateful to Dr. Peter Adamson, Chair of the Children's Oncology

Group, for also contributing to the back cover copy text of this book. Dr.

Adamson's dedication to children with cancer as a clinician, and his strong

leadership as chair of the world's largest pediatric oncology clinical trial research

group, is inspirational.

Finally, I wish to thank Ryan and Maria Reilly for sharing the picture of their

precious son Liam which graces the cover of this book. Liam responded to

radiation and was given the "gift of a honeymoon period." His "bucket list" during

that brief time included visiting the special place where this photo was taken.

By sharing Liam in this way, Ryan and Maria have personalized the disease for

many, and are building awareness of DIPG as a result. anks as well to Marie-

Dominique Verdier of Sand Point Photography for her help with enhancing and

cropping the photo for the book cover. My sincere gratitude is also extended to

ACCO board member Nicole Roman for suggesting the title of the book as a

result of her daughter Sophia's childhood cancer journey.

Book Composition

is book is written for both parents of children diagnosed with DIPG, as well

as health care providers. Chapters are written independently so parents and

providers are encouraged to read those chapters that most directly apply to a

Preface

XII

XIII

Preface

child's current medical needs. For example, parents with a newly diagnosed

child might want to start with chapter 10: e Use of Steroids in Patients with

DIPG. Others might want to read the book from start to nish.

e book is divided into six major sections. Part I: Understanding the

Diagnosis provides an overview of diuse intrinsic pontine glioma including

the diagnosis and typical history, pontine anatomy and function, and DIPG

imaging.

Part II: Treatment outlines treatment related issues including clinical trial

design, surgery, radiation, radiosensitizers to treat DIPG, chemotherapy and

biologics, as well as the use of steroids.

Part III: Other Care Issues identies additional treatment concerns including

caring for your child at home, and provides information to assist with

communication when a child can no longer speak.

Part IV: Research provides an overview of the hurdles to DIPG research, as

well as the hope found through genomic and proteomic techniques, animal

model research, neural stem cell research, convection-enhanced delivery, and

vaccine treatment strategies for DIPG.

Part V: End of Life Decisions addresses the dicult questions that families

face as they come to the end of life stage. ese include autopsy tissue donation,

organ and tissue donation, as well as integrating palliative care while making

dicult decisions. e book concludes with a letter of hope written by two

physicians to families of children with DIPG.

Finally, there are four useful appendices at the end of the book.

• Appendix A includes a sample medications form.

• Appendix B provides a glossary of medical and research terms used

throughout the book.

• Appendix C lists a sampling of resources—books, websites, listservs, and

organizations that assist families of children with DIPG.

• Appendix D is a compilation of journal articles that provides further

reading opportunities for those wishing to dig deeper into a specic topic.

Acknowledgements

is book would not have been possible without nancial support. I am indebted

to Mr. and Mrs. A. James Clark, and Courtney Clark Pastrick of the Clark

Charitable Foundation for their generous donation that made the printing of this

book possible. eir commitment to making a dierence in the lives of children

is inspirational. ey are true heroes to children with cancer.

My heartfelt thanks to Joseph E. Robert, Jr. and e Team Julian Foundation,

founded by his family in loving memory of courageous Julian B. Boivin, for their

nancial support to cover additional expenses related to the distribution of the

book to families.

Finally, I am deeply grateful to Christine Martin for her nancial support from the

Just One More Day Foundation, which she started to honor the memory of her

daughter Alicia. rough her generosity, parents of children diagnosed with DIPG

will have access to information that will provide them with an understanding of

this dicult journey and assist them with the decisions they must make.

I come away from this book with a renewed burden for our nation's children

with cancer and their families. It is not good enough that 80 percent of America's

children with cancer survive. It is not acceptable that children diagnosed with

DIPG don't grow up to live out their dreams. We must never tire of the need

to increase awareness of the impact of childhood cancer in the United States.

As parents of children with cancer, and their advocates, we must continue to let

our voices be heard. We must continue to knock on politicians' doors and insist

that research for childhood cancer receive priority funding. We must continue

to do our part to raise funds to build programs that help children being treated

for cancer today, as well as research funds that will help children diagnosed with

cancer tomorrow.We must continue to work together in the belief that doing so

is the only way to make a dierence, and doing less is simply not good enough.

Ruth I. Homan, MPH

Executive Director, Editor

American Childhood Cancer Organization

Preface

XIV

“If there ever comes a day when we can’t be together, keep me

in your heart, I’ll stay there forever.”

Winnie the Pooh

Chapter 1: Brain Tumors 101

Chapter 1

Brain Tumors 101

Violette Renard Recinos, MD

George I. Jallo, MD

Brain tumors are the most common solid tumor found in the pediatric

population. Each year, approximately 3,400 children are diagnosed with a

primary tumor of the central nervous system (CNS)—comprising the brain and

spinal cord. While all primary brain tumors arise from cells originating in the

brain, these CNS tumors can dier signicantly with regards to location, cell

origin and pathology, clinical manifestations, prognosis, and treatment options.

Some of these tumors may exhibit a slow benign (noncancerous) growth pattern,

while others are more aggressive and classied as malignant or cancerous. Due

to the sensitive, important structures of the CNS, even a benign tumor may

cause signicant clinical symptoms if located in or near critical brain or spine

structures. Similarly, surgical access to these so-called “benign” brain tumors can

be limited or dangerous, making the tumor inoperable and thus the potential

to act as a more malignant lesion over time.

Advances in imaging with computed tomography (CT) and magnetic resolution

imaging (MRI) allow clinicians to better visualize the mass and determine

key characteristics that may help dierentiate one tumor from another. By

evaluating the tumor size and shape, identifying its location and eect on

adjacent structures, and examining patterns of contrast enhancement (a

substance that enhances the contrast of body structures on medical imaging),

clinicians may be able to diagnose the tumor with imaging alone. Sometimes

further studies, such as blood work or cerebrospinal uid (CSF) analysis by

lumbar puncture—also called a spinal tap—can also help with the diagnosis.

When feasible, direct histological evaluation by either biopsy or tumor resection

is the gold standard in diagnosing the specic tumor type. Often, however,

the imaging, together with clinical presentation and a laboratory workup, can

help clinicians formulate the best suitable

treatment option for the patient.

Treatment of brain tumors can vary widely

Dr. Recinos is a Pediatric

Neurosurgeon at the Cleveland

Clinic Foundation, Cleveland, OH.

Chapter 1: Brain Tumors 101

and may include close clinical observation with interval imaging, surgical

resection, chemotherapy, radiation, or a combination of these modalities. e

exact combination of therapies will depend upon the expected behavior of

the tumor, and clinicians will need to carefully weigh the risks and benets of

the treatments. Pediatric tumors and their treatment dier from their adult

counterparts, especially as long-term eects from chemotherapy and radiation

have a greater impact on the developing CNS of a child.

Epidemiology of Brain Tumors

Brain tumors are the leading cause of cancer death in the pediatric population.

ey are the second most common malignancy in children behind leukemia, and

the most common solid tumor found in the pediatric population. According to

the 2009 statistical report of the Central Brain Tumor Registry of the United

States, 7% of all reported brain tumors are found in patients younger than

20 years of age. e overall incidence of brain tumors found in the age group

comprising 0–19 year olds is 4.58 per 100,000 individuals. Overall, there is a

slight male predominance in pediatric brain tumors, however, depending on

the individual histology, certain tumor subtypes are found more frequently in

females. Brain tumors are also more common in whites than blacks. e age

distribution varies depending upon the specic tumor, with certain tumors

such as pilocytic astrocytomas, malignant gliomas, and medulloblastomas more

common in the younger pediatric population of 0–14 year olds, while germ

cell tumors are more common in 15–19 year old age group.

e majority of pediatric tumors are located in the cerebral hemispheres, mainly

within the frontal, parietal, temporal, or occipital lobes, overall making up 24%

of brain tumors. Sixteen percent of tumors are found in the cerebellum, 12%

in the brainstem, 6% within the ventricles, 11.6% in the pituitary, and 3.2%

in the pineal region. e remaining less common sites include the meninges,

the cranial nerves, the spinal cord, and other brain areas.

Brain Tumor Histology and Classication

ere are more than 120 dierent classications of tumors, most of which are

classied by the cell type from which they arise. A better understanding of this

classication system can be gained through

a brief review of the cells that comprise the

central nervous system and its coverings.

As a very general overview, the majority

of CNS cells can be divided into two groups: neurons, which are cells that

send and receive electrochemical stimulation to and from the brain and spinal

cord, and glial cells, the cells that support neurons. ere are many dierent

types of neurons found throughout the brain which carry a variety of signals

depending on their function and location. Unlike many other cells in the body,

neurons, do not regenerate after damage, although there have been notable

exceptions to this rule. Glial cells are far more plentiful than neurons, making

up about 90% of brain cells. ese cells are further specialized to provide specic

functions to support the neuronal tissue. Some glial cells function to provide

structural or nutritional support, while others help to insulate the neurons,

provide defense against pathogens, and clean up cellular debris. e most

common glial cells are astrocytes, oligodendrocytes, Schwann cells, microglia,

and ependymal cells. Covering the brain and spinal cord is a membrane called

the meninges, comprised of meningothelial cells. Tumors may arise from any

of these subtypes and thus be named according to their cells of origin. Hence,

the terms astrocytoma, oligodendroglioma, ependymoma, etc. may sound

familiar. You may frequently hear of tumors referred to as gliomas, or glial

tumors. ese are generally referring to tumors arising from astrocytes as these

are most commonly the cell of origin.

e World Health Organization (WHO) has categorized gliomas into four

classications based on tumor aggressiveness and malignancy. WHO grade I

tumors are low-grade lesions that are non-inltrating and have well-dened

borders. ese tumors can be cured if in a location amenable to surgical

resection. ey are slow growing and may remain inactive, even if they are

not completely excised. Examples of WHO grade I tumors include pilocytic

astrocytomas and pleomorphic xanthoastrocytomas. WHO grade II tumors are

more inltrative. ese tumors tend to invade normal tissue, making complete

surgical resection more challenging than WHO grade I lesions, especially if

the tumors are located in critical brain structures. ese tumors tend to be

slower growing than the higher-grade lesions, but they may evolve into WHO

grade III or IV lesions over time. Examples of WHO grade II lesions are

oligodendrogliomas and low-grade astrocytomas. WHO grade III tumors are

known as anaplastic astrocytomas. ey are considered malignant because they

are inltrating, fast growing, and often require treatment with surgical resection,

chemotherapy, and radiation. Grade IV lesions, also known as glioblastoma

multiforme (GBM), are even more aggressive than anaplastic astrocytomas and

may grow so rapidly that they outgrow their blood supply and cause tumor

necrosis. GBMs are malignant lesions with poor prognosis regardless of the

treatment (e.g., surgery, radiation, and chemotherapy).

Dr. Jallo is a Professor of

Neurosurgery, Oncology, and

Pediatrics at the Johns Hopkins

Children’s Center, Baltimore, MD.

Chapter 1: Brain Tumors 101

Another cell type to note is the “embryonal” cell. In development, the neurons

and glial cells are thought to derive from a common progenitor cell that

dierentiates at dierent stages depending on certain genetic signaling and

other local factors. Several tumors in the pediatric population have features

that resemble this more primitive “embryonal” cell. ese tumors can be very

undierentiated or they can contain certain features that place them into a

more specic category depending on cytoarchitecture or immunohistochemical

staining. Included in this group are tumors such as medulloblastomas, primitive

neuroectodermal tumors (PNET), and atypical teratoid/rhabdoid tumors (ATRT).

Germ cell tumors are another group of tumors requiring special note. As with

embryonic tumors, germ cell tumors arise from cells that are not commonly

found in the adult brain. ese tumors originate from cells in the developing

embryo’s yolk sac endoderm that migrate throughout the embryo. ey

frequently are found in the pineal and suprasellar/pituitary region, as well as

the third ventricle and posterior fossa. Germinomas are the most common germ

cell tumors in the pediatric population.

Classication of Brainstem Gliomas

Overall, the most common brain tumors found in the pediatric population are

pilocytic astrocytomas, malignant gliomas, and medulloblastomas. Within the

glioma category, brainstem gliomas constitute 10–20% of all pediatric CNS

tumors. We will narrow the scope of our discussion to brainstem gliomas, as

they tend to present a unique and challenging tumor with its own classication

scheme that provides a framework to predict growth patterns, surgical

resectability, and overall prognosis.

Many classication schemes have been devised to categorize brainstem tumors

based on imaging and tumor characteristics. All of these systems categorize

tumors based on diffuse or focal imaging characteristics. Several more

complex classication systems further divide the tumors based on location,

growth pattern, and presence of hydrocephalus or hemorrhage. All of these

characteristics can be determined with a high-quality MRI image [Table 1].

1986 Diuse

Focal

Circumscribed mass less than 2 cm, no edema

Cervicomedullary

1991 Location

Midbrain, pons, medulla

Focality

Diuse or focal

Direction and extent of tumor growth

Degree of brainstem enlargement

Exophytic growth

Hemorrhage or necrosis

Evidence of hydrocephalus

1996 Focal

Midbrain, pons (dorsal exophytic pontine glioma), medulla

Diuse

Table 1: Classication Schemes for Brainstem Tumors

Figure 1a: Sagittal T1-weighted MRI showing the diuse pontine glioma with expansion

of the pons.

Chapter 1: Brain Tumors 101

One of the main characteristics determined on imaging is the degree of focality;

in other words, is the tumor diuse and inltrating or does it have a clearer

demarcation of margin? Diuse gliomas make up 58–75% of all brainstem

tumors and are the most common tumor found in this location. On MRI

imaging they have indistinct margins and

are characterized by diuse inltration

and swelling of the brainstem [Fig.

1 a, b, c]. ese tumors are usually located

within the pons, however they may also extend into other areas of the brainstem.

ese tumors have variable contrast enhancement and tend to be high-grade

lesions. e usual histopathology is typically a malignant brillary astrocytoma,

WHO grade III or IV.

Figure 1b: Axial Flair MRI sequence showing the pontine glioma, which involves the

entire pons.

Focal tumors have more clearly dened margins and, when in the brainstem,

are usually found in the midbrain, pons, or medulla [Fig. 2]. ey usually

are not inltrating and are not associated with swelling of adjacent structures,

also known as edema. ese focal tumors are often benign on histology and

Figure 1c: e axial T1 image shows the noncontrast enhancing and inltrative tumor.

graded as WHO grade I or II, although cases of more aggressive tumors have

been reported.

In addition to degree of focality, some classication schemes also consider

whether the tumor is primarily inside the brainstem, which is dened as

intrinsic, or if it resides mostly outside the brainstem, which is dened as

exophytic. Exophytic brainstem gliomas arise from the subependymal glial

tissue and the majority of the tumor is located in the fourth ventricle. ese

are usually well-dened tumors that are almost always low-grade gliomas.

Location of brainstem tumors is also a consideration when classifying them.For

example, cervicomedullary tumors, found where the lower part of the brainstem

connects to the top of the cervical spinal cord, tend to be slow growing and

focal lesions and thus are considered benign low-grade astrocytomas. However,

more aggressive cervicomedullary tumors, which are more inltrative and grow

up into the brainstem, have been found in this location.

Chapter 1: Brain Tumors 101

Figure 2a

Figure 2b

Using these classication schemes—combining degree of focality (i.e. diuse

or well delineated), intrinsic or exophytic, and tumor location—health care

providers can formulate a dierential diagnosis and establish a reasonable

treatment plan. Characteristics that may help further classify the tumor include

direction and extent of tumor growth, degree of brainstem enlargement,

hemorrhage or necrosis, and evidence of hydrocephalus.

Another simpler classication scheme divides brainstem tumors into typical and

atypical brainstem gliomas. e term typical brainstem gliomas is synonymous

with the term diuse intrinsic pontine gliomas (DIPG). As mentioned earlier,

these tumors are diuse and inltrative, located in the pons but potentially

extending into other areas of the brainstem. Surgery or biopsy of these lesions

is not usually recommended at this time, unless the diagnosis is in question.

Figure 2c

Figure 2a: Sagittal T1-weighted MRI with contrast shows a focal enhancing tumor in the

pons and midbrain. Figure 2b: T2 weighted axial image shows the focal noninltrative

or diuse nature of the tumor. Figure 2c: T1 weighted axial image shows a focal tumor,

which is not invading the pons or brainstem; this is a benign juvenile pilocytic astrocytoma.

Chapter 1: Brain Tumors 101

Parent Perspectives

Our world splintered into millions of pieces on Sunday, February 1st, when

Bryce at age 13 was sitting in church with us and he turned to look at me.

His eye turned in toward the center. Then it went back. I almost wasn’t

sure that I had seen it happen. Then, later in the day, Bryce had a hockey

game, and came off the ice to tell us that he could see two hockey nets, not

just one, and that “he had shot at the wrong one and missed.” We knew

something was wrong, and on Monday, we called for an appointment with

our family doctor. He had us in to see an eye specialist by that afternoon.

On February 10th, Bryce had a CAT scan, which didn’t show anything.

Luckily, the specialist was persistent, and he ordered an MRI. He told us

that at 13, an eye turning in was not “normal” if he didn’t have it at birth.

And so, Bryce’s journey began. On Feb. 26th, Bryce went for an MRI

where we were whisked out of the waiting room by a radiologist and sent

to Bryce’s pediatrician, who told us about the growth—a diffuse intrinsic

pontine glioma, which is a tumor located completely inside the brainstem.

He told us that treatment would involve going to Children’s Hospital, and

that he wanted us there that night. We were floored. I don’t remember much,

but I remember looking at Bryce’s face, and his eyes filling with tears. He

didn’t say much. None of us did, I think we were in shock. We went home

and packed a bag, and of course, family started pouring into our house

as we were preparing to leave. I was crying, and he just looked at me and

said, “It’s just cancer, mom. It will be fine.”



Blood was drawn and another series of neurological tests were performed.

Ellie was incredibly brave for the scan and held very still as the machine

whirled around her head. I remember being outside her room trying to find

water and hearing the emergency room doctor being paged by a doctor we

know through the girls’ school. My stomach jumped to my throat. An IV

was administered and an MRI was ordered. Ellie was very scared as she

felt fine and did not understand what was going on and why she needed

all these tests. She was exhausted.

My husband stayed with Ellie while my father, Ellie’s pediatrician and I

Atypical gliomas include the focal lesions which are well circumscribed. ey

may be contained in the brainstem or may grow out in cysts or outside of the

brainstem. Unlike typical brainstem gliomas, the atypical gliomas tend to arise

from the midbrain (the top of the brainstem) or the medulla. ese atypical

tumors tend to be lower grade lesions which may be amenable to some degree

of surgical resection or biopsy.

e majority of brainstem tumors are diuse pontine gliomas that are mainly

high grade on histological examination and have poor prognosis. In this book,

we will review the current treatment strategies, role for surgery, radiation and

chemotherapy, and future directions in the treatment of this disease.

Chapter 1: Brain Tumors 101

met with the neurosurgeon in a private area to view the scan. I really had

no clue what I was looking at but a child’s head. I looked around at the

three doctors and watched my father and our pediatrician find chairs. Their

faces said it all. Ellie’s golf ball size inoperable tumor was situated in the

pons of her brain stem and had grown to the point where it was sitting on

nerves that obviously affected her left side.

We spent the next three nights in the hospital medicating, testing and

meeting an army of staff to try and assist us in navigating through this

whole new world. We heard the words diffuse intrinsic pontine glioma…

can you please write that out? We were told surgery was not an option nor

was biopsy. We were devastated and heartbroken and my husband and I

challenged each other every moment of every day to keep our spirits high,

in order to be strong for Ellie.



The diagnosis came quick after a trip to Children's Hospital’s emergency

room. We were in a complete haze. I knew I needed to get a second opinion

and didn't know how to go about it and unbelievably I felt sheepish about

asking for the copies of the results—even though I did.

The second opinions came slow but we knew we had to act fast for any

treatment. We weren't given much hope but were told that radiation would

be the only thing that would relieve her symptoms and buy her some time;

maybe a year or two.

There was no chemo that anyone had any confidence in but we could always

try one that is well tolerated by some other kids. We did the exhausting

process of radiation and they said it would get worse before it gets better

and it did. After the radiation we thought we saw signs of the honeymoon

period. Unfortunately, the honeymoon was held off by an infection of her

shunt. After that was cleared we saw a fast improvement and we finally had

our old Tatumn back! But that time was soooo quick. By the time the steroids

were totally out of her system and her hair started to grow back from the

radiation her symptoms subtly started to reappear. Then her journey ended

very quickly. It was about 5 1/2 months total from diagnosis.



Lovis first had a CT scan at our local hospital after which we were told

about a mass in her cerebellum, most likely to be operable. Because it

was a Saturday night, we had to wait to be transferred to the Children's

Hospital where an MRI was done on Sunday night. The wait for the results

was terrible. Lovis was completely exhausted, weak and almost could not

speak or drink.

On Monday morning at 10:00 a.m. we were shown the scans and were

told that Lovis had diffuse intrinsic pontine glioma that presents itself as

tiny little spots all over the pons in the brainstem—thus inoperable and

sentencing our daughter to death in about 9 months even if we chose to

radiate. We fell apart. I remember screaming "No, no" and then turning

back to the screen, wanting to know EVERYTHING about this tumor. So

one nurse left and printed off more information right away.

We immediately opted for radiation, both my husband and I. But Lovis was

too weak for the daily sedation that goes with it since she had just turned

three. We were told to wait, try steroids and temozolomide for lack of better

agents, aware that the latter would not be a great help. The doctors thought

that even one general anesthetic would have been enough to kill Lovis if

we had started to radiate right away. If she didn't get better within a few

days, stronger and able to be sedated, she might likely die within the next

10 days. That was the diagnosis.



I was diagnosed with breast cancer on a Monday afternoon. Three days later

we ended up in the emergency room with my 6 year-old-son Andrew. After

a CT scan, a young physician's assistant came to talk with us, and I will

never forget her words. "There is a large area of swelling in the brainstem.

We suspect a mass." Andrew responded casually, "My mom has a mass!"

When I think of a mass, I think of a ball or an egg or something that can be

removed. I remember being told that there were parts of the mass reaching

out like fingers into the brain. It was not until eight months after diagnosis

that I truly understood the meaning of the word diffuse. We were not dealing

with fingers reaching into the brain. We were dealing with cancer cells

sprinkled among healthy brain cells in the pons (part of the brainstem).

Andrew's neuro-oncologist explained it by using the idea of sand (cancer

cells) in grass (healthy brain tissue). I have also heard people use the idea

of marbling in steak.



Chapter 1: Brain Tumors 101

Our oncologist and neurosurgeons we consulted with, told us the hard

truth but to the point that my husband and I were so discouraged that

we almost did nothing. Because of Connor's age they did not recommend

radiation and the evidence of effective chemo was null. We almost felt as

if we were dismissed with all of our questions and concerns because of the

known outcome with this type of tumor. We did go ahead with the radiation

and Connor was great for several months until the tumor didn't follow the

"typical course" so we were then sent for a third opinion and subsequently

a biopsy.

Six months after the original diagnosis we found out that Connor's pathology

report came back with a different tumor type. He had a new diagnosis of

a PNET which was some positive news we thought. The only problem was

by the time we found this out it had progressed in the brain and into the

spinal cord.



We did not know until a few months after diagnosis that a pediatric

oncologist is not a specialist in pediatric brain tumors. We were very

happy with our son's medical care, but we wish we would have understood

earlier the importance of having a pediatric neuro-oncologist involved

in the situation. Our level of understanding about our son's brain tumor,

possible treatments and related issues changed drastically as soon as we

established a relationship with a pediatric neuro-oncologist. Even though

this specialist was located in another state, she worked well with our son's

local team to manage his medical care. Looking back, that was the best

decision we made.



My mom, Bizzie and I headed to the emergency room. When we got there

we were taken into a room and told we were going to have to get Bizzie to

lie still for a CT scan. Well, when they talked about possibly sedating her,

I called my husband. Funny, but back then I could not even think about

holding her while she was sedated or undergoing a procedure. That would

change. I did get her to stay still for the CT scan by singing Row, Row, Row

your Boat to her repeatedly. I remember looking into the booth and seeing

the emergency room doctor look at the results. The technician walked us

back to the emergency room. They all knew. We did not—yet. My husband

was there when I returned. The emergency room doctor came in and spoke

to us, “There is a mass on her brainstem.”

I ran out of the room hysterical; but I returned in a minute. I needed to hear

this and be there for Bizzie. I remember snippets. She needed an MRI, which

meant an IV and sedation. The doctor told us that he suspected that it was

a diffuse intrinsic pontine glioma. The MRI would confirm this. She also

needed surgery to drain the fluid around her brain caused by the mass. We

would be admitted and she would be started on steroids. My husband asked

on a scale of 1 to 10 how bad was this? The doc quickly replied, “It’s bad.”

So Bizzie had her MRI. The anesthesiologist was impressed by Bizzie’s

strength when she came to. “Wow, she would do great in a bar-fight.” She

was kicking and hitting. I finally got her to calm down and we settled into

room 4 of the PICU. The pediatric neurosurgeon was sent the images from

the MRI and came in to talk to us about them. I sent my husband out to

talk to her. I stayed with Bizzie. When they came back, he had his poker

face on. He explained to me that it was a big tumor, and it could not be

removed surgically.

At that point I cut him off and turned to the neurosurgeon. "So, it’s

inoperable. What now?” She explained that standard treatment was

radiation followed by chemo, but that chemo was proven ineffective with

these types of tumors. I knew what she was saying. “So, how long?” I asked.

“Six to twenty-four months,” was her reply.

At that point Bizzie pulled my face back towards the book we were reading.

“Momma…READ!” I kissed her sweet little head. “Of course Bizzie, how

silly of me to not be paying attention to you.”

And that was diagnosis day.



At 3:00 p.m. I received a call from Liam's pediatrician's office. They asked

that we come in and that it would be better if we could leave our children

with a friend. I begged the woman who called to please tell me what was

wrong over the phone. She was very kind, but of course could not. They told

us we needed to come as soon as possible. I called my husband who was

at work a half hour away. I sat on my bathroom floor with the door locked

barely able to tell him he needed to come home, that something was wrong

with Liam's scan. It was the longest 30 minutes of my life while I waited

for him on our front porch. We drove in silence and my heart pounded. We

Chapter 1: Brain Tumors 101

sat for only moments in the doctor’s waiting room. They brought us into

an exam room where Liam's pediatrician gave us the news that they found

a lesion on his brain. I looked right at this woman and every part of me

thought she had to be to be lying to us and I just couldn't understand why.

Before I even realized, I heard myself calling this poor woman a liar and

asking her why she would lie about our son like that. She quickly came and

took my hand. I apologized after a moment. With great compassion she told

us what needed to happen next and that those plans had already been set in

motion. We would take Liam to the University Hospital the next day. Our

appointment was with a pediatric neuro- oncologist. In those very moments,

everything became marked with a new definition of time. Everything was

now defined as "before" and "after."

Chapter 2: Typical History of DIPG

Chapter 2

Typical History of DIPG

Eric H. Raabe, MD, PhD

Kenneth Cohen, MD, MBA

e brainstem is divided into three major areas—midbrain, pons and medulla—

and dierent types of tumors can occur in any of these locations. A glioma is a

tumor that arises from a cell in the brain called a glial cell. One type of glioma

is called an astrocytoma, which is a tumor that arises from a specic type of

glial cell called an astrocyte. e two major types of astrocytomas are pilocytic

astrocytomas and diuse, inltrating astrocytomas. e term DIPG specically

refers to a diuse, inltrating astrocytoma that develops in the pons.

Who is Aected by DIPG?

Each year approximately 200 children in the United States are diagnosed with

DIPG.e age range is broad, but the most common age at diagnosis is 7 to 9

years. All races and both sexes are equally aected.

Why do certain children get DIPG?

In short, doctors don’t know why. ere are no known associations of DIPG

with any environmental or infectious agents. Most researchers who study

DIPG believe these brain tumors, similar to other tumors aecting children,

arise when normal developmental and maturational processes go awry. In

this case, developing brain cells accumulate alterations in their DNA that

prevent them from properly maturing. ese alterations allow the developing

brain cells to continue growing, and this growth eventually becomes out of

control, leading to cancer. During the process of uncontrolled growth, DIPG

cells can gain DNA alterations that allow

them to resist the eects of radiation and

chemotherapy, making these cancer cells

extremely dicult to kill.

Dr. Raabe is an Instructor

in the Divison of Pediatric

Oncology, and Physician-

Scientist at the Sidney Kimmel

Comprehensive Cancer Center

at Johns Hopkins, Baltimore, MD.

Chapter 2: Typical History of DIPG

Clinical signs of DIPG

e signs and symptoms of DIPG can start gradually. As described in chapter 3,

the pons contains nerve centers that control eye movements, facial movements,

swallowing, and speech. As pontine glioma tumors grow, the cancer cells

interfere with these centers, causing disruption of their functions. Sometimes

parents notice odd eye movements, slurred speech, diculty swallowing, and

trouble maintaining balance, or drooping of one part of their child’s face. e

pons also contains nerves that run from the brain to the rest of the body. Pontine

tumors can press on and interfere with the function of these nerves, leading to

weakness in an arm and/or a leg.

Tumors in the brainstem can also cause increased pressure within the skull.

e swelling from the tumor can cause increased pressure directly, or it can

block the ow of spinal uid from the skull (where it is made) to the spinal

cord (where it is absorbed). Increased pressure can cause patients to complain

of persistent headaches and in some patients can lead to nausea and vomiting.

ese daily signs of increased pressure inside the skull will get worse over time,

as the tumor grows.

DIPG Appearance on MRI

A magnetic resonance imaging (MRI) scan is the best non-invasive way to

determine the size and properties of brain tumors. DIPGs have a characteristic

appearance on an MRI, which other tumors that grow in the pons or other

parts of the brainstem do not share. e boundaries of a DIPG are dicult to

determine, because the tumor cells invade the surrounding tissue of the pons.

A DIPG generally does not have portions of the tumor that push outside of

the pons’ normal structure. In contrast, a pilocytic astrocytoma, another less-

aggressive brainstem tumor, has a more focal appearance, is more likely to have

a part that buds out of the normal structure of the brainstem, and will displace

rather than invade surrounding brain tissue. e dierences between how a

pilocytic astroyctoma and a DIPG appear on an MRI are summarized in the

following table [Table 1].

DIPG Pilocytic Astrocytoma

Diuse Focal

Invasive into surrounding tissue Displaces surrounding structures and

tissue

Diuse brightness on T2 weighting

on MRI; no enhancement on T1

weighted images

Tumor well dened on T1 and T2

weighting MRI

Associated with brainstem swelling Minimal brainstem swelling

Located centrally in pons with

extension to midbrain or brainstem

Located in midbrain and brainstem

without extension

Table 1: MRI Characteristics of DIPG Compared with Pilocytic Astrocytoma

Because the MRI appearance of the two most common types of pediatric

brainstem tumors, DIPGs and pilocytic astrocytomas, are so dierent, they

can be accurately identied the vast majority of the time by MRI alone. In rare

cases where the diagnosis is uncertain based on MRI results, neurosurgeons

can perform biopsies to obtain small amounts of tissue for examination under

a microscope by pathologists (doctors trained to identify the type of tumor

by examining it under a microscope). e biopsy is performed very carefully,

but because the pons contains many important neurologic centers, including

those that control breathing and swallowing, there can be complications of

biopsy, including additional neurologic impairment. For these reasons, biopsy

is generally only performed in cases where the diagnosis is not clear from an

MRI scan. In the future, some clinical trials may include a biopsy to nd out

more information about the tumor prior to starting therapy.

Pathologic grading

Pathologists grade a tumor based on its features. e characteristics that

pathologists examine include cell growth, cell death, invasion of surrounding

normal cells, and the architecture of the tumor itself—this refers to how mature

or immature the cells look, among other factors.

Pathologists grade brainstem tumors on a 1 to 4 scale. e lower numbers

generally indicate less-aggressive tumors, including pilocytic astrocytomas.

e lowest grade consistent with a DIPG is a grade 2 tumor, but many DIPG

tumors will be grade 3 or 4 (the most-aggressive, fastest-growing grades).

Dr. Cohen is Clinical Director

of Pediatric Oncology and

Director of Pediatric Neuro-

oncology at the Sidney Kimmel

Comprehensive Cancer Center

at Johns Hopkins, Baltimore, MD.

Chapter 2: Typical History of DIPG

Clinical Course of DIPG

Once the diagnosis of a DIPG is suspected, anti-inammatory steroids (such

as dexamethasone) are usually started. e steroids can improve symptoms

quickly by decreasing the swelling associated with the tumor. Steroids can cause

side eects including increased moodiness, agitation, weight gain, increased

appetite and high blood pressure and blood sugar. ese last two side eects

can be controlled with medication, if they become severe.

e only treatment that is routinely recommended for the treatment of all

children with a DIPG is x-ray radiation therapy (XRT). XRT can be given

either alone or with chemotherapy and usually takes 4 to 6 weeks to complete.

Side eects during radiation can include mild nausea and fatigue.

Many chemotherapeutic drugs have been tried for DIPG, with studies looking

at the use of chemotherapy before XRT, during XRT, immediately following

XRT, and at the time of tumor progression. e results have been disappointing,

with no drug(s) to date improving survival. While pediatric oncologists continue

to develop new therapies for DIPG, the mainstay of current treatment remains

XRT. ere are ongoing clinical trials for DIPG, which allow new drugs to be

tested in this disease. While there are always risks when enrolling in clinical trials,

they are the best way to get your child the most promising new medications

and to make sure the pediatric oncology community learns all it can about

what therapies work best for DIPG.

Most DIPG tumors in the beginning respond to a combination of radiation

and steroids. e child’s neurologic decits will very often decrease and may

disappear completely. Over the course of weeks to months, the steroids can be

decreased and then stopped in many cases. e child can often return to school,

take special trips, and almost return to normal life. During this time, the child

has regular MRI scans to measure the regression of the tumor and monitor if

the tumor is coming back.

In almost all cases, after about 6 to 12 months, the DIPG tumor starts to grow

again. Sometimes the neurologic symptoms are the same as when the child was

rst diagnosed with DIPG. Sometimes new nerves and systems are aected.

e child will often begin to show neurologic symptoms even if the MRI scan

of the tumor appears largely unchanged.

Once the tumor has started to grow again, no further treatment has been shown

to improve survival. When children start to have neurologic symptoms, they are

often restarted on steroids. is treatment can sometimes improve symptoms for

a short time. However, the tumor will continue to grow, and even if the steroid

doses are increased, the child’s symptoms will continue to worsen. Eventually

the tumor grows until it aects nerve centers that are important for swallowing,

breathing, and controlling heartbeat.

If the tumor is blocking the ow of cerebrospinal uid (CSF), some parents—in

discussion with the doctors—may decide to have a neurosurgeon place a VP-

shunt to help with pressure symptoms. A VP-shunt is a exible plastic tube

that bypasses the blockage in the brainstem and allows the CSF uid to pass

out of the skull. Neurosurgeons place the shunt into the uid cistern in the

brain, and then pass it out of the skull, under the skin, and to the abdomen,

where the CSF is absorbed. is procedure can improve some of the headache

and nausea symptoms of increased intracranial pressure, and it can extend the

life of children with DIPG; it does not, however, change the ultimate outcome.

Only very few children are long-term survivors of DIPG. Because biopsies are

not performed on these children with typical appearing DIPGs, it is unclear

whether or not they actually had DIPG to start with, or in fact had a dierent

tumor or condition that looked like a DIPG on the MRI. ere is no one

treatment that these children received that set them apart from the vast majority

(more than 95 percent) of children who die from DIPG. Pediatric oncologists

are actively looking for new treatments and are trying to learn more about

DIPG. ey hope that by learning more from tumor tissue taken at autopsy

from children who die from DIPG they can help children who develop DIPG

in the future.

Chapter 2: Typical History of DIPG

Parent Perspectives

My son Andrew was diagnosed with DIPG following a couple months of

not feeling well. Initially we thought he had the same virus as his brother.

Perhaps he did, but he did not recover. He was clearly ill—sleeping more

than usual, feeling dizzy and unstable. Someone mentioned to us that it

was funny to watch him go upstairs. We began to notice that his gait was

not right. He looked like he was walking with one foot on the ground and

one foot on a curb, but there was no curb. He struggled to control his

left hand in a piano lesson, and almost fell leaving the studio that day.

When we thought about it, we realized that he had been falling regularly—

either from a standing position or while riding his bike. One night I had

difficulty rousing him from a nap, and had to hold his hand to help him

walk to Children's Church. That same night a nurse in our church noticed

that one side of his face was drooping. By the next morning he was clearly

feeling worse. He could not climb onto my bed, so he lay on the floor in

my bedroom while I called our primary care physician. He vomited, and

we settled him on my bed to rest. When we took him to the doctor that

afternoon, the physician's assistant sent us to the emergency room. All

along they had been thinking it was a virus or a problem with his ears; no

one was thinking it was a brain tumor.



We took our daughter in as a healthy looking beautiful child with only a

bit of drooling, facial numbness, and a bit of balance concern. All of these

symptoms were MINIMAL. If I hadn't insisted on an MRI (the neurologist

didn’t think it necessary but agreed to do it) we wouldn't have found the

tumor when we did. From there it was a whirlwind and you do what you do.



Although it is a blur in some respects, I clearly remember my first thoughts

and words when I was told that my grandson, Miguel had a diffuse intrinsic

pontine glioma. I remember the room clearly. It was a small room in the

PICU area of the hospital. My daughter told me that the doctor said that

if we were lucky Miguel would be with us for two years but the average

survival was around eight months and even then much of that time may

not be good. I remember saying to my daughter, "two days, two months,

two years, whatever it is I'll take it." He was alive at that moment and that

was all that mattered.

In retrospect, there were signs something was wrong but they could mostly

be attributed to normal things (allergies, eating too much too quickly,

tripping over his own growing feet). Over a weekend he began to hold his

head to the side (probably compensating for double vision) so a doctor's

visit was in order. Perhaps there was something wrong with his vision. At

the doctor's office, his pediatrician asked him to lie down and he wouldn't

lay flat. I am sure that he also saw something with the tracking in his eyes.

Miguel's pediatrician decided an MRI was in order and scheduled it for

that same week. Immediately following the MRI Miguel was admitted

to the hospital and placed in the PICU where he stayed for five days

while a plan was put in place. His treatment, we were told, would involve

radiation to try and shrink the tumor. If it responded well, he would have

a "honeymoon period.” His tumor was about 6 mm and the response to the

radiation was nothing short of amazing. All of his symptoms subsided and

he was even able to return to school to finish out the year.



After you’ve swallowed the words “average survival is less than 1 year,”

the next phrase you grasp onto with all of your might is “the honeymoon

period.” Now you don’t know for sure what this is yet but you know

honeymoons are good so, initially you are pretty happy to hear something

that even comes close to positive. As a parent, you find yourself really

looking forward to it as somewhat of a light at the end of a dark and

unknown tunnel.

In the first few days after diagnosis, things tend to be a blur. As we advance

and options change for our kids your road may be slightly different than

mine but for the time being it goes something like this. Your relatively

normal looking child begins to exhibit symptoms of some sort. Eye issues,

balance issues, headache, and nausea, just to name a few. Depending on

how you respond, you eventually find yourself in a pediatric oncologist’s

office where you can feel the air being sucked from your lungs as if you’ve

just had the wind knocked out of you.

Chapter 2: Typical History of DIPG



I decided to take Bizzie to see our pediatrician because she just seemed—

off. She was only two, about to turn three. For the past few months we had

noticed that she wasn’t developing as quickly as we thought she should

be. But, her well visits went fine. She was drooling a little and stumbled

from time to time. Then she started to choke on some foods. Finally, I just

decided to bring her in for a sick visit. My mom was down for a visit, so I

brought her along with me. The pediatrician examined Bizzie. After a few

minutes of looking in ears, mouth, etc. she still did not state any specific

issue. “I’m not worried about her, but…” She talked about sending her in

for a blood test, maybe a CT scan to rule out anything serious. Then she

tested Bizzie’s reflexes. Now she seemed to change her plan. She said she

would be right back—that she wanted to arrange those tests for us.

She left and a minute later someone closed the door to our room. I started

to wonder—that seemed odd. When she came back, she let us know that we

should go right over to our local Children’s emergency room for testing,

that there was a doctor there with whom we should connect.



Our Kayla was diagnosed with DIPG on Aug 23rd. It was her first day

of kindergarten. She had been drooling, she was seeing double, she was

choking sometimes when she ate, and she was getting clumsy. Even a few

months prior I had noticed that she couldn’t keep her right flip flop on when

she walked. So we had an MRI done after our optometrist realized this was

more than a case of misaligned eyes and we were told that Kayla had 6 to

9 months to survive if we did the radiation treatment and 10% chance of

surviving a year with Temodar—a type of chemotherapy. We were in such

disbelief that this could happen to our family but we could clearly see that

she was not well. This was a huge turning point in our lives.

Once this bomb was dropped on us, we instantly went into survival mode.

We came up with hundreds of questions and searched the internet all day

and night trying to understand the disease that we were dealing with.



Courtney was diagnosed with DIPG on April 19th. The only symptoms she

had prior to her diagnosis were fatigue and she had a period of time where

she had dizzy spells about 6 months before her diagnosis. April 14th we

noticed her eye turning in, and took her to the eye doctor on the 16th. He

sent her to the emergency room where they did a CT scan and told us she

had some type of brain tumor but they weren't sure what kind. They sent

us home and told us to come back on Monday the 19th for an MRI. That

is when we found out she had DIPG and that it had spread to her upper

spine. I think we started grieving that day. Not because we didn't hope

that she would make it, but because we knew that the odds were greatly

against her survival. It felt like we walked into that conference room with

a normal life and when we walked out it felt like we had walked into a

whole new world—one that would sometimes feel like a bad dream.



Our son Liam was diagnosed with DIPG in April, just days after his sixth

birthday. The previous month Liam had what we all thought was a nasty

virus. He woke one morning vomiting and continued to do so throughout

the day. At one point I had emailed my husband with concerns that this did

not seem like typical vomiting. It seemed almost more violent than a normal

stomach bug. I remember asking Liam if his neck hurt at all, if anything

else hurt at all, trying to ease the nagging feeling that something wasn’t

right. He ran no fever and the vomiting continued intermittently throughout

the day until evening. The following day the vomiting had stopped but he

suddenly was running a fever. We decided to call his pediatrician who had

us come in. At that time Liam had no other symptoms that were worrisome

to us. His doctor thought that he probably had a case of the flu and did a

rapid test for strep. That came back positive. In hindsight, that was most

likely coincidental and the intense vomiting of the day before was our first

real look at the beast we would come to know so well.



Sam's case is a little on the atypical side—first because he was 19 when

diagnosed, and second because his tumor extended into the cerebellum

from the brainstem. He was fine until January—no hint of anything at all

out of the ordinary. On Jan 11th he woke up with a bad sore throat and

because his band had a show that weekend we went in to our regular doctor

to see if he needed any antibiotics. It wasn't strep but he went ahead and

gave him antibiotics because Sam was prone to sinus infections. Two days

later he woke up with a horrible earache so back we went to the doctor

Chapter 2: Typical History of DIPG

who switched his antibiotics. That seemed to do the trick and he felt better

enough by the weekend to perform with his band.

The next week he was really, really tired, taking naps in the afternoon

which was very unlike him. Towards the end of the week he mentioned the

right side of his face was feeling numb. Since it was the same side as the

ear infection we assumed the infection had not cleared up and figured if

it's not better by Monday we'll go back to the doctor. Over the weekend

he mentioned his left leg feeling tingly like it was asleep. That worried

me, but I still thought it would be something minor. So we went to the

doctor on Monday and he said the ear infection was all cleared up and he

had no idea what was causing the facial numbness and leg tingling. He

suggested we see a neurologist and get an MRI so we saw the neurologist

on Wednesday who also noticed an issue with his right eye and agreed

that an MRI was in order. We had that the next day and within half an

hour of being home the doctor called and told us there was a mass on his

brainstem and we needed to see a neurosurgeon.

The next morning Sam was admitted, and we consulted with the

neurosurgeon and the neuroradiologist on Saturday. They explained that

Sam had a pontine glioma that was diffuse in nature with tumor extending

into the cerebellum making it extremely difficult to control. They never

gave us an estimate of time, in fact when we asked they said, "Every case

is different." The radiologist was the most upfront, telling Sam that this

was a very difficult tumor to beat. Sam asked, “Is it possible to beat it?"

and her response after some hesitation was, “Well, it's not impossible."

Chapter 3: Pontine Anatomy and Function

Chapter 3

Pontine Anatomy and

Function

Sven Hochheimer, MD

Javad Nazarian, PhD

Suresh N. Magge, MD

Children who are diagnosed with DIPG often experience varying clinical

symptoms. Families are sometimes left wondering why their child exhibits a

particular symptom, while another child may not. Additionally, families may

feel overwhelmed when trying to decipher their child’s MRI, leaving them

unsure how to interpret the ndings on the MRI as they relate to the clinical

signs evident in their child. Understanding pontine anatomy and function

can assist with interpreting MRI reports, as well as explain the variable clinical

symptoms of children diagnosed with DIPG.

General Overview of the Human Nervous System

e human nervous system is divided into the peripheral and central nervous

system (CNS). e peripheral nervous system consists of:

• e somatic nervous system, which is responsible for functions under

conscious control such as body movement and reception of external stimuli;

• The autonomic nervous system, which regulates functions under

subconscious control, such as blood pressure, heart rate, breathing, and

digestion.

e central nervous system is subdivided into the spinal cord and brain, which

includes the cerebrum, cerebellum, and

brainstem. e brainstem consists of the

midbrain, pons, and medulla and serves as

a passageway between the brain and spinal

cord. Above the pons is the hypothalamus,

and to the back sits the 4th ventricle [Fig. 1].

Dr. Hochheimer is a

Neurosurgery Resident at

Walter Reed National Military

Medical Center, Bethesda, MD.

Chapter 3: Pontine Anatomy and Function

Figure 1: Basic anatomy of the Central Nervous System

e pons—which means “bridge” in Latin, is an approximately 3.5 cm. long

“knob-like” structure that occupies the central portion of the brainstem between

the midbrain and the medulla [Fig. 2a]. Any messages descending from the

brain or ascending to it must cross this critical “bridge-like” structure. Anatomy

and function of the pons will be the focus of this chapter.

Figure 2a: Schemata of brainstem cross section

Neurons and Tracts

To best understand anatomy, it is important to gain an understanding of the

terminology of the system being described—in this case the nervous system.

e basic cell of the nervous system is the neuron. Humans have billions of

neurons, yet neurons only make up approximately 10 percent of cells in the

human brain. e remaining 90 percent of cells are support cells called glia.

Neurons

A neuron is composed of dendrites, a cell body, and an axon. Dendrites receive

information for the neuron. e information is then passed through the cell

body and on to the axon. e axon then passes the information along to

dendrites of other neurons. In this way, a neural message gets passed from one

neuron to the next. Axons are covered by myelin, which is produced by glial

cells and serves as an insulation that allows rapid signal transmission.

Collections of neurons that serve a particular function are called nuclei. eir

axons are bundled into collections of thread-like bers called tracts. Tracts that

carry information from the peripheral nervous system up toward the brain are

called ascending tracts, while those that carry signals from the brain to the spinal

Dr. Nazarian is a Molecular

Geneticist and Assistant Professor

in Integrative Systems Biology

and Pediatrics at Children’s

National Medical Center, and The

George Washington University

School of Medicine and Health

Sciences, Washington, DC.

Dr. Magge is a Pediatric

Neurosurgeon and Assistant

Professor of Neurosurgery

and Pediatrics at Children’s

National Medical Center, and

George Washington University

School of Medicine and Health

Sciences, Washington, DC.

Chapter 3: Pontine Anatomy and Function

cord and peripheral nervous system are called descending tracts.

Organization of the pons

e pons consists of a) the basilar pons in the front (ventral portion), and b)

the pontine tegmentum in the back (dorsal portion). e basilar pons and the

pontine tegmentum contain nuclei and tracts [Fig. 2b].e basilar pons contains

a complex combination of tracts (bundles of axons) and nuclei (collections of

cell bodies of neurons). e pontine tegmentum is made up of cranial nerves

which serve the head and neck, associated nuclei, the reticular formation

(neural network involved in functions including cardiovascular control, pain

modulation, sleep and awakening), and tracts (both ascending and descending).

Figure 2b: Cross section of the pons (at the level indicated in Fig. 2a) showing various

tracts and nuclei

Ascending tracts of the pons

e major ascending tracts include the dorsal columns, spinothalamic tracts,

and spinocerebellar tracts, which are described below.

Dorsal columns: e dorsal columns convey information about position sense

(proprioception), vibration, and discriminatory touch. Before reaching the pons,

the bers from these columns cross at the level of the lower medulla to form a

structure called the medial lemniscus, which then traverses the pons. Damage

to the medial lemnisci, at the level of the pons, results in sensory problems on

the opposite side of the body.

Spinothalamic tracts: ese tracts convey sensations of pain, temperature, and

light touch. e tracts cross shortly after entering the spinal cord and do no

change sides as they ascend through the pons. Damage to the spinothalamic tracts,

at the level of the pons, results in sensory problems on the opposite side of the body

Spinocerebellar tracts: These tracts convey subconscious information

pertaining to proprioception (position sense) to the cerebellum, the part of the

brain concerned primarily with posture, tone, and balance. ese tracts travel to

the cerebellum via structures called cerebellar peduncles. Also, there are several

nuclei within the pons whose axons unite to form one of the cerebellar peduncles

which play a role in the function of the cerebellum. erefore, damage to these

tracts result in problems with posture, tone, and balance.

Descending tracts

e most important descending tracts of the brainstem include the

corticospinal,

corticobulbar, and corticopontine bers, which are described below.

Corticospinal tracts: ese tracts are critical for voluntary movement of the

body. ey originate from the motor areas of the brain and pass through the

basilar pons before crossing at the level of the lower medulla on their way to the

spinal cord. Damage to the brain or corticospinal tract at the level of the pons

results in weakness or paralysis on the opposite side of the body (remember,

these tracts cross to the opposite side in the medulla while on the way to the

spinal cord).

Corticobulbar and corticopontine tracts: Corticobulbar tracts originate in

the brain and control voluntary movement of the muscles of the head and neck.

Corticopontine bers provide a connection between the brain and cerebellum

to coordinate and rene movement. ese tracts also cross, so damage to

corticobulbar bers result in diculty moving the opposite side of the face,

while lesions of the corticopontine bers result in lack of coordination of the

opposite arm and leg.

Other tracts

Two other important tracts, which convey both ascending and descending

information and are prominent in the pontine tegmentum, are the medial

longitudinal fasciculus (MLF) and the central tegmental tract (CTT).

MLF: e MLF is important in coordinating eye, head, and neck movements.

Damage to this tract results in problems associated with double vision, and

diculty with coordination of head and eye movements.

Chapter 3: Pontine Anatomy and Function

CTT: T

he CTT provides an avenue for ascending tracts involved with taste,

as well as provides a path for descending tracts to connect the midbrain to the

cerebellum.

Cranial Nerves and Nuclei of the Pons

As previously mentioned, a number of nuclei (groups of cells that serve a

particular function) reside within the pons. In the basilar pons (front/ventral

portion) reside the pontine nuclei, which serve to connect the brain and

cerebellum. Lesions here result in diculty with coordination of the opposite

arm and leg. Cranial nerves are the nerves that control functions of the head

and neck, and the pontine tegmentum (back/dorsal portion) contains several

of these nuclei.

e lower pons contains cranial nerves (CN) VI and VII [Fig. 3 and 4]. CN

VI, known as the abducens nerve, controls a muscle of the eye known as the

lateral rectus muscle. is muscle allows the eye to move away from midline

toward the temple, a motion known as abduction.

Figure 4: Schemata of the pathways of the cranial nerves

Damage to the nerve results in diculty abducting the eye on the same side

and results in double vision, which is also known as diplopia. e nucleus of

the abducens coordinates the lateral rectus muscle of one eye with the medial

rectus muscle of the other eye, making it possible to move both eyes to the same

side. For this reason, damage to the abducens nucleus results in an inability of

both eyes to look toward the side where the tumor is located, rather than the

double vision seen in abducens nerve lesions.

CN VII, the facial nerve, also resides in the lower pons. Damage to the facial

nerve or its nucleus, results in weakness or paralysis on the same side of the

face. Clinically, this manifests as asymmetric facial expressions and can result in

diculty with eating and speaking. Additional important structures that reside

in the lower pons include the vestibular nuclei, portions of the spinal trigeminal

(the fth cranial nerve, also called CNV) nucleus and tract, and the superior

olivary complex. e vestibular nuclei are involved in balance, so damage here

results in dizziness, vertigo, and postural unsteadiness. e spinal trigeminal

nucleus and tract mediate pain and temperature sensation from the face. Damage

to the spinal CNV nucleus results in sensory disturbances in the face. e

Figure 3: Schemata of the origin within the brain of the cranial nerves

Chapter 3: Pontine Anatomy and Function

superior olivary complex contributes bers to a structure known as the lateral

lemniscus and these structures are involved in hearing. Lesions of the superior

olivary complex or lateral lemniscus result in diminished hearing.

e middle portion of the pontine tegmentum is home to three nuclei (called

the trigeminal nerve) of CNV—the motor, mesencephalic, and principle

sensory nuclei. e motor nucleus controls the muscles that are involved in

chewing, while the mesencephalic nucleus is involved with the position sense

of these muscles. e principal sensory nucleus is primarily involved with

touch sensation from the face. Damage to the motor, mesencephalic, and

principle sensory nuclei result in diculty for the child to coordinate chewing

movements, weakness when chewing, as well as facial numbness. e lateral

lemniscus that forms in the lower pons, and is involved in hearing continues

its ascent through the middle pons. As previously mentioned, damage here

results in diminished hearing.

Other Structures Impacting Function

Reticular formation

e reticular formation is a collection of small neural networks that courses

through the center of the brainstem, including the midbrain, pons and medulla.

It is involved in various functions, including modulation of consciousness, sleep

cycles, pain, posture, tone, and balance. Damage to this critical structure can

cause sleepiness, coma, and death.

Fourth ventricle

e brain has ventricles or cavities that naturally produce cerebrospinal uid

(CSF). is uid circulates throughout the brain acting as a cushion to the

nervous system. In a normally functioning brain, this uid circulates and

provides nourishment to the nervous system, and it is subsequently reabsorbed

into the bloodstream. If the tumor compresses the 4th ventricle, which is

located near the pons, cerebral spinal uid can build up thereby creating

abnormally high pressure within the skull. It is essential that the pressure be

relieved so that the tissues in the central nervous system aren’t damaged and

the blood ow throughout the brain can be restored. Failure to do so can

result in compromised or lost neurological function. Treatment for this uid

buildup—termed hydrocephalus, and also often referred to as “water on the

brain,” is most often achieved through the surgical placement of a shunt or an

endoscopic third ventriculostomy. As is true with the above mentioned clinical

manifestations of DIPG, not all children with DIPG develop hydrocephalus.

Conclusion

An understanding of the anatomy of the pons and the structures it contains

provides the framework for deciphering the various neurological decits that

can be seen in patients aicted with tumors that damage or displace these

structures. A number of problems, including weakness, paralysis, numbness,

incoordination, hydrocephalus, diculties with taste, balance, chewing,

hearing, vision, and disturbances of consciousness, may occur if these important

structures or nearby structures are aected.

Chapter 3: Pontine Anatomy and Function

Parent Perspectives

Every child has a different journey with DIPG. The tumors don't always

grow in the same place, or at the same speed. The brainstem where the tumor

grows controls motor functions. The tragedy of DIPG is that it slowly robs

the patient of motor functions such as walking, arm movements, speech,

sight, eating and breathing while leaving their brain completely intact. That

means that children with DIPG are aware of their decline and continue to

grow and develop cerebrally in every other way.

For Stella, the first thing to disappear was her ability to walk which left

her in August. She has been unable to grasp small objects and do things

like feed herself since mid-September. Her eyesight is compromised, but

she is still able to see some things although we're not sure how much, as

it is difficult to communicate with her. However, Stella's smile remains

intact and the fundamental parts of her personality—fearlessness, humor

and mischievousness are still completely present.



Wednesday May 5th, Ellie stubbed her left toe while swimming with friends.

The next day her tennis coach called because she felt weak and complained

she was not seeing the ball right. It was hot and she said she had not taken in

enough water so we assumed she was a bit dehydrated. Friday she traveled

for the fourth grade field trip for a day of swimming. She had a blast! She

spent the weekend with her good friend playing at the beach.

The following Tuesday on the way to tennis practice she complained her left

leg and arm felt weak. We attributed her left leg to her toe injury but the

arm weakness definitely did not make sense. I called my brother-in-law, a

local physician. He ran through a series of neurological tests and definitely

noted weakness on her left side. We left for the emergency room where we

were met by family and Ellie’s pediatrician. A virus was suspected but a

CAT scan was ordered as a precaution.



Johnny came bounding toward me juice box in hand, when he started to

stumble. His eyes shifted to the left and his head tilted to the left as his gait

fumbled before the fall. He caught himself, but staggered to our meeting

place and finally fell right before he got to me. I helped him up, asked him

if he was alright, made a mental note to call the doctor, and we finished

out a fun afternoon.

That night Johnny had a baseball game and we decided to stop for pizza

before the game. While eating his pizza, Johnny was turned around in his

chair. Always the squirrely kid, Rob and I both told him to turn around

and eat. As he did, he fell out of his chair. We both exchanged concerned

glances since this had happened a few times over the last couple of weeks.

This was not normal. Johnny was our most coordinated child. He was the

one on a skateboard at one, roller skates at one and half, and road a bike

with training wheels before his second birthday. Something wasn’t right.

Again, making a mental note to call the doctor in the morning, we headed

to his ball game.

The next morning I called the doctor’s office to schedule an appointment.

They asked me why I wanted to bring him in and I recalled the incidence

from the day before, stating I thought it might be an inner ear issue. Thirty

minutes later we were at the doctor’s office. The doctor asked me about

the symptoms I noticed. I told him about his eyelids only opening halfway,

giving him a sleepy look. I also recalled his clumsy balance, his appetite

decrease and sleep increase. I had noticed most of these changes within the

last couple of weeks, except his eyelids. They had been slightly drooping

for around a month. Since I had all the kids with me, I was quite distracted

and let the doctor do his assessment without my engagement. I could see

Johnny walking up and down the hallway and the physician’s assistant

shaking her head no, with a concerned look. A few minutes later the doctor

came in and said he was going to schedule an MRI because Johnny had

failed a neurological assessment, and to not leave until he came back with

the time for the MRI. Being unknowledgeable about this, I smiled, agreed

and waited. A few minutes later, he came back in to say we had an MRI

scheduled at 2:30 that day. The doctor also said to not eat anything since

they might want to do sedation. It was starting to sink in. Something was

wrong, very wrong. Before I left, I called my husband to fill him in on all

the details. I also called our parents for support.



As the days went on Liam seemed to recover to a certain degree from the

strep and what we thought was a bug, but never in a way that left us totally

Chapter 3: Pontine Anatomy and Function

comfortable. We began to notice his eyes were at half-mast at times. We

would ask him about it and he promised that he really wasn't doing it

on purpose. These symptoms seemed to come and go. He went to school

every day and overall seemed ok. However as March turned to April those

concerning things we were seeing began to happen more frequently. Liam

came home from school one day with some school pictures. He took them

out to show me and said, "Look Mom, I don't think I know how to smile

anymore." I looked down at his picture and his crooked grin. It was around

this time that things began to change at a rapid pace and Liam's health

changed daily. We become very concerned. His affect began to be flat

and we noticed balance issues. I remember waking up early just to watch

him walking to the bathroom to see how his balance seemed when no one

was watching. He walked the long hallway bumping into the wall and I

remember thinking his walking reminded me of a child with cerebral palsy.

By his birthday weekend our concern grew to alarm. At his birthday party

he did not look well at all. We had watched in a matter of days the brutal

symptoms of his disease come into full view and we voiced our deepest

concerns to family.



Brendan was diagnosed at age 6. Two weeks before diagnosis we noticed

several things. His eyes were cloudy and unfocused which we mistakenly

attributed to conjunctivitis. He had given up napping when he was a

toddler but was very tired and he fell asleep in the middle of the afternoon.

We thought he may be having a growth spurt or was coming down with

something. We noticed he was laughing and talking restlessly in his sleep

where previously he had been a very quiet sleeper. He had difficulty

swallowing and chewed very slowly where he never ate slowly before. His

voice was raspy and he didn't smile anymore. He was experiencing painful

urination and was constipated. He was holding books very close and putting

his face up close to the computer and we and his teacher thought he needed

an eye exam. We finally took him to the doctor when he began falling and

saying he was dizzy. We noticed these symptoms for about 2 weeks before

his falling really alarmed us. Any of the other symptoms alone could be

dismissed as something else but all of it and his falls made it very serious.

We were told his tumor was DIPG. It was in the pons and was typical. They

wouldn't biopsy it because it could cause harm and possibly death, and it

wouldn't change the treatment options available.

He responded well to radiation and was symptom free for 10 months. Upon

progression his eyesight became blurry and he told us he was seeing double

again. He lost dexterity in his right hand so he began to write with his left

until he lost his left side too. He became very clumsy and was falling so we

got him a walker with wheels which he loved to zip around on.

He responded well to re-irradiation and was symptom free for another

6 months. Upon his second progression he experienced the same sorts

of problems with eyes, first his right side then left, and speech, chewing,

swallowing and finally lost neck control and had breathing difficulty. There

were no other options which could give him another “honeymoon.” He

progressed rapidly this time and was gone within 6 weeks of the recurrence

of his first symptom of blurry vision.



Looking back after diagnosis on July 29th I can see things that were red

flags but not nearly as significant as many children have displayed. At some

point near the end of the school year Hope drooled a couple of times and

had food on her face at meal times. I remembered these things that first week

in August but nothing rang any bells then. I remember her brother coming

in the house complaining that she couldn’t even ride a bike straight after

they had been on a ride on their tandem bike. Again nothing tied together

until after her diagnosis.

On July 7th we were watching a little league ball game. Hope sat in a

lawn chair between her brother and me. I looked over and saw that she

had drooled down her chin and onto her blouse. When I asked her if she

realized it she replied, “Mom, how would I feel that? My face has been numb

for 6 weeks.” You can insert a healthy dose of 12 year old attitude to that

statement and then you can imagine my face. As we drove home from the

game several things came to light—like while away for a week at a choir

camp with her best friend, they developed a signal for when Hope had food

on her face. That way she could wipe it off and wouldn’t be embarrassed.



Aimee started complaining of headaches in January, noting that they were

nothing that Motrin couldn’t take care of at first. Then they became more

severe in late February early March. Upon a trip to the doctor, without

tests being done, it was determined she had migraines and was put on meds

for her headaches. Aimee was a cheerleader and had several competitions

Chapter 3: Pontine Anatomy and Function

between May and August and began losing her balance, started getting

hiccups even with just a sip of water. Then she began complaining she

couldn’t breathe. After several more trips to the doctor’s office—again

with no tests done, she was given acid reflux medicine, as well as asthma

medicine. We were told she was dehydrated and to push the fluids. They

also gave her several antibiotics for an inner ear infection. They claimed

that was causing the dizziness and loss of balance. Finally, at the end of

August she began to vomit and needed to sleep often. She told me that the

doctors were crazy, because the only thing wrong with her was that she

had a brain tumor. I of course told her she was crazy, because “kids don’t

get brain tumors.” Then she made a bet with me for $10.00 because she

said she felt it growing.

September 25th, I took Aimee to see a new doctor; he did several

neurological examinations and referred us to a neurologist. The earliest

appointment we could get was in October. Upon leaving the office Aimee

began to vomit profusely, refused to go back in to see the doctor and just

wanted to go home and sleep. She stayed home from school the next day,

and slept and vomited off and on all day. Then on Thursday the 27th, Aimee

woke up with an extreme headache but still wanted to go to school because

it was picture day. Her balance worsened as well. A few days later, we began

to ride our bikes and Aimee was swerving all over the road. I joked that

she was going to get a DUI for her riding. Upon returning to the house I

called the doctor who was not in. His nurse called me a few minutes later

and advised me to get her to the emergency room right away—they are

expecting you.



Gunner was not himself the whole Thanksgiving holiday. He was pretty

lethargic and was complaining of headaches for over a week. He said it was

in the back of his head and moved up and forward to the front. We decorated

for Christmas and he usually is right in there helping, but most of the time

he just laid or slept (which is really unusual for him). He complained of

being hot all the time (which again is not his character). He is usually cold.

He didn’t have a fever at all. He always runs a fever when he is not feeling

well. He also began to just stare off into space—a couple of times while

in the middle of a conversation with me. Gunner started walking and then

sitting down with his head bent down. It made me very uncomfortable to

watch him. He just seemed to have no posture anymore. He started playing

with, and twisting his ears. He also started this mouth swishing thing—it

sounds like when you are washing your mouth out with mouth wash.

I also think he was hard to understand at times. I really had to listen to what

he was saying. Could his speech be getting worse? When I asked Gunner

about his headaches he told me that sometimes he has trouble seeing the

board at school. When I told him that we could get his eyes checked, he got

upset and told me that he was joking. I didn’t think he was joking. He just

didn’t want to go to another doctor appointment. When I tried to calm him

down about his headaches and his eyes, he told me that the TV was split in

half and that when I walked into the room my upper body was not attached

to my legs. He continued to complain of a pain in the back of his head. He

also complained about being dizzy, and tingling in his left hand. I took him

to counseling, a behavior specialist, occupational therapy, an optometrist,

our local doctor, and was given the diagnosis of autism. I felt like we just

kept hitting walls and weren’t getting the help we knew we needed.



Johnny’s tumor is in the pons. It is actually in the back side of the pons

close to the cerebellum. The cerebellum controls motor function. The tumor

is growing and pressing into the cerebellum which is why he is having

difficulty walking and with his balance. The pons controls all his involuntary

functions—his heartbeat, his breathing, swallowing, muscle control and

many other life giving functions. The pons is like grand central station in

the brain. This tumor is taking over those functions and shutting them down.



Julian’s heart rate had slipped into the 30’s in PICU which led to an emergency

midnight ight from Detroit to Memphis. It was one week before Christmas.

That morning, I found myself sitting in the basement of a brand new hospital

waiting to speak with one of St. Jude’s neurosurgeons while Julian was having

an MRI. There was intense debate about whether the dangerously low heart

rate was the result of tumor progression or continued hydrocephalus. Sleep

deprived and practically a shell of myself, our surgeon sat next to me on an

exam table and began to draw a diagram of Julian’s tumor on the sterile white

paper between us.

To my horror, the picture looked like a snake wrapping itself around our beau-

tiful son’s control center as if holding his life for ransom.

Only there was no

bargaining. The site of the tumor controlled his heart rate and respiratory

Chapter 3: Pontine Anatomy and Function

func

tion and through the middle ran the critical basilar artery making it too

risky to attempt to surgically debulk. When tears came, I explained that this

was the rst time anyone had shown me the anatomy of this monster. It was

then that the disease earned my respect. It was the most formidable of foes and

it held the upper hand. No drugs had any proven effect. So sly, so cunning, it

reminded me of an evil serpent almost taunting us with its advantage. It was

explained to us that even with intense radiation therapy, we could never kill

every single cell. With even two or three microscopic cells left behind, it would

come back. And when it did, it would return with a vengeance.

Months after we lost Julian, I read how a DIPG researcher described the deadly

glial cell’s shape under a microscope as a preschooler’s illustration of sunshine.

I found it so ironic.

Chapter 4: Imaging

Chapter 4

Imaging DIPG

Jonathan Finlay, MD

Girish Dhall, MD

John Grimm, MD

Stefan Bluml, PhD

e understanding of brainstem tumors, including diuse inltrating pontine

glioma (DIPG), has advanced considerably over the last few decades largely as

a result of advances in imaging technology. Nevertheless, the understanding of

brainstem tumors by imaging has always been, and continues to be, limited by

the lack of histopathology (microscopic evaluation of tumor tissue) correlating

to the imaging characteristics. is is primarily related to the risk involved to the

patient through the biopsy of these tumors accompanied by the questionable

direct therapeutic benets for the child.

e development of Magnetic Resonance Imaging (MRI) has signicantly

improved our understanding of these tumors. MRI allows improved

visualization and characterization of brainstem tumors in comparison to

Computed Tomography (CT). MRI provides superior imaging of the posterior

fossa of the brain in comparison to CT, which is limited secondary to artifacts

related to the thick bones of the skull base. Furthermore, in comparison to CT,

MRI has superior soft tissue contrast resolution, which aids in characterization

of these tumors [Fig. 1a, 1b]. e recent development of advanced imaging

techniques including magnetic resonance spectroscopy and magnetic resonance

perfusion imaging will continue to improve our understanding of these tumors.

History of the Imaging of “Brainstem Glioma” and the

Recognition of DIPG

Historically, tumors in the brainstem

were both regarded and treated as a single

entity, namely “brainstem glioma.” In the

early 1990s, as MRI became more widely

available and utilized, several attempts

Dr. Jonathan Finlay is Director

of the Neural Tumors Program at

Children’s Hospital Los Angeles,

and Professor of Neurology and

Neurosurgery at the Keck School

of Medicine, University of Southern

California, Los Angeles, CA.

Chapter 4: Imaging

were made to characterize brainstem tumors based on MRI criteria. An early

classication system based on MRI was established by Dr. A. James Barkovich of

the University of California, San Francisco, and several of his North American

colleagues. Specically, tumor characterization was based upon:

• the site of primary involvement in the brainstem;

• the longitudinal and axial extent of the tumor within the brainstem;

• the tumor growth pattern (diuse or focal);

• the enlargement of the brainstem;

• and the presence or absence of exophytic growth (i.e. growth extending

outside the brainstem) enhancement, cysts, hydrocephalus, hemorrhage

or necrosis.

Later correlation of such MRI criteria against survival statistics found several

imaging characteristics to be signicant. e particular segment or region

of origin within the brainstem was found to be important. Tumors arising

from the midbrain have the best prognosis. Tumors arising from the medulla

have an intermediate prognosis. Tumors arising from the pons have the worst

prognosis. A diusely inltrative appearance of the tumor was also found to

have a signicantly worse prognosis. A diusely inltrative appearance referred

to tumors that had ill dened margins and involved more than one half of

the brainstem segment of origin, or inltrated the segments of the brainstem

both superior and inferior to the segment of origin (i.e. inltration of both the

midbrain and the medulla if the segment of origin was the pons).

Finally, enlargement of the brainstem by the tumor was found to be negatively

related to survival, with a tumor that enlarges the brainstem having a poorer

survival [Fig. 2a, 2b].

As a result of these ndings, attempts were made to develop new classication

systems that better reected prognosis. Dr. N.J. Fischbein and colleagues of

Germany proposed a classication system in which tumors were divided into 6

groups, each having its own prognostic implications. e six groups included:

1) focal midbrain tumors, 2) diuse midbrain tumors, 3) tectal tumors, 4) focal

pontine tumors, 5) diuse pontine tumors, and 6) cervicomedullary tumors.

It soon became clear that brainstem tumors were a diverse group of tumors

with variable prognoses. Accordingly, management of the tumor needed to be

tailored to the suspected tumor type. Studies in which biopsies were obtained for

larger numbers of patients conrmed this observation. Of note, Dr. Paul Fischer

and colleagues working at Stanford School

of Medicine found that most brainstem

tumors could be divided into two classes:

pilocytic astrocytomas (World Health

Organization grade I tumor) or brillary

Figure 1a: Axial CT demonstrating poor visualization of the tumor, made worse by

artifact from the adjacent thick skull base.

Figure 1b: Axial T2 MRI of the same tumor demonstrates the improved soft tissue

contrast resolution, improving visualization and characterization of the tumor.

Dr. Dhall is an Assistant Professor

of Pediatrics in the Department of

Hematology/Oncology at Children’s

Hospital Los Angeles, CA.

Chapter 4: Imaging

astrocytomas. Pilocytic astrocytoma had a favorable prognosis (5 year survival

of 95%) and were associated with a location outside of the ventral (anterior)

pons and a dorsal (posterior) exophytic growth. Fibrillary astrocytomas had a

poorer prognosis (5 year survival of 15%) and were associated with a location

in the ventral pons that engulfed the basilar artery [Fig. 3a, 3b].

In addition to these two main tumor types, other tumor types which are less

frequently found within the brainstem include: ganglioglioma, primitive

neuroectodermal tumor (PNET), atypical teratoid rhabdoid tumor (AT/RT),

Figure 2a: Sagittal T2 MRI of a normal brainstem demonstrating the normal anatomy of

the midbrain, pons and medulla.

Figure 2b: Sagittal T2 MRI demonstrating a diuse intrinsic pontine glioma originating

from the pons, diusely inltrating and enlarging the pons.

Figure 3a: Axial T2 MRI of a brillary astrocytoma (diuse intrinsic pontine glioma)

demonstrating a mass arising from the pons, enlarging the pons and engulng the basilar

artery.

Figure 3b: Axial T2 MRI of a long term survivor of a “brainstem glioma” which is likely

not a brillary astrocytoma. is image demonstrates more benign features including a

focal mass with well-dened margins centered in the dorsal (posterior) pons with a dorsal

exophytic growth.

Chapter 4: Imaging

oligodendroglioma, and lymphoma.

Conventional Imaging

It is now generally accepted that there is a distinct subtype of brainstem tumor

which can be identied on imaging as a diuse intrinsic pontine glioma (DIPG).

ese invariably correspond to brillary astrocytomas on pathology and have

an extremely poor prognosis, the worst of any type of brainstem tumor. ey

demonstrate many of the characteristics that have been outlined above. ose

characteristics include:

• ey generally arise from the pons, more specically the ventral pons.

• ey are diuse tumors, inltrating greater than half the transverse diameter

of the brainstem segment of origin and having indistinct margins.

• ey also tend to expand the segment of the brainstem from which they

arise.

• is expansion coupled with the common location in the ventral pons

results in the tendency to engulf the basilar artery.

• ese masses are generally iso- to hypo-dense (equal to or dark) to normal

adjacent brain on CT, hypointense (dark) to normal adjacent brain on T1

weighted MRI, and hyperintense (bright) to normal adjacent brain on T2

weighted MRI.

• ese imaging characteristics generally reect the increased water content

of these tumors.

• e presence of enhancement after the administration of contrast, cysts

or necrosis, and hemorrhage is variable in these tumors [Fig. 4a, 4b,

4c, 4d]. Necrosis is generally described as areas of relative increased T2

signal and decreased T1 signal within the tumor with peripheral or “ring”

enhancement.

ese typical ndings of DIPG, considered to represent brillary astrocytomas,

are in contrast to focal tumors of the brainstem, which usually represent tumors

of dierent histopathologies.

Several studies focusing on DIPG have

attempted to determine if any conventional

MRI characteristics at the time of tumor

presentation are helpful in predicting

Dr. Grimm is an Assistant Professor

in Pediatric Neuroradiology at

Children’s Hospital Los Angeles, CA.

Figure 4a

Figure 4b

Chapter 4: Imaging

prognosis. No ndings on conventional MRI at tumor presentation have been

found to be correlated to response to therapy, progression, or overall survival.

Imaging characteristics that have been analyzed include: volume and extent of

tumor, signal intensity on T1 and T2 images, appearance of borders, peritumoral

edema, exophytic components, encasement of the basilar artery, necrosis or cysts,

hemorrhage, gadolinium enhancement, and metastatic disease [Fig. 5a, 5b, 5c].

It is now thought that regardless of the histopathology of the DIPG at the

time of diagnosis, even if the tumor is a low grade WHO II astrocytoma at

diagnosis, most diuse intrinsic pontine gliomas will progress to WHO III

anaplastic astrocytoma or WHO IV glioblastoma multiforme at the time of

Figures 4a, 4b, 4c, 4d: Axial T2 (a), sagittal T2 (b), axial T1 post contrast (c) and sagittal

T1 postcontrast (d) MRI of a diuse intrinsic pontine glioma demonstrating a diusely

inltrating and ill-dened mass of the pons which involves more than one half of the pons

and enlarges the pons, having mass eect on, but not yet engulng the basilar artery. It

is predominantly hyperintense (bright) on T2 and hypointense (dark) on T1 with small

areas of enhancement and possible necrosis.

Figure 4c

Figure 4d

Figure 5a: More images of diuse intrinsic pontine gliomas. Axial T2 MRI demonstrates

a mass originating from and enlarging the pons. Subtle areas of increased signal intensity

(brighter) may represent small areas of necrosis.

Chapter 4: Imaging

Figure 5b: Axial T2 MRI demonstrating a mass originating from and enlarging the right

side of the pons with ill-dened margins.

Figure 5c: Axial T2 MRI demonstrating a smaller mass originating from the right side of

the pons with ill-dened margins and subtle, if any, enlargement of the pons.

death. Although a small percentage of DIPG will demonstrate areas of necrosis

at presentation, almost all will develop areas of necrosis during the course of

the disease. ere is debate regarding whether the development of necrosis

indicates treatment related changes (i.e. radiation necrosis), or reects the

natural malignant degeneration of low grade tumors (WHO II) to high grade

tumors (WHO III and IV). Although positron emission tomography (PET)

has been used to make this distinction with other brain tumors (see section

below on advanced imaging), there has been diculty in applying this to DIPG.

Nevertheless, many consider the development of new areas of enhancement

or necrosis a grave prognostic indicator that often precedes death [Fig. 6a, 6b,

6c, 6d].

In addition to developing areas of necrosis, most tumors will continue to

inltrate more portions of the brainstem during the course of the disease.

ey preferentially grow in a cranial direction through the midbrain into the

cerebral peduncles and thalamus, and it is suggested that this nding may also

be a poor prognostic indicator.

Figure 6a

Chapter 4: Imaging

Despite the fact that conventional MRI has not been helpful in the development

of prognostic criteria for DIPG at initial presentation, there continues to be a

small subset of patients that have an unexpectedly long survival. It is uncertain

if the lesions in these patients represent a more benign tumor type other than a

brillary astrocytoma or even lesions other than tumors, such as inammatory

lesions that mimic DIPG on imaging. Furthermore, perhaps these tumors are

less biologically active or are more sensitive to treatment. e advent of new

advanced imaging techniques including magnetic resonance spectroscopy and

magnetic resonance perfusion imaging may soon improve our understanding

of the biology and natural history of

DIPG and lesions that mimic them on

conventional MRI.

Figure 6b

Figure 6c

Figure 6d

Figures 6a, 6b, 6c, 6d: Axial T2 (6a) and axial T1 post contrast (6b) MRI at presentation

and axial T2 (6c) and axial T1 postcontrast (d) MRI one and one half months later

demonstrating the development of necrosis visualized as an area of peripheral enhancement.

Dr. Bluml is an Associate Professor

of Research Radiology at Children’s

Hospital Los Angeles, CA.

Chapter 4: Imaging

Advanced Imaging

Magnetic resonance spectroscopy

Proton magnetic resonance spectroscopy (MRS) can currently be performed

on most standard MRI machines. e interaction of protons with their

environment helps to identify and measure various substances within the

brain. e most commonly measured substances include:

• choline (Cho, 3.2ppm), related to the synthesis of cell membranes and

increased in states of high membrane turnover (example tumor);

• creatine (Cr, 3.0ppm), a reection of cellular metabolism and generally

used as an internal reference;

• N-acetyl aspartate (NAA, 2.0ppm), located primarily in neurons and con-

sidered a normal neuronal marker, decreased with neuronal destruction;

• lactate (Lac, 1.3ppm), a product of anaerobic metabolism which is in-

creased with abnormal blood ow, abnormal metabolism or necrosis;

• lipids (Lip, 0.9ppm), a constituent of cell walls which is increased as a

product of necrosis and cell membrane destruction.

eoretically, malignant lesions should demonstrate high Cho to Cr ratios and

high Cho to NAA ratios due to the rapid turnover of cell membranes increasing

Cho, and the destruction of normal neurons decreasing NAA. Accordingly,

Smith and colleagues found that MRS may be helpful to distinguish neoplastic

from non-neoplastic lesions in the brainstem, with neoplastic lesions having high

Cho and low NAA levels and non-neoplastic lesions having normal to low Cho

and low NAA levels. Furthermore, MRS may be helpful to dierentiate between

dierent tumor histopathologies when the conventional MRI appearance

is uncertain. MRS may be helpful to suggest other histopathologies such as

pilocytic astrocytoma or PNET, which can often have characteristic proles

on MRS [Fig. 7a, 7b].

Although no metabolic measures on MRS at tumor presentation have been

found to be signicantly associated with survival, several studies have reported

the changes on MRS over time to help to understand tumor biology. Dr.

Laprie and colleagues examined the changes in MRS with radiotherapy. ey

found that Cho to NAA ratios initially decreased within 2 months following

radiotherapy corresponding clinical and conventional imaging responses.

Subsequently, Cho to NAA and Cho to Cr ratios were observed to increase at

the time of relapse. Furthermore, in some patients, changes in MRS preceded

both clinical and MRI deterioration by 2 to 5 months. Similar results were

Figure 7a

Figure 7b

Figures 7a, 7b: Magnetic resonance spectroscopy comparing diuse intrinsic pontine

glioma (a) to pilocytic astrocytoma (b). MRS of a DIPG demonstrating elevation of

myoinositol (mI), choline (Cho), lipid (Lip) and lactate (Lac) with decreased creatine

(Cr) and NAA. MRS of a pilocytic astrocytoma demonstrating a high choline to creatine

level with a characteristically low absolute creatine level and a relatively preserved NAA.

Chapter 4: Imaging

obtained by Dr. Panigrahy and colleagues who also found that metabolic

changes on MRS preceded clinical deterioration. Serial examination of tumors

demonstrated increasing levels of Cho and Lipids and decreasing levels of NAA,

Cr, and myo-inositol relative to Cho. ese changes likely reect malignant

degeneration and possible transformation from low grade to high grade tumor

[Fig. 8a, 8b].

Magnetic resonance perfusion

Magnetic resonance perfusion imaging (MRP) has recently been studied in

supratentorial gliomas in adults and has been found to be a good predictor

of world health organization (WHO) tumor grade, progression free survival,

progression and death. MRP of tumors is typically performed using dynamic

contrast enhanced perfusion imaging techniques.

MRP techniques rely on the magnetic susceptibility signal loss that intravenous

gadolinium produces on T2* sequences during MRI. By measuring the degree

of T2* signal loss caused by the gadolinium in blood vessels over time, one

can determine the relative volume of blood, or relative cerebral blood volume

(rCBV), within a tumor. Similarly, the relative cerebral blood ow (rCBF)

and the mean transit time (MTT) can also be measured. ese measurements

Figure 8a

are thought to be surrogate markers for blood vessel proliferation within

malignant brain tumors—an important feature in the grading of gliomas on

histopathology. Accordingly, several studies have shown that gliomas with low

rCBV, and theoretically lower tumor blood vessel proliferation, have longer time

to progression and gliomas with high rCBV, and theoretically higher tumor

blood vessel proliferation, have shorter time to progression. is was found to be

true regardless of WHO grade on biopsy. Some studies have even suggested that

measurements of rCBV were more predictive of prognosis than histopathology

and WHO grade on biopsy. It has been proposed that this nding is most likely

the result of either sampling error on biopsy (as tumors are heterogeneous and

the portion of the tumor with the highest WHO grade may be missed on biopsy)

or variability in consistency of diagnosis among pathologists.

To date, little research has been performed utilizing MRP in the analysis of

DIPG. is may be a promising avenue to help stratify patients based on the

aggressiveness of their tumors and their prognosis [Fig. 9].

Figures 8a (previous page), 8b (above): Magnetic resonance spectroscopy demonstrating

signs of progression with interval increase in choline (Cho) and the choline to creatine

(Cr) level over a period of 5 months from 8a to 8b.

Chapter 4: Imaging

Positron emission tomography

Positron Emission Tomography in combination with CT (PET/CT) is a tool

that helps radiologists understand the metabolic activity of tumors. PET/CT

measures the accumulation of tracers in cells that are incorporated into the cells

during metabolism. e most commonly used tracer in PET/CT is 2[18F]

uoro-2-deoxy-D-glucose (FDG). FDG is a measure of glucose metabolism,

and most tumors have increased glucose metabolism in comparison to normal

tissues. A less frequently used and less widely available tracer in brain tumor

imaging is 11C-L-methionine (MET), which is involved in amino acid

transport, also increased in tumors. MET may be more sensitive for low grade

tumors, in comparison to FDG, due to the lower background activity of MET

in normal brain.

Several studies focusing on brain tumors have shown that PET/CT can help

to separate less aggressive tumors from more aggressive tumors, tumor from

radiation necrosis, and tumor from scar tissue. Fewer studies have focused

exclusively on brainstem tumors in children. ese studies have suggested that

PET/CT may also be helpful in the evaluation of DIPG to dierentiate low

grade tumors from high grade tumors, with FDG uptake being increased in high

grade tumors. Dr. Kwon and colleagues found that only WHO IV glioblastoma

multiforme tumors were FDG hypermetabolic (“hot”) [Fig. 10a, 10b, 10c].

Furthermore, Dr. Pirotte and colleagues noticed that patients with the highest

FDG uptake had shorter survival times. PET/CT has also been found to

be useful in planning biopsies. In comparison to utilizing contrast MRI for

planning biopsies, PET/CT has a higher diagnostic yield, requiring a fewer

number of biopsies. Furthermore, PET/CT guidance yielded an equivalent

or higher tumor grade in comparison to MRI guidance. As mentioned

previously in the section on perfusion imaging, DIPG are heterogeneous in

their histopathology, and PET/CT can help to guide a biopsy to the areas of a

tumor with the highest grade. is will help to prevent the under-grading of a

tumor with a conventionally guided biopsy. ere have only been a few small

studies of PET/CT in brainstem tumors and further work is needed to develop

this promising technology.

Figure 9: Magnetic resonance perfusion imaging of a diuse intrinsic pontine glioma

measuring relative cerebral blood volume. e graph plots the signal intensity of the

tumor over time. e signal intensity decreases when the contrast bolus enters the blood

vessels within the tumor.

Figure 10a: Axial T2 MRI (a) demonstrating a diusely inltrating mass involving the

left pons and left cerebellar hemisphere.

Chapter 4: Imaging

Figures 10b, 10c: Corresponding axial CT (b) and axial FDG PET (c) demonstrate a

hypometabolic (cold) lesion.

Figure 10b

Figure 10c

Summary

Advances in imaging techniques over the last several decades have improved

our understanding of brainstem tumors. It is now generally accepted that there

is a specic subtype of brainstem tumor that can be identied on imaging as

a diuse intrinsic pontine glioma (DIPG). is tumor invariably represents a

brillary astrocytoma on histopathology and has an extremely poor prognosis—

the worst of any type of brainstem tumor. On imaging this tumor is typically:

• T2 hyperintense (bright);

• arises from the pons;

• is diusely inltrating with ill-dened margins;

• involves more than one half of the pons;

• expands the pons often engulng the basilar artery.

Despite advances in imaging technology, we have yet to nd imaging features

that can help to predict prognosis. New imaging techniques, including magnetic

resonance spectroscopy (MRS), perfusion imaging and positron emission

tomography (PET), may someday help us to better understand the biology of

this tumor, and in turn improve the treatment of this tumor.

Chapter 4: Imaging

the time to try and show me comparative scans—then and now from the same

angle. I saw some stuff I didn’t like but I also saw the reduction in size in spots

and some clean edges of the brainstem where before I saw that diffuse haze. It

was very good to refuel my hope.

When her tumor started to progress a month later she was rescanned. I knew it

was back. This time they scanned her spine and it had spread there too. I didn’t

need to see any more scans at that point in time.



Tumor measurements were very important to us following the rst few scans.

It was six months after diagnosis when we began to realize that measuring a

diffuse tumor was not an exact science. The cancer cells are sprinkled among

healthy brain cells. So how do you know where to start measuring? It was about

this time that we understood the importance of having the same radiologist

read and compare scans. One radiologist’s measurements may differ substan-

tially from another’s. We also realized by this time that DIPG scans need to be

read by someone who has a good amount of experience with DIPG. We got a

copy of every scan and sent it to Andrew’s neuro-oncologist for her opinion.



I feel that the MRIs that Noelia had done were sufcient to get an accurate

diagnosis. I personally did not try to read them though. I listened to our doc-

tors explain them to us (usually the day after the scan was done) and I have re-

viewed the written reports which did not give me any more information I would

understand. Our doctors did a great job explaining each scan. They took the

time to answer all of our questions and even explain the scans to other family

members that had questions in Spanish. My rst impressions were mind numb-

ing though, because the doctors we spoke to were very direct in the prognosis

of the tumor. They did not try to sugar coat it. I understand that there is no cure.

I understand it’s inoperable. I understand that there is no reason why. Noelia’s

tumor was located in the middle of the pons and we could see it very clearly

in the scans. We also saw the change in the tumor after radiation. It reduced

in size about 50 percent, but obviously it grew back. We did not have any more

scans done after the symptoms came back. We knew what was happening.



Parent Perspectives

I think that imaging is important in this diagnosis because it can be very risky

to do a biopsy. However I highly recommend sending scans to a few other doc-

tors that deal with this tumor regularly for their opinions. We did try to read

and understand the scans and it was difcult and overwhelming often. I would

try to print off comparable images from different scans. A few times our doc-

tors did pull up our scans right at the hospital to talk to us about them directly.

Our doctors were very kind and spoke to us about our child’s prognosis (when

it was good and bad) while reviewing the scans with us.



When Tatumn was diagnosed we asked for copies of the MRI scans so we could

send them to other centers for second opinions. I felt a little strange about di-

agnosing her tumor with just an MRI. My personal background taught me the

only way to really be sure of cancer is a surgical biopsy. But all of the doctors

were in agreement that this was a DIPG and this was how they did it now. To

be sure I had them sent to other hospitals and received the same response.

After being home from the hospital a week or so we decided to open one of

the discs on our own computer because we were still trying to wrap our head

around what was going on in her sweet little head. So we downloaded a pro-

gram to open the scans on our computer. A lot of the pictures were hard for

me to decipher and I was trying so hard to remember what the doctors had

explained to me on that overwhelming night.

I found what I call a prole shot. It showed her tumor from the side of her

head. I saw that hazy mass and was overtaken by nausea. That picture was so

hurtfully powerful and so ugly at the same time. I knew I couldn’t look at any

more of the pictures and neither could my husband. We never opened them

again. When she had her rst scan after radiation, the doctors were excited

to tell us that there was about a 25% reduction. Since there are so many pic-

tures and angles I couldn’t sort through everything I saw. So I asked to see an

original diagnosis image and a matching after radiation image from the same

perspective. I wanted to see a difference. I don’t know why I had to ask that

and it wasn’t just shown to me that way. Nonetheless our neurosurgeon took

Chapter 4: Imaging

Fear was written all over Johnny’s body, as he faced the unknown of an MRI.

An MRI requires the patient to hold very still for at least fteen minutes. The

technician offered two options. Johnny could have sedation but I would not lay

on the table with him or he could go without the sedation and I would lie on the

table during the MRI. Johnny chose to have me on the table and gave up the

sleep medicine. The tech explained everything that was going to happen and

about how long it would take.

As he lay down on the table, they put a brace around his head with a mirror

on it. Instead of moving his head to see me, he could look in the tilted mirror.

It is a small tube that you slide into and when they turn on the machine the

magnets bounce around making a horrendous noise. My husband and I were

given ear plugs. Johnny had on headphones and was able to listen to the radio.

As I lay on the bed, I watched as my seven year old son showed more tenacity

than most adults. He lay there with his eyes closed. Periodically he would open

them, and look at me. I would smile and he would smile. I would wink and he

would smile. I would close my eyes and he would return to closing his eyes.

At one point he even fell asleep and I watched as his breathing evened and his

chest rose in rhythm. The noise was deafening even with ear plugs in. I didn’t

nd out until later how terried he was and how much comfort I was to him.

The magnets slowed in their bounce, the technician came in and told us he did

a great job and we headed toward home.

In the morning, we had an appointment to meet with the doctor. As we entered

the doctor’s ofce we were taken to a room with large windows. The room had

a wooden porch bench, a computer, a stool and a patient table. We sat down

on the wooden bench with the doctor sitting on the stool next to the computer,

and the physician’s assistant standing on the other side of the monitor. The

MRI scan was displayed on the computer. The doctor explained that there was

a mass around four centimeters in the middle of the brain called the pons. He

gave us a photocopy of a brain and circled the pons. He went on to explain,

“This area of the brain controls all the involuntary functions of the body—ev-

erything a body does without thinking.”

We nodded with partial understanding and amazed disbelief. He turned on the

monitor to show us the scan. He showed us exactly where the mass was, outlin-

ing the perimeter. The scan was very clear showing to us that Johnny had done

a great job holding still. There were multiple frames and angles of the brain

and the mass. The doctor asked if we had any questions. We were speechless.

It was an unbelievable moment to nd out that our son had something in his

brain and we would drop life to do anything to x the problem so he could be

healthy again.

We learned that Johnny had a cancer called DIPG. The tumor is inoperable

and the cancer is incurable. At the sound of those words, I buried my face in

my hands. In the background I heard details about radiation and experimental

chemotherapy. The doctor recommended not taking a biopsy or attempting to

remove the tumor due to its location, but if we did want to pursue that option

there was a hospital in France that was taking biopsy tissue. We both nodded

in agreement that this was not a course of action we were interested in pursu-

ing. After answering questions, he briey discussed the protocols available

and we began an eight week treatment plan.

Upon discharge, we were given a CD copy of all of his scans. We went back

every eight weeks for a follow up MRI to monitor tumor changes.



We met with Liam’s neurosurgeon who showed us the CT scan done the day

before. This was our rst time seeing the image. I knew almost instinctually

that this could very well be our worst case scenario playing out. The doctor

pointed out the lesion and then the area around it. Liam’s doctor said that area

was what we needed to understand better and would with an MRI. His words

and direct eye contact struck me. I turned back to the image and couldn’t take

my eyes off that area.

Later that same day, Liam had his MRI. We were given the news the next morn-

ing. We were taken to a small room lled with at least four doctors, a nurse and

a social worker. The MRI image was brought up on a screen. It was clear it

was in his brainstem. His neurosurgeon told us it was a brainstem glioma that

originated in the pons of Liam’s brain. It was inoperable. The rst words from

my mouth were: “How long do we have with him?” Our doctor answered,

“Possibly a year but most likely less.” As strange as it may sound I felt relief.

Based on how quickly Liam’s health had declined and how sick he was when

we brought him to the hospital I had thought surely he had, at the most, only

months. I was trying desperately to squash the terror that we may not be able

to even bring him home from this place. A year seemed, in this strange and ter-

rifying new world, like a blessing. It was our rst lesson in the gift of perspec-

tive that this journey gave to us.



Chapter 4: Imaging

Around November, I began to notice very small changes—changes even Liam’s

Dad did not sometimes see without me pointing them out. Soon though, he

began to notice them as well. Intermittent vomiting returned. Strangely this

came with no nausea or warning and once nished did not bother Liam at

all. He took to calling it his “party trick.” In December and early January

we noticed balance issues here and there. He was scanned after the holidays

but his scan appeared relatively stable. We did not believe this was the case

based on what we were seeing at home and we were blessed to have doctors

that listened when we voiced our concern. We were told, “If mom or dad tells

us that something is not right, we believe them. That’s all we need to hear. We

will always treat Liam not his scan.” How blessed were we! It was decided

to rescan Liam in 4 weeks vs. the two months that was previously the norm.

We had learned that sometimes a scan doesn’t always reect how a child is

presenting clinically, especially with DIPG. It’s that old sand analogy again.

Hard to sometimes visualize the subtle changes that are occurring in the brain

on a scan but that are clear as day when spending time with the child himself

and especially when viewed under the VERY, and by this point, practiced and

careful eye of his parents! In four weeks, Liam’s scan matched what we were

seeing in our every day. Nine months from diagnosis the “honeymoon period”

was over and tumor progression had settled in.



Initially our son was given a CT scan of the brain ordered by his local pedia-

trician. This image only showed the area of necrosis within his tumor and an

area of abnormality around that. However, the area of concern around the

“lesion” could not be denitively diagnosed without an MRI which was done

two days later.

In subsequent images taken, the MRI in general was a good marker for prog-

ress. However, later when his symptoms slowly started to re-appear his MRI

image did not reect what we were seeing symptomatically. Thankfully his

doctors recognized that it can take the scan image some time before it reects

what a parent may be seeing clinically.

We were very fortunate that the same person sat with us every time to review

his scans. This is not always the case and can be problematic at times. It’s im-

portant to establish continuity of care as much as possible. It’s also advisable

to have someone (maybe not too many doctors though) review your child’s

scan who is very experienced in reading scans of DIPG kids.



We were extremely fortunate to have our son’s neurosurgeon read and review

every one of his scans with us personally while he was recovering from anes-

thesia. At times the radiologist also called us in if there were any areas she had

a particular concern over so that we might be able to discuss them then and

not wait. Because this time was taken, we always walked away from each scan

with a peace and understanding about what the results said. This practice is

not the most common but if possible can do so much to aide in the continuity of

care for families. It was a blessing in the midst of so much uncertainty.



We took Gabby to see her pediatrician after she was having problems with

her balance and her speech seemed off. The pediatrician didn’t seem too con-

cerned with her reex test as well as her balance, but she wanted to keep get-

ting her tested to ease our minds. We were scheduled for an MRI a week later

and in that time we went for blood tests and an eye exam. Over the following

weekend Gabby’s balance got so bad that she was holding on to furniture to

walk. We decided not to wait the extra day for her MRI and took her to the

emergency room. She had a CT scan in the emergency room that day and we

were told there was some uid buildup but they were not really impressed by

it. She was going to be admitted and they would schedule her MRI for the next

day. When we went for the MRI they decided since she would be sedated they

would do a lumbar puncture as well. After the MRI while she was in recovery

from the sedation they had decided against the lumbar puncture and were

sending her back to her room.

That’s when we rst knew something was wrong. The same doctors we saw in

the emergency room came to deliver the news to us that she had a tumor and

it was not good. They were assembling a team and they would be back in an

hour to discuss it with us. Left in total shock and disbelief, my husband and I

waited more like 3 hours to hear from the doctors again. They brought us into

a room and showed us her slides from the MRI. They described the tumor as

being in the pons of her brainstem and diffuse so they were calling it DIPG,

but it was also in several other areas of her brain that made it atypical for this

disease. They recommended an additional MRI with contrast, and a biopsy of

her cerebellum to be sure we knew what we were dealing with. The additional

MRI did not show anything else.

Chapter 4: Imaging



I sat in the balcony for the nal performance of a play that Hope was in that

summer. I was surprised to see her stumble over a simple dance step but no

one else noticed and she didn’t miss a beat so I let it go. On Sunday night I

was not connecting this to the other symptoms. I would begin to do so by Tues-

day. On Monday the neurologist also thought I was crazy. He reiterated our

family doctor’s diagnosis saying that she had Bell’s palsy, that it would take

some time, but if I was worried he’d order an MRI to make me feel better. I

remember very clearly seeing him backing out of the room smiling, somewhat

like I was a crazy over-protective mother, saying he was sure this was nothing.

As “luck” would have it there was a cancelation at the MRI suite at our local

hospital on Tuesday. We took it thinking it would be great to get this over and

done with so we could move on with our summer. On Tuesday, the look on the

MRI technician’s face—who practically held my hand as he walked us to the

door—spoke volumes. He sent us directly back to the neurologist’s ofce who

gave us the news that there was a “mass” on the brain.



When Sam was rst diagnosed and we were in the hospital the neurosurgeon

made a point of showing Sam and my husband the MRI and the tumor and

where he was going to remove what he could. I was not there at the time so

missed that. Later when we had MRIs done after the radiation and when he

was on chemo the neuro-oncologist always showed us the MRIs but he went

so fast from view to view. I understood what he was showing us at the time

but could never nd those views once I got home with the CD. We have all the

MRIs on a CD along with the radiologist’s reports but there are hundreds of

views on the CD for each MRI done and I can’t gure out which ones are the

ones we looked at in the hospital. It was frustrating at the time and still is a

source of frustration that I can’t see the images of his tumor on the CD.

Chapter 5: Clinical Trials for DIPG

Chapter 5

Clinical Trials for DIPG

Adam Cohen, MS, MD

Howard Colman, MD, PhD

Many researchers are working hard to develop new treatments for DIPG. To

date, no therapies are available that provide a lasting cure for this disease. As

new treatments become more readily available, parents will be given additional

opportunities to enroll their children in clinical trials. is chapter is focused on

clinical trial design. Parents who are familiar with study design terminology and

who have a basic understanding of the purpose of clinical trials are better equipped

to make informed treatment decisions. Every child is unique, and treatment

decisions are also unique to individual children and families.

What is a Clinical Trial?

A clinical trial is a way to test possible new treatments. Clinical trials are done in

cancer to nd out:

• whether a treatment is safe;

• whether a treatment has the eects on cancer cells that scientists think it will;

• whether it is eective at shrinking tumors, delaying growth of tumors, or making

people live longer.

A clinical trial is a scientic experiment that must follow certain rules to ensure patient

safety and that the results are true and not due to chance or bias. A clinical trial may

test several dierent types of experimental treatments including:

• A brand new drug (usually not already FDA approved for other cancers or uses).

• A new combination of drugs (that could include new or existing drugs).

• A new technology.

• An old drug that is being used in a new

way or on a new population of patients.

Dr. Cohen is an Assistant

Professor in the Division of

Oncology, and Department of

Internal Medicine at the Huntsman

Cancer Institute, Salt Lake City, UT.

Chapter 5: Clinical Trials for DIPG

ere are many types of clinical trials. When participating in a clinical trial, it is

important to know:

1. What kind of trial it is.

2. What the purpose of the trial is.

3. What is new and experimental about the trial.

Clinical trials are an essential part of medical research. Without clinical trials, medical

knowledge cannot grow and new treatments that may save or improve the lives of

future cancer patients would not be identied.

What a Clinical Trial Is and Is Not

Clinical trials must have specic characteristics that qualify them as well-

designed scientic experiments. Not every study is a clinical trial. In this

section, we give examples of studies that are not clinical trials and give some of

the qualities of a good clinical trial.

Clinical trials must study a predetermined group of people, given a predetermined

treatment and use statistics to analyze results. “Case reports” or “case series”

are reports by physicians giving the results of a specic treatment observed in

just a few patients. While potentially useful to other physicians, case reports

of one or two patients are not true clinical trials because not enough patients

are treated with a specic therapy to know if the results are due to luck, to the

treatment given, or to some unknown factor. Because everyone likes a happy

ending, examples of patients who seemed to respond to a treatment are much

more likely to be published than examples of patients who did not respond to

a treatment.

Retrospective series are also not true clinical trials, but generally provide more

data and reliability than case reports. Retrospective studies look backward in

time to study a group of patients with the same disease. Retrospective series

are not clinical trials because the group of people and the treatment were not

dened before the treatment was given. erefore, the results may be biased

by the choices both doctors and patients

make. For example, healthy people tend

to be treated aggressively, and healthy

people tend to live longer; but that does

not mean that more aggressive treatments

make people live longer.

A well-designed clinical trial needs to include:

1. A clear research question.

2. A hypothesis.

3. A specically dened population.

4. A description of the treatment so that everyone in the trial gets treated the

same way.

5. A follow-up plan that describes how often the eects of the treatment will

be reassessed.

6. A statistical plan that describes how to determine at the end of trial, the

answer to the initial question.

A clear research question describes the purpose of the clinical trial. Examples

of clear questions are:

1. How often do people taking this drug experience severe side eects?

2. How often do tumors shrink when people take this drug?

3. Which drug makes people with a brain tumor live longer?

A clear question prevents misinterpreting unexpected results that could be due

to chance.

e hypothesis is the researcher’s educated guess at the answer to the question.

e hypothesis spells out how safe or eective a treatment should be for the trial to

be considered a success. e hypothesis also makes it clear how to know if the trial

does not succeed, so that unsafe or ineective treatments are not studied again.

Clinical trials are conducted in specic, well-dened populations. e

population may be limited by specic diagnoses (cancers), ages, symptom

levels, overall health, or other factors. ese limitations are called the inclusion

and exclusion criteria. For example, a clinical trial of brainstem gliomas may

allow adults and children, just children under 18, or just children under 12,

etc. Most, but not all, clinical trials require participants to have normal liver

and kidney function and exclude patients with other major medical problems

or multiple cancer types. Limiting the population for clinical trials helps to

ensure the scientic validity of the trial. However, clinical trial results may not

apply to people outside of these limits. For instance, results from a clinical

trial allowing adults with brainstem glioma may not apply to children with

diuse intrinsic pontine glioma if they were excluded from that trial.

Dr. Colman is an Associate

Professor and Director of

Medical Neuro-Oncology in

the Department of Neurosurgery,

at the Huntsman Cancer

Institute, University of Utah,

Salt Lake City, UT.

Chapter 5: Clinical Trials for DIPG

A clinical trial must have a treatment plan, follow-up plan, and statistical

plan set out before starting the trial. is ensures that everyone in the trial

is treated the same way and that the doctors running the trial cannot change

things to make the trial results appear better than they actually are. It also

potentially limits the treating doctor because tests or treatments may need

to be done at specic times that are less exible than they would be with

treatments outside of a clinical trial.

Clinical Trial Phases

Clinical trial phases correspond to the dierent stages of testing that a drug goes

through before approval. For people with brain tumors, the clinical trial phases

are phase 0, phase 1, phase 2, or phase 3. e phases are sometimes referred to

using the Roman numerals 0, I, II, III.

Phase 0 studies

Phase 0 clinical trials are usually done very early in the testing of a new drug.

Phase 0 clinical trials test whether a drug gets into the brain or brain tumor

cells and whether it “hits” the expected target. For example, if a new drug is

developed to inhibit the growth protein EGFR, a phase 0 study can look at

the activity of the EGFR protein in the brain tumor before and after treatment

with the new drug. Phase 0 studies usually require surgery to obtain a sample

of the tumor after treatment with the drug; however, depending on the specic

drug and the expected target, testing of drug eects can sometimes be done

on blood samples or other tissues. A common way of doing phase 0 studies is

to have someone take a drug for a week before a planned surgery and then use

some of the tumor removed during surgery to determine the eects of the drug

on the tissue. One important aspect for patients to understand about Phase 0

studies is that they generally are not expected to benet the individual entering

the study. ese studies are often done very early in the development of a drug

before the optimal dose is determined, and treatment is often continued only

for a short period of time. ese studies do, however, potentially allow for a

better understanding of how a drug works; this, in turn, aids in the planning

of further trials. Phase 0 studies are generally not applicable for patients with

inoperable tumors, such as diuse intrinsic pontine gliomas, which some believe

cannot be biopsied safely.

Phase 1 studies

Phase 1 clinical trials are done early in the testing of a new drug or new treatment

combination to nd what doses of a drug are safe to give. Phase 1 clinical trials

often also test how long the drug stays in the body and how the body processes

and gets rid of the drug. ere are sometimes a number of extra tests required

in phase 1 studies, such as blood tests, urine tests, EKGs of the heart, etc., that

test for toxicity to dierent organs and to see how long the drug is staying in

the body and how it is getting out of the body.

For traditional chemotherapy drugs, phase 1 studies often have the goal of

dening what is called the Maximum Tolerated Dose, or MTD. e maximum

tolerated dose is the dose just below where a high proportion of people have

unacceptable side eects from a drug. e maximum tolerated dose is the highest

dose that should be used for that drug because higher doses are generally too

toxic. Sometimes, particularly for modern drugs that target specic molecules

in cancer cells, phase 1 studies do not go all the way to the maximum tolerated

dose, but stop at a dose where the drug is expected to completely inhibit the

molecule it is targeting. is is called the Biologically Eective Dose.

People are enrolled in phase 1 studies as part of a group, which typically is called

a cohort. Cohorts usually consist of three people but can vary in size from 1

person to many people. Each cohort is given a dierent dose of the drug being

tested. e rst cohort gets a very low dose. If the side eects are tolerable,

the next cohort gets a higher dose. is continues until too many people in

a cohort get intolerable side eects. ese intolerable side eects are called

Dose Limiting Toxicities (DLT). e highest dose whose cohort did not get

intolerable side eects is the Maximum Tolerated Dose (MTD).

Phase 1 trials are a very important step in developing new cancer drugs, and

everyone in a phase 1 trial is helping patients in the future. Traditionally Phase 1

studies have not focused on how well a drug works—just the safety and dosage.

In most phase 1 studies, once you are in a cohort, the dose of the drug will

stay the same for you. Other people who are in other cohorts may get a higher

dose of the drug. erefore, people in the earlier cohorts of a phase 1 study

may get a dose of the drug that is below the dose that is thought to be needed

to shrink the tumor. For this reason, as well as the fact that most drugs tested

in Phase 1 will not go on to demonstrate signicant ecacy in future studies,

the expectation is that most people in a phase 1 trial are not likely to personally

benet from the treatment being tested. erefore, phase 1 trials are often most

appropriate after patients have failed standard treatments with proven benet

or when there are no proven treatment options available.

However, as drug companies have become more focused on drugs targeting

specic proteins and molecular pathways in tumors, the role of Phase 1

Chapter 5: Clinical Trials for DIPG

testing has started to change. In the case of these drugs, the specic targets

are sometimes known before the study. us, it is possible in these specic

situations to hypothesize that patients whose tumors have that specic molecular

target may be more likely to respond to that specic drug. So, in addition to

dening the Maximum Tolerated Dose, some more recent Phase 1 studies also

include initial measurements of tumor response or drug eects on tumors.

is approach has been used successfully by scientists to demonstrate potential

ecacy of promising drugs early in their development, which has accelerated

the subsequent Phase 2 and 3 studies and FDA approval. It is possible that in

the future, patients participating in Phase I trials of targeted drugs may have a

higher chance of getting benet from the treatment in the situation in which

the patient and the physicians know that the patient’s tumor has that molecular

target.

Phase 2 studies

Once the safe dose of a drug is known, phase 2 clinical trials are used to see if the

drug is eective against a certain kind of tumor. Phase 2 trials may have many

dierent designs. In some Phase 2 studies, called single arm studies, everyone

gets the same drug and dose. In multi-arm or randomized studies, there are

several dierent treatments being tested or compared. Patients may get a specic

treatment based on particular criteria of the study, or patients may be randomly

assigned to treatment arms. Randomly assigned, also called randomization,

means that neither you nor your doctor can choose what treatment you get.

Such randomization is necessary because otherwise conscious or subconscious

biases can inuence the results of a trial. For example, if doctors gave everyone

with small tumors the new drug and everyone with big tumors the old drug,

then the new drug might look better even though it might not be better than

the old drug.

e goal of a phase 2 study is to see if a new drug or combination of drugs

has some benecial eect on the tumor or other preferred patient outcomes.

However, even though some Phase 2 trials include more than 100 patients,

they are generally not large enough to conclusively prove whether people live

longer when they take the new drug or to prove absolutely that a new drug

helps. Instead, phase 2 trials often look at endpoints other than how long people

live that can indicate whether a drug is helpful. ese alternate endpoints can

include:

• Response rate: the percent of tumors that shrink a certain amount (usually

25%) with a treatment.

• Disease control rate: the percent of tumors that shrink or stay the same size

with a treatment. Because of random variation between scans, tumors must

grow by at least 20% to 25% to not be considered the same size. us, if a

tumor grows 10% or shrinks 10% it is considered stable, i.e., the same size.

• Progression Free Survival (PFS): the amount of time from the start of

treatment until someone either dies or the tumor progresses, which means

it grows more than a set amount. PFS is often described as a median, the

amount of time until half of people die or have tumor progression. For

example, if the median PFS is 6 months, then by 6 months after the start

of treatment, half of the patients have either died or had their tumor grow

and half of the patients are alive with tumors that are either the same size

or smaller.

• PFS3 or PFS6: the progression-free survival at 3 months or 6 months

respectively, after the start of treatment. is is the percent of people who

are alive with tumors that are the same size or smaller at the specied time

point.

While it seems intuitive that treatments that shrink tumors or that delay tumor

progression will make people live longer, there are occasional cases where this

has turned out not to be true. For example, sometimes tumors can grow back

faster after a drug stops working or a tumor may appear to shrink on an MRI

but the cells are continuing to grow and invade new parts of the brain. Because

the study is testing how eective a drug is, patients participating in a phase 2

trial have a higher chance of personally beneting from taking the drug than in

earlier Phase studies. However, trial participants may not benet if the treatment

turns out to be ineective or if the treatment only works at certain doses or

in certain people. Often as part of a phase 2 trial, tests are done on tumor

specimens or on blood samples to try to identify which people are more likely

to benet from the drug. A test that can distinguish people who might benet

from a drug and those who will not benet from a drug is called a biomarker.

Phase 3 studies

Phase 3 clinical trials are large trials designed to denitively prove whether or

not a treatment really works. Phase 3 clinical trials are done to compare a new

treatment to something else, often the treatment that is considered “standard

of care” for that disease and situation. is standard treatment may be another

older treatment or in some cases may not involve active treatment against the

tumor. Phase 3 trials must be randomized; meaning the treatment you receive

is decided randomly by a method determined by the study designers, not by

Chapter 5: Clinical Trials for DIPG

you or your doctors. Random means no one can control what treatment you

get, as if it is determined by the ip of a coin or the roll of a die. e group

you are randomized into is called an arm of the trial. Randomized phase 3 trials

are needed because the results of non-randomized trials, such as many phase 2

studies, can be misleading. Non-randomized trials compare their results to what

one would expect to happen to the usual patient in that situation. However,

non-randomized studies can give a falsely optimistic view of a new drug because:

• People who volunteer for clinical trials are usually healthier and physically

stronger than those who do not volunteer. e inclusion criteria for clinical

trials, as discussed above, weed out people who have other health problems

or are expected to be very sick soon.

• People who can travel to big hospitals for clinical trials tend to have slower

growing cancers than people who cannot travel.

• Over time doctors have gotten better at preventing and managing symptoms

and side eects, so people may live longer.

• People in clinical trials may see their doctor or be contacted by nurses more

often than people not in clinical trials. erefore, problems can be dealt

with early before they become untreatable.

• When doctors and patients think a treatment is working, they are more

likely not to see evidence that it is not working.

Although not very common in oncology, when there is no known eective

treatment for a particular situation, then it is considered ethical and appropriate

to compare a new treatment to giving no anti-tumor treatment. Giving no

anti-tumor treatment does not mean “doing nothing.” It may be called Best

Supportive Care, which means treating all of the symptoms of the tumor but

not giving anything to ght the tumor. Giving no anti-tumor treatment may

also involve a placebo. A placebo is used so that neither the person in the study

nor their doctors know whether the person is getting the new drug that is being

tested. When people and their doctors do not know what treatment someone is

receiving, they are said to be blinded. Placebos prevent doctors and patients from

being subconsciously biased in interpreting MRIs and symptoms by knowing a

person’s treatment arm. Placebos also prevent people from dropping out of the

trial and entering another trial if they are randomly assigned to the arm with

no tumor treatment. A placebo will be a pill or infusion that looks and feels

identical to the active drug, but it does not have any drug in it. Some people

call placebos “sugar pills” because they used to contain sugar instead of drugs.

Many people do not like the idea of getting a placebo or of getting randomized.

Rarely is the outcome without treatment so certain or a treatment so good that

randomized trials are not needed. Some people like to joke that randomized,

placebo-controlled trials are not needed to show that parachutes are helpful if

you jump out of an airplane. However, most cancer treatment situations are

not that clear cut. Although clinical trials are done when it is believed a new

treatment is a good thing, sometimes it turns out that the new treatment is

worse than not treating the tumor as there are unexpected additional side eects.

Some phase 3 trials allow people to receive the experimental treatment from the

other arm of the trial when the tumor grows. is is called crossing-over. For

example, a trial may randomize people between receiving drug "A" or a placebo.

When the tumors of the people receiving the placebo grow, those people may

be able to cross-over to the other arm and receive drug "A". Not all trials allow

crossing over. Whether crossing over is permitted or not depends on the purpose

of the trial, the resources available for the trial, and regulatory requirements.

Side Eects in Clinical Trials

ere is a special vocabulary for talking about side eects in clinical trials. e

side eect of a treatment during clinical trials is called an Adverse Event (AE).

e National Cancer Institute (NCI) has established a standardized way to

measure the seriousness of an adverse event. is is called the Common Toxicity

Criteria for Adverse Events (CTCAE). Over the years these criteria have changed,

and in 2012 the most current version is version 4. e complete CTCAE can

be found at the NCI website: http://ctep.cancer.gov/protocolDevelopment/

electronic_applications/ctc.htm.

Adverse events are graded on a scale from 1 to 5. (Grade 0 refers to not having a

symptom or problem, so someone with grade 0 pain has no pain at all.) Grade

1 adverse events are mild and generally not bothersome. Grade 2 events are

bothersome and may interfere with doing some activities but are not dangerous.

Grade 3 events are serious and interfere with a person’s ability to do basic things

like eat or get dressed. Grade 3 events may also require medical intervention.

Grade 4 events are usually severe enough to require hospitalization. Grade 5

events are fatal.

Most clinical trials and doctors focus on grade 3 or higher events, because those

are the most dangerous. Grade 2 events however, can signicantly impact the

patient’s quality of life, even if they are not medically dangerous. For example, a

grade 1 headache is mild. A grade 2 headache keeps the patient from doing things

Chapter 5: Clinical Trials for DIPG

like shopping or cooking. A grade 3 headache keeps the patient from getting out

of bed even to go to the bathroom.

Consent and Assent

One basic principal of medical ethics is that no person should be included in

any sort of experiment without his or her agreement. is agreement is called

consent. In the past, heinous examples of medical experiments occurred where

people were given injections of experimental drugs or even diseases without

knowing it. However, since the Nuremburg trials in the 1940s and particularly

since the 1970s, experimenting on people without their agreement and consent

has been considered unacceptable in the U.S. and the rest of the civilized world.

Informed consent refers to the idea that not only should people know they

are in a clinical trial, but that they also must understand what will happen to

them during the trial. Informed consent is a process that involves both talking

to someone involved in running the trial to learn about the trial and signing a

paper, called the consent form, that explains the trial. e process of informed

consent should include:

• What is known about the experimental treatment.

• What will happen during the clinical trial, including what medicines will

be taken, when and how they will be taken, and what and when tests or

procedures will be done.

• What parts of the trial are considered standard, i.e., they would happen

even if you are not involved in the trial, and what parts of the trial are

experimental. Experimental parts of the trial can be treatments, oce

visits, tests, etc.

• What the alternative is to being in the trial and what the treatment and

testing would be like if you do not participate in the trial.

• Whether there will be any nancial costs to participate in the trial.

• Whether the trial is expected to benet the participants personally or

whether it is to benet patients in the future.

• Whom to contact if you have questions or complaints about the trial.

• What the procedure is to stop participating in the trial.

All clinical trials are overseen by an Institutional Review Board (IRB), which

is a group of scientists and non-scientists that ensure that clinical trials are done

in an ethical manner. Each university or cancer center has its own institutional

review board. e institutional review board approves all aspects of clinical

trials, including what is included in a consent form. e consent form should

have contact information for the institutional review board in case you ever

feel uncomfortable with what is happening in a clinical trial.

Giving informed consent requires that someone has the mental capacity to

understand his or her options and to make a rational and consistent choice.

Some patients, such as children or people with mental impairments, are

thought to need special protection because they may not understand enough

to give informed consent. In that case, two things are needed. First, the person’s

guardian, such as the parent for a child, must give informed consent. Second,

if possible, the child or impaired person needs to agree to the trial, which is

called giving assent. Sometimes this is impossible, for example for young infants

or people who cannot communicate. e age at which assent is required will

vary from trial to trial, but national groups such as the American Academy of

Pediatrics, and the Children’s Oncology Group recommend that children 7 years

of age or older not be enrolled in clinical trials without their assent. Requiring

assent allows a child to say no and to have some control over what happens

to his or her body. Not only are uncooperative children dicult to get useful

scientic results from, but some children may tire of participating in medical

research before parents, who naturally hope for a miracle.

Questions to Ask

If you are considering participating in a clinical trial, here are some questions

you may want to ask:

1. What phase is this trial?

2. What do we know right now about the treatment being tested and what

is unknown?

3. What is the purpose of the trial?

4. What is the chance that this trial will benet my child?

5. What would my child’s treatment be if he/she does not participate in the

trial?

6. Are there extra tests my child would have to undergo if he/she participates

in the trial?

7. What will I or my insurance be charged for and what will the trial pay for

Chapter 5: Clinical Trials for DIPG

during the trial?

8. If my child get sick or is hospitalized during the trial, who will pay for that?

9. Is the trial randomized?

10. Is there a placebo or blinding, or will I know what treatment my child is

taking?

11. Who is paying for the clinical trial research? Is it the company producing

the drug?

12. Does my child receive any type of nancial reimbursement for participating

in this trial?

Conclusion

All of the advances that have developed to successfully treat many types of

cancers have come from clinical trials. Millions of people are alive today because

of people who participated in clinical trials. However, while clinical trials have

the potential to benet the individual patient and future cancer patients, clinical

trials are scientic experiments and there are important considerations that need

to be understood before patients agree to participate. ere are pros and cons

to participating in clinical trials. A clinical trial may or may not benet the

patients in the trial. Clinical trials limit the exibility of doctors and patients

because it is necessary to get scientically valid results. Asking questions of

your doctor is the best way to get information about any clinical trial you are

considering for your child.

Parent Perspectives

When Caleb’s DIPG was diagnosed, he was less than three months from

his 4th birthday. His tumor was diagnosed in the Emergency Room after an

MRI, and the doctors were crystal clear at the immediate outset that he could

not survive this tumor. Even given this clear-cut, seemingly straightforward

assessment, we decided that a review of our available options was vital.

We were at one of the best Children’s Hospitals in the country; however,

we thought it beneficial to seek other opinions.

Of course, the first thing one does is usually an Internet search. In 2006,

there was considerably less material available for DIPG. Only a few

parents had brought their story to the Internet (we found two); there were

no DIPG support groups, Facebook pages, parent communities, or the like.

The medical literature that was available publicly was clear—long-term

survival with DIPG was unlikely. The parent stories we did find also echoed

that sentiment, and both children had passed away.

We visited one of the premier cancer centers in the US in Houston, Texas, and

found doctors very willing to discuss options with us. They had treatment

protocols for DIPG. I recall the discussion with the doctor vividly: he told

us that long-term survival was not possible. We asked about extension of

life, and he said that this was definitely possible—he could promise a longer

life for Caleb. We asked him what the “extension” would likely be and he

felt certain that “a few months” was possible.

While we were consulting with him, other children were there. One was

vomiting violently from the treatment she had been given. The doctor

shared the details of what Caleb’s treatment would be, and he described the

mouth sores and other side effects the treatment would probably produce.

We were not willing to compromise Caleb’s quality of life for a few extra

months of him being sick from treatment. We wanted what life he had left

to be full of living.

Knowing that Caleb’s long-term survival was not likely, and that treatments

with severe side effects would perhaps extend his life “a few months,” we did

not want to pursue them. Our doctors at the Children’s Hospital provided

us with an option: a Phase II clinical drug study at NIH which was testing

Chapter 5: Clinical Trials for DIPG

the effectiveness of a proposed treatment. Side effects were minimal if any.

We opted to participate in this study, for two reasons: first, it would provide

information to researchers; and second, we did feel like we were doing

something to help Caleb. This treatment, in the end, did not help Caleb.

But it also did not compromise his quality of life.

Caleb survived about ten months past diagnosis. While the initial few

months were challenging with the radiation and Decadron treatments,

his quality of life overall was quite good. He struggled off-and-on with

some neurological problems which were treated with medications, and

his abilities did diminish as the disease progressed. Up until the last few

days before his death, he was alert, aware, and until his last week or so,

he could participate in activities. He was never sick to his stomach, had

just one hospital stay related to the tumor, and was a cheerful little boy.

It’s hard to say, now, that we would have done the same thing as more

treatments are available and some differing degrees of success have been

seen. However, the process would be the same—the compromise to his

quality of life, versus an expected benefit. And, in the end, every parent

has to weigh that carefully for their child and make their own decisions.



Quality of life was absolutely number one from the first day. We told our

doctor that we would NEVER prolong Hope's life without a guarantee

that she would have top quality. We even chose some of our clinical trials

including lack of hair loss as criteria. It was a balance of feeling like we

were doing something to give her a fighting chance (hoping we'd get our

honeymoon and more good days) and not putting her through things that

were for naught.



Lovis just loves to be home. Coming back from a trip, I can see so much what

this means. She really wants to be home. When it comes to trials, yes, we

are interested (of course), but then I couldn't think of taking her somewhere

far away, by plane, when the only thing I hear from her is "When are we

going back home?" I am still stunned by how much travel families do for

and with their children to make treatment possible.

I am still not sure what to do. The inner fight we all know: How much am

I going to compromise my child's quality of life versus a slight chance of

maybe doing something against the tumor with unproven drugs that might

have terrible side effects?



The conversations we always had with her doctors stemmed from the need

to preserve her quality of life—hence no other meds or trials. They would

have provided them to us if we asked, but we both agreed that none of the

approaches were a cure. They helped us understand and accept that there

were trade-offs—her quality of life versus the need to keep her with us

longer. And they leaned very much towards her quality of life.



Emma's case was constantly reviewed. Emma stumped some of the doctors,

because she was on no medications at all—no chemo, no trials—just

radiation and at the end a small dose of dexamethasone to help her swallow.

She survived 16 months. Her doctor said, and I quote, "If we could teach

other parents the approach we had in dealing with our daughter we could

do so much good. We just don't really know how to describe that approach."

I found that interesting to hear, as I don't think we did anything overly

different than what other parents have done—but perhaps we did.



We sent Liam's scans to be reviewed by a leading doctor in the DIPG

community to get her thoughts and opinions going forward. It was agreed

that in fact Liam's tumor had progressed. We also sought the opinion

of another doctor well versed in the care of DIPG patients. We wanted

opinions of studies and clinical trials that might have benefited Liam. We

were told very forthrightly that generally children live six months following

the diagnosis of progression and that oftentimes had little to do with what

new treatments were tried. This weighed heavily on us. We decided (and

were also advised) that what our current hospital could offer Liam for care

would be just as effective as anywhere else. We made the very personal

decision not to pursue a clinical trial at that time in large part because of

Liam’s rapidly declining health. We decided to do a combination of two

chemo drugs in the hopes that they would keep things relatively "quiet" for

as long as possible. Liam by this point was back on higher doses of steroids

and they were increased as needed.



Chapter 5: Clinical Trials for DIPG

During Brendan’s symptom-free periods he regained full abilities and

appeared healthy. He was always doing some sort of treatment though

whether it was off label or clinical trial. His quality of life was very good

aside from the expected side effects of the treatments he endured. He wanted

to fight so he participated in 2 clinical trials—one before progression and

one after. We took our cues from him and as long as he wanted to fight and

live we found treatment options for him.



This decision to not try to prolong her life using treatments was not one we

took lightly, and we are extremely pleased with the high quality of life we

have been able to offer Stella, free of the burdens of invasive medications,

side effects, sedation, etc. that a 2-year old would not have understood.

Because of this decision, we were able to spend the summer taking Stella to

cottages, the zoo, Riverdale Farm, the library and on play-date after play-

date instead of being chained to the hospital. In fact, Stella has been home

the entire time since her diagnosis which has been wonderful for all of us.



Clinical trials were discussed only as a second option if/when the radiation

failed. In hindsight I wish we had gone home and taken a few days to do

some research and consider second opinions. We could have become better

informed and Sam would have had a few days to enjoy his friends while he

was still feeling pretty well. As it turned out Sam never had a "honeymoon"

period so if we had gone home to think and research he could have had a

few days more of "normalcy."

We knew very little about DIPG at that point yet felt like we had to make

critical decisions quickly without the information needed to make informed

decisions. I'm still not convinced that the surgery did anything other than

cause him to forfeit the honeymoon period. There is no way to know if the

surgery did anything to extend his life at that point. Perhaps the radiation

would have stopped the tumor in the cerebellum from growing as it did the

tumor in the pons (at least temporarily). But our goal at the beginning was

to be one of the few to beat the horrible odds and it seemed like surgery

would help that goal.

I wish when Sam was diagnosed that someone could have said, “Here is what

he has, here is the typical timeline, here is our most up to date information

on DIPG, and here are the options including clinical trials. Take it home

and then come back in a few days with questions, and to discuss the path

to take that would be best for Sam.”



At diagnosis there were no choices to be made. If Miguel was going to

have a chance to survive he would need weeks of radiation. My daughter

(Miguel’s mom) spoke with Miguel about his diagnosis and the treatment

he was about to receive. Miguel had just turned eight a month before and

was a very bright child. There really was not an option of keeping things

from him. Miguel’s mom always kept him informed, including showing him

the scans so that he could see for himself.

At progression, it was different. There were choices to make. How do you

know which treatment option to go with when you are given five? My

daughter decided that this decision could not be made alone and that Miguel

would have the final say. There were four primary caregivers for Miguel:

my daughter, her boyfriend, my youngest daughter and myself (Miguel’s

grandmother). My daughter decided that the best approach would be to

analyze and rate each clinical trial individually and then we would come

together to assess the results. The top two options were clear and we all

agreed that there was one that was probably a better approach for Miguel.

Now that there was a choice of two, she presented them to Miguel. It was

important that he was aware of the treatment, including how the medication

would be delivered into his body, and any side effects that were almost

certainly going to occur. The decision was made and the final choice by

all, including Miguel, was Nimotuzumab.



Aimee didn't do any clinical trials; she only did radiation, 6 weeks, 5 times

each week, with external-beam radiation therapy. …She was supposed to

do some new trial that was gadolinium based. She was not eligible for any

trials once she was put on the ventilator….



As parents who knew that radiation was the only thing that had some impact

on DIPG, we were ignorantly devoted to the Phase II clinical trial which

was causing such horrific side effects. We knew that the fact that a therapy

was in Phase II did not mean that it had been effective in Phase I. At the

same time, we mistakenly believed that it would not have moved from Phase

Chapter 5: Clinical Trials for DIPG

I to Phase II if it hadn’t shown some promise in the first trial—if children

who received the maximum tolerated dose hadn’t responded positively.

Had we known that the children who received the treatment in Phase I,

even at the maximum dose, did not have a better course than children who

received radiation therapy alone, I don’t know if we would have made a

different choice. In retrospect, I wish we had. If we had had that knowledge

and understood that radiosensitizers were not “new” or “novel,” as we

were told they were, but had been tried in various forms for years, I know

we would have been better informed. We would not be living with the feeling

of regret compounded by guilt as a result of our ignorance.



We had been in a hospice mindset for a few days when we received a phone

call from Andrew’s neuro-oncologist letting us know that a clinical trial

slot (we had previously planned to do) had opened. She knew that we would

most likely choose not to do the trial, but she wanted to allow us to be the

ones to make that decision. Andrew surprised us by saying that he wanted

to participate, so we made a final trip to NIH. An MRI there confirmed

that the tumor had spread throughout the brainstem and to other parts of

the brain. He qualified to do the trial, but when he realized all the pills

that he would need to swallow, he told us that he did not think he could do

it. We were so overwhelmed by the extent of the tumor spread, and by how

well he was doing in light of that, that we could not imagine asking him

to swallow all those pills. Andrew, age 8, and his neuro-oncologist spent

a few moments alone together to talk about the clinical trial and what he

wanted to do. That conversation, between our son and the physician he

loved and trusted, confirmed in our hearts that he was truly ready to stop

treatment. It was clear to all of us that after living life to the fullest for

over 25 months in spite of DIPG, he was tired. He made the decision to

stop treatment understanding exactly what that meant.

Chapter 6

Surgery: What It Can

and Cannot Offer DIPG

Michael H. Handler, MD

e problem with operating on diuse intrinsic pontine gliomas (DIPGs) is

captured immediately by the name itself—they are diuse, they are intrinsic,

and they are in the pons. Tumors elsewhere in the brain tend to grow as a

lump that pushes aside more normal brain tissue, but DIPGs do not. Lumps

of DIPG cells are generally not large individual masses that a surgeon can try

to take out. Instead, the cells making up the tumor project diusely in ngers

that sit widely among other areas of normal brain tissue.

With DIPGs, it isn’t possible to separate normal from abnormal tissue when the

surgeon looks at it. us, an attempt to remove large pieces of tissue to try to

control the tumor (and improve the child’s outcome by getting enough of the

tumor out) is not possible. Instead, attempts to remove abnormal tissue result

in pieces of normal brain tissue being removed. Removal of normal tissue can

also happen during surgery on other parts of the brain, but in other parts of

the brain the nearby normal tissue usually doesn’t have as important a function

as pons tissue.

e Pons

e pons is a small area of the brain about 3.5 cm. long and 2.5 cm. wide.

In it are the brain centers that control sleeping and waking, eye movements,

facial movement, and hearing. e major pathways for movement of the arms

and legs, and for most of the body’s sensations, pass through it in a complex

manner (see chapter 3). e cerebellum

which sits behind the pons sends bers

from one side of the brain to the other

through the pons. e cerebellum controls

smooth muscular movements and balance,

Dr. Handler is a Professor and

Chairman of Pediatric Neurosurgery

at the Children’s Hospital Colorado

and the University of Colorado

School of Medicine, Aurora, CO.

Chapter 6: Surgery

and some of the balance centers of the brain are located in the pons. Additional

centers controlling balance are located in the medulla. us, the pons is a

critical structure that highly inuences the entire body’s ability to function

properly. When the pons is damaged, it can have an extremely wide impact on

the body’s ability to sustain itself. Any surgeon should be extremely cautious

when attempting an operation in this region. Taking small amounts of tissue

may be possible without inicting serious neurologic damage, but taking large

amounts of tissue simply is not.

History of DIPG Diagnosis and Imaging

Surgeons’ current thinking about DIPG tumors is based on the tumors’ history.

In the past, surgeons would generally try to remove brain tumors. But that was,

and is still, rarely possible in the pons. With tumors in other areas of the body,

surgeon’s usually try to take a small amount of tissue with a “needle biopsy”

to gain a better understanding about the tumor before considering a larger

operation. Biopsies, however, were rarely done on brain tumors, because biopsies

were much more dicult in the brain than elsewhere in the body. e reason for

the diculty was that it used to be very dicult to know exactly where in the

skull, and therefore where in the brain, a needle should go to make a diagnosis.

While surgeons used a variety of external landmarks for placing needles in the

brain, this technique—called stereotactic biopsy—was not good enough for

widespread use. Forty years ago, that began to change. New computerized

brain imaging technology suddenly made it possible to see anatomic details in

a remarkable way. e technique of stereotactic biopsy became feasible, and

surgeons began to use it.

Meanwhile, brain imaging itself became much more precise. In particular, MRI

revolutionized surgeons’ ability to understand and visualize the location of

tumors, particularly in the posterior fossa—the back of the brain where the pons

is located. MRI and stereotactic technology were now linked in a constructive

way, and surgeons began to try stereotactic biopsy in the pons.

Clinical Study Recommendations for Standard of Care

Pediatric oncologists have long worked collaboratively to try and develop the

best new treatments for tumors, in the most ecient way. One such collaborative

study, organized through the Children’s Cancer Group (the CCG study 9928),

looked at patients with diuse pontine gliomas and proposed new treatments.

is study, published in 1993, concluded that when an MRI shows specic

characteristic features of changes in the pons, it was sucient evidence to make

a DIPG diagnosis without a biopsy. It also turned out that when a biopsy was

taken, the result of the pathology was not helpful in planning a particular

treatment strategy and did not appear to alter a child’s subsequent outcome.

erefore, the recommendation became that no biopsy should be undertaken

in cases that appear to be typical pontine gliomas.

At that time, the risk for harm from a biopsy was not yet well known, because

the technology for stereotactic biopsy was still relatively new. But because the

benet from biopsy is so small, the risks were too large for it to be undertaken.

Based on this historical data, the accepted standard of care has become that no

biopsy need be done for DIPGs.

When the neurosurgeon, oncologist, and radiologist agree that a tumor does

not appear to be a typical DIPG it is considered appropriate to proceed with a

biopsy. Since the publication of the CCG study, many more publications have

documented the safety of stereotactic biopsy in the posterior fossa with relatively

little inicted harm. us, the decision to do a biopsy is based on whether the

tumor appears enough atypical that a dierent diagnosis could be considered.

In addition, some tumors—in the opinion of the surgeon, oncologist, and

radiologist—remain so unusual that an open operation (removal of a ap of

the skull and entering the brain tissue with instruments larger than a needle)

is more appropriate.

Stereotactic Biopsy

A stereotactic biopsy is based on obtaining a computerized image on which

a target (tumor) can be identied; that image can be an MRI or CT scan.

Technology is then used to calculate the position of the target in relation to the

scan. Several dierent technologies are available to do that, some using a rigid

frame that is attached to the head before the scan, and others that can map the

surface of the face and use that as the basis for determining the tumor’s position.

With the head in a xed position and the trajectory calculated, a very small hole

is made in the skull to allow the needle to pass to the target and obtain the tissue.

e tissue is then removed and prepared so as to identify the pathology; other

studies may also be done. Stereotactic biopsy has the advantage of a very small

incision, a small hole in the bone, and less risk than a larger open operation.

Most studies of stereotactic biopsy have shown relatively little damage as a result

and a very low rate of death from the procedure (less than 1%).

Chapter 6: Surgery

Deciding When to Operate

e decision whether or not to operate must be based on the imaging features of

the tumor and on whether the treatment is appropriate for the individual child.

e DIPG’s location presents a problem (in addition to that of the tumor itself).

e brain produces cerebrospinal uid (CSF), which circulates through a series

of spaces in the brain called the ventricles, which include:

• Lateral ventricles: One lateral ventricle is found in each cerebral

hemisphere, and each lateral ventricle communicates through a small

channel (called the foramen of Monro) to the third ventricle.

• ird ventricle: e third ventricle sits on the midline at the base of the

brain and ends in a channel, called the aqueduct of Silvius that goes to the

fourth ventricle.

• Fourth ventricle: e fourth ventricle sits behind the pons and medulla,

in front of the cerebellum.

CSF goes downstream from the lateral ventricles to the third and fourth,

then leaves the fourth ventricle through channels that connect to the space

around the brain (the subarachnoid space) where CSF is absorbed into the

bloodstream. Because DIPGs sit adjacent to this uid pathway, as they grow

they may at times block the ow of CSF. is blockage causes uid pressure

in the brain to go up and the uid spaces to enlarge—a condition called

hydrocephalus. When the uid pressure builds up, it can cause headaches,

vomiting, mental changes, and even coma. us, sometimes children with

DIPGs need procedures to control the uid pressure.

Treating Hydrocephalus

e most common and well-established procedure to treat hydrocephalus is the

ventriculoperitoneal shunt (VP shunt). A tube is placed from the outer surface

of the head through the skull and brain into a lateral ventricle. e shunt is

connected to a device—the valve—which determines how much pressure must

build up before CSF starts to ow, and makes sure CSF only ows out of the

ventricle and not back in. e valve sits under the skin and connects to a tube

that leads to a place in the body where the CSF can be absorbed back into the

blood stream (where it would have gone from the brain directly, if it could).

e most common end point of shunts is the peritoneal cavity—the belly—but

other times shunts go to the chest, through blood vessels to the heart, or even

to the gall bladder. Eective shunts have been around for about 50 years, and

they save and improve the lives of tens of thousands of kids each year.

Shunts, however, have their own problems. ey are foreign to the body, so

the body may react to them and block o their ow. ey are also mechanical

systems that can break or malfunction. e most common way they become

a problem is when they become infected. Infections happen between 5 to 14

percent of the times they are implanted. (Neurosurgeons are very focused on

how to reduce the rate of these infections.) When a shunt is infected, it has to

be removed, and—after a period of time—replaced with a clean system.

Because of the problems with shunts, another way to drain uid from the

ventricles is the endoscopic third ventriculostomy (ETV), which creates an

alternative pathway from the third or fourth ventricle when the normal pathway

is blocked. Whether the ETV is an option depends on the particular anatomy of

a child with hydrocephalus due to a DIPG. is is a matter only the surgeon can

assess. (e pons sits behind the area where CSF goes after an ETV. If a DIPG

can block the CSF pathway behind it, it can block the pathway in front as well.)

Biopsy of More Routine Tumors: Why or Why Not?

A fundamental ethical dilemma raised by the current standard of care is that

when the tumor looks typical on MRI, the recommendation (based on research

completed 20 years ago) is that no biopsy should be done. e potential risk

for the individual child, as interpreted at that time, could not be balanced by

the potential benet. Since then, two things have changed:

1. Many more patients have undergone safe biopsy of brainstem masses than

had done so when that observation was made;

2. e ability to study tumors has been vastly advanced by genomic analysis.

DIPG tumors will not be understood as other pediatric brain tumors are,

unless more tissue is obtained for study by contemporary techniques. e

cancer community will have to decide the most appropriate course of action

with DIPG tumors.

Federal Guidelines for Clinical Research

Federal guidelines for conducting research, particularly in children, stipulate

that there must be the potential for benet for the individual child if he or she

is to undergo a procedure with more than a minimal amount of risk. What

will be the benet to undergoing a procedure; will the procedure allow us to

better understand the nature of the tumor; and will it benet a particular child?

How should we measure benet? If the child and his or her family decide that

Chapter 6: Surgery

to help advance knowledge is a very signicant benet to that child, is that

substantial enough to oset the notion that because “the child’s survival won’t

change,” there is no potential benet? is is the overarching question that has

no easy answers.

Parent Perspectives

Our son Caleb, had his DIPG diagnosed at a critical point where his tumor

had grown to the point of obstructing cerebrospinal uid (CSF) circulation be-

tween the brain and the spinal cord. The higher ventricular pressure, from the

CSF obstruction and resulting hydrocephalus, was visible on the MRI and a

syrinx (pocket of uid) was also evident. Clinically, Caleb was sluggish, limp,

couldn’t keep his eyes open, and was clearly having problems from the hydro-

cephalus. So we had an immediate problem which needed to be addressed.

His medical team recommended a ventriculoperitoneal (VP) shunt be placed

immediately.

We struggled with the decision of what to do. This was “Day 1” for us. The

idea of DIPG, shunts, radiation, what we would do to treat Caleb—these

things were all questions we faced immediately. The shunt issue, however,

seemed to be the most pressing since the hydrocephalus needed to be promptly

addressed. We needed time to gure out what to do about the base DIPG diag-

nosis, and the shunt bought us that time.

Nonetheless, the idea of operating on Caleb’s brain was not an attractive one.

We assembled his medical team in the room, and the question we put directly

to them was, “If this was your son, what would you do?” With zero hesitation

the neurosurgeon quickly said, “I’d place the shunt.” In hindsight, this was

one of the most simple and straightforward procedures performed on Caleb.

After the surgery, Caleb was awake and ready to play. His body adjusted to the

shunt almost immediately.

Caleb’s VP shunt worked well. We never had problems with it. As the tumor

progressed, he did have other neurological problems which occasionally

brought him to the emergency room—and the very rst thing the doctors would

do was check the operation of the shunt.

In hindsight, we would do that part of Caleb’s treatment the same way again.

If his DIPG had been diagnosed at an earlier stage when hydrocephalus was

not already a problem, it might have been a different question for us. However,

given the point we were at, the shunt was the treatment that bought us the time

to treat him with radiation and consider our other options.

Chapter 6: Surgery



Quickly our attention became focused on what we needed to do next to help

Liam. Liam's neurosurgeon reviewed with us the most pressing issue at the

moment which was the uid that had accumulated on his brain. We opted for

a 3rd Ventriculostomy. Not every child is a candidate for this surgery nor is

it performed by every doctor. The signicant risk was explained to us. We felt

extremely condent in our doctor and felt this would be the best option for

Liam going forward.

After this decision was made we walked the long hallway back to Liam’s room

to give him the news. Not ALL of the news mind you, but a small piece and the

next steps that needed to take place. The three of us sat with Liam, told him

that his doctor needed to help him feel better and that there was too much uid

in his brain that shouldn't be there and he would need surgery. We explained

that he would be asleep and wouldn't feel anything and would wake up and be

able to see Mom and Dad right away—which the operating room staff made

happen for us. At this point in time, Liam was so sick and weak he barely re-

sponded but simply nodded his understanding. Our sweet boy looked every bit

of his little six year old self in that hospital bed and our hearts were absolutely

broken but also incredibly resolved to do everything we needed to protect and

help him on this journey.

As the weeks and then months went on, and with the help of a successful 3rd

Ventriculostomy, surgery, effective radiation treatment, and the use of steroids,

Liam's symptoms greatly improved. He returned to school and eventually came

completely off steroids and became symptom free. His meds and periodic vis-

its to his oncologist were just a minor interruption to the real business of the

day—being a kid.



Our experience with neurosurgery was brief, I suppose. The neurosurgeon put

in Tatumn's shunt at diagnosis since she did have some hydrocephalus. It did

relieve the pressure but it was always an uncomfortable question to ask our-

selves, "so how long will this thing be in her head?" when we knew the answer

wasn't relevant given the prognosis.

After Tatumn's six week run of radiation we started to see signs of the “hon-

eymoon period,” and we were reducing her steroids. We saw some light at the

end of the tunnel! Tatumn was using her hands again and was speaking better

and we had hopes of her staring to walk again. Well, high fevers set in and she

started to be very uncomfortable to move. We had to be slow to move her and

she had denite abdominal discomfort. They checked her blood for infection

but couldn't nd anything. They did an x-ray and didn't see anything either.

Our neuro-oncologist wasn't available. It was during Thanksgiving week so

the doctors we saw said maybe it was the tumor and her body temperature

wasn't being regulated right. But I could sense it was more. So we went on

her wish trip and fevers kept spiking. I called her radiation oncologist when

we got back and he said to take her in immediately and have her shunt tested

for infection. He was right. Tatumn had an infection probably caused by the

shunt and since it emptied into her peritoneal area I think that is why she had

the discomfort. The shunt was removed and during our 10 day hospital stay on

antibiotics (right before Christmas) they monitored her cerebral uid and said

she would be ne without it and they didn't put a new one in. We felt so good

to have that gone.

What do I wish I had done differently? I wish I had listened to my intuition

more. I knew Tatumn's fevers were more than tumor related. Maybe we would

have caught it sooner and her wish trip would have been better.



About a year after diagnosis, our son began to show symptoms of tumor pro-

gression. It was at this point that we chose to meet with a pediatric neurosur-

geon to explore the possibility of surgical intervention, if necessary, to treat

hydrocephalus. We were more interested in an ETV than a shunt because it

seemed less invasive to us. The neurosurgeon conrmed what we had heard

from others—that surgical intervention to treat hydrocephalus is not recom-

mended for most patients with DIPG. While surgical intervention may prolong

life, and even help with quality of life in some ways, it does not stop the tumor

from growing and affecting the body in other ways. So it's possible to treat

hydrocephalus successfully and prolong the child's suffering.



As I understand it, many of Bizzie's initial symptoms were related to hydro-

cephalus. We were told that she needed surgery; it was not presented as a

choice of having surgery or not, but rather ETV or shunt.

This was presented

to us along with her diagnosis, so we were at the hospital, in the PICU,

Chapter 6: Surgery

gesting the diagnosis. In fact, the pediatric neurosurgeon was the one who

ofcially diagnosed Bizzie. We were still so shell shocked when we made the

decision. We chose the ETV surgery. We did so based on the facts as they were

presented to us. My husband also spoke with another neurosurgeon so that we

had a second opinion about the surgery. We decided that we should go ahead

with the ETV and then consider moving to a large cancer center for treatment.

I don't think we understood, though, how important the facility and nursing

staff is in recovery.

We were admitted on Friday and Bizzie's surgery was scheduled for Monday.

We were given the impression that Bizzie's level of hydrocephalus presented

an emergent situation, but that they also wanted the steroids (dexamethasone)

to be given a chance to do some work. Of course, it was also Friday. Monday

morning came and it was time for Bizzie's surgery. I was sick. I was shaking

holding her as the nurses and transport fought over stupid logistics. When I

sputtered out a plea for help, the nurse looked at me and said in a testy voice

"What? I can't understand a word you say." That memory still sticks with me.

I wasn't looking for sympathy, but I really needed some help getting through

that moment.

Bizzie refused to take off her princess dress and wear the standard green gown.

My husband and I begged and pleaded. Finally, we convinced her that it was a

Tinkerbell costume because it was green. I rode down on the bed with Bizzie in

my lap. They sedated her and the surgery began. The surgery was successful.

She came back up to the PICU for recovery. In the early morning following

her surgery, Bizzie was transported by the PICU nurse, the receptionist, and a

technician to the MRI area. My husband was with them while I tried to sleep.

When they returned, Bizzie had a seizure and they intubated her. The doctors

went back and forth as to the cause—low sodium levels, or the monitoring

piece near her brain perhaps brushed something in transport. Bizzie remained

on the vent for two days. They told us that she would not be able to breathe

on her own when they pulled the tube, but she did. She did not talk for several

days after that. She just stared. Our PICU neighbor thought that Bizzie had a

twin—the girl she saw before the surgery who was making quite a racket in the

PICU, and this other girl who did not respond to anything. Bizzie did recover

slowly, although she didn't walk again for several months. But that was the

worst she was until the day before she died.



Sam's tumor extended into the cerebellum and the neurosurgeon recommended

we do surgery to remove what he could from that area. I was under two mis-

conceptions at the beginning—one that the tumor in the cerebellum was a fo-

cal rather than diffuse tumor and second that diffuse was more like tentacles.

Later I learned that that the cerebellum tumor was also diffuse and that dif-

fuse was more like sporadic tumor cells spread throughout, and not really

connected like you would think of a tentacle being. I don't know that either

misconception affected our decision to do surgery but I wish I had had a better

understanding in the beginning nonetheless.

I know most kids with DIPG never go through surgery like this but perhaps

Sam's experience will be informative anyway. The surgery itself lasted 4 to 5

hours and was terrifying to think of him in there where anything could happen.

Everything went smoothly though, and he actually recovered well in the rst

few days. They had “PT, OT, and Speech” evaluate him and it was decided he

could handle outpatient rehab as opposed to inpatient. We were so excited to

have him come home. At that point he needed a little help walking but other-

wise seemed ok. That was on a Wednesday. When he was released I went over

the prescriptions he would need at home, specically asking the resident dis-

charging him if he needed to still be on the steroids and was told that he didn't

need them anymore. What a fool I was to accept that answer.

The next few days Sam seemed ne. There was nothing unusual, considering

his surgery. Then by Sunday he seemed to be having more trouble walking and

was a lot more tired. He'd had a lot of friends visiting so we thought it was

from trying to do too much too soon. Monday night he threw up and Tuesday

he could barely walk so we headed off to the emergency room where they did

an MRI and said the tumor was reacting to the surgery. The neurosurgeon said

the area in the cerebellum was ne but that the tumor in the brainstem was

causing problems. They bumped up the schedule for radiation and gave him

lots of steroids. By now he could not even sit on the side of the bed without

help, let alone walk; his right eye was turned inward causing double vision; he

had lost his hearing in his right ear; and he had difculty swallowing. He was

released to inpatient rehab for 10 days then home again. He started on the 6

week course of radiation and the Temodar while in rehab. When he came home

from rehabilitation he was so much worse physically than when he came home

from the surgery. It broke my heart to think that it could have been prevented

had he been on steroids at home.

Sam spent the next three months working so hard with his therapists to get bet

ter.

Chapter 6: Surgery

By June he was walking with a cane and able to do much more for himself

again. He was even on track to get prism glasses for his double vision. He

stayed pretty stable from mid-June until mid-August then had problems with

his balance. Within a matter of days he could not walk again—this time from

the balance issues. So off to the emergency room again where they determined

he had a cyst growing in the cavity in the cerebellum where they had removed

the tumor before. It was pressing on the fourth ventricle causing his balance

problems. So he had another surgery to remove that and came home again—

this time with steroids. Unfortunately, the tumor in the brainstem seemed to

have been aggravated because he never bounced back from that surgery and

in fact on his next MRI there was progression.

In hindsight knowing what I know now I might have pushed for no surgery

and just gone with radiation and some other chemo. I think he may have had a

longer time until progression and a better quality of life during that time. But

there is no way to know. Others think that without the surgery he may have had

less time.

Chapter 6: Surgery

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101

Chapter 7: Radiation Therapy

Chapter 7

Radiation Therapy

Arthur Liu, MD, PhD

Radiation therapy is the standard treatment for children with diuse intrinsic

pontine gliomas (DIPGs). is type of therapy uses high-energy x-rays, similar to

those used in a computed tomography (CT) scanner but at much higher doses.

ese x-rays deposit energy within the tumor, causing damage to the DNA of

cells. e tumor cells are then unable to repair the damage, and ultimately die

when the tumor cells try to divide.

e Radiation erapy Process

Before starting radiation, parents of a child with a DIPG consult with the radiation

oncologist to discuss the planned therapy and potential side eects. After this initial

consultation, the child undergoes a planning session (also referred to as a simulation).

At that time, a mask will be custom-made for the child. e mask allows accurate,

consistent positioning of the head for each treatment and helps the child remain still

during treatment. e mask is made out of a special type of plastic that becomes

moldable when heated in a water bath. After the mask is completed, a special CT

scan is performed. is entire process takes approximately 1 hour.

After the planning session, the radiation oncologist uses the CT scan to dene the

area that corresponds to the tumor and the regions of the brain that should not receive

radiation. With the assistance of dosimetrists (who specialize in calculating the dose

of radiation to ensure the tumor gets enough radiation) and physicists (who develop

and direct quality-control programs for radiation equipment and procedures), a

radiation therapy plan is developed to maximally treat the tumor while minimizing

the amount of radiation delivered to normal brain tissues and surrounding tissues.

Radiation therapy is then delivered daily,

Monday through Friday, for about 6 weeks to

a total dose of about 54 Gray (Gy). Smaller

daily fractions accumulating to the total dose

over weeks is intended to allow normal tissues

the chance to repair some radiation-induced

Dr. Liu is the Director of

Pediatric Radiation Oncology

and Program Director of the

Radiation Oncology Residency

Program at the University of

Colorado, Denver, CO.

Chapter 7: Radiation Therapy

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103

Chapter 7: Radiation Therapy

DNA damage while still destroying the tumor.

As radiation patients must lie still and alone on a table, some children are too young

or too ill to tolerate the radiation treatments while awake. In these cases, the planning

session and treatments can be performed under general anesthesia. A commonly

used anesthetic agent in radiation therapy is propofol. Propofol is an intravenous

anesthetic that allows for rapid induction and recovery, and—most importantly—

does not require intubation (insertion of a tube) for protection of the airway. Even

with daily use, the risks of complications with propofol are very low. Typically, the

child is brought into the room awake, with the parents, and the anesthesia is initiated.

After induction of anesthesia, the parents leave the room and the radiation therapy

procedures are performed.

Eectiveness of Radiation erapy

Radiation therapy is an eective palliative treatment that improves symptoms

in about 80% of children with DIPGs. e dose of radiation therapy is limited

by the tolerance of the surrounding normal brain tissue. However, given the

high rate of response, in the 1980’s a number of institutions increased the dose

of radiation therapy from 54 Gy to greater than 70 Gy and had promising

preliminary results. To escalate the dose of radiation delivered, smaller doses

per treatment were used (referred to as hyperfractionation). ese smaller doses

allow greater recovery of normal tissues, and thus a higher total dose can be

given. However, a Pediatric Oncology Group randomized trial showed that

while the higher dose of radiation was well tolerated by most children, there

was unfortunately no dierence in survival rates.

Medical professionals have an interest in exploring agents that may be given

along with radiation to improve the eects of this therapy; these agents are

referred to as radiosensitizers. Some types of chemotherapy, such as carboplatin,

can be used as radiosensitizers. Other experimental agents are also being studied.

For example, arsenic trioxide given concurrently with radiation therapy is

undergoing clinical trials to determine safety and to provide information that

can be used for studies of eectiveness.

Possible Complications of Radiation erapy

A common complication of radiation therapy in children with a DIPG is

radiation necrosis—cell death of brain tissue. is may cause swelling and

potentially lead to neurologic symptoms such as headache, nausea, vomiting,

cranial neuropathies, and ataxia (loss of muscle movement coordination).

Radiation necrosis can be very dicult to distinguish from tumor recurrence

by manifesting clinical symptoms or by imaging. Steroids are typically used

for the symptomatic treatment of radiation necrosis. However, steroids can

also cause side eects, including behavioral issues, insomnia, and weight gain.

ese steroid-related complications can signicantly impact the child’s quality

of life. e exact mechanism of radiation necrosis is poorly understood, but

vascular endothelial growth factor (VEGF) appears to play a role. Bevacizumab

is a monoclonal antibody that interferes with VEGF and is being studied as a

possible treatment for radiation necrosis.

Technologies for Delivering Radiation erapy

Many dierent technologies are used to deliver radiation therapy. e most

common radiation therapy machine is a linear accelerator, in which high-

energy electrons impact a target to generate high-energy x-rays. ere are a

number of dierent manufacturers, but most of the machines only have slight

technical dierences. Some machines provide the ability to perform a CT

scan for localization; these machines include Tomotherapy (Tomoerapy

Incorporated, Madison, WI), Trilogy (Varian Medical Systems, Inc., Palo Alto,

CA), and Synergy (Elekta, Stockholm, Sweden). e Novalis Tx (BrainLAB,

Westchester, IL) uses orthogonal planar x-ray imaging for localization. ere is

no clinical dierence in any of these machines. From a technical standpoint, the

Cyberknife (Accuray, Sunnyvale, CA) is the most dierent from other machines.

e Cyberknife mounts a linear accelerator on a robotic arm and is primarily

used to treat small tumors throughout the body. Due to the relatively large

size of the brainstem tumor in children with DIPGs, Cyberknife is typically

not an option.

Proton radiation therapy (PRT) is a form of radiation therapy that has very

limited availability. PRT uses protons to deliver therapeutic radiation. Protons

dier signicantly from the photons used in conventional radiation therapy

because they have no mass or charge, compared to protons, which have mass and

are positively charged. e mass and charge of protons results in a phenomenon

called the Bragg Peak, which results in no energy deposited after a certain depth

in tissue depending on the energy of the proton (higher energies go deeper). is

technique allows protons to potentially deliver less radiation therapy to normal

tissues, with fewer late eects of therapy. Numerous theoretical modeling studies

have shown benet to using proton radiation. For children with DIPGs, the

potential benet of protons is unfortunately minimal. e dierence in normal

tissue radiated between PRT and current photon radiation therapy techniques

Chapter 7: Radiation Therapy

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105

Chapter 7: Radiation Therapy

is small, and late eects in these children is not yet a signicant concern due

to the extremely low survival rate in this population.

In summary, radiation therapy is the current standard treatment for children

with a DIPG. Radiation therapy improves clinical symptoms in the majority of

children, but that improvement is temporary. e most active areas of research

are exploring the addition of therapeutic agents to a backbone of standard

radiation therapy.

Parent Perspectives

Radiation is the ONLY thing that has proven to help SOME of our kids so

we chose to do it. I don't regret it necessarily as we were fighting for our

child. The steroids took way more than the radiation did. While our daughter

didn't get the “honeymoon period” that many children do, we continued

to believe that we would be the recipient of a miracle. She only lost some

hair in the back but no one knew it because her hair was long enough to

cover the loss. She did not lose her eye lashes.



Andrew's pediatric oncologist called the tumor a pontine glioma. She said

that the standard treatment was radiation, and that it could possibly shrink

the tumor temporarily. She told us that sometimes people use chemotherapy

in an attempt to make the radiation more effective. Andrew started radiation

with two chemotherapies, but we quickly chose to stop that part of the

treatment. We decided that the possible benefit of the chemotherapies was

not worth the definite side effects (nerve pain, nausea, etc.) Radiation alone

was the right choice for us. Andrew's tumor did not begin to grow again

until a year from diagnosis.



Hope got no “honeymoon.” Hope saw no relief from the radiation. We

were devastated as her tumor barely shrunk at all. It began to grow almost

immediately and had areas of necrosis which caused further harm to our

beautiful girl. Hope was courageous. She continued to speak in terms of,

“when I get better” and “after treatment.” She attended therapy even when

it hurt because she knew it was “good for her.”



The first time our son had radiation as an outpatient, we arrived at the

hospital by 8:00 a.m. The nurse and aide checked him over, hooked him up

to I.V. fluids and monitors, and took him down for sedation and radiation

at 9:00 a.m. A nurse changed the dressing for his port while he was still

sedated. Another nurse monitored his vital signs while he recovered and

made sure he was able to drink, eat, and use the restroom. We didn't get

Chapter 7: Radiation Therapy

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107

Chapter 7: Radiation Therapy

home until noon. I had not expected to be there for the whole morning.

The radiation treatment takes moments, but the preparation and recovery

take more time.

He began to lose some hair two or three weeks into radiation. It looked

like someone had taken clippers and shaved off one to two inches around

the outline of his ears. We had his hair cut short so that the hair loss was

not as obvious.



We were able to get a second round of radiation. When we first talked to

our neuro-oncologist about re-irradiation she said it simply was not an

option. A couple of weeks later I spoke to her about the work being done

at another treatment center and she was mildly accepting of it; then when

I presented her with the ISPNO abstract she began to consider the idea

and was willing to look into it further. Bringing concrete information to

her definitely helped.

If parents are interested I would suggest starting to talk about re-irradiation

early. We had been told radiation was a one-time deal. I found that talking

about it each time I saw his doctor was helpful. At first she said, “No way,

absolutely not." As time went on and I presented her with more information

she became more open. By the time progression happened she knew we

wanted re-irradiation and went to bat for us with the radiation oncologist.

The radiation oncologist who did the first round of radiation decided she

would not do it so our doctor found another that was willing. The radiation

oncologist that did the second round said that the swaying factor was that

she knew that we knew it was not a cure. She knew we were looking for a

second “honeymoon period” and she felt that was reasonable.



My nephew had an experimental new radiation course that a radiologist

was studying. He had just five days of a higher dose of radiation instead

of 30 days at a lower level.



I spent days and nights on the computer and on the phone with numerous

doctors; we sent Ellie’s scans everywhere. We were given the typical

radiation/chemo option knowing very well radiation could not be put off

for long. We also learned that jumping into a treatment option may preclude

you from others. While with this monster there is no right or wrong we

wanted to receive a good feel for all available options. We explored both

proton beam radiation and IMRT (intensity-modulated radiation therapy).

After consulting with two neuro-oncologists we opted for IMRT and were

very happy with this decision.

During Ellie’s six week IMRT we were determined to pinpoint what next

steps we would take. Ellie tolerated her radiation therapy in very good

health. She really did very well. She never had to be sedated and with the

exception of fatigue, experienced little side effects. Her determination to

gain her strength back and get back to all the activities she sorely missed,

served her well.



We met with the radiation oncologist, who explained to us, and to Bryce,

about what radiation would be like. Bryce had another MRI to plan his

treatment. Then we went home to face our family and friends after being in

hospital for 5 days. We were home for one week, and Bryce chose to go to

school, to keep things normal as much as possible. I think back on that now,

and even that is telling of his character and how Bryce handled all of this.

I remember asking his doctor how long Bryce would have had without

treatment, and was given the answer of one month. These radiation

treatments would give us time to learn to live with this new reality, and

hopefully the treatment would make him feel better because he was already

having headaches and dizziness, as well as having difficulties with poor gait.

So, from March 10th to April 23rd, we stayed at Ronald McDonald House

from Monday to Friday as Bryce underwent radiation. We made another

good decision—to keep our whole family together during treatment. By the

end of it, Bryce was 50 pounds heavier from steroids and had lost his hair,

but the earlier dizziness and headaches had gone away for the most part.

I have to tell you that when treatment was over, I was scared to death. So

what were we supposed to do now, go home to wait for him to die? We

were so happy to be going home, and yet terrified, because we knew that

at some point, Bryce would lose his battle—the tumor would resume its

growth. Bryce deserved to go home and just be 13—not go home to wait

for the other shoe to fall.

Chapter 7: Radiation Therapy

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Chapter 7: Radiation Therapy



We chose to do radiation treatment concurrently with Temodar® and the

tumor shrank considerably. We stopped chemotherapy after much prayer

and used a nutritionist to fully change Kayla’s diet. We used many, many

alternative therapies and her tumor shrank further. We were incredibly

blessed with 4 ½ years of generally symptom-free living for Kayla. She

was in piano, ballet, and did well in school. When she was 10, her cancer

returned and she died 5 months later on June 18, 2010.



Courtney was admitted to the hospital and started on steroids. We were given

the option of the standard chemo/radiation treatment. We considered taking

her to a well-known children’s hospital or somewhere else for treatment,

but decided that since they couldn't offer us anything that would give her a

better chance of survival we would stay close to home. We were confident

that she would get as good of care at our local children's hospital as she

would anywhere else.

She had 6 weeks of radiation and about 5 weeks into it she started having

more muscle weakness in her legs. By the time she had completed radiation

she was in a wheelchair. Courtney was on Avastin®/Temodar® after she

completed radiation. I wish we had just given her the radiation treatments

and left off the chemo. The Temodar® wiped out her white blood cell counts

and because of this it really affected her quality of life. She had to spend

114 of the 186 days she lived after diagnosis in the hospital. She was taken

off the chemo in August because of this.

October 6th we had to take her to the hospital because she had a severe

headache. An emergency MRI was done and it showed the tumor was

progressing in the spinal area. At this point there was nothing else we

could do. She couldn't start on chemo because her white count still had not

recovered and she was ineligible for re-irradiation because it had only been

4 months since she had completed her first round. We took her home and

planned to cherish the time we had left with her. Three days later she had

to be admitted to the hospital because she was having difficulty breathing

and severe headaches that we couldn't get under control. She spent her last

22 days of life there and died on October 31, 2010.



After quite some pushing from our side, radiation started and was successful.

The doctors still felt uncomfortable sedating her but I remember thinking

"If she is going to die because of this tumor right now, we might at least

try radiation. I wouldn't blame anyone if the sedation did go wrong.” At

the same time I was wondering how I was able to think that without losing

my mind.



Liam endured the standard six week protocol of radiation along with a bolus

not always done at the end of that standard time. We were told radiation was

the only thing known for this kind of cancer that truly had the possibility of

shrinking the mass. DIPG was much like sand sprinkled in Jello we were

told. Radiation was very effective. Liam's tumor shrank considerably.



Stella is not, and has not, received any treatment. Because Stella was barely

2 years old at the time of her diagnosis, the standard treatment of radiation

therapy would have entailed 6 weeks of Stella being sedated on a daily basis

to receive the therapy. With no guarantee it would work, Stella's young age,

and the fact we wanted desperately to enjoy our remaining time with her, we

opted for no treatments. She was on steroids for one week post-diagnosis,

but we despised the changes we saw in her (huge appetite, tantrums known

as "roid-rage," discomfort, etc.) so we took her off immediately with no

plans to put her back on.



We did the proton radiation at a facility near where we live. I was told that

there would be fewer side effects than regular radiation. Warren started

off doing fine. He only lost a small amount of hair, and you really couldn’t

tell. He was tired but not overly tired. But at the same time he was doing

radiation he was also doing physiotherapy, so that played a role in him

being tired as well.



Joseph responded well to radiation. Our neuro-oncologist told us that the

first post treatment MRI showed remarkable tumor reduction however,

his clinical response was poor even after the second MRI showed more

reduction in tumor size.

Chapter 7: Radiation Therapy

110

The radiation-oncologist told us to expect fatigue. He slept twenty-two

hours a day. After our second visit to the neuro-oncologist after radiation

therapy they called it somnolence and increased the dexamethasone which

kept him awake twenty-two hours a day and totally changed his personality.

I remember looking at the MRI wanting to find something solid not a white

cloudy section. It was never truly explained to me what size a normal pons

should be or why my boy did not respond to treatments after evidence

of radiological improvement. We had set up second and third opinion

appointments but Joe did not make it to them.

I wish I had known that not all DIPGs respond to radiation. I would not

have waited for him to improve clinically to do more activities together

as a family.



When my 17 year old brother Daniel was diagnosed with DIPG, our family

was very overwhelmed. The doctors tried very hard to get my brother to

begin radiation immediately and this worried my parents very much. As

Daniel's oldest sibling, (and not living at home for many years) I was close

enough but not too close to be paralyzed by the fear and pressure from the

doctors. I realized that it would be wise to devote a few days to get second

opinions, and research all the options and make an educated decision rather

than just rush into the radiation. After looking at all the options my brother

chose not to proceed with the standard treatment of radiation and/or chemo.

Instead we began looking into alternatives including supplements, dietary

changes and Chinese medicine. We don't know the future, but the tumor is

stable eight months after diagnosis. We hope he will beat the odds, having

done something different.

111

Chapter 8: Radiosensitizers for DIPG

Chapter 8

Radiosensitizers for

DIPG

Roger J. Packer, MD

Radiation therapy remains the only eective treatment for brainstem gliomas

in children. Because its eectiveness is transient for most patients, attempts to

improve the benets of radiation therapy have been a focus of clinical research.

ese eorts have included increases in the total dose of radiotherapy delivered,

and alterations in the fractionation of radiation received (i.e., times per day

radiation is given and the dose at each delivery). ese modications to date have

not resulted in improved survival. e use of multiple small doses of radiation

per day to allow for a higher total daily dose (called hyperfractionated radiation

therapy) resulted in increased toxicity. Radiation damage to the brainstem (called

radionecrosis) is associated with increased neurologic decits.

Radiosensitizers

Radiosensitization is another means to improve the therapeutic balance between

ecacy and toxicity of radiation therapy. is research has been explored over

the past two decades, and continues to be studied. Radiosensitizers are dened as

compounds that, when combined with radiation, achieve greater tumor inactivation

than would have been expected from just the additive eects of the two modalities

of treatment. e premise that underlies radiosensitization is that the toxicities of

the chemical agent used and the radiation do not signicantly overlap, thereby not

increasing toxicity. Also, the chemical agent

chosen should not make the radiation therapy

more toxic to the normal brain cells within

the region of the brain receiving the radiation.

Optimally, the benets of radiosensitization

should allow the tumor site to be exposed to

an eectively higher dose of radiation without

increased toxicity. In reality, this hoped-for

Dr. Packer is the Director

of the Brain Tumor Institute

and Senior Vice-President of

Neuroscience and Behavioral

Medicine at Children’s National

Medical Center, and Professor

of Neurology and Pediatrics

at The George Washington

University, Washington, DC.

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Chapter 8: Radiosensitizers for DIPG

synergistic eect of radiosensitization is a balance between how much more eective

the radiosensitizers make radiation in killing more tumor cells, compared with how

much more damaging the treatment will be to normal cells that are exposed to the

radiotherapy.

Another basic concept that has been dicult to prove with brainstem gliomas is that

increasing the eective dose of radiation therapy actually improves disease control.

At best, most radiosensitizers increase the dose intensity of radiotherapy by 20%

to 30%, yet it is unclear whether such an increase results in improved long-term

disease control.

Types of Radiosensitizers

Hypoxic cell sensitizers

e largest early experience with radiosensitizers was the use of agents that

act to sensitize hypoxic cells to radiation therapy. e use of these agents was

based on the assumption that a chronic state of tumor hypoxia (when tumor

cells exist in an environment low in oxygen) occurs in brainstem gliomas.

Using agents that make these hypoxic tumor cells more sensitive to radiation

therapy may provide a therapeutic advantage by killing more hypoxic cells and

sparing better oxygenated cells (in theory, normal cells) from the damaging

eects of radiation. A series of hypoxic cell sensitizers have been utilized

for other cancers, but they have not been used in brainstem gliomas due to

concerns about toxicity, including enhanced neurologic toxicity, and lack of

any clear benet when used on other types of tumors.

An alternative means to radiosensitize hypoxic cells is to make the tumor less

hypoxic—in other words, get more oxygen to the cells. Dierent methods

that have been used to accomplish this include hyperbaric oxygen, the use

of red blood cell transfusions, and the delivery of oxygen carrier substances.

e combination of nicotinamide and carbogen has been used based on the

theory that nicotinamide will decrease the presence of intermittent hypoxia

(a deciency in the amount of oxygen reaching tissues), and the carbogen will

re-oxygenate tumor cells. Other approaches have included using drugs such

as nitric oxide, which causes vasodilation (widening of the blood vessels), to

alter the tumor vasculature.

Non-hypoxic cell sensitizers

Some of the earliest work in non-hypoxic cell sensitizers was the use of cell-

cycle-specic radiosensitizers that act independently of the eect of oxygen.

Drugs such as BUDR (bromodeoxyuridine) and IUDR (idoxuridine), which

are halogenated pyrimidine analogs, have been tested. It is presumed they

would primarily sensitize rapidly proliferating cells, with the drug sensitizing

tumor cells to a much greater degree than the normal surrounding cells. For

ecacy, these drugs require extended exposure to allow incorporation into

the tumor cell’s DNA. e use of halogenated pyrimidine analogs has not

been shown to be eective in adults with high-grade gliomas, and has not

been extensively studied in children.

Gadolinium-texafyrin is a molecule that penetrates well into enhancing

regions of the brain. Gadolinium is the primary contrast agent used for

magnetic resonance imaging (MRI) studies. Gadolinium-texafyrin is an

oxygen-independent radiosensitizer with a low toxicity prole. A phase I

dose-limiting toxicity study (see chapter 5) in children with brainstem gliomas

demonstrated minimal side eects. A phase 2 study of this drug regimen given

on a Monday through Friday schedule has recently been completed through

the Children’s Oncology Group (COG). Arsenic trioxide is another non-

hypoxic radiosensitizer which remains in phase 1 study for pediatric gliomas.

Chemoradiation

Chemotherapeutic agents have been widely used in children with brainstem

gliomas during radiation therapy in an attempt to radiosensitize the tumor

cells. e major diculties in choosing the most appropriate chemotherapeutic

agent to study include:

• e independent eectiveness of any drug in children with recurrent or

newly diagnosed brainstem glioma has been dicult to prove.

• Most phase 2 or pre-radiotherapy neoadjuvant studies (administration

of therapeutic agents prior to the main treatment) have demonstrated

minimal ecacy. Experimental data to support the synergistic benets of

chemotherapy, when added to radiation therapy in experimental models,

has been limited.

• e drug(s) may have limited ability to get to the tumor site because of

a relatively intact blood-brain barrier.

• e toxicity prole of the drug has to be “reasonable,” given the impaired

neurologic status and probable shortened life-span of the child, so as not

to detract from the remaining quality time that the child and family can

share.

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Chapter 8: Radiosensitizers for DIPG

Despite these considerations, there are multiple reasons to consider the use

of chemotherapeutic agents. For example, the radiation eect on tumor cells

may be enhanced by drugs that inhibit DNA repair after sublethal radiation

damage. Drugs such as cisplatin, hydroxyurea, and nitrosoureas have shown

this type of activity in experimental studies. Several drugs have been shown to

potentially enhance the ecacy of radiotherapy by changing the cell cycling

of tumor cells—putting more cells into a phase of the mitotic cycle, which

makes them more sensitive to radiation therapy.

Another potential benet of chemotherapy would be the independent eect

of the chemotherapeutic agent to decrease the size of the tumor cell. is

would potentially make radiotherapy more eective. Similarly, if radiotherapy

made the tumor smaller, it might allow greater vascular access for the

chemotherapeutic agent, resulting in a greater concentration of the drug in the

tumor and increased tumor kill. Some chemotherapeutic agents are relatively

eective in killing hypoxic cells. For this reason, drugs such as cisplatin may

have synergistic ecacy if used with radiation therapy. Chemotherapeutic

agents may also enhance apoptosis (programmed cell death) and subsequently

tumor death, especially in cancer cells sublethally damaged by concurrent

radiotherapy.

Delivery of Chemotherapy and Radiation

e timing of chemotherapy and radiation delivery is often based not only on

the principles of when the chemotherapy may be most eective in enhancing

radiation, but also the practicality of delivering such treatments to children. e

toxicity of some chemotherapy agents precludes treatment throughout the entire

6 to 7 weeks of prescribed radiation therapy. In addition, the need to transport

the child to the radiation therapy facility, which is often at an institution other

than where the chemotherapy has been given; the time needed to sedate young

children; and the concern of overburdening both the child and the family for

an unproven treatment, often results in severe logistical issues and compromises

in treatment schedules. In reality, these issues and compromises have resulted

in chemotherapeutic agents being given with radiation therapy in a sequential

fashion in order to reduce the temporal separation as much as possible.

e benets of chemoradiation have been suggested in a variety of dierent

tumor types, including head and neck tumors, small cell lung cancer,

gastrointestinal cancers, and cancers of the genital and urinary organs. However,

a clear-cut benet in adults with primary central nervous system tumors has

been dicult to prove. Pediatric tumor studies to date have been disappointing

as well, with the possible exception of medulloblastoma, where a preliminary

trial suggested improved survival.

Platinum derivatives

e use of platinum derivatives such as chemoradiation sensitizers is based

on the ability of drugs such as cisplatin and carboplatin to inhibit DNA

repair or sublethal radiation damage and to have cytotoxic eects on hypoxic

cells. Cisplatin has been used as a backbone of a study comparing standard

fractionated radiation to hyperfractionated radiation, without a clear survival

advantage in either arm of the trial. Another study utilized carboplatin twice

weekly during hyperfractionated radiation therapy without any clear-cut

benet. A subsequent carboplatin study coupled carboplatin with a bradykinin

derivative to enhance delivery of the carboplatin to the brainstem. In this trial,

carboplatin was given on Monday through Friday basis throughout radiation

therapy with good tolerability, but overall, survival did not dramatically dier

from that seen in historical controls treated with radiotherapy alone.

5-FU derivatives

e drug 5-FU has been extensively utilized in the treatment of adult cancers for

both its antineoplastic eects and radiosensitization properties. 5-FU interacts

with radiotherapy through disruption of cell kinetics and direct eects on

repopulation of cells. Experimental work has shown that 5-FU is truly synergistic

with radiotherapy. Its toxicity prole however, makes its concurrent use in

pediatrics dicult. A sister drug, Capecitabine, has recently completed phase

1 and phase II testing as a radiosensitizer given concurrently with radiation

therapy on a daily basis in children with brainstem gliomas. Results from the

data is pending.

Topoisomerase inhibitors

Etoposide is an oral topoisomerase inhibitor that has shown ecacy in one

trial of children with recurrent brainstem gliomas. e drug penetrates into

the central nervous system well. However, a COG phase II trial of etoposide

in combination with vincristine, concurrently with radiation therapy showed

no clear-cut benet.

Another topoisomerase inhibitor, topotecan, has been studied in a phase 1 study

concurrent with radiation therapy for children with newly-diagnosed brainstem

gliomas. A phase 2 study was initiated through the Children’s Oncology Group

but not completed.

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Chapter 8: Radiosensitizers for DIPG

Temozolomide

Results of adult trials with high-grade gliomas led to enthusiasm for the

use of temozolomide, concurrent with radiation therapy, for patients with

newly diagnosed brainstem gliomas. In children with recurrent brainstem

gliomas, temozolomide has not shown signicant independent activity and

there is little experimental data to show that temozolomide is synergistic with

radiotherapy. But based on the adult data and the relatively good toxicity

prole of temozolomide when used at a low dose on a daily basis, a study was

performed through the Children’s Oncology Group that coupled temozolomide

with radiation therapy, and followed the completion of radiotherapy. e results

of this study have been disappointing.

Radiosensitization with Molecular-Targeted Drugs and Other

"Biologic Agents"

Over the past decade, a host of biologic agents have become available and tested

in children with brain tumors. Molecularly targeted agents have included:

1. Antiangiogenesis drugs;

2. Agents that block growth factor receptors;

3. Drugs that interfere with intracellular signaling essential for tumor growth.

e lack of biologic information about brainstem gliomas has hindered, to a

great degree, a biologic rationale for deciding which drug, or drug combinations

would be most eective if combined with radiation. In phase 1 trials to date,

these biologic agents have demonstrated minimal ability to shrink tumors,

although some have resulted in possible prolonged stable disease. Because of

the relative low toxicity of many of these agents and, in some cases, theoretic

evidence that they may be at least additive—if not synergistic—with concurrent

radiotherapy, multiple studies have utilized biologics with, and following,

radiation therapy. ere is great interest in continuing such approaches, with

the caveat that experimental evidence for independent ecacy or synergy is

often minimal, at best.

alidomide and Interferon

alidomide is an agent that has been in clinical use for many years for a

variety of indications, including sedation and leprosy, and was found to be a

potent teratogen in pregnant women. Among its multiple properties, including

being an anti-inammatory agent, it is also an angiogenesis inhibitor, which

probably underlies much of its teratogenicity. It has been used in combination

with radiotherapy for children with brainstem gliomas without clear benet.

Another drug that was utilized with radiotherapy is interferon. Interferon,

of which various types including alpha, beta, and gamma being utilized, has

shown variable benets for adults and children with malignant gliomas. Based

on radiographic objective responses in 4 out of 18 children with recurrent

malignant cerebral or brainstem glioma, and clinical improvement or disease

stabilization in 5 out of 9 children with recurrent brainstem gliomas treated

on a beta-interferon protocol for children with recurrent disease, a study of 32

children with diuse intrinsic brainstem gliomas were treated with concurrent

recombinant beta interferon and hyperfractionated radiation therapy (7200

cGy). is study was disappointing in that not only did 30 of 32 patients

develop progressive disease at a median of 5 months from diagnosis, but more

than one-third of the patients required dose modications due to a hepatic

(liver related) or hematologic (blood related) toxicity. One patient developed

severe neurotoxicity.

Molecularly targeted trials

A variety of biologic agents have been studied concurrently with radiotherapy.

Iressa, an epidermal growth factor receptor antagonist, was studied in both

phase 1 and phase 2 studies through the Pediatric Brain Tumor Consortium

(PBTC). Early experience with this drug raised the issue of whether the use

of such agents would increase symptomatic brainstem hemorrhage. is study

highlighted how little was actually known about the rate of occurrence of

spontaneous hemorrhages of brainstem gliomas prior to, or during, conventional

radiotherapy. Intrabrainstem hemorrhages did occur, but it is unclear how much

more frequent their occurrence was than the rate of such episodes during and

after standard radiation therapy. Although there was no clear-cut benet from

the use of the drug, survival rates one year from study were more than 50%.

e farnesyl transferase inhibitors are drugs that interfere with intracellular

signaling by blocking the activation of ras—a key protein involved in

intracellular signaling often overactive in growing tumors. An oral farnesyl-

transferase inhibitor drug was utilized in phase 1 and phase 2 studies through the

Pediatric Brain Tumor Consortium with a low rate of intratumoral hemorrhage

and toxicity, but no evidence of ecacy. Antiangiogenic agents are likewise in

clinical use for patients with newly diagnosed brainstem gliomas. ere is little

data, as of yet, concerning their toxicity or ecacy.

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Chapter 8: Radiosensitizers for DIPG

Summary

Radiosensitization remains an appealing approach for the treatment of

children with newly diagnosed brainstem gliomas. As outlined, although there

are theoretic benets to their use, there is little evidence to date to validate

improved ecacy. Work continues with standard chemotherapeutic agents,

hypoxic and non-hypoxic radiosensitizers, and biologic agents. Until more is

known about the basic biology of brainstem gliomas, most studies will remain

empiric. Delivery of agents to the brainstem remains an extremely critical and

potentially limiting factor. In addition, as better agents are developed, their

selective capabilities of killing tumor cells and relatively sparing the normal

surrounding brain cells will remain a critical issue.

Parent Perspectives

When our daughter Ella was diagnosed with DIPG the only trial available

was a radiosensitizer. So we opted to do it because we had no other options.

Her first treatment was a couple weeks after diagnosis. She was to have

the radiosensitizer and then radiation within a couple hours. Within 30

seconds of the radiosensitizer entering her body she began sweating, having

stomach cramps and nausea. We asked the doctors to stop the treatment

and were told they would give her additional anti-nausea meds and anti-

anxiety meds. She finished the treatment, but due to the constant vomiting

she was unable to have radiation as she would be strapped to the table

and the fear was that she could choke on her own vomit. We opted out of

the trial the next day.



Although our journey began a day prior to April 11th, I mark that as the day

the world effectively ended for us. On that day, we were brought into a small

cramped room next to the nursing station, given no more than ten minutes

with the attending oncologist and told that Alexis, our then twenty-seven

month old daughter, had only six to nine months to live, maybe a year at

the outside. Wind taken out of our sails, devastated beyond belief, we were

effectively set out to drift in the new and confusing world of pediatric cancer.

We were barely familiar with the words diffuse intrinsic pontine glioma.

Within several hours, we found ourselves frantically driving from one

hospital to the next to meet with another doctor to discuss treatment options

and prognosis. Within a very short amount of time, we were provided with an

amount of hope that, although not a guarantee of survival, at least allowed

us to gain some level of comfort with moving forward.

During that initial meeting late on a Friday afternoon, we discussed several

approaches and treatments. Each option was presented with its own caveat,

and each was discussed in a manner which allowed us to appreciate that

it was not a home run cure. Ultimately, our decision was between one of

two treatment paths: a chemotherapy cocktail with overly used agents, or

standard radiation with a radiosensitizer. Ordinarily, chemotherapy has

proven ineffective for children with DIPG. The thought process behind this

option in Alexis’ case was based upon her age at diagnosis and a hunch

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that her tumor was low grade. This option necessitated lengthy stays in the

hospital, which worried us beyond belief. Personally, we were concerned

about Alexis’ psychological welfare during the course of extended stays in

the hospital as well as her overall quality of life. In addition, this course

had no statistical efficacy. Truth is, we would have done anything in the

world to save Alexis, regardless of course.

Ultimately, the decision was made to proceed with a course of thirty

radiation treatments and a Phase II clinical trial utilizing a radiosensitizer.

The hope was that the addition of the radiosensitizer would allow the

radiation to be more effective. The theory behind radiosensitizers is that

the compounds are taken up by the blood vessels in the tumor and thus

direct the radiation directly to the tumor. At the time we chose this course of

treatment, there was no data presented to us, either statistical or anecdotal

in nature, and thus, it was simply a blind dart thrown at a wall. You hope

and you pray that the dart sticks. Hindsight taught us that in rare instances

a single dart would find its target with no rhyme or reason. Since Alexis

was very young at the time of diagnosis, we did not believe that she could

aide in any reasonable fashion with making critical decisions. Accordingly,

the guiding factor in all decisions was based upon Alexis’ quality of life.

At diagnosis, Alexis’ main symptom was an inverted right eye that was

infrequent in nature. While watching television, we noticed that Alexis had

to turn her head to the side to view. We feared that radiotherapy would cause

swelling and thus we would witness an increase in symptoms. Within the

first three days, these fears were realized and we noticed some right-sided

weakness. Obviously, this was extremely frightening and disconcerting.

Thankfully, this abated within a day or so of additional treatment and Alexis

sailed with flying colors through the remaining twenty six or so treatments

until she “graduated” from radiation on June 19th.

Our days during radiation therapy grew to be routine, and again, we

normalized life as much as possible. Each morning, we frantically rushed

to the hospital by 5:45 a.m. If we were late, the entire schedule and timing

of the actual radiotherapy was delayed. Upon arrival, we marched straight

to one of two treatment rooms on the pediatric hematology/oncology ward.

Shortly thereafter, Alexis received several pre-medications and then the

radiosensitizer was brought into the room and pumped into Alexis’ veins

over the course of fifteen minutes. The first several times she was given

this combination we sat with breath held, worried about what side effects

may present. Thankfully, none ever manifested. We of course were forced

to wear rubber gloves when changing Alexis due to the potential toxicities

to those who came in contact with the drugs. Such an odd juxtaposition—

Alexis could have these substances dripped into her veins, but there was

concern over us touching them with our bare hands. After the combination

was finished, we then waited three hours for the sensitizer to “find” its way

throughout her diminutive little body and on to the tumor. It was always

a tormenting thought: just inches inside of Alexis’ head sat this uninvited

beast. And nothing that we could do could ever change that. This realization

continually taunted me during my waking moments and beyond.

Alexis’ course was not typical in the DIPG community. Within several days

of beginning radiation in combination with the radiosensitizer, all symptoms

were erased and that remained true up until the end of January.



Our son was 10 years old when he was diagnosed with DIPG. Like most

10 year old boys, he was active and vibrant—full of life. He lived life to

the fullest and was happiest when he was playing baseball.

There weren’t many clinical trials available for children newly diagnosed

with DIPG. The only trial available via the pediatric oncology clinic easily

accessible for us was a Phase II COG trial involving motexafin gadolinium

as a radiosensitizer. We were told that radiation therapy is the only treatment

which usually makes a difference for kids with DIPG. Therefore, the most

logical focus in clinical trials was to increase the effectiveness of radiation.

This made sense to us, so we entered Caleb in the trial.

Each morning, Caleb received an infusion of the bright green motexafin

gadolinium compound. The hour-long drive to the clinic, the hour-long

infusion, and the two to five hour wait time before Caleb could have

radiation all turned out to be blessings to our family. We had good times

together during those days—time focused on Caleb and crafts, games or

reading. Often, Caleb’s brothers or his best friends would come along with

us. We developed dear friendships and learned to treasure the moments.

Within a week of beginning the trial, Caleb began to develop unusual side

effects. He became very sensitive to the sun; he felt a prickly sensation

that quickly developed into full-fledged pain when he was outdoors. Within

days of this, blisters began appearing on his face, hands, neck, arms, and

ears. At first they were just little water blisters. Soon, they became huge

bubbles—some of them as large as a small apple on the backs of his hands.

Chapter 8: Radiosensitizers for DIPG

122

His fingernails turned a milky white and began to separate from his nail

beds.

All the while, Caleb continued to play baseball. We saturated him in sun

screen and covered his skin with cloth and bandages. The pain was intense.

He could hardly stand to be in the field. After the third out was called, he

raced into the dugout where we had ice chests filled with cold and warm

rags in which to wrap him—one of the few efforts that brought some relief.

We rubbed topical anesthetic on his skin and, when it was time for him to

hit, he wore thick gloves to dull the pain of the blisters as his hands tightly

gripped the bat. He wore an eye-patch on his left eye. The green chemicals

gave his skin a green tint and even produced green stripes down his neck

and back and across his shoulders. Add the blisters, various bandages and

big gloves and he looked like quite a character. He was devoted to the game.

I greatly regret that we allowed him to suffer so—even required it of

him. He never complained about the therapy; never once did he consider

withdrawing from the trial. We believed it held promise and was the only

hope we had of beating the evil disease.

That does bring to mind regret, however. While he never considered stopping

the therapy, he did consider taking a year off from baseball. Now, I know

a lot of boys love baseball, but Caleb suggesting he take a year off from

baseball is akin to most of us taking a year off from food. It proves how

difficult it was for him. And, because we knew that he likely wouldn’t have

another year, we felt we had to explain to him that he had to make the most

of the current season. We were blunt—it might be his last season.

Again, in retrospect, I wish we hadn’t been so forthright. He increased his

resolve and will to fight. But it also caused him to be fearful at times. Caleb

surely would have eventually figured out his prognosis. I wish, though, that

the circumstances had been different—that we hadn’t forced the knowledge

on him out of desperation and baseless hope.

We do not blame ourselves or our healthcare team for these painful

memories. We do, however, wish that our healthcare team had been more

forthright with us and told us that radiosensitizers in general had never

shown much promise in DIPG, and that this specific therapy hadn’t helped

a single kid. It was just the only thing they knew to try at the time.

Who knows? We might have forged on, convinced that Caleb would be “the

one.” That’s what we all hope, isn’t it? But at least we would’ve known.

123

Chapter 9: Chemotherapy and Biologics

Chapter 9

Chemotherapy and

Biologics

David N. Korones, MD

e cure rate for children with cancer has improved dramatically over the past

few decades, rising from less than 50% in the 1960s to close to 80% today.

is is a remarkable story of laboratory research, which has given us a better

understanding of how children’s cancers work. It is the story of unprecedented

collaboration between hundreds of pediatric cancer centers around the country

and the world. It is the story of pediatric oncologists, radiation oncologists, and

surgeons working together to improve the lives of children with cancer. And it

is the story of strength, heartbreak, resilience, inspiration, and advocacy on the

part of children with cancer and their families, who have contributed more than

anyone in moving this eld of medicine forward.

Yet the successes in curing children with cancer have been unequal. Remarkable

strides have been made in treating some types of childhood cancers, but cure rates

for others remain stagnant. Such is the case for children with brainstem glioma, for

whom success has sadly eluded us. Surgical removal of this tumor is not possible.

In fact, these children rarely undergo a biopsy, so tumor samples are not available

to help researchers understand this disease. Radiation has proven to be quite

eective, but only for a short time. is leaves chemotherapy and biologics. It

would seem that for a tumor that cannot be removed surgically and that responds

only temporarily to radiation treatment, chemotherapy might be the best approach

to this challenging disease. But this has not

been the case. Despite decades of research

and clinical trials, researchers have yet to

nd a chemotherapeutic or biologic agent

that improves the survival of children with

brainstem glioma. But this does not mean

we never will. In fact, it could be a new

drug or some sort of targeted therapy based

Dr. Korones is Board Certied in

Pediatrics, Pediatric Hematology/

Oncology, and Hospice and

Palliative Medicine. He is Director

of the Brain Tumor Program

and the Pediatric Palliative Care

Program at Gosliano Children’s

Hospital, Rochester, NY.

Chapter 9: Chemotherapy and Biologics

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Chapter 9: Chemotherapy and Biologics

on a better understanding of the biology of brainstem gliomas that will lead to

future success in treating children with this disease. at day has not yet come,

but it will. is chapter reviews what chemotherapy is, why it has not worked for

children with brainstem glioma, what has been tried, and what holds promise.

Also discussed are biologic therapies (i.e., treatment that more specically targets

some of the mechanisms tumor cells use to grow).

Chemotherapy

What is chemotherapy?

Chemotherapy is simply any medication that kills cancer cells. Just as

“antibiotic” refers to the broad class of drugs used to treat infections,

chemotherapy refers to the broad class of drugs used to treat cancer.

Chemotherapy can be given intravenously (IV), through an injection into

the skin or muscle, orally, or even injected directly into a body cavity (e.g.,

injection of chemotherapy into the spinal uid via a spinal tap [lumbar

puncture]). Most chemotherapy is given by IV or orally. Chemotherapy works

by targeting cells that are actively dividing thereby stopping the cancer cells

from reproducing. Many dierent types of chemotherapy drugs exist, and

each one targets one of the many dierent aspects of tumor cell division. For

example, two commonly used chemotherapies to treat children with brain

tumors, temozolomide and CCNU (lomustine), bind directly to DNA (the

building block of cell division) and prevent the DNA from duplicating itself,

thereby preventing the cell from dividing, leading to its death. Another

example is vincristine, which targets spindle-like structures that allow one

cell to become two cells.

For many pediatric cancers, it has been shown that by using combination

chemotherapy—two, three, or more drugs together—the child’s survival is

improved. is is because several drugs together work better to kill cancer

cells than any one drug alone. In addition, if a tumor is resistant to one drug,

it may be killed by one of the others given.

A disadvantage of chemotherapy (particularly in treating children with brain

tumors) is that it circulates everywhere in the child’s body, and therefore has

the potential to kill or damage normally dividing cells. is fact accounts for

many of the side eects of chemotherapy, such as low blood counts, risk of

infection, bleeding, fatigue, mouth sores, and nausea and vomiting.

Challenges of using chemotherapy for children with brainstem glioma

Finding effective chemotherapy for children with brain tumors is more

challenging than nding eective chemotherapy for children with other

malignancies. A major challenge with brain tumors is the blood-brain barrier.

Blood vessels in the brain are unique; they are designed to be very selective

about what can penetrate them to get into brain cells. ey selectively allow

nutrients to reach brain cells, but block many unrecognizable, potentially

toxic substances including many types of chemotherapy. From an evolutionary

standpoint, this makes perfect sense (i.e., protecting our brains from toxins),

but when it comes to getting chemotherapy into brain tumors, it is a problem.

erefore chemotherapy must be designed to penetrate the blood-brain barrier.

e list of drugs that can do this is small, leaving us with fewer weapons to use

for children with brain tumors. It is thought (but not proven) that the blood

vessels in brainstem gliomas are particularly restrictive and allow very few

substances to penetrate them.

Another challenge is the tumor itself. For reasons that are unclear (and still not

denitely proven), it appears that the tumor cells that make up brainstem gliomas

are extremely resistant to chemotherapy. at is, even if the chemotherapy gets

into the tumor, it cannot kill the tumor cells.

Clinical Trials Using Chemotherapy for Children with

Brainstem Glioma

As noted above, chemotherapy has been used in every way, shape, and form

possible to date to treat children with brainstem glioma. e most common

approaches have been giving chemotherapy after radiation (termed adjuvant

chemotherapy), administering chemotherapy before radiation (called

neoadjuvant chemotherapy), and giving high-dose chemotherapy with stem cell

rescue (also referred to as autologous bone marrow transplant). Chemotherapy is

also used during radiation treatment as a radiosensitizer (discussed separately in

chapter 8). ese various approaches to using chemotherapy are discussed below.

Adjuvant chemotherapy

The first large-scale multicenter clinical trials testing the effectiveness of

chemotherapy for children with brainstem glioma were published in the late

1980s. is was around the time that chemotherapy had been proven eective

for children with other types of brain tumors, such as medulloblastoma,

glioblastoma and low-grade astrocytoma. At that time there was considerable

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Chapter 9: Chemotherapy and Biologics

hope that the successes of chemotherapy for children with other brain tumors

would extend to children with brainstem glioma. In one of the rst studies,

Jenkins et al. conducted a national clinical trial through the Children’s Cancer

Study Group (CCSG) from 1977 to 1980. All 74 children enrolled in the study

received radiation; half received radiation alone, while the other half received

radiation plus chemotherapy—lomustine (CCNU), vincristine, and prednisone

(a combination used successfully for children with medulloblastoma and high-

grade astrocytoma). e 5-year survival for both groups was only around 20%,

suggesting that this particular combination of chemotherapy was not eective for

children with brainstem glioma. It should be noted that survival in both groups

was actually somewhat higher than what we see today. is is probably because

the study was conducted in the pre-MRI era, and some of the tumors that were

thought to be brainstem glioma may have actually been less aggressive variants

of brain stem tumors that would not be classied as DIPG today.

rough the 1990s, researchers explored other types of chemotherapy for

children with brainstem glioma. Walter et al. treated nine children with an MRI-

documented DIPGs with carboplatin and etoposide during and after radiation.

ese two drugs have been shown to have activity against other types of brain

tumors, so the hope was that they would also prove eective for children with a

brainstem glioma. However, this treatment did not work—survival at 1 year was

44%, and at 2 years only one child (11%) was alive. In another study, Chamberlain

tried an innovative approach to treatment, which comprised daily low doses of

oral chemotherapy. e thought was that daily low doses of chemotherapy given

orally might work better than larger IV doses of chemotherapy given every few

weeks. In addition, side eects seemed to be less of a problem when this type of

dosing had been used in other clinical trials. Chamberlain used this approach,

treating 12 children with a recurrent brainstem glioma with oral etoposide

(VP-16). Unexpectedly, the tumor shrunk in 5 of these 12 children. is result

generated considerable excitement about this new approach to treatment. Based

on Chamberlain’s observations, the Children’s Oncology Group (COG) launched

a national clinical trial of oral etoposide and IV vincristine during and after

radiation. Disappointingly, all 30 children on this trial died, with one and two

year survival of only 27% and 3% respectively. Other types of chemotherapy

have been tested, mostly in small trials, and they, too, were ineective. Drugs

including idarubicin, trophosphamide and oral etoposide, cisplatin, etoposide,

ifosfamide, and oral topotecan have been tried, but none prolonged children’s

lives or improved cure rates. A summary of these trials is illustrated in Table 1.

One exciting new chemotherapeutic agent developed and studied extensively in

Table 1: Representative clinical trials of adjuvant chemotherapy for children with newly diagnosed diuse brain stem

glioma.

Author (see

Appendix D)

Group study

N RT dose

(GY)

Chemotherapy Median

OS (mo.)

Survival (%) at

1 yr 2 yr 3 yr 5 yr

Jenkin (1) CCG 33

50-60

none

pCV

26* 17

35* 23

Walter (2) St. Jude 9 70.2 (1.17

b.i.d)

carboplatin

IV VP-16

10 44 11

Korones (4) POG 30 54 (1.8

q.d.)

oral VP-16

vincristine

9 27 3

Wol (6) GPOH 20 54 (1.8

q.d.)

oral trophosphamide

oral VP-16

8 40 15 5

Wol (7) GPOH 37 54 cisplatin

IV VP-16

Vincristine

Broniscer (9) St. Jude 33 55.8 temozolomide 12 48

Cohen (10) COG 63 temozolomide 10 40

* 18 mo. survival

CCG = Children’s Cancer Group POG = Pediatric Oncology Group COG = Children’s Oncology Group

GPOH = German Society of Pediatric Oncology RT = radiotherapy pCV = prednisone, CCNU, vincristine OS = overall survival

Chapter 9: Chemotherapy and Biologics

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Chapter 9: Chemotherapy and Biologics

the last 10 to 15 years is temozolomide (Temodar®). is drug is given orally,

has fewer side eects than most chemotherapy, and has proven to be eective

for adults with grades 3 and 4 astrocytomas (similar to brainstem glioma). e

successes with adults led pediatric neuro-oncologists to conduct clinical trials

of this drug for children with brainstem glioma. In one of the rst studies of

temozolomide for children with a newly diagnosed brainstem glioma, 33 children

at St. Jude Children’s Research Hospital received temozolomide in monthly cycles

for up to 6 months. Although the 1-year survival was 48% (higher than in most

studies), all 33 children eventually died. e COG conducted a similar study

with children with brainstem glioma receiving temozolomide during radiation, as

well as following it. e results were similarly disappointing. Of the 63 children

enrolled, all but one had died after 25 months of follow-up (and that child could

not be tracked down to verify whether he/she survived). In ve other studies of

temozolomide for children with a DIPG, (including one using cis-retinoic acid and

another using thalidomide), the outcomes were also poor. In sum, as promising

as temozolomide rst appeared to be, and as few side eects as it has, it is not the

breakthrough in chemotherapy we had so hoped it would be.

Neoadjuvant chemotherapy

As noted above, neoadjuvant chemotherapy is chemotherapy that is given before

the more denitive treatment for a tumor. In the case of a brainstem glioma,

neoadjuvant chemotherapy is chemotherapy given before radiation. is approach

was investigated in several clinical trials in the 1990s and early 2000s. e rationale

for neoadjuvant chemotherapy was based on the general enthusiasm at that time

for chemotherapy for children with brain tumors. In addition, it was felt that the

best way to assess the eectiveness of chemotherapy against a brainstem glioma was

to give it before radiation, as it is hard to assess tumor response to chemotherapy

after radiation. e hope was that eective drugs would quickly be identied and

then given to children after the radiation, as well. is approach was undertaken

with some trepidation, because if chemotherapy was not eective, the children

might suer from side eects of chemotherapy and a growing tumor, and get

sicker, not better. ere was concern that these children might become too sick

to tolerate radiation, the one treatment known to give them a little more time.

e rst clinical trial published taking this approach was a Pediatric Oncology

Group study of 32 children with brainstem glioma who were treated with two

to three cycles of cisplatin and cyclophosphamide before starting radiation.

Although 3 of the 32 children had shrinkage of the tumor and another 23 had

no increase in tumor size, the overall survival for the children was not improved

compared with giving radiation alone; the median survival was only 9 months. In

Table 2: Clinical trials of neoadjuvant chemotherapy for children with newly diagnosed diuse brain stem glioma

Author

(

see Appendix

Group

study

N Chemotherapy Response RT dose

(Gy)

Median

OS (mo.)

Survival (%) at

1 yr

2 yr 3yr -

Kretschmar

(16)

POG 32 cisplatinum

cyclophosphamide

3 PR

23 SD

6 PD

66 (1.1 b.i.d.)

9 30

Jennings

(17)

CCG 32

carboplatin

VP-16

vincristine

cisplatinum

cyclophosphamide

VP-16

vincristine

2 PR

1 MR

12 SD

12 PD

1 PR

4 MR

8 SD

9PD

72 (1 b.i.d.)

10*

30* 18*

30* 10*

Doz (18) SFOP 36 carboplatin 4 MR

6 SD

11 PD

54 11

Broniscer (9)

St. Jude 16 irinotecan 10 SD

5 PD

55.8

*estimated from Kaplan-Meier curve PR=partial response, MR=minor response, SD=stable disease, PD=progressive disease

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a second, larger study of 63 children with a newly diagnosed brainstem glioma, 32

children received carboplatin, etoposide, and vincristine, and 31 received cisplatin,

cyclophosphamide, etoposide, and vincristine before going on to receive radiation

therapy. Only 10 to 20% of the children had tumor shrinkage, and again, their

overall survival was poor—no better than it was with radiation alone. Similarly

poor results were seen when 38 children received neoadjuvant carboplatin and

neoadjuvant irinotecan. ese studies are summarized in Table 2.

Based on these disappointing results and the disappointing results of multiple

other clinical trials of chemotherapy after radiation, the approach of trying

chemotherapy before radiation has largely been abandoned.

High-dose chemotherapy and stem cell rescue

Another innovative approach undertaken in the quest to cure children with

brainstem glioma was high-dose chemotherapy with stem cell rescue (also referred

to as autologous bone marrow transplantation). is type of therapy is not really

a bone marrow transplant at all; rather, it is simply a way to more safely give

children higher doses of chemotherapy. e rationale for using such high doses

of chemotherapy for children with brainstem glioma is two-fold. It was thought

that 1) it might take higher doses of chemotherapy to kill the brainstem glioma

cells, and 2) higher doses might somehow “push” more chemotherapy through

the blood-brain barrier and allow enough chemotherapy to reach the tumor cells

and kill the tumor.

Neuro-oncologists were particularly hopeful about this approach because it

seemed to improve survival of children with recurrent medulloblastoma and

glioblastoma. How does it work? First, the very youngest of blood cells (called

hematopoietic stem cells) are removed (often referred to as “harvested”) from

children with brainstem glioma. is is done by taking samples of bone marrow

or removing these specialized cells from the blood through a procedure called

pheresis. ese cells are frozen until they are needed. e children then receive 3

to 7 days of extremely high doses of chemotherapy, so high in fact that it almost

destroys their ability to ever make their own blood cells again. But after they

receive the chemotherapy, the stem cells that were removed and frozen are thawed

and given back to the children. ese resourceful stem cells are given through an

IV (like a blood transfusion), circulate through the blood, nd their way back to

the bone marrow, and over the next several weeks, repopulate the bone marrow

and the blood with new, normal blood cells, thus “rescuing” the children from

what otherwise could be a lethal dose of chemotherapy.

Several clinical trials of high-dose chemotherapy with stem cell rescue were

Table 3: Clinical trials of high-dose chemotherapy with stem cell rescue for children with newly diagnosed diuse brain

stem glioma

Author (see

Appendix D)

Group

study

N RT dose

(Gy)

Chemotherapy Median

OS (mo.)

Survival (%) at

1 yr 2 yr 3 yr

Bouet (21) SFOP 35 50-55 busulfan

thiotepa

10 40

Bouet (22)* France 5 not stated BCNU 10

Jackaki (23) Indiana U 6 54-59.4 procarbazine

CCNU

vincristine

Kedar (24)* U Florida 6 75.6 (1.25

b.i.d.)

cyclophosphamide

thiotepa

12.5

Dunkel (25)* CCG 6 72-78 (b.i.d.) BCNU

thiotepa

VP-16

11.4

*Chemotherapy given prior to radiation

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A number of clinical trials of biologic therapies have been conducted. One of

the rst trials tested interferon, a natural substance made by the human body

in response to viral infections. It was hoped that interferon would stimulate the

immune system to ght the tumors and perhaps inhibit the blood supply to

the tumor. In a 1991 phase I-II clinical trial that included eight children with

brainstem glioma, two children had partial responses to the treatment, and in

another three children, growth of the tumor was halted for several months. In

a subsequent larger study of 32 children with a DIPG who received interferon

along with radiation therapy, overall survival was not improved.

Another innovative approach is using agents that can “open up” the blood-

brain barrier. As previously noted, chemotherapy has diculty reaching brain

tumors because it cannot penetrate brain tumor blood vessels. A substance called

RMP7 was found to open up these blood vessels, making them “leaky,” so that

chemotherapy can go right through them and reach the tumor. ere were

two very small clinical trials for children with brainstem glioma using RMP7

along with chemotherapy. In one phase I study of RMP7 and carboplatin, the

treatment was well tolerated but the number of children was too small to assess

its eectiveness. In a second study, eight children with brainstem glioma received

RMP7 along with various types of chemotherapy through an artery (instead of

intravenously). ese children did somewhat better, but again the number treated

was small and the intra-arterial approach is not one that can be easily done at

most centers. RMP7 was also studied in adults with malignant brain tumors

and was not found to be eective. e drug has limited availability at this time.

One additional approach to penetrating the blood-brain barrier is the use of

cyclosporine A along with chemotherapy. is drug helps “trap” certain types

of chemotherapy inside brain tumor cells so the chemotherapy remains in the

cells long enough to kill them. A COG trial using cyclosporine, vincristine, and

oral etoposide (VP-16) was launched to study this eect, but unfortunately, the

number and severity of side eects was unacceptably high.

Another promising biologic approach is anti-angiogenic therapy. is is the use of

drugs that kill or inhibit blood vessel growth into growing tumors. e rationale

for anti-angiogenic therapy is that if one can prevent blood vessels from growing

into the tumor, the tumor will be deprived of oxygen and nutrients and stop

growing. e most promising anti-angiogenic agent to date is bevacizumab, an

antibody that attacks a protein called vascular endothelial growth factor (VEGF).

VEGF is a natural substance that stimulates blood vessels to grow into brain

tumors as the tumors themselves get bigger. is treatment has proved eective

in adults with high-grade astrocytomas, and there was hope it might also prove

conducted in the 1990’s, but unfortunately this approach did not seem to help.

Perhaps the largest clinical trial using this approach was a study by Dr. Bouet

and colleagues. e researchers enrolled 35 children in the study, all of whom

received radiation, and 24 of whom were able to then go on and receive high

doses of chemotherapy (busulfan and thiotepa). All 24 of these children died,

three from complications of the therapy, and the remainder from regrowth of the

tumor. e average life expectancy of the group was only 10 months, not any

better than the life expectancy of children who received radiation alone. Four other

studies of high-dose chemotherapy with stem cell rescue included children with

brainstem glioma. Although tumors shrank in a handful of children, it did not

improve their overall outcome, and several children died of complications from

this very aggressive approach. A summary of trials using high-dose chemotherapy

with stem cell rescue is presented in Table 3.

Based on the experience with these children, high-dose chemotherapy with stem

cell rescue is no longer being investigated for children with brainstem glioma.

Although high doses of chemotherapy can be very eective for children with

certain types of cancer, it is clearly not the case for children with brainstem glioma.

We need other innovative approaches to tame this type of tumor.

Biologics

As is painfully clear from the above discussion, chemotherapy does not appear

to be the answer for children with brainstem glioma. Over the past decade,

investigators have come to realize the answer may lie in rst gaining a better

understanding of how these tumors work. Once we have that understanding,

we can nd drugs that target the tumor cells very specically; this is the concept

of biologic therapy. Chemotherapy is a rather blunt sword that kills any cell

that divides, be it cancerous or not. Biologic therapy is more nely tuned and

targeted. It is treatment that is based on the abnormal biology of a cancer cell.

Biologic therapy targets the very biologic mechanisms that cause cancer cells to

grow uncontrollably, and unlike chemotherapy, biologic therapy often spares the

normal cells.

A big challenge in using this approach for children with brainstem glioma is that

we do not know what makes these tumors tick. ese children seldom undergo

biopsy of their tumors, so researchers do not have many tumor samples to examine

to help them understand the biology of brainstem glioma. However, this is starting

to change, as some centers are doing biopsies again, others gather tumor samples

at the time of autopsy, and new techniques are being used to analyze old tumor

samples obtained decades ago.

Chapter 9: Chemotherapy and Biologics

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Chapter 9: Chemotherapy and Biologics

eective for children with brainstem glioma. In a recently published study of

bevacizumab and the chemotherapy drug CPT-11 (irinotecan) for children with

recurrent brainstem glioma, only 5 of 13 children had a temporary halt in the

growth of their tumors, and the average time until the tumor starting growing

again was only 2.3 months. Although this particular anti-angiogenic therapy had

little eect, there are many new anti-angiogenic drugs being developed, so there

is still hope that this approach may eventually work.

Another hopeful approach to treatment is blocking growth factor receptors on

tumor cells. Growth factor receptors are proteins found on the surface of tumor

cells. When these growth factor receptors bind with a matching protein called

a growth factor, the two proteins link together and stimulate tumor cells to

grow uncontrollably. Based on studies of old tumor samples from children with

brainstem glioma, investigators have learned that brainstem glioma cells seem to

have increased numbers of a growth factor receptor called epidermal growth factor

receptor (EGFr). Clinician-investigators are hopeful that EGFr may be a new way

to attack these very resistant tumors. For example, in Germany, an antibody to

the EGFr was developed; this antibody (called nimotuzumab) binds to the EGFr

and seems to prevent EGF from binding to it and stimulating tumor cell growth.

In a clinical trial of nimotuzumab, 22 children with a recurrent brainstem glioma

were treated; 9 had stable disease and one child’s tumor actually became smaller.

Based on these encouraging results, a larger study of this drug was conducted,

but the results are not yet available. In another recently published clinical trial,

43 children with newly diagnosed brainstem glioma were treated with erlotinib,

another inhibitor of EGFr function. is drug was well tolerated, and children

on this study fared slightly better than average, including three children who

are alive more than 3 years from diagnosis. Blockage or inhibition of the EGFr

remains a hopeful approach for treating children with brainstem glioma, but

much work still needs to be done.

Other biologic therapies have been tried, but with no major successes. Some

(but not all) of the agents studied include tamoxifen, cis-retinoic acid, and

antineoplastons. e COG and Pediatric Brain Tumor Consortium have taken the

lead in the United States in exploring new and innovative approaches to treating

children with brainstem glioma. e COG is currently studying the addition of

vorinostat, a drug representing a new class of biologics called histone deacetylase

inhibitors (they unravel DNA), to standard radiation therapy.

Looking to the Future

As noted in the above discussion, clinician-scientists have exhaustively investigated

many dierent combinations of chemotherapy and radiation for children with

brainstem glioma. Sadly, after all this, they have discovered more about what

does not work than what does. We have learned that radiation works for a short

time, but chemotherapy does not seem to help at all. We have also learned that

there is genuine hope on the horizon. We now have the tools to examine the most

intricate details of the inner workings of brain tumor cells, including those of

brainstem glioma. Furthermore, we have a rapidly growing arsenal of new biologic

therapies that may be able to target the abnormal molecules/DNA/proteins that

cause brainstem glioma cells to grow. It is dicult to comprehend how hard it

must be for a parent, grandparent, family member, or friend to thumb the pages

of this book and read through the long list of therapies that do not work. But

we are on the verge of developing a list of therapies that will work, and our hope

is that with the next edition of this book, family and friends will read through a

long list of all the treatments that do work.

Chapter 9: Chemotherapy and Biologics

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Chapter 9: Chemotherapy and Biologics

Parent Perspectives

Treatment, well really at this point there is none. You are told that steroids

and radiation will most likely shrink the tumor initially and help with

symptom management. Then you will get your “honeymoon period” before

the tumor begins to grow again and how soon that will be is anybody’s guess.

Chemo you ask? Yes of course, try this, or this, or this, but we have little

to no data indicating that any are effective in extending the life expectancy

of the child beyond 24 months. And well there is quality of life to consider.



We also opted to do chemotherapy in the hopes that in combination there

might be some added value. We agreed to known chemotherapies that were

generally well tolerated by children. I'm not sure we can ever be certain

how well they helped Liam's overall condition however, he had few side

effects. He took all his pills orally like a champ.

When scans showed that Liam's tumor had progressed on the combination

chemotherapies, we tried another course of a different combination therapy.

However Liam developed an allergic reaction to one of the medications and

we had to stop. His latest scan showed even further progression in parts of

his brain far from the confines of the brainstem. We tried one more drug and

it would prove to be his final chemotherapy. By this time Liam was not able

to walk at all on his own. He had significant hearing loss, and his speech,

when he spoke at all, was very hard to understand. He was growing tired.

When it was discovered that this treatment too did not have the effect that

was desired we decided to end treatment and begin palliative care. It was

not an easy decision but one that needed to be made for Liam.



As a result of our son’s chemotherapy we saw slow, steady improvement

of symptoms for over six months. But we were faced with a new challenge

during this time, a complication of long term steroid usage. Our son’s skin

began to thin, and his stretch marks opened. We were horrified to realize that

the treatment regimen (Avastin) that had made such a dramatic difference

against the cancer was delaying the healing of the open stretch marks. In

time this issue became more of a problem than the cancer itself, and we had

to face the reality that losing our son to wounds would be no less difficult

than losing him to brain cancer.



Our daughter underwent 6 weeks of radiation and chemotherapy. She did

not start steroids until she was almost complete with her treatment. She had

finished her treatment and 4 weeks later had to have a shunt placed due to

increased pressure. The following week she had her follow-up MRI from

the treatment and they saw new tumor growth in another area of her brain.

That weekend we went back to the ER and she had a seizure overnight. She

went into a coma and only came out once long enough to open her eyes and

we were able to look into her beautiful eyes again and tell her how much

we love her. She passed away exactly 3 months and 12 days from diagnosis

even with a full treatment of radiation and chemotherapy.



We used Capecitabine, 1300 mg. daily for sixteen weeks. There were

absolutely no benefits, just side effects. Joseph had hand and foot syndrome,

gas, and diarrhea.

I knew that at that time there were no known chemo treatments that worked

and had terrible guilt using my son as an experiment. My wife needed to

be doing something to save our boy. I wish the doctors would have been

clearer about the odds of this chemo working. I would have stopped much

earlier and concentrated on quality of life over treatments.



It was exactly one year after diagnosis that we learned the tumor was

growing again. With Andrew’s only symptom being headaches, we chose

to attempt to slow the progression of the tumor with a chemo cocktail of

vincristine, irinotecan and temozolomide given every three weeks. After

two cycles the scan showed continued growth, and we made the decision

to try temozolomide at full dosage in 28 day cycles in a second attempt

to slow tumor growth. We celebrated Christmas at home with a bald (but

happy) Andrew.

A scan in January showed further progression. Andrew’s doctor wondered

if the combination of Avastin and irinotecan might have a positive impact

against the tumor. We forged ahead with the new treatment plan, but felt

that Andrew was slipping away from us. We were pleasantly surprised

Chapter 9: Chemotherapy and Biologics

138

when Andrew’s scan in March showed a significant response to therapy:

shrinkage of the tumor, resolution of much of the cystic component and less

enhancement. We had hoped for slowed progression or possible stability;

instead we received an unexpected gift of time. Having already made peace

with what we thought was Andrew’s imminent death we were faced with the

challenge of changing our mindset back to one of living rather than dying.



We decided not to do chemo because at the end of the day we didn't see

much benefit to it. We didn't want Peyton being sick for what would be left

of her short life. We didn't want her suffering more than needed. We just

felt that the side effects of chemo outweighed any benefit the drugs "may"

have provided.

139

Chapter 10: Use of Steroids in DIPG

Chapter 10

The Use of Steroids in

Patients with DIPG

Eric Bouffet, MD

Ute Bartels, MD

Steroids play a major role in the management of patients with diuse intrinsic

pontine glioma (DIPG), particularly at the time of presentation. Corticosteroids

have been used to control cerebral edema in various conditions, particularly in

the context of aggressive brain tumors. Dexamethasone is generally considered

the steroid of choice because of its superior brain penetration and longer half-

life (time it takes for a drug to lose half of its pharmacologic activity). e role

of steroids in the management of disease at the time of progression and during

palliative care remains controversial. e aim of this chapter is to review the role

of steroids during the care of patients with diused pontine glioma.

Steroids During the Early Management of DIPG

At the time of diagnosis, steroids are usually the rst treatment oered to patients

with diuse intrinsic pontine glioma. Although their role has never been properly

assessed, most physicians prescribe steroids, and in particular dexamethasone,

once the diagnosis of DIPG is established. e doses used may vary individually

according to the clinical signs and symptoms of the child, but many physicians use

large doses, up to 10 mg/m

/per day in two or three doses. e aim of the treatment

is to a) improve neurological symptoms, b) reduce the edema surrounding the

tumor that may sometimes impact the ow of the cerebral spinal uid (CSF) and

cause some degree of hydrocephalus, and

c) prevent or minimize the edema induced

by the initiation of the radiation treatment.

Traditionally, physicians would keep the dose

of dexamethasone unchanged during the rst

week of treatment, and would then gradually

decrease the dose as neurological symptoms

Dr. Bouffet is the Director of the

Neuro-oncology Program and

a Senior Associate Scientist in

the Research Institute at the

Hospital for Sick Children, as well

as Professor of Pediatrics at the

University of Toronto, Canada.

Chapter 10: Use of Steroids in DIPG

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Chapter 10: Use of Steroids in DIPG

improve with the radiation treatment. Some physicians prefer to keep a high dose

of steroids maintained throughout the 6 weeks of radiation therapy.

Steroids, however, are associated with signicant side eects that may aect the quality

of life of patients with diused pontine glioma. One of the most signicant side eects

is hyperphagia—a feeling of extreme excessive hunger. As a result, children with DIPG

often experience signicant weight gain during the rst weeks of treatment. e use

of steroids is also associated with personality changes, such as mood swings, anxiety or

sometime aggressiveness (see below). Cutaneous complications are not uncommon,

particularly in teenagers who can develop severe acne and stretch marks (or striae).

All of these side eects will improve within a few weeks of decreased or discontinued

use of steroids. ey will persist if the steroids are continued throughout treatment.

Steroids Following Radiation

Up to 50 percent of DIPG patients will present with symptoms of so called

“somnolence” in the weeks following completion of radiation treatment. e

onset of these symptoms is usually observed 2 to 4 weeks after the last session

of radiation, but can occur earlier or later.

e somnolence syndrome consists of symptoms ranging from mild drowsiness

to marked lethargy with prolonged periods of sleep, irritability, anorexia, low

grade fever, nausea and vomiting, cerebellar ataxia, dysarthria, dysphagia, and

headaches. For many parents who have not been informed of this complication,

the somnolence syndrome is suggestive of the initial manifestations of the

disease. e physiopathological mechanisms of this complication are not fully

understood, but somnolence is thought to be related to radiation-induced

disruption of myelination. e period of somnolence usually lasts 2 weeks,

and symptoms usually subside spontaneously. However, some patients can

experience symptoms for up to 4 to 6 weeks. When symptoms are signicant,

the use of steroids can be benecial. e optimal dose of steroids needed in this

context is unknown. However, spectacular improvement of both appetite and

sleepiness can be observed with small doses of dexamethasone, in the range of

0.5 to 1 mg per day.

Steroids at the Time of Progression

Because of their benecial eect at the time

of initial diagnosis, steroids are often used

at the time of recurrence of symptoms and

during palliation of DIPG patients. ey

often provide a marked improvement of recurrent neurological symptoms and are

usually prescribed with the short objective to relieve the symptoms of progression.

eir ecacy, however, is generally transient, and progressive symptoms recur

within one or two weeks following the prescription of the corticosteroids. At

this stage, the dilemma is whether to further increase the dose to alleviate these

symptoms or discontinue the steroids because of their potential adverse eects.

e choice is not easy for physicians and families and the decision should be

made with a clear understanding of the consequences of prolonged use of steroids

during palliation.

Although they can provide a transient improvement of neurological symptoms,

steroids have side eects that are of particular concern in the context of progressive

DIPG. Increased appetite and the resulting hyperphagia can lead to massive

weight gain and body transformation, in particular the cushingoid appearance

with the classic moon face. ese changes can have signicant cosmetic and

social implications leading to stigma and isolation. ey can also aect parents,

siblings and relatives at the time of bereavement when they remember the

cosmetic consequences of steroid usage. In addition, specic aspects of palliative

care and symptom progression of DIPG patients need to be taken into account

when steroids are considered. Lower cranial nerve decits lead to swallowing

disturbances and a risk of choking (see chapter 3). In this context, steroids can

have an unwanted eect, as they increase the appetite and therefore the risk of

choking of a permanently hungry patient. As swallowing disorders worsen, the

eects of steroids on appetite can become a nuisance and an obsession for the

child who is unable to eat or drink. In addition the combination of oro-pharyngeal

stasis of secretions and immunosuppression often leads to the development of

painful thrush that will require specic management with mouth wash and in

some cases antimicrobial medications against Candida.

Other side eects of steroids can have a signicant impact on the quality of

palliative care. In particular the behavioural side eects can alter the quality of

the interaction of the patient with his family.

Overall, the decision to use steroids at the time of progression should be made

with a clear understanding of the potential consequences of this choice. is

includes the risk of facing a vicious cycle as the progressive deterioration of the

disease leads to increasing the dose of steroids and subsequently to increasing the

side eects. Management of DIPG patients without steroids is possible, and some

neuro-oncology teams prefer to avoid their use at the time of disease progression.

Dr. Bartels is an Oncologist in

the Neuro-oncology Program at

the Hospital for Sick Children,

and Assistant Professor at the

University of Toronto, Canada.

Chapter 10: Use of Steroids in DIPG

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Chapter 10: Use of Steroids in DIPG

Side Eects of Corticosteroids

Steroids are associated with a number of potentially serious side eects. e

onset and severity of these side eects usually correlate with the dose and

duration of the treatment. In the context of a short duration of administration

(2 to 3 weeks), most side eects will resolve after cessation of corticosteroid use.

However, some children may require prolonged steroid treatment because of

persistent or recurrent symptoms, or some physicians are reluctant to decrease

steroids during radiation. In this context side eects may persist or even worsen

over time and signicantly aect the child’s quality of life. Using the lowest

possible dose of steroids will reduce the risk of these complications.

Cosmetic side eects include cushingoid appearance, truncal obesity, hirsutism

(excessive hair), acne, and stretch marks. Other side eects include increased

appetite, immunosuppression, hypertension, glucose intolerance, electrolyte

disturbance, uid retention, peripheral edema, gastrointestinal side eects,

osteoporosis, avascular necrosis, growth retardation and ocular problems.

Complications of corticosteroids are summarized in Table 1. Among the

common side eects of steroids, weight gain, steroid myopathy, Pneumocystis

carinii pneumonia (PCP) and behavioral changes are of particular concern in

DIPG patients.

Hyperphagia

e introduction of high dose dexamethasone at the time of initiation of

radiotherapy is associated with an immediate increase in appetite. As a

consequence, children can show a dramatic weight gain within days and attempts

at controlling their appetite are often dicult because of the associated mood

swings and behavioural changes. e use of calorie-free drinks may help limit

the weight gain. When patients can be weaned o the steroids, the weight gain

is transient and most children go back to their baseline weight within weeks.

However, when steroids are continued, hyperphagia may lead to massive weight

gain that will limit even further the mobility of an already neurologically

handicapped patient.

Mood disturbance

e neuropsychiatric eects of steroids are probably the most common and

most stressful for parents and caregivers who often report that “their child is

not the same.” Steroids can cause anxiety, insomnia and irritability. Sometimes,

discrimination of these complications from manifestations of gliomas, cerebral

irradiation or changing intracranial pressure can be dicult in clinical practice,

and it is not uncommon that clinicians request a CT or MRI scan to rule out

complications such as intratumoral hemorrhage. However, steroids given at a

very high dose have without any doubt a signicant impact on behavior in some

children and negatively aect their quality of life. e management of these

neuropsychiatric side eects involves discontinuing or reducing the steroids as

much and as soon as possible. e use of neuroleptics can be considered on an

individual basis when discontinuation of steroids appears impossible.

Common Occasional Rare

Happens to 21-

100 children out

of every 100

Happens to 5-20

children out of

every 100

Happens to less

than 5 children out

of every 100

Early: within

days

• Hyperphagia

• Insomnia

• Gastritis

Prompt: within

2 to 4 weeks

• Immunosup-

pression

• Personality

changes

• Acne

• inning of

the skin

• Stretch

marks

• Weakness

• Infections

• Pancreatitis

• Increased

intraocular

pressure

• Hypertension

• Psychosis

• Vertigo

• Headache

• Spontaneous

fractures

• Growth sup-

pression

• Peptic ulcer

and gastro-

intestinal

bleeding

• aseptic ne-

crosis of the

femoral heads

Delayed: usu-

ally after several

months of treat-

ment

• Cataract(s)

Table 1: Side eects of Corticosteroids

Chapter 10: Use of Steroids in DIPG

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Chapter 10: Use of Steroids in DIPG

Myopathy

Steroid myopathy is a complication that may signicantly impact the quality

of life of DIPG patients. e clinical manifestation of steroid myopathy is a

progressive weakness aecting mostly lower limbs that can have an impact on

walking abilities. Some children may require a wheelchair as a result of steroid

myopathy. Other consequences include the diculty to go up and down stairs

and an inability to run. Back pain is not exceptional and seems to be the result

of both myopathy and osteoporosis. Steroid myopathy usually improves when

the drug is discontinued or if the dose can be reduced. However, recovery can

take several months after steroid discontinuation. Not all patients will develop

steroid myopathy and the exact mechanism of this complication is unknown.

Some patients will present with severe symptoms of myopathy after 2 or 3 weeks

of steroid use, whereas other patients treated for months may have minimal or

no symptoms. It seems that regular exercise or physiotherapy programs may

help reduce the severity of myopathy.

Gastrointestinal bleeding and ulcers

Patients treated with corticosteroids are also usually treated with medications that

reduce the risk of gastric ulcer and hemorrhage. Although no signicant association

between steroid usage and gastrointestinal bleeding or ulcers has been identied in

children with brain tumors receiving steroids, it is prudent to use H2 antagonists

(like Pepcid) in DIPG patients treated with corticosteroids for a prolonged duration,

in particular when patients are treated with unusually high doses of corticosteroids.

However, in most patients treated with 1 or 2 mg. per day of dexamethasone, the

systematic use of H2 antagonists appears unfounded and twice-daily corticosteroid

dosing during meals reduces the risk of stomach irritation and spares the risks of side

eects and the expense of H2 antagonists.

Eects of corticosteroids on the immune system

Dexamethasone and other corticosteroids can cause immunosuppression by

inhibiting immune and inammatory responses and reducing the pool of

lymphocytes. e use of glucocorticoids will therefore increase the risk of

opportunistic infections. Pneumocystis carinii (PCP) is a fungal infection

responsible for life-threatening lung infections in immunocompromised

patients. ere is increasing evidence that patients with brain tumors receiving

high doses of steroids have an increased risk of PCP and in several DIPG studies,

cases of PCP have been reported as a result of the exclusive use of steroids

(without any concomitant chemotherapy). It is therefore recommended to

consider PCP prophylaxis when steroids are used for prolonged periods of time,

in particular when patients cannot be weaned o steroids.

In the context of progressive disease, swallowing disturbances can cause

signicant oro-pharyngeal stasis of secretions. e immunosuppressive eect

of the steroids will increase the risk of oral thrush (fungal infection) that can

be extremely painful and dicult to treat.

Alternatives to Corticosteroids

e large number of complications associated with prolonged or repeated use of

corticosteroids has led to the search for alternative therapies for the management

of peritumoral edema in brain tumors, and in particular in DIPG.

Xerecept® is a synthetic analog of the naturally occurring human peptide

corticotropin-releasing factor (CRF). Several animal studies have indicated the

ability of CRF to reduce the brain edema caused by brain tumors. Corticotropin-

releasing factor appears to reduce peritumoral edema by a direct eect on

blood vessels, independent of the release of adrenal steroids. Clinical trials have

shown promising activity against peritumoral edema in adult brain tumors. A

randomised trial has shown that Xerecept® benets patients with symptoms of

peritumoral edema associated with primary or metastatic cerebral tumors by

allowing them to reduce/stop their dexamethasone treatment, thereby reducing

the incidence of the steroid-related adverse eects of myopathy, cushingoid

symptoms, and skin disorders. A clinical trial is ongoing in children with

recurrent brain tumors (http://clinicaltrials.gov/ct2/show/NCT01369121).

Preliminary results suggest improvement in emotional, physical and fatigue

scores, and the possibility to reduce or even discontinue steroids.

Cyclooxygenase-2 inhibitors (like Celebrex) have been utilized by several

physicians for the management of progressive DIPG, either alone or in

combination with steroids. ere was indeed some suggestion that they might

be eective in treating cerebral edema. However, the cardiac complications of

this class of drugs have signicantly reduced the use of these agents in children.

Since VEGF plays an important role in the pathogenesis of peritumoral

edema, the use of inhibitors of VEGF, such as VEGF antibodies (for example

bevacizumab/tradename Avastin®) appears to be a logical option in the search for

alternatives to corticosteroids. In the context of DIPG a small study described

the ecacy of bevacizumab in children with DIPG with suspected radiation

necrosis. Four symptomatic children received bevacizumab for a period of 3

weeks to 3 months following completion of radiation at a dose of 10 mg/kg

every other week for a total of 3 to 6 infusions. Treatment was well tolerated

Chapter 10: Use of Steroids in DIPG

146

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Chapter 10: Use of Steroids in DIPG

without evidence of side eects. ree of the 4 children were able to discontinue

steroids and had signicant clinical improvement in neurologic symptoms.

Further studies are planned to better delineate the role of this agent in the

management of children with DIPG.

Conclusion

Steroids and in particular dexamethasone have a major role in the management

of DIPG patients. However, due to the lack of prospective studies on the use of

steroids in this condition, our knowledge on the optimal dosing and schedule

of administration including weaning remains limited and most physicians

rely on their own experience when prescribing steroids in this context. ere

is currently signicant diversity in clinical practice and it is hoped that future

studies will provide more insight into the optimal use of steroids in DIPG, as

well as potential steroid alternatives.

Parent Perspectives

Initially you see the steroids as your saving grace. You hear the side effects

of extreme hunger and weight gain as possibilities but your pre DIPG

self knows that you can control your child’s portions and just encourage

healthier choices. There is no reason for significant weight gain for your

child. Sleeplessness won’t be a problem because your child sleeps like a rock.

Incontinence isn’t even mentioned in those early days. Muscle deterioration?

No problem, your child is active and strong. Anger management has never

been an issue at your house, tantrums are not acceptable.



After only a few short weeks you begin to find yourself thinking that since

your child is being put through all of this (until you get your miracle) he

or she deserves to eat mashed potatoes at all three meals and snack times

if he or she wants to. I mean carrots don’t really fill you up so what made

you think they would fill your child up? Slowly but surely over the course

of the next six weeks you find yourself looking at a completely changed

human being. The little person you took into the clinic on day one is not

the same person you are taking in some six weeks later.



It was difficult to see the effects of the Decadron on Andrew's six-year-old

body. His face was very full, and he did not look like himself. He saw his

reflection in the mirror a few weeks after diagnosis and commented, "My

cheeks are more puffy than they were." That was an understatement! The

weight gain was a direct result of his steroid-induced appetite and the

drastic decrease in his mobility. He liked to eat things that were good for

him, but he would sometimes cry because he was so hungry.



My daughter Hope was one of the children who (with the exception of 48

hours) was never off of the steroids. She gained over sixty pounds in just

six months and lost the use of her right arm. She was able to walk assisted

short distances until about five weeks before she died but other than that

was confined to a wheel chair. Her stretch marks were worse than any

Chapter 10: Use of Steroids in DIPG

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Chapter 10: Use of Steroids in DIPG

pregnant woman I’ve ever met and eventually those marks became open

wounds in some areas. It was her great diligence and desire to persevere

that allowed her to wean off of steroids even if it was only for two days.

Hope was a hero.



In some respects, I felt that I lost Mara very soon after diagnosis. Her

personality was so markedly different that I felt the child I knew had already

left my home due to the steroids. The steroids make these kids turn into

something that they are not. That is our psychological horror as parents.



Oh, life with a child on steroids! Food becomes so important. Caleb is so

hungry all of the time. He told me yesterday that even though his tummy is

full, he still feels like he needs to eat. He cannot stop thinking about food.

Last night, he would not go to bed until he had two bananas on the bedside

table in case he woke in the night and needed a snack. My husband assured

him that we would be there and would get him something to eat if he needed

it. That wouldn't do. We had to have those bananas by the bed, ready at hand.

He awoke at about 6:00 a.m. and ate a banana. I helped him with that and

then fell back asleep. Every time I would drift off, Caleb would talk about

what he was planning to eat today. “When I get up, I am going to eat a

bowl of cereal and some scrambled eggs. Then I am going to go sit on the

back porch and eat a Pop Tart. Okay, Momma?” “Okay, Caleb,” I replied.

“Please just let Daddy and me sleep a little bit more and then we'll get

you some breakfast.”

Ten minutes passed, when Caleb said, “I want to be sure you pack my

lunch today when we go to the clinic. Okay, Momma? I want you to pack

spaghetti and meatballs, lasagna and a Caesar salad. Will you pack that

for me?” My reassuring reply was that we didn’t have to leave for the clinic

until noon, so he would be able to eat all of that before it was time to leave.

“Then can you be sure you pack a snack?” Content for five minutes that a

snack would be packed Caleb asked “Can we go to Krispy Kreme today?

We can get a hot and fresh for free and then get a dozen to bring home.”

…It's really quite comical from the outside, but I know he is just so tired

of it already.



From the day of diagnosis until the day he passed away, Bryce took steroids

to reduce the fluid surrounding the tumor. When we tried to take him off

of steroids after radiation, the headaches and nausea increased, so he

was always on a mild dose. We could tell the days when his cancer was on

his mind. He would become irritable and he would say, “This sucks, or I

hate this. Why does this have to happen to me? I don’t deserve this.” Our

response would always be a confirmation of his feelings. And it became

really difficult at times, because we knew that he was dealing with all of

these emotions, and so were we, but that we still had to parent.



Liam began Decadron immediately upon admission to the PICU however

we did not begin to see the side effects other than an increase in his

appetite until we returned home from the hospital. That’s when our love/

hate relationship began. Unfortunately Liam experienced many of the

difficult side effects from steroids. His appetite was massive. Ask anyone

whose child has had to take any significant amount of steroids and they

will tell you that eventually their child can turn any conversation, TV show,

game, whatever, into a conversation about food. Liam was no sooner half

way through breakfast when he was asking what was planned for lunch.

Fortunately for us and Liam during this time he craved only healthy things.

Fruit, vegetables (You’ve never seen a kid devour broccoli like our boy!),

seafood. He gained quite a bit of weight but thankfully not too, too much.

We were worried for a bit towards the end of radiation that his big cheeks

would not fir into his radiation mask and he would require a new one.

Thankfully though, that never happened. Although one would think having a

giant appetite would be the least of concerns when your child has cancer, it

is extremely difficult to see your child’s complete obsession with it. His love

of all things food though was not what was most difficult for Liam during

that time. Steroids brought huge mood changes, auditory hallucinations

that whispered horrible things to him. His anger was heartbreaking for us

to see, but also for Liam to feel. It sometimes made him lash out in ways he

never would have done before. He would cry after some of these moments

feeling awful that he may have hurt someone’s feelings, particularly mine.

Later when he would feel angry he would sit in his room and later when he

would call out to me, I knew he had settled down and was ready for a big

hug. Those were very difficult moments. Eventually Liam came to understand

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that his medication would cause these moments and we all learned ways to

help him feel less out of control. As his symptoms improved, he was weaned

further and further down and eventually was able to completely come off

the steroids all together.

When Liam’s tumor began to progress, he was put back on steroids. That

was a difficult day. Liam however reassured me that it would all be ok. He

didn’t think he would have any of the troubles he had on the medication

previously and he was right! This time however he gained a huge amount

of weight. He became far less mobile in these months but the appetite

continued. We did our best to give him healthy foods to help combat the

lack of physical activity. Still he held a tremendous amount of weight for a

little guy who started out very small. His disposition however, was always

cheerful. Always. He did not have any of the problems with mood swings

and anger that he had previously. What a blessing!

Steroids do just what they are supposed to do in most cases. They help

alleviate swelling and really combat some of the scary symptoms that

children experience but they also come with some side effects that were

difficult to see. We tried our very best to help Liam manage those symptoms

as best we could. We talked a great deal about all of his medication and

their effects and we were careful to respect Liam’s feelings about how the

drugs were making him feel. After all it was his body, not ours. There were

several times when we asked to make adjustments whether it was changing

a dosage, changing a pill size, asking for a medication to be flavored or

crushed—whatever it took. There are many, many options available and

sometimes it’s just a matter of asking the question of your child’s provider.

If your child has difficulty swallowing pills, is that medication available

in a suspension? Always ask the question. Your child being diagnosed with

cancer presents parents with the steepest learning curve they will ever

encounter. Never, ever be afraid to ask questions!



The neuro-oncologist discussed some of their primary concerns going

forward. He indicated that they were concerned about the level of

hydrocephalus (an accumulation of cerebrospinal fluid on her brain) and

the impact that may have on her functioning. He also recommended that

Stella be taken off the steroids. While the steroids control the effect of

the hydrocephalus, they also caused her to have a significantly increased

appetite and to be agitated and angry. These side effects of the steroids

are problematic since one of the most common symptoms of the tumor is

difficulty swallowing. There is a concern that should that occur while she

is on the steroids, the anger that may result from the hunger and inability

to eat may cause choking.



When Caleb was first diagnosed with DIPG he was started on steroids. At

that time he took them for about three weeks during the first half of radiation.

The dose was fairly small and it helped with his speech and his balance.

When he first started them his initial side effect was extreme hunger and

after about a week we began noticing the mood swings. I remember the first

time I really saw what the steroids could do to his personality. We had taken

him bowling. He was trying so hard and wanted to do well but it just wasn't

going his way. He became very agitated and I can remember thinking that

this was not my child. He was 8 years old at the time and although he had

always had a competitive streak, he was very even tempered. Here he was

having a mini tantrum after each throw of the ball. I was horrified thinking

I would never see my sweet natured boy again. Of course as the steroids

were weaned he became more and more like himself. I was so relieved and

truly thought I never wanted to put him on that wretched drug again—he

no longer looked the same and at times he certainly didn't act the same.

Once he was off the steroids he stayed off them for two months. We had

learned of tumor progression the month before and had opted for a second

round of radiation. He was nearly finished the second round when one

morning his whole left side became paralyzed and he could barely speak.

We took him to the hospital and they started him on a fairly high dose of

dexamethasone again. I remember thinking it would just be temporary

and I wouldn't agree to long term use. We did a slow wean but as we got

closer to being off he would begin with symptoms again. We were being

told the symptoms were likely due to swelling from the radiation and as the

swelling came down so would the dexamethasone, so we would increase

again while we waited for the swelling to go back down. This went on for

months... wean the “dex,” increase the “dex,” wean the “dex,” increase

the “dex,” and each time we needed to increase the dose, he would need

a bigger increase to get him back to baseline.

At this point, it was thought the symptoms were likely caused by radiation

necrosis. Caleb was so hungry and became agitated and food obsessed, he

gained over 36 lbs. in 3 months and the weight gain continued. I remember

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him trying to control it. His moods were crazy at times, thankfully these

bouts of insanity were usually short lived but his mood swings would

upset him. He would feel so badly for acting irrational and no amount of

reassurance would make him feel better about it. He knew right from wrong

and sometimes the steroid would make him behave wrong. It was our double

edged sword. On one hand it helped the tumor symptoms but at what cost

to his quality of life? I feared if we lowered the steroids completely we

would lose him faster, I wasn't ready, I knew I never would be.

So, we started Avastin, which was thought to possibly reduce the

effects of radiation necrosis, in hopes that we would be able to stop the

dexamethasone. I am not sure if it helped. I think it might have, as we were

able to lower the dose but at this point in time no amount of the steroid

would help him to walk again, He was in his wheelchair full time, had no

use of his left side, could no longer swallow liquids or solids that hadn't

been pureed, and his speech was greatly affected. On top of all that his

skin had been stretched beyond its capabilities and he had open wounds

on his body. Thankfully most of them caused no pain but he had two, one

under his arm and the other between his bum cheeks that caused him a lot

of pain. We were able to get topical morphine for the wounds which helped

a lot. At this point we knew the steroid was causing more harm than good

so we did a fairly rapid wean.

Caleb took his last dose of steroid on a Tuesday and joined the angels the

following Saturday. Through it all, Caleb had tons of beautiful moments

of pure joy, days when he was all smiles and would enjoy the company of

those around him. He planned things and wanted to do them and it was

days like this which made the steroid decision so hard for us. I know the

steroids caused him a lot of anguish especially in the end but I also know

it gave us a lot of beautiful, happy, loving days.

153

Chapter 11: Caring for Your Child at Home

Chapter 11

Caring for Your Child at

Home

Deborah Lafond, DNP, PNP-BC, CPON, CHPPN

If your child has been diagnosed with diuse intrinsic pontine glioma (DIPG),

your family will inevitably face some challenges while caring for him or her at

home. For example, your child may have trouble taking or tolerating medicines

or have problems with swallowing/eating, walking, sleeping, and other aspects

of daily living. Many parents feel anxious about taking their child home after

treatment. Figuring out what your child needs and how to care for your child at

home can be very stressful.

You may have spoken with other parents of children with DIPGs and may have

heard about some challenging situations. Although it is dicult, try not to

compare your experience with any other child and family. Each child and family

is special and each situation is unique.

To prepare you for caring for your child at home, this chapter will describe

common problems you might encounter and oer advice about how you and

your child can best manage these issues.

Your Child’s Health Care Team is Available to Help You

Remember that your child’s health care team is there to help you and your child cope

with the challenges of DIPG. Your family may not encounter any of the challenges

listed in this chapter, or you may experience only some of them. While the health

care team tries to anticipate what you and your child might need, not all situations

are easy to predict. Don’t hesitate to contact your child's health care team whenever

you have questions or concerns.

Know whom to call

You have likely met many members of

your child's health care team since the

Dr. Lafond is a Nurse

Practitioner in Neuro-

oncology and Palliative Care

at Children’s National Medical

Center, Washington, DC.

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time your child was diagnosed with a DIPG. Each person has a special role

in caring for your child. Make sure you have the name, phone number, and

email contact information for the person on your child's health care team

that you should contact for routine questions and concerns. Also, be sure

you have the contact information for those you should contact during an

emergency, after hours, and on weekends. e American Childhood Cancer

Organization provides a free journal entitled Along the Way to assist with this

type of record keeping. is journal is available without charge by request

to all parents of children with cancer. is journal includes designated pages

to include contact information for your child’s healthcare team. Keep the

contact information:

• Next to every phone in your house.

• In your cell phone. (If you own an iPhone, there is a helpful “app” called

iCANcer, available through iTunes, where you can store all contact

information, as well as the diagnosis, treatment, and medical information

of your child.)

• In your wallet or purse.

• Near your phone at work (if you have a private oce or desk space).

• At your child's school—with your child's teacher and the school nurse

and at your other children’s school(s), if applicable.

• With people who care for your child, either at your home or theirs, while

you are gone (such as grandparents, daycare, or babysitters).

Your child's social worker

Get to know your child's social worker well. e social worker is there to help you

and your child navigate the many feelings and emotions you might experience as

you go through the DIPG journey. If you have not been assigned a social worker,

call your child's nurse and ask to have a social worker assigned to your family.

Medical problems are not the only issue you, your child, and the rest of your

family will face. Having a cancer diagnosis is a scary and emotional experience.

ere will be times when you are sad, times when you are angry, times when you

are frustrated, and times when you feel joyful. Your social worker can help you

and your family as you deal with these dicult emotions.

Your child’s nurse or nurse practitioner

In general, social workers cannot answer medical questions about your child's

diagnosis and treatment. us, your child’s nurse is another important contact

on your child's medical team. Your child will likely have a primary nurse (RN)

or nurse practitioner (APN) who will take the lead in answering all your medical

questions. e role of APNs is similar to the role of doctors; they can serve as a

patient’s primary health care provider and prescribe medications, whereas RNs

do not. e nurse/nurse practitioner is usually the rst person you call with

routine questions and concerns. If that person does not know the answer, she

or he can readily nd your child's doctor. is does NOT mean your child's

doctor is not routinely available to you. You may talk with your child’s doctor

at most any time, but your child's nurse/nurse practitioner is a great resource

for practical information about the day-to-day challenges you may face. Do not

hesitate to call the nurse/nurse practitioner if you have questions or concerns.

e nurse/nurse practitioner usually serves as a central contact for parents and

helps get them to the right person when questions or concerns arise.

Your child’s case manager

Another key person to get to know is the case manager assigned to your child

from your health insurance company. If a case manager is not assigned to you,

call your insurance company and ask to be assigned one. Tell the insurance

company that your child has “a brain tumor with complex health care needs;”

this is common terminology you can use to help your insurance company

understand why you are asking for a case manager. If your insurance company

is not responsive, be persistent.

You will need the following information when you talk with your insurance

company. is is information that you can get from your child's nurse/nurse

practitioner.

• e diagnosis: diuse intrinsic pontine glioma (ICD-9 code is 191.7);

• Date of diagnosis;

• e name of all hospitals where your child receives treatment;

• e type of treatments your child is receiving, (e.g., chemotherapy,

radiation therapy, physical therapy, occupational therapy);

• The contact information for your child's doctor and nurse/nurse

practitioner.

Be willing to give your insurance company permission to contact your child's

doctor and/or nurse/nurse practitioner for more information about your child

and the care your child will need. e insurance company may have other

questions regarding your child's diagnosis. Do not hesitate to ask the insurance

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representative to contact your child's doctor or nurse/nurse practitioner to

get answers to these questions, especially if you do not know the answers or

are unsure of the details.

Having a case manager at your insurance company usually allows you to have

a central contact person who can help you obtain referrals and approvals for

your child’s care. By having one person (your case manager) to call for help

with insurance-related issues, you can often avoid the long process of trying

to nd the right department for needed help. Your case manager may also be

able to arrange for someone to help care for your child at home.

Home care nurses

Sometimes parents can arrange nursing care in the home for a short while.

is is not possible in every situation, but it may be possible for short periods

of time. Talk with your child's case manager, social worker, or nurse/nurse

practitioner to nd out whether or not you are able to have home care nurses

come in for short periods to help you, especially when your child rst goes

home or if your child's symptoms worse

n and he/she requires more care at home.

General Physical Care

Every child is unique in the symptoms and care needs they will have at home.

Your child may have none of the needs mentioned here, some of them, or all

of them at any given time during the DIPG journey. At times, it may feel as

if you have to be your child's at-home nurse. It is important to know what to

expect and how to provide care for your child so he/she can stay at home and

out of the hospital as often as possible.

is caretaking can be overwhelming at times, but the goal is for your child

to live as normal a life as possible, doing the things that he/she enjoys, such

as playing with friends, going to school, and being with family. Knowing how

to care for your child may help prevent some of the most common problems

or help resolve them sooner. is section covers such issues as prevention,

medications, breathing problems, nutrition/feeding issues, constipation, skin

breakdown, nausea/vomiting, pain, mobility issues, sleeping, caring for central

lines, and some common symptoms children with DIPG experience.

Prevention

Discuss with your health care team any potential problems your child might

have. Ask about what you may need at home to care for your child. Be sure

that you understand what complications the health care team thinks your child

may experience, what medications they are sending home, and the possible

side eects of these medications. Also, ask your health care team what signs of

medical problems to look for if your child's condition changes.

Infection

Infection can be a serious risk for your child, especially if he/she is receiving

steroids, such as dexamethasone or certain chemotherapy agents. Being

on certain other medications can also make your child more susceptible to

infections. Having an infection can cause serious complications for your child,

so ask your doctor or nurse/nurse practitioner if your child is at increased risk

of developing infections. Infections can be bacterial, viral, or fungal.

You don’t need to keep your child away from other people unless someone is ill.

You can let your child go to school or play with other children. But if another

child is obviously ill, it is best not to be around that child until he/she is well.

If other family members are ill, it is often dicult to keep your child separated

from them, and it is not recommended that you keep your child in another

room or house. Just try to be as careful as possible about close contact.

e most important way to prevent infection is to have good hand washing

practices. You may use regular soap, wash for at least 30 seconds and have

several bottles of alcohol-based hand sanitizers available in your home and

small ones to keep in your purse, car, and your child's backpack or diaper bag.

Teach your child to wash his/her hands well (including under the ngernails)

after using the bathroom, before and after eating, after playing with pets, after

touching other people, or anytime his/her hands are dirty. Also ask other people

including other children who are in contact with your child to wash their hands

well before they interact with him/her.

Medications

Ask the nurse how to give your child his/her medications and at what times

each one should be given. e nurse can make a schedule of all medications

with a place for you to record the day and time you give the medications; this

type of form is helpful when your child takes several medications. Having a

schedule and a record of when you gave each medication will help you remember

when to give them to your child. A sample medication form is included in

Appendix A. An online medication program is available at: http://www.

medactionplan.com/medactionplan/mymedschedule.asp.

Ask your doctor or nurse practitioner the following questions about each

medication your child has been prescribed.

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• Why has this medication been prescribed (why it is needed)?

• When should I give this medication to my child (what schedule)?

• How should I give this medication to my child (with or without food)?

• If pills are prescribed, can they be split or crushed for easier swallowing?

Do not crush pills or dissolve pills or capsules in liquid without talking to

your pharmacist or nurse/nurse practitioner rst. Some medications cannot

be safely crushed or dissolved.

• What are the side eects of this medication and what can I do to manage

or prevent them?

• Are there any other medications, including over-the-counter medications,

that I should avoid giving my child?

• Are there any foods that I should avoid giving my child that might interact

with the medications?

• What should I do if I forget to give a dose of a medication or if my child

vomits up the dose/pill?

If your child has any diculty taking the medications or experiences side

eects, let your doctor or nurse practitioner know as soon as possible so they

can advise you about what to do. Not all medicines have unpleasant side eects

or interactions with other medicines. Hopefully, your child will have no side

eects with the medications he/she is taking, but it is best to be prepared for

what to expect, possible side eects, and how to deal with any that may occur.

Additional tips for medications:

• Keep all medications in a safe place, out of reach of children.

• Record the time you give each medication on the daily schedule and keep

track of any side eects your child experiences. Keep this list up to date

and bring it with you to every doctor’s appointment or emergency room

visit so everyone knows exactly what medications your child is taking and

the last time he had each one. is information can be documented in the

iCANcer app if you own an iPhone, iPod Touch or iPad.

• Keep medications in a cool, dry, place, especially if the weather is hot

and humid. Do not refrigerate medications that are not supposed to be

refrigerated, but do not leave medicines in direct sunlight or in a hot car.

• If your child has trouble swallowing pills or liquid medications, ask your

nurse for help in nding the best way to give them. For example, some

medications can be mixed with special avors at the pharmacy to make them

taste better or can be crushed and put into pudding, ice cream, chocolate

syrup, or applesauce.

• For older children and teenagers, consider getting a pillbox to organize

medications to be given at certain times of the day. Most drug stores and

large grocery store chains sell pillboxes in one day/time or multiple day/

time versions.

• Measure all liquid medications with a syringe, if possible, rather than a

teaspoon. Regular kitchen spoons can be dierent sizes and you want to

make sure you give the right amount of medicine each time.

• Make sure you understand each medication and why it is being prescribed.

In addition to your doctor or nurse/nurse practitioner, your pharmacist

can provide you with information about each medication. If you use the

Internet to nd information, please double check that information with

your pharmacist, doctor, or nurse/nurse practitioner to ensure you get

accurate information.

• Do not use medications that have not been specically prescribed for your

child. And do not share your child’s medicines with anyone else, even if

that person takes the same prescription.

• Do not give your child any herbal or vitamin medications without checking

with your doctor or nurse/nurse practitioner. Some common herbs and

vitamins can interfere with chemotherapy and radiation treatments, as

well as possibly interact with other medications your child is taking. More

information about complementary and alternative medicines (CAM) is

discussed in a section later in this chapter.

Pain

Pain can occur in children of any age and at any time. ere are dierent types of

pain depending upon the cause, the location, your child's special characteristics,

the treatments your child is receiving, and your child's past experiences with

pain. Not every child with DIPG will experience pain. Some children feel no

pain at all. If your child does experience pain, the goal is to relieve that pain

as quickly as possible, with the least amount of side eects. is section will

describe some ways you can help your child manage pain.

It is important to be able to recognize when your child is in pain. Your child

will experience the normal aches and pains of childhood, but sometimes it can

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be dicult to gure out whether a complaint of pain is a normal childhood

experience, such as bumps and bruises from play, or something more serious.

Depending on the age of your child, it can be dicult to gure out whether

your child is even experiencing pain. For example, infants normally cry, so it

can be hard to determine if a cry is from pain or something else. Older children

and adolescents may not admit to feeling pain because they may associate

pain with having to go to the hospital or taking more medications, which

may make them sleepy or nauseated. If you think your child might be in pain,

please talk with your doctor or nurse/nurse practitioner about ways to manage

your child's pain. Remember that while pain is physical, it can also have an

emotional component. Each child reacts dierently to pain, so it is important

to understand how your child expresses pain. Indications that your child may

be in pain include:

• A high-pitched cry or change in an infant's normal cry;

• Changes in facial expressions;

• Rubbing particular areas on the body that may indicate pain;

• Irritability or restlessness;

• Being inconsolable;

• Being less active or mobile than usual and playing less;

• Loss of appetite or changes in eating patterns;

• Changes in sleep patterns.

If your child can talk, ask him/her if he/she has pain and ask him/her to show

you where the pain is, what it feels like (e.g., sharp, stabbing, shooting, burning,

cramping), what he/she thinks is causing it, and what he/she thinks will help

it feel better. You may also choose to show your child pictures of faces that

represent no pain to severe pain and ask him/her to point to the picture that

best represents how he/she is feeling [Fig. 1]. e answers to these questions

can help you decide how to help your child.

Figure 1: Faces Pain Scale, used with permission by the International Association for the

Study of Pain (IASP)

Ways to treat pain without using medications include:

• Reassure your child that pain does not always mean the DIPG is getting

worse; explain that all children experience pains during childhood.

• Create a calm and nurturing environment by turning down any bright

lights, minimizing noise, and creating a comfortable room temperature.

Experiment to nd out what works the best to calm your child.

• Use distraction (e.g., singing, reading books, blowing bubbles, telling stories,

watching a favorite movie DVD, etc.), relaxation techniques, visual imagery,

or play to get your child's mind o his/her pain. Ask your child life specialist,

social worker, or psychologist for other strategies to help your child.

• Apply a heat pad or ice pack, whichever your child prefers, to areas of pain.

• Run a warm bath or shower to help your child relax.

• Use massage or gentle touch, but only if your child wants to be touched,

because sometimes touch is not comforting. Massaging your child’s hands,

feet, and shoulders can help your child relax and give you a way to connect

with your child. Many hospitals oer massage classes to teach you how to

perform massage techniques eectively.

• Play music—soothing music is best but use music that your child enjoys;

or try a sound machine with sounds such as running water or ocean waves.

• Have your child's favorite blankets or stued animals or other favorite toys

readily available.

• Hold your child to cuddle or rock him/her, or lie in bed next to him/her

(if he/she wants you to, as older children may like to be left alone to sleep).

• Let your child cuddle up with the family pet.

Ways to manage pain with medications include:

• In general, start with milder medicines such as acetaminophen or ibuprofen.

However, these medicines cannot be given with certain chemotherapy

medications or when blood counts are low, so always check with your child’s

doctor or nurse practitioner before giving your child any over-the-counter

pain medications.

• With prescription pain medications, read the directions carefully. ese

medications are prescribed based on your child's age and weight. Do not

give more than the recommended dose unless you are told to do so by your

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child's doctor or nurse practitioner.

• If your child has more moderate to severe pain, your doctor or nurse

practitioner may prescribe stronger medicines, such as opiates (morphine,

codeine, methadone, etc.). Many types of opioids can be safely used for

children. Your doctor or nurse practitioner will explain the directions for

giving opioid medications and the expected side eects.

• In general, it is best to give pain medications throughout the day on a regular

schedule, or when your child’s doctor or nurse practitioner tells you to give

them. Giving medicines on a regular schedule avoids the peaks and valleys

that occur when they are only given when your child experiences pain. Just

be sure not to give your child more medication than recommended by the

doctor or nurse practitioner, or more than is recommended on the bottle

for over-the-counter medications.

• If your child is experiencing increasing pain, even though he/she is on

strong pain medication, other medicines can be added to help the pain

medicines work better.

• Every child is unique, so the plan for managing your child's pain should

be the one that works best for him/her.

Common concerns about pain medicines include:

• Addiction and tolerance: Children who are in pain may need strong

medications to help relieve it. If your child needs pain medications for a

long period of time, he/she may need increasing doses of pain medicines

to help relieve the pain. is need for higher dose is known as tolerance,

meaning your child needs a higher dose to get the same eect. Tolerance is

NOT the same thing as addiction. Addiction is a physical and psychological

craving for medication, usually to achieve a "high." Children in pain do

not become addicted to pain medications if they are used appropriately and

only as your doctor or nurse practitioner tells you to give them.

• Medicine is too strong: Parents may worry that if a strong pain medication,

such as morphine, is prescribed it means their child is getting worse.

However, morphine is a very good pain medicine and works well for

children of all ages, from infants to adolescents. Morphine has been used

for many years and doctors and nurse practitioners know a lot about

this medication. ere are other pain medications that can be used, but

morphine is frequently used because it relieves pain so well. If the doctor

or nurse practitioner prescribes morphine, or a similar opioid medicine, it

does not necessarily mean your child's condition is getting worse. Don't

be afraid to ask your doctor or nurse practitioner why a particular pain

medication is being prescribed.

• Multiple pain medications: Sometimes medicines may not work too well

by themselves, but in combination with other medicines work very well.

You may even be able to use smaller doses of each medication when they

are combined. Sometimes pain has several dierent causes, so one pain

medication does not treat all the causes. Talk with your doctor or nurse

practitioner about why your child is taking each medication and ask them

if you can eliminate any of the medicines.

• Side eects: If your child is taking opioid medications, be sure to start

him on a stool softener to prevent constipation. Opioid medicines slow

down the intestines, which can cause constipation. Itching, nausea, and/or

increased sleepiness may also be caused by certain medicines. Be sure to tell

your doctor or nurse practitioner if your child has any of these symptoms

so you can get advice about how to handle the side eects. Generally these

types of symptoms happen in the rst few days that your child is taking

opioid medicines. Talk to your doctor about any other side eects that you

think your child might be experiencing from other pain medications as well.

Nutrition and Feeding Issues

Good nutrition is important for your child’s growth and general health. If your

child is having issues with feeding/eating, it is important to nd out why. For

example, if your child is nauseated from chemotherapy, medicines can be given

to help calm his/her stomach. If your child is too tired to eat, nding ways to

deal with fatigue might help him/her have times when he/she feels better and can

eat. Having a meal schedule might also help your child eat regularly, as multiple

doctor appointments, other family obligations, and the chaos of daily life can be

overwhelming and cause a child to lose his/her appetite or forget to eat.

If family members and friends have asked how they can help, consider letting

them make meals for your family so you can concentrate on caring for your child.

Your child’s illness may change over time, and there may be times when he/she

wants to eat more or eat less. ings that will aect nutrition and the ability to

eat for a child with DIPG include the following:

• Weight gain: Your child may gain weight rapidly when he/she is on steroids.

You may notice that he/she has a ravenous appetite often way out of

proportion to what he/she normally eats. It can be very dicult to control your

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child’s appetite, but some tips include limiting high-calorie foods and salty

foods. is can be dicult, because your child may want to eat only certain

foods. Let him/her eat his favorite foods but in moderation. For example,

you may try saying something like, “You can have the chocolate ice cream one

time today. If you eat it now, then you cannot have any more until tomorrow.

Are you sure you want to eat it now, or would you rather try _______ now and

save the chocolate ice cream until later today?” is approach does not always

work because children often live in the present moment and to them "later"

really does not exist; later means never! You can also try a sticker chart or

some reward system so your child has to eat certain “good/healthy” foods in

order to earn the privilege of eating the less-healthy foods. is can be a real

challenge, so don’t hesitate to talk with your child’s social worker, nurse, or

child life specialist about tips to help you manage your child’s food cravings.

Consulting with a nutritionist or dietitian may be helpful for learning ways

to decrease calories in your child’s diet.

• Weight loss: On the opposite side of the spectrum, your child may lose

weight. is might happen while your child is getting certain chemotherapy

medicines or radiation therapy, or when being weaned o steroid medicines.

As frustrating as it may be to have your child eating all the time, many parents

nd it as frustrating to see their child not eating and losing weight. ings that

can help counteract weight loss are using supplements, such as Pediasure©,

Boost©, or Carnation Instant Breakfast©, or other supplements that your

doctor or nurse practitioner recommends. Your health care team will tell you

which supplements they recommend and how much to give your child each

day. Consulting with a nutritionist or dietitian may be helpful for gaining

tips about increasing calories in your child’s diet. ere are also medicines

that can be used to stimulate your child’s appetite, but before using any you

should ask your health care team if they think an appetite stimulant would

be helpful for your child. Also remember that if your child is tired and less

active, his/her metabolism slows down and he/she does not need as many

calories. Your child may also have cravings for a certain food and then only

take one or two bites. is can be quite frustrating for parents. Try to let

your child eat and drink what he/she wants. Sitting down to a big plate of

food or large glass of a liquid beverage can be overwhelming for a child. Try

to oer small, frequent meals. You will be surprised by how the calories add

up by just taking a few bites many times a day!

• Diculty swallowing: Many children with DIPG have diculty swallowing.

is is most common with thin liquids as they move more quickly through

the mouth and throat which can result in aspiration, but can happen with

any food or liquid. If your child coughs or chokes when he/she eats, it may

be a sign that he/she is having trouble swallowing. If your child has diculty

swallowing solid foods, try cutting food up into very small bite-sized pieces,

serving soft foods, and encouraging him/her to chew food thoroughly and

not rush while eating. If your child has diculty swallowing thin liquids,

try using a syringe to get a stream of liquid down, using thickening agents

to bulk up thin liquids, or using thicker versions of similar liquids

(e.g., milk

shakes or liquid yogurts instead of milk, and applesauce instead of apple juice)

• Inability to eat by mouth: ere may come a time when your child cannot

take food or liquids by mouth, so this is a challenge to think about in advance.

Ask your child’s doctor or nurse practitioner about the dierent causes of the

inability to eat or drink. Knowing about possible causes will help you notice

signs and make decisions about how to help your child if that time comes.

If your child reaches this point, the doctor or nurse practitioner will conduct

a physical exam to nd out the cause of the problem. If it is a mechanical

problem, such as the vocal cords not closing properly or aspiration (when food

goes down to the lungs instead of the stomach), then maybe your child can

receive uids and nutrition through an alternate method, such as a nasogastric

tube (NG-tube) or gastrostomy tube (G-tube). If the DIPG is quite advanced

and your doctor or nurse practitioner thinks your child is nearing the end

of life, then putting your child through the discomfort of having a tube

placed to receive uids and nutrition may not be the decision you want to

make. If your child’s DIPG is advanced, he/she may not want to eat as his/

her metabolism and digestive system slow down. It is not uncommon for the

appetite to signicantly decrease as a child’s illness becomes more advanced.

More about these dicult decisions will be discussed later in this chapter.

• Articial uids and nutrition: is is the term the health care team uses

for giving uids and nutrition through a nasogastric tube (NG-tube) or

gastrostomy tube (G-tube). e term “articial” simply means that the

uids are given through a tube rather than orally. An NG-tube is a small

exible tube inserted through the nose, down the back of the throat, and

into the stomach. e tube can stay in from a few weeks to a few months,

and it is used as a temporary way of giving uids and nutrition. If your child

has problems with nausea or vomiting, he/she may vomit up the tube and

the tube may have to be replaced more often. A G-tube is a bit larger and is

placed directly into the stomach or intestines by an interventional radiologist,

gastroenterologist, or surgeon, usually while your child is under anesthesia or

sedation. A G-tube can stay in for about 6 months but can be easily changed

by a home care nurse or—in some cases—you may be taught how to change

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the tube. Either an NG-tube or G-tube can be hooked up to a feeding bag to

give liquid nutrition through either several bolus (large) feedings at dierent

times during the day or by a small amount being dripped in with a feeding

pump over 10 to 12 hours at night. Dierent types of liquid feeding formulas

are used depending upon the nutritional needs of your child. Your child's

nurse or nutritionist will go over the best type of schedule for your child and

explain how to manage these feedings at home.

ese types of feedings are not without complications, so your doctor or nurse

practitioner should review the risks and benets with you so you can make

an informed decision. In general, if the benets are great and the risks are

small, a feeding tube might make a lot of sense. If your child is at great risk for

complications from a feeding tube (for example, if he/she is not able to process

and eliminate the feedings, causing swelling and uid accumulation in the lungs)

then a feeding tube may not be the best choice. Having open, honest discussions

with your health care team will help you to make these decisions.

Nausea and vomiting

Nausea (feeling sick to your stomach) and/or vomiting can occur for many

reasons. Your child may have initially had nausea and/or vomiting as one of the

rst symptoms of his/her DIPG. Usually this is due to increased intracranial

pressure caused by swelling and pressure on sensitive areas of the brain. To

combat sickness, medications such as steroids can help decrease swelling in the

brain. Other things that can cause nausea and/or vomiting include constipation,

uid and electrolyte imbalances, chemotherapy, and certain medications (such

as opioids). Tips for decreasing nausea/vomiting include:

• Giving anti-nausea medications, such as Ondansetron or others that your

doctor or nurse practitioner might prescribe for your child, about 30

minutes before chemotherapy and/or radiation treatments and as instructed

at other times of day, as needed.

• Giving your child's medications with food or after a meal, depending on

the medication.

• Feeding your child small, frequent meals.

• Giving your child smaller amounts of liquids with meals and avoiding

carbonated beverages.

• Avoiding greasy, fatty foods.

• Avoiding foods with strong odors.

• Putting a drop of peppermint oil or other strong-avored oil of your child's

preference (available at your local nutrition store and some pharmacies) on

your child's upper lip, just below the nose.

• Using aromatherapy (described in more detail in the section below about

complementary and alternative therapy).

• Taking your child outside to be in the fresh air or having your child sit

near a fan.

Constipation

Constipation, or diculty having a bowel movement, can cause discomfort

for your child and lead to pain, nausea, vomiting, decreased appetite, and

irritability. Constipation is generally dened as not having a bowel movement

in more than 3 days, pain or crying with passing stool, or the inability to pass

a stool after 10 minutes or more of trying. You may notice that your child's

bowel movements are hard or small pellets, which are also signs of constipation.

Constipation is a common problem in childhood and can be even more of a

problem for a child with DIPG when taking certain medicines or when the

tumor involves the spine. Track your child’s normal bowel movement routine.

For example, do they usually have a bowel movement every day, several times

per day, every other day, etc.? If your child does not have a bowel movement

per his/her usual routine or you notice that the stools are hard or dicult to

pass, contact your child’s doctor for advice.

Several things can help prevent constipation:

• Have your child drink plenty of uids, especially water.

• Increase ber in your child’s diet and encourage him/her to eat fresh fruits

and vegetables.

• Increase your child’s physical activity.

• Establish a bowel regimen (i.e. having your child sit on the toilet for 5–10

minutes after meals and at bedtime).

• Consider giving your child a stool softener or stimulant (laxative), but rst

talk with your child’s doctor or nurse practitioner for advice about which

type is best for your child.

• Avoid suppositories or enemas unless recommended by your child’s doctor

or nurse practitioner.

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Skin Issues

Skin problems are common in children with DIPG and are usually related to taking

steroid medicines (e.g., dexamethasone). Common skin problems include striae

(stretch marks) and dry skin. In addition, some children with decreased activity and/

or decreased mobility may be prone to developing pressure sores. Common places

for pressure sores to develop are on the lower back, buttocks, hips, or heels. Striae

can develop anywhere on the skin surface.

Some tips to help manage skin problems in your child include:

• Changing your child’s position frequently to relieve pressure on any one area (if

your child’s mobility is limited).

• Bathing your child daily and looking carefully at the skin for changes.

• Using moisturizing lotions/creams. (Be careful about this if your child is receiving

radiation therapy. First talk with the radiation doctors.)

• Using sunscreen (SPF 30 or higher) when outside, even if your child has a dark

complexion.

• Having your child drink plenty of uids to stay well hydrated.

• Using extra padding on the bed or wheelchair.

Fatigue

Many children with DIPG feel very tired from time to time, which can be

distressing for the child and family. Children want to be able to play, go to

school, and do all the things they used to enjoy doing. Fatigue (feeling very tired)

can be caused by muscle weakness, low blood counts, nutritional deciencies,

stress, and certain medications or treatments, especially radiation therapy.

Many children experience a great deal of fatigue during and for a few weeks

after radiation therapy; this is called radiation somnolence syndrome. Ask

your doctor or radiation oncologist to explain this condition. It goes away by

itself and usually does not require any treatment.

ings you can do to help your child if they have chronic fatigue include:

• Planning important activities for the time of day when your child is usually

most awake.

• Giving your child pain medicines or using some of the non-medicine

methods of managing pain, as pain is often a cause of fatigue.

• Making sure your child gets adequate sleep/rest; consider putting a "DO

NOT DISTURB" sign on the door when your child is resting during the

day.

• Limiting visitors to allow for rest time.

• Letting your child go to school for just one class, or half a day if he/she can;

consider home schooling or a tutor (if your child is unable to go to school

for a full day). Also, your social worker can help arrange for a home tutor

from the school system.

• Talking with your doctor or nurse practitioner to nd out if using a

stimulant medication would be helpful for your child. ere may be

stimulant medications that can be used if the other methods do not help.

Some children become more fatigued as their disease becomes more

advanced, often sleeping many hours a day. is can be scary for parents

and other family members. Talk with your health care team about this.

Allow your child to rest, but reassure your child that you are never far away

and that you will be there when needed.

Breathing Problems

Some children with DIPG have diculty breathing. is issue can be due to

increased secretions (drooling) in the mouth and back of the throat, weight

gain associated with use of steroid medications, infection, coughing, wheezing,

low blood counts, or the tumor aecting the nerves that control breathing. It

can be scary for you and your child if he/she has trouble breathing. One of the

most important things you can do when your child has trouble breathing is

to remain as calm as possible and help your child remain calm, as anxiety may

increase breathing diculties.

Here are some tips to counteract common causes of breathing diculties for

children with DIPG:

• Reduce anxiety: Create a calm environment. Even though the moment

may be frightening, take some deep breaths to calm yourself down so you

can remain calm and in control. Ask your child’s social worker or child life

specialist to teach you techniques to help calm your child down. Sometimes

playing soft, quiet music, speaking in a slow calm voice, and doing some

deep breathing exercises can help your child calm down and relax so he/

she is not as short of breath.

• Combat shortness of breath: Teach your child to take slow, deep breaths

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when he/she starts to feel short of breath. Other tips include using a small,

hand held fan to blow air gently in your child’s face; keeping the room well

ventilated or opening a window; changing your child’s position—such as

from lying to sitting, to lying on his/her side, to elevating the head of the

bed or using another pillow to raise up his/her head and shoulders.

• Avoid smoke: Do not smoke around your child and don’t let other people

smoke around your child.

• Reduce increased secretions: Your child may have diculty swallowing

his/her saliva, or may make noisy or gurgling sounds when he/she breathes.

is is usually due to saliva pooling in the back of the throat. You may also

notice that your child is drooling more from his/her mouth. ere are some

medicines that can be used to help dry up the saliva, and an oral Yankar

suction machine can also be helpful; this device is similar to the suction

straw used in your mouth at the dentist oce. Ask your doctor or nurse

practitioner if medicines or a suction machine might help.

• Treat infections: Sometimes antibiotic medicines can help if your child

has a respiratory infection. If your child has a fever, a lot of coughing, or

greenish sputum (coughing up phlegm), he/she may have an infection.

A chest x-ray might be taken to help your doctor or nurse practitioner

diagnose an infection.

• Treat wheezing: If your child has wheezing due to constriction of the

bronchial tubes in the lungs, which can be similar to what a child with

asthma experiences, your doctor or nurse practitioner may prescribe a

nebulizer or inhaler medicines to open up the tubes that go to the lungs to

help your child breathe better.

Elevating the head of the bed or using extra

pillows can help with wheezing, as well as keeping smoke away from your child.

• Check for low blood counts: Hemoglobin carries oxygen around our

bodies. If your child has a low hemoglobin (Hgb) level, he/she may develop

shortness of breath or breathing trouble. If low blood counts are found to

be the cause of the breathing diculties, a blood transfusion can be given.

Seizures

Seizures are uncommon in children with DIPGs; however, sometimes they do

happen. Seizures can look dierent in each child. Some seizures are just mild

twitching or staring spells, while others involve shaking of an arm or leg or full

convulsions. Talk with your health care team and ask them if they think it is likely

your child might experience seizures. If you see any behaviors that are dierent

than normal in your child, ask your health care team if these behaviors might be

related to seizures. If your child has a seizure, the most important thing is to keep

him/her safe. DO NOT put anything in your child's mouth, such as a spoon or

your ngers. DO keep your child safe from things in the area that might hurt

him/her, for instance, move furniture away from your child and keep other people

(except medical help) away. It can be very scary to watch your child have a seizure,

but if you can remember, or ask someone else to remember, write down the time

the seizure started and stopped and what behaviors you saw. is will help your

health care team determine the best treatment for your child. Most seizures can

be controlled with medications.

Sleeping Problems

Certain medications can make it dicult for your child to sleep, especially

steroids. Anxiety and worry can also make it hard for your child to fall asleep

or stay asleep all night. Let your health care team know if your child is having

diculty sleeping. ings you can try to help your child sleep include:

• Having a regular bedtime routine every night.

• Starting quieter activities at least an hour before bedtime to wind down

an active child.

• Having your child take a warm bath or shower before bed.

• Wrapping your child in his/her favorite blanket or cuddling with him/her

before bed.

• Playing quiet, soothing music.

• Avoiding use of bright nightlights.

• Reading your child a story.

• Avoiding giving medications that may cause insomnia (sleeplessness) before

bedtime.

• Avoiding drinks or foods with caeine at least 2 to 3 hours before bedtime.

• Asking your doctor or nurse practitioner if a sleep medication might help.

Other Medical Issues

Your child may have medical devices, such as a central venous access device

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(e.g., Broviac® catheter, Hickman® catheter, PICC line, Port-a-Cath®, Infuse-a-

Port®), a tracheostomy (a surgically created hole through the front of the neck

and into the windpipe), or a ventriculoperitoneal shunt (used to treat brain

swelling). Not every child with a DIPG has these types of medical devices, but

this section will give you some information about the use and care of some of

these devices. ese are only guidelines; you should follow the directions your

health care team gives you about how to care for any medical devices.

is section will also discuss complementary and alternative medicine (CAM).

Please discuss any CAM therapies that you might be considering with your

child’s doctor or nurse practitioner. Some CAM therapies interfere with

chemotherapy and radiation therapy,

so it is very important to let your health

care team know about any supplemental medicines you are using with your child.

Central venous access devices (central lines)

Central venous access devices are longer-term intravenous (IV) lines that can

be very useful for administering chemotherapy, blood product transfusions, IV

uids, total parenteral nutrition (TPN), and drawing blood. ese types of lines

are placed in large veins and the tip of the catheter ends in a large vein, just

above the heart. It is important to know that the catheter is NOT in the heart.

ere are several dierent types of central lines, and the decision about which

type of line is best will depend upon your child’s age, how frequently venous

access is needed, your child's activity level, and the ability of someone to care

for the line at home. e vast majority of children with a DIPG do not need a

central line, or if they do, it is usually for only a short period, such as needing

daily IV access for approximately 6 weeks with anesthesia during radiation

therapy for young children. Several dierent types of central lines are discussed

below. Your doctor or nurse/nurse practitioner is a great resource in helping you

decide if your child needs a central line, and if so, which type is best for your

child. e tips provided in this section are only general recommendations. You

should talk with your child’s nurse to nd out the specic care your hospital

recommends, who is responsible for providing the care, and who will teach you

how to care for the line at home.

Peripherally inserted central catheter (PICC line)

• Use: A PICC line is a more of a temporary line, which is often used for

shorter-term IV needs, such as with radiation therapy or a few weeks of

antibiotic therapy. It can be used to administer IV medications, blood

transfusions, and IV uids. A PICC line can also be used to draw blood.

• How it is placed: A PICC line is usually inserted under sedation or

anesthesia by an interventional radiologist or a surgeon. It is a small, exible

catheter that is usually inserted in the upper arm, with a couple of sutures

(stitches) to hold it in place, and then covered with an adhesive bandage

over the exit site. Part of the line will be external, coming out from the exit

site. e PICC line is usually loosely wrapped with an elastic bandage to

hold the line up out of the way until it is needed.

• Flushing the catheter: A PICC line requires daily ushing of the catheter

with a heparin ush solution, which keeps the blood inside the catheter

from clotting. e heparin ush solution is injected inside the catheter

and will not aect the ability of the blood in the rest of the body to clot.

• Dressing changes: e adhesive dressing over the exit site usually needs

to be changed once a week, or per your hospital's policy, or if the dressing

becomes soiled. Some health care teams recommend changing the dressing

less frequently, or only allowing a trained nurse to change the dressing, so

be sure to check your hospital's policy.

• Restrictions: It is recommended that children with PICC lines NOT swim

or submerge themselves in water (including bathwater). In general, contact

sports are discouraged. e PICC line is the easiest line to accidently pull

out, so you will need to take care to protect the line and teach your child

to protect it while playing or at school. If the PICC line is accidentally

pulled out, hold gauze or another clean bandage over the exit site until it

stops bleeding. Call your child’s doctor or nurse practitioner if the line

comes out and save the line so the doctor or nurse practitioner can be sure

all of the line was pulled out and none remains broken o inside the body.

If it is broken o, the catheter may need to be retrieved through a surgical

procedure.

• Home care: Your child’s nurse will teach you how to care for the PICC line

at home, including how to ush the catheter, how to change the dressing,

and how to administer medications through the PICC line (if needed).

e nurse will also arrange for the supplies that are needed to care for the

PICC line to be delivered to your home, and it is usually possible to have

a home care nurse come to your home for a few visits to help you care for

the PICC line until you are more comfortable doing it on your own.

Broviac® or Hickman® catheter

• Use: A Broviac® or Hickman® catheter is a longer-term central venous

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access device. It can usually stay in from a few months to several years,

as long as it still works. A Broviac® or Hickman® catheter can be used to

administer IV medications, blood transfusions, and IV uids, as well as to

draw blood specimens.

• How it is placed: is type of catheter is usually inserted under sedation

or anesthesia by an interventional radiologist or a surgeon in an operating

room. It is a small exible catheter that is usually inserted in the upper

chest with a couple of sutures (stitches) to initially hold it in place; then

an adhesive bandage is placed over the exit site. Part of the catheter will be

external, coming out from the exit site. is type of catheter is also called

an external tunneled catheter, because the line has a cu made out of a

material called Dacron that helps your child's skin adhere to the catheter

and hold it in place. e surgeon makes an incision in the upper chest and

tunnels the catheter under the skin to the neck, where it is inserted into a

large vein. Generally, the sutures are not removed unless they are irritating

your child's skin or they fall out. Once the Dacron cu is anchored, usually

after about 1 to 2 weeks, it is dicult to accidentally pull it out. is type

of catheter can have one tube or be split into two or three tubes (called

lumens); each lumen requires daily care.

• Flushing the catheter: e catheter requires daily ushing of each lumen

of the catheter with a heparin ush solution, which keeps the blood inside

the catheter from clotting. e heparin ush solution is injected inside

the catheter and will not aect the ability of the blood in the rest of the

body to clot.

• Dressing changes: e adhesive dressing over the exit site needs to be

changed, usually once a week, or as per your hospital's policy, or if the

dressing becomes soiled. Some health care teams recommend changing

the dressing less frequently, or only allowing a trained nurse to change the

dressing, so be sure to check with your hospital's policy.

• Restrictions: Recommendations dier about swimming with a Broviac®

or Hickman® catheter. Check with your doctor or nurse/nurse practitioner

to see if your hospital recommends swimming with these types of central

catheters. Bathing is usually allowed, but the dressing needs to be changed

if it becomes wet. In general, contact sports are discouraged. If the Broviac®

or Hickman® catheter is accidentally pulled out, hold gauze or another clean

bandage over the exit site until it stops bleeding. Call your child’s doctor

or nurse practitioner if the line comes out and save the line so the doctor

or nurse practitioner can be sure all of the line was pulled out and none

remains broken o inside the body. If it is broken o, the catheter may

need to be retrieved through a surgical procedure.

• Home care: Your child’s nurse will teach you how to care for the Broviac® or

Hickman® line at home, including how to ush the catheter, how to change

the dressing, and how to administer medications through the catheter (if

needed). T

he nurse will arrange for supplies that are needed to care for the

Broviac® or Hickman® catheter to be delivered to your home, and it is usually

possible to have a home care nurse come to your home for a few visits to help

you care for the catheter until you are more comfortable doing it yourself.

PORT-A-CATH® or INFUSE-A-PORT®

• Use: A PORT-A-CATH® or INFUSE-A-PORT® (commonly referred to

as a port) is a longer-term central venous access device. It can usually stay

in for months to several years, as long as it still works. A port can be used

to administer IV medications, blood transfusions, and IV uids, as well as

to draw blood specimens.

• How it is placed: A port is usually inserted under sedation or anesthesia

by an interventional radiologist or a surgeon in the operating room. It is a

small, exible catheter with a port that is usually inserted in the upper chest

under the skin. Initially, one or two steristrips (buttery-type bandages) will

be placed over the areas where the port is inserted in the chest and where

the catheter is inserted into a large vein in the neck. is type of catheter

is also called an internal tunneled catheter, because the line is totally inside

the body. e surgeon makes an incision in the upper chest to put in the

port and tunnels the catheter under the skin to the neck where it is inserted

into a large vein. Generally, the steristrips are not removed and will fall o

by themselves with normal bathing. e port does not require the same

care at home as a PICC or Broviac®/Hickman® catheter.

• Flushing the catheter: Because the port is totally under the skin, it requires

a special kind of needle (a Huber needle) to reach the port for venous access.

In some cases, parents can be taught how to access the port, but in general

most of the port care will be done by a nurse. A port requires a heparin

ush once a month, but a ush may be needed more often if your child

receives medicines through the port. e port needle should be changed

once a week, if it is accessed.

• Dressing changes: No routine care is required for the port at home, unless

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the port is accessed. If the port is accessed, the dressing should be changed

once a week with the changing of the port needle. Your nurse or home care

nurse will generally take care of the port.

• Restrictions: Unless the port is accessed, there are generally no restrictions

on swimming or bathing, but contact sports are discouraged.

• Home care: ere is usually no care to provide at home, unless the port

is accessed for medicines. If needed, home care nurses can come to your

home to teach you how to care for the port.

Complementary and Alternative Medicines (CAM)

Complementary and alternative medicines (CAM) are non-traditional

approaches to health care, but they are becoming more widely used in

conjunction with traditional medical care. Some CAM therapies can help your

child be more comfortable, but some can interfere with certain chemotherapies

or radiation therapies, so be sure to check with your health care team before

trying any CAM approaches. Make sure you go to a reputable CAM practitioner.

Check out the qualications and experience of CAM practitioners, just as you

would your doctor or nurse practitioner. Ask your health care team if they

recommend certain practitioners.

Some of these therapies may be provided in your

hospital by nurse practitioners and doctors who have specialized training in CAM.

Some CAM practitioners can come to your home. Examples of CAM include:

• Acupuncture

• Aromatherapy

• Art therapy

• Biofeedback

• Herbal therapies

• Hypnosis

• Massage

• Meditation and prayer

• Music therapy

• Pet therapy

• Play therapy

• Reexology

• Relaxation and guided imagery

• Reiki

• Tai Chi

• erapeutic touch

Practical Care Issues

ere are several other issues that may arise as you take your child home. Some

children have problems with balance and walking, communicating with others,

anxiety or emotional concerns, or central venous catheters or tracheostomy

tubes to care for. is section will discuss how to handle these challenges and

discuss other concerns for managing day-to-day life, such as traveling with your

child and practical tips.

Mobility

Some children with DIPG have ataxia (poor balance) or diculty walking due

to muscle weakness. Physical rehabilitation with physical and occupational

therapy may be very helpful to help strengthen your child, help your child learn

new ways to walk or be mobile with his/her physical challenges, and help you

to learn how to safely manage your child at home. Ask your doctor or nurse

practitioner to recommend a physical medicine and rehabilitation (PM&R)

doctor for an evaluation to help plan the best therapy approach for your child.

Inpatient rehabilitation services may be helpful, and outpatient or in home

services may be available.

Younger children can be carried, but it is helpful to have a good stroller for

longer distances. Remember that your child will grow, and the stroller you

had when he/she was an infant or small toddler may not be safe for him/her

as he/she grows. You will want to have a sturdy stroller to hold any additional

equipment or supplies your child might need. ere are several companies

that make heavy-duty strollers for medically fragile children. Ask your nurse

or social worker to help you nd the most appropriate stroller for your young

child. Some insurance companies will pay for this as a medical expense.

Older children may benet from having a wheelchair. Wheelchairs come in

many dierent sizes, so there is one that is the right size for your child. Ask

your doctor or nurse/nurse practitioner if they think a wheelchair might help

your child be able to move around better. Many parents feel a wheelchair is very

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helpful because they can take their child outside and to places they like to visit.

Mobility concerns are not just related to walking or transportation from one

place to another. Your child may also have diculty standing or sitting, which

can impact daily activities such as taking a bath or shower, watching TV or

playing games, or even going to the bathroom. Discuss with your nurse/nurse

practitioner what strategies you can use to help your child manage his daily life.

Rehabilitation with physical and occupational therapy may improve strength

and balance so your child is able to do more things independently, but in the

meantime you may nd some assistive equipment particularly helpful. e

PM&R team may have even more suggestions, but some practical items to

consider are a shower or bath chair, rails on bathtubs or showers, walkers, canes

(there are many dierent types), hospital beds at home, and bedside toilets.

You

may want to consider moving your child's bed to a location in your house that

is easier for him/her to manage. For example, you can place the bed in a location

where your child does not need to go up or down stairs, or you can place it closer

to a bathroom.

Handicap parking permits

It may be possible for you to get temporary handicap parking tags or a placard

for your car to help you park closer to the hospital and other places you take

your child. is is particularly helpful if your child has impaired mobility. You

can obtain an application for handicap parking from your state Department

of Motor Vehicle Administration. Many applications are also available online.

ere is a section for you to ll out with the information about your car and

there is a section for your doctor or nurse practitioner to ll out to verify that

handicap parking permits are appropriate for you. Usually a temporary permit

is valid for 6 months but can easily be renewed. A placard is a good option if

you drive multiple cars, because it can be moved between cars.

Travel tips

Traveling with children can be challenging for any parent, but it may seem

overwhelming when you have an ill child. Travel is generally quite safe and your

doctor or nurse/nurse practitioner can help you nd ways to make things easier.

e following are some helpful tips that might help traveling go a bit smoother.

• Have the name, address, and phone number of a local hospital in the area

where you will be traveling, just in case your child needs medical attention.

• Ask your doctor or nurse practitioner to write a letter that summarizes

your child's history, the current treatment and medications your child

is taking, and how to contact him or her in case of an emergency. is

can be helpful in case you have to go to a local emergency room or visit a

doctor while you are traveling. If your child requires opiate medications

or injectable medications and you will need to carry syringes and needles,

ask your doctor or nurse practitioner to write a letter of medical necessity

for you to hand carry during air travel.

• If ying, take extra medications with you and pack at least a few days’ worth

in your carry-on luggage in case your luggage gets lost. If medication needs

to be refrigerated, remember to take cooler packs and notify ight attendants

that you need to refrigerate medications if it is a long trip.

• Call the airline, train, or bus company in advance and let them know

about your child's special needs. Ask for seats that have extra leg room.

Also let them know if your child has a wheelchair, walker, or other medical

equipment. When you arrive at the airport (or train or bus station), check

in early and again remind the attendants of any special needs your child has.

• If your child has other medication equipment (e.g., suction machine,

oxygen, feeding pump), ask your nurse or social worker if there is a way

to have this equipment supplied in the location where you are traveling so

you don’t have to carry all the extra equipment with you. Sometimes this

is not possible, so arrangements can be made to transport your equipment

with you as needed.

• Plan activities during the part of the day when your child usually feels best.

If your child needs to rest frequently, remember this and build that time

into your daily vacation plans.

• Plan your meals around your child's special dietary needs, if they have any.

• If possible, take an extra person with you to help with the logistics of travel.

• Keep things simple! Many family vacations create wonderful memories, but

not if everyone is stressed.

Build in time to relax and take things slowly so your

child does not become overly tired. Cranky children are no fun to travel with.

• Consider having friends and family travel to you. If travel is being planned

to visit relatives and friends it might be less cumbersome for your child and

family if visitors travel to you.

Communication Challenges

Many children with DIPG have trouble communicating at points during their

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treatment. ese communication problems can stem from many causes such

as: swelling from the tumor, weak muscles in the neck that help the tongue

and mouth to form letters, or from the tumor irritating or damaging certain

cranial nerves that control the vocal cords. Some children with DIPG have

speech that is dicult to understand. Speech therapy may help. Children may

recover their speech over time if loss of speech is due to a reversible cause, such

as swelling. Sometimes speech does not improve much, even with therapy. is

can be quite frustrating for you and your child. Remember to be patient and

let your child have extra time to try to communicate with you. Here are some

helpful hints to improve communication.

• Speech therapy: Ask your doctor or nurse practitioner if he or she thinks

speech therapy would be helpful and, if so, to help you arrange the therapy.

• Picture boards: Your speech therapist can help you make a picture board

to identify common things that your child may be trying to communicate.

You can also do this as a family project. Find pictures in magazines, print

pictures from online, or draw pictures of common things your child may

want to communicate, such as being hungry/wanting food, being thirsty/

wanting a drink, wanting to go to bed, wanting to go to the bathroom,

wanting to play, wanting to watch TV or a DVD movie, having pain,

feeling nauseated, etc. Some speech therapists have picture boards that are

already made for dierent ages of children. You can teach your child to point

to the picture of what he/she is trying to communicate. ere is an iPad

application (app) called Picture Board that is available for free download

from the Apple store.

• Voice communication devices: ere are computer programs or hand-held

electronic devices that allow your child to push a picture of what they want

and the computer "speaks" the word or phrase. ese may not be available

in your hospital, but you can ask about ways to order them. ere is a useful

iPad application (app) that can be downloaded for free called “Talk Assist”

for those children who can type text that is then converted to speech; and

another free application called “Small Talk, Conversational Phrases,” which

provides a vocabulary of pictures that subsequently talk in a human voice.

• Pencil and paper: Have pencils (or markers or crayons) and paper readily

available for your child to write down what he/she is trying to communicate.

Save the common cards so they can be used over again. If your child cannot

write but can read, consider writing common phrases out on 5 x 8 cards for

your child to use to communicate what he/she needs or wants.

• Take your time and allow your child to take their time: Diculty

communicating is very frustrating for most children. Try not to rush your

child or ask him/her over and over to repeat what he/she is trying to say.

Begin to use picture boards or the written cards early, when your child is

not having much diculty communicating, so that it is natural to him/

her when he/she is no longer able to speak clearly.

Chapter 12 in this book provides additional information on the communication

needs of the child diagnosed with a DIPG.

Other Helpful Tips

Other challenges may arise that are not anticipated. Every child and every

family is special and may have special needs. Ask your health care team about

any issues that have not been mentioned here. In addition, here are a few things

to consider.

• Clothing: Your child may gain weight or lose weight as a result of

treatments. Some children develop sensitive skin, where some fabrics are

irritating. Have a supply of loose-tting clothing that is easy to get on and

easy to remove. If your child has muscle weakness or is not able to stand,

he/she may not be able to dress himself/herself like he/she used to. Clothing

with elastic around the neck and leg openings is particularly helpful. You

may also need to have several sizes of clothing available for times when

your child gains or loses weight. Buying new clothing can be expensive,

especially when your child may not be the same size for any length of time.

Consider visiting second-hand or discount clothing stores to get basic items

and save more expensive clothing purchases for special occasions. If family

and friends ask how they can help, consider asking them to provide gift

cards for clothing stores that your child might like.

• Financial worries: e costs of treatment and medical equipment can

be substantial, even if you have great insurance coverage. Most insurance

companies do not pay for everything your child will need. Anticipate out-

of-pocket costs and try to budget for them, if possible. Ask your social

worker if your child might qualify for Supplemental Social Security Income

(SSI) or other possible sources of additional funding to help with some of

the costs. Consider letting family and friends who are asking what they

can do for you, to help with fundraising events to raise money for these

unanticipated medical and personal expenses. In addition, many hospitals

charge for parking and meals in the hospital’s cafeteria and these can add

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up after a while. Extra funds can come in handy for these types of expenses,

which are usually not covered by insurance.

• Durable medical equipment: Equipment that your child needs is called

durable medical equipment (DME). It is important to know this term,

because this is how benets for payment of equipment are determined by

your insurance company. Your nurse should review any equipment that your

child might need at home, but most equipment is provided by an outside

company that your insurance company recommends. e equipment that is

used in the hospital may dier slightly from what is delivered to your home.

Make sure you are given instructions about how to use the equipment,

how to troubleshoot common problems, who to call 24 hours a day in an

emergency, and who to call when you have routine questions. You should

also ask to have a home care nurse come for a few visits to help you learn

how to use any DME. If the equipment company does not provide a set of

written instructions for each piece of equipment, ask for them. Keep this

information in a binder or notebook in a place that is easily accessible to

anyone who might be caring for your child. Be sure to put the emergency

phone numbers for each company that provides DME in the beginning of

the notebook or in a place that can be found quickly, if needed.

Making Dicult Decisions

Your child has a rare and challenging tumor and many dicult decisions will

have to be made along the way. It is helpful to have conversations about the

dierent types of situations that may come up before they actually do; that way

your family and your child (if he/she is old enough to help make decisions about

his/her health) will be able to talk about these situations openly and honestly.

Some of these decisions may be dicult to talk about, so talking about them

early, when there is no urgency, can make it easier if the need arises to make

urgent decisions. Your social worker will be a wonderful resource to help you,

your family, and your child talk together about dicult decisions. ese are

some helpful tips about making dicult decisions.

• Honesty: Have open discussions with your family and your child (if he/

she is old enough to understand and participate in decisions about his/her

health) about your child's diagnosis of DIPG and what the prognosis is,

according to your doctor or nurse practitioner. Most children are thinking

about these things, even if they are not talking about them. Sometimes

your child's imagination may be worse than reality, so talking about what

may or may not be happening will actually help him/her worry less. Be

honest and do not lie to your child. Children are usually very good about

guring out when parents are lying to them.

• Hope for the best and prepare for the worst: Your health care team is

working very hard to treat the DIPG and help your child. ey may or may

not have given you statistics about cure rates and/or relapse rates for DIPG.

However, statistics really do not mean a thing, because for your one child,

there will either be a 100% cure or not. Try not to let statistics keep you

from enjoying life in the moment. Enjoy every day with your child. Keep

your hopes up that your child will be that 100%, but talk with your health

care team about what to expect if your child does not survive the DIPG.

• Five Wishes™ or My Wishes™ or Go Wish™ Cards: Some children and

families nd it hard to talk about making dicult decisions and/or facing

end-of-life care decisions. Be sure to talk with your social worker about

your concerns.You may also nd it helpful to talk with a counselor or

psychologist. Several other tools can also help you with these conversations,

such as Five Wishes™ and My Wishes™, which are decision-making tools.

Five Wishes™ is a set of questions for older children, adolescents, and

young adults, and My Wishes™ is better suited for younger children

or developmentally delayed children. ese tools have several dierent

questions about who your child might want to make decisions for him/her

if he/she is not able to, and other health care decisions he/she might want

people to know about. Go Wish™ Cards are like playing cards that have

phrases about health care decisions written on them. Ask your health care

team if you can have a copy of these tools to use at home. Your local hospital

might use other tools that are equally as good as the ones mentioned here.

• Other books and pamphlets: Several wonderful books are available to

help you with making dicult decisions. Ask your health care team to

recommend some of these to you. ere is also a list of books in the appendix

at the back of this book that you might nd helpful as well.

While the journey through DIPG treatment can be physically and emotionally

challenging for both you and your child, the advice listed in this chapter can

help you feel more prepared to care for your child at home. Remember that

your health care team is there to support you through this dicult time, as

are parent support groups led by others who have walked the same path your

family is now walking. Reach out and ask for the help you need to best care

for your child with DIPG.

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Parent Perspectives

I didn't understand all that would be involved in Andrew's care at home until

we left the hospital. There were medications to dispense. He could not be

left alone for extended periods of time as he was very unstable. If he was

in his hospital bed or strapped into his wheelchair, we could leave him for

a short time—as long as we were close enough to hear him if he needed

us. He could not walk or get down on the floor without our help. He also

needed help with bathing and toileting. In the hospital we had people to

help with all of these different things. At home we were on our own. This

did not change how we felt about having him home; it just made being home

very different from what that meant before he was diagnosed with DIPG.



Stella eats very little and requires liquids to be thickened to enable her

to swallow them. Her diet at the moment consists of avocados, mashed

potatoes, apple sauce, hamburgers, ice cream and milk. Since October

she has been incapable of sitting up unassisted, and as of December she

is unable to hold her head up without support. She drools constantly and

has begun to suffer from seizures.



When our son was diagnosed with DIPG, each of our lives were impacted

in some way. While he bore the physical effects of the tumor itself, each of

us were changed because of it. As we lost the child we knew to steroids—

not once, but twice—we grew to understand that the real boy we knew was

not the body we saw with our eyes, but the soul we loved with our hearts.



I am a single parent and had to care for Warren alone. Warren’s dad would

take him on the weekends so that gave me a much needed break. I also had

family and friends that would watch Warren when I needed to go to the

store or something, but Warren didn’t want me to leave him so I naturally

tried not to.

I took a leave from work after Warren was diagnosed. I live in income-based

housing so that worked in my favor. Even with all that, I had no way to pay

other bills and pay for gas to get us back and forth to the doctor and such.

Then our community stepped in and helped out with fundraisers and such.

The people around where I live were so wonderful and caring and because

of them I didn’t have to worry about paying the bills.



From the beginning, I believed that complimentary care was an integral

aspect to Alexis’ overall treatment, and medical plan. In our initial

discussions with Alexis’ treatment team, it was important to discuss

complimentary care. From those first few moments we landed headlong

in the childhood cancer community, we were given the proverbial “green-

light” to use supplements as long as we cleared them with the team first.

Initially, we had a minor debate regarding the use of antioxidants. The

conventional wisdom of the past suggested that the use of antioxidants

could negatively impact the efficacy of radiation. After doing research on

the topic, I was able to demonstrate that this in fact was nothing more than

anecdotal information. We quickly began consulting with a nutritionist that

many other pediatric and adult brain tumor patients worked with. Whether

the use of supplements and the complimentary care had any impact upon

Alexis’ overall course we ultimately will never know of course. I certainly

would like to think that it did. For around twenty months of Alexis’ battle,

from sun-up to sun-down, Alexis willingly took approximately twenty

different natural supplements and vitamins. I tasted everything prior to

administering them to her. Some were simply awful so we devised strategies

for getting them into her. In the end, Alexis took everything like a trooper.



It seems to be taking more effort for our son to chew and to form words. So

he is not chewing things as well as he was last week, and he is choosing not

to use his words as much as he normally does. (I need to throw in here though

that he uses his words quite loudly and clearly when he wants me and I'm

not responding quickly enough!) He has been vomiting periodically—almost

always later in the day. This has become more of a problem over the past

week, so there has been some concern regarding nutrition. The vomiting

is believed to be a gastrointestinal issue rather than a neurological issue,

and a scope this afternoon did show delayed gastric emptying. We have

made some medication changes and some food changes, and have begun

using an NG tube for supplemental nutrition.

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

AmbuCab arrives about 7:15 a.m. on dressing change mornings. By the time

we load and unload, we end up at the hospital by 8:00 a.m. The AmbuCab

driver pushes my son to the fourth floor while I push another wheelchair

piled high with our stuff (dressing change supplies; his Bi-PAP; a backpack

filled with a change of clothes, medications, and other necessary things;

my purse, and my laptop). We arrive and I begin to arrange the room in

preparation for the big event. Shortly before 9:00 a.m. I set up the Bi-PAP

for use while my son is under sedation. A nurse or tech prepares him by

attaching electrodes to his chest to monitor vital signs. The wound team

arrives to open dressing change supplies, and the intensivist arrives to

administer propofol for sedation. By 9:00 a.m. the tiny room is full with at

least five people, and the dressing change begins. Someone from phlebotomy

arrives just after 9:00 a.m. to draw blood, and someone from the I.V. team

still comes on Mondays to change the needle in the port. We have noticed

that the dressing changes are getting shorter and that we are using fewer

supplies. The few wounds that remain are clean and steadily improving,

and my son now rarely experiences pain.



Caleb was not able to eat and I was worried he would be hungry. He hated

being hungry. So, they put in an NG tube and kept food going into his tummy

to make sure he would not ever feel hungry. He was restless at times and we

had valium on request. If he indicated pain, we had morphine on request.

He was still able to get up (with assistance) to use the bathroom, sit in a

chair, watch TV. He could not talk very well but we developed methods of

communication during those days—first with hand signals, then with eye

movements.



To help control her eating we implemented the use of a timer and a second

hand clock that would show time running down using color. When either

thing beeped Peyton knew it was snack time. We would get sneaky once in

a while and add more time to the timer when she wasn't looking. We also

provided little snacks and made sure we had an activity planned for after

snack so she would be focused on something else. Sometimes I made stuff

up like, "Oh we are out of butter to make cookies." Distractions help.



On a side note one of the best things we did during our daughter's illness

was strabismus surgery. It fixed her eyes, hence eliminating the need

for blacking out one lens of her glasses. Most importantly, it gave her

confidence, made her feel better, and gave her a sense of accomplishment.



We are settling into a routine at home—though we are still in limbo in some

ways. Our living room looks like a Pediatric Intensive Care Unit, with the

focal point being our son's hospital bed. We've done our best to organize

so that the medical equipment and supplies are easily accessible, but not

obvious to the casual observer. We are set up to use oxygen; to administer

I.V. fluids and medications; to take care of wound care and our son’s port;

to monitor oxygen saturation, blood pressure, heart rate and temperature;

to use Bi-PAP and suction. We find ourselves using Bi-PAP and oxygen only

when he sleeps; he has not required suctioning since he had a cold in early

July. We do administer I.V. medications and fluids daily as there is question

regarding his ability to absorb oral medications and fluids.



We met with the neurosurgeon, who explained that surgery was not possible,

nor was a biopsy because of the location. She answered questions that we

had written down, and ultimately told us that other children who had this

tumor did not survive. When we asked how long Bryce had, we were told

that with treatment, these children typically had “more or less than a year.”

I remember looking at my husband, and saying that one year was going to

go too fast. And I remember looking at the doctor and doing what I now

call the most important thing that helped us to live through this. I asked

her to hook us up with anyone and everyone who could support us through

this—psychologists, social workers, doctors, whomever. And she did. We

thank her every day for that.



We were told to talk about everything that was important, and about

what was coming, so that we could be sure that we had those important

conversations before speech became an issue, as it typically did with DIPG.

That’s not to say that we didn’t continue to research, to check out a trial

offered in Toronto, or search the world over for a cure. But we also decided

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at that point that if the treatment available would not allow Bryce to LIVE

the way he chose to every day, then we would respect that. He was 13, and

at that point he had already voiced that he did not want surgery, or to have

chemo because he was afraid of having a port put in. So because nothing

was curative, we did not have to try to change his mind.

We went back home. The thing that became obvious over the next few weeks

was that Bryce just wanted to go back to school, to a regular routine, and

to be a regular kid. He didn’t want to be in the spotlight, babied, coddled,

or have all of the attention that others wanted to give him. He even went

on his Grade 8 graduation trip. And not until months later, did he know

that we were also in Cleveland that day, just in case something happened

and he needed to be rushed home. Thankfully, he never needed to know.

Bryce’s progression surprised everyone because the doctors thought that

if the onset of new symptoms were swift, that Bryce would only survive a

very short time. He, however, actually survived for two months after his

progression date. Over that time, he also developed pain—neuropathic

pain—in his knees, and feet. We tried everything—massage, ice, heat,

arnica cream, A535, Reiki, Dilaudid. Nothing gave him much relief. And

we had to step up and become his advocates with everyone—medical staff

and visitors to make sure that his wishes were met. That was no small feat.



At first eating wasn’t much of an issue. For most of the time Warren could

feed himself, but would need a little assistance. As he started to struggle

I had him eat softer foods like mashed potatoes and I pureed things in the

blender. His biggest problem was he couldn’t get his mouth open very wide so

getting food in was difficult. I had to buy smaller spoons and deeper spoons

so he could get a decent bite. He also could only drink using a straw. The

straw had to be placed in the right side of his lips or he couldn’t get a drink.

Meal time took about an hour. Warren would eat in his "stander"—a big

wooden device that I strapped him into. He was in a standing position

and there was a tray in front for games and food and such. Sometimes he

would sit on the floor but he couldn’t hold himself up so I had to prop him

up against the couch and slide our coffee table over him so he was stuck

in between. I then had to put pillows on either side of him to keep him from

falling over. Once Warren started taking steroids he wanted to eat more

often, so rapidly began growing out of his clothes. I had to buy all new

pants (with elastic bands), shirts, underwear and jammies.



We bathe Andrew and dress him daily. We move him—by Hoyer lift—from

bed to wheelchair and from wheelchair to bed several times on any given

day. We do our best to keep his hands busy because the more he uses them,

the better. He enjoys shooting various Nerf guns at targets we hang from

his Hoyer lift. (He also enjoys "shooting" at his brother!) Andrew has

physical therapy at home three times each week. We do our best to guard

that precious time with his therapists and to work with him ourselves—-as

time allows—on other days.



Long shirts that look like dresses were awesome for our daughter. Paired

with stretchy leggings; it was a good thing. All the name brand stores had a

wonderful selection of different colored leggings. We didn't want Peyton to

feel constricted in her clothes, so I usually bought the next size up as well.



I was stunned. Sick. I was left alone in a room in the PICU to take care

of my very sick daughter while also trying to accept the fact that I would

have to watch her die. My brain tried to reject the concept like my stomach

would reject tainted food. At that point, I shut down. I let the doctors know

that they should only talk to Joe, not to me. I could not handle it. I was

struggling to keep myself from letting the panic and disbelief take over. I

couldn’t eat. I couldn’t sleep. I didn’t know what to do with myself. One

thing I did know. No matter what I was feeling, I had to get over it and be

there for Bizzie. So I did…somehow.



Our families reacted much how we suspected they would—with tears of

course, but with tremendous support and strength as well. We are certain

many other emotions were felt privately but in our presence and in the

presence of our children there was nothing but complete strength displayed.

Everyone spoke honestly about Liam's illness; however in those early days

we made a decision that we would not tell our kids or Liam about the course

this disease generally takes. Their little hearts were already burdened with

so much. As Liam's condition improved or declined we had honest age-

appropriate discussions at every step. Our kids were a tremendous help to us

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and to Liam. We included them as much as we could in his care. Our oldest

child, then in third grade, would read to him; his twin brother "assisted"

me with dressing changes and his little brother, only three, came to every

day of radiation and every clinic visit. But mostly and most importantly

they continued to play and treat Liam as they always had. Liam loved this.

He did not want to be different. It was a wonderful gift they gave to him.



On April 1st, my son was admitted into hospice care. With my nursing

background, hospice acted in his case more as a sounding board for us

as we did all of his care ourselves. In crisis moments they helped with

medication calculations, gave suggestions on meds that might help ease

his pain and they offered a wide range of therapies. He enjoyed Reiki and

therapeutic touch. He received weekly visits from therapy dogs. This was

such a blessing for a little boy who had a strong and special connection with

animals. We had artists who are friends and teachers to our other children

come and do art projects with our kids and at one point near the end of our

son’s journey a friend came with his guitar, invited all the neighborhood

kids to come and they sang songs together. It was a beautiful afternoon.



Brendan welcomed the idea to have an NG tube, then G-tube then "Micky"

button so we could deliver meds and nutrition easily. He felt better when

he could get meds without choking and nutrition without having to chew

and swallow. Keeping him hydrated and fed was key to keeping him strong

and enjoying a good quality of life especially when the chemo caused GI

issues and he lost his appetite.



A few weeks later, Aimee woke with a severe headache, and was partially

paralyzed on the right side. When I called her new doctors, they put her

back on the dexamethasone. I also began her on a drink I heard about from

another mother whose child also had a brain tumor. The drink was called

Vemma, which is made from the Mangosteen fruit. Once she began taking

the Vemma she regained full strength on her right side.

Aimee was doing well since she began the Vemma, so she demanded to

return to school in September. She was entering the 7th grade in a brand

new school in a new state and knew no one in her class. I personally did

not want her to attend but she felt it was something she needed to do. A

few days after school started I found a letter that she had written to her

classmates.

"Hi, I am Aimee. I am 12 years old, and I am just like you. I love reading,

music, go-kart racing, cheerleading and making crafts. Yes, I may be

sitting in a wheelchair, and my face may look funny and talk funny, but

please don’t be afraid of me because you cannot catch what I have. I have

a brain tumor and the doctors say I am going to die. But I just want to be

as normal as possible, just like you. So please don’t be afraid of me. I am

not afraid of you even when you make fun of me. I will still be your friend,

so can you please be mine."



We were very busy. My son had his radiation done an hour and half from

our house. So while he was doing radiation we would get up about 7:30

or 8:00 a.m., have breakfast, go to physical therapy and/or occupational

therapy for 1 to 2 hours. We'd then go home and have lunch and rest and

play, then leave about 3:00 p.m. for a 5:00 p.m. or 6:00 p.m. radiation

appointment. We would be there for 30 minutes or so then would drive back

home. We would get home about 7:00 p.m. or 8:00 p.m., eat if we hadn’t

already, and take a bath when needed or felt like it. Then we would go to

bed because Warren would be tired.

If we had a doctor’s appointment then we would skip physiotherapy and

occupational therapy and drive the 3 ½ hours to the doctor, then stop on

the way back home to have radiation if it was scheduled.

My son didn’t go back to school after diagnosis because we were too busy

with radiation and such and after that I just wanted him home. He couldn’t

write or walk and had a hard time speaking and would have had to have

constant care with feeding and going to the bathroom.



By April he began to require the use of narcotics to manage pain as a result

of steroid-induced skin breakdown. Just before he was transferred to PICU

on April 9th, he was placed on a continuous drip. As we began to prepare to

go home in May, the importance of oral (as opposed to I.V.) medications was

discussed, and he was slowly switched from Fentanyl (by I.V.) to Methadone

(by mouth). He was on such a small amount of Methadone that we began

Chapter 11: Caring for Your Child at Home

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to wean him off the medication completely last weekend. We noticed that

he did not seem well, but it was not until Tuesday that we began to realize

it was the lack of Methadone that was causing him to feel miserable.

We discussed the way our son was feeling with his doctor that afternoon, and

she made the decision to put him back on Methadone. When he received a

bit of fast-acting morphine to help him until the Methadone had opportunity

to take effect, it was almost immediately as if we had flipped a switch. He

went suddenly from misery to contentment. One moment he was telling us

repeatedly that he could not get comfortable; the next moment he turned

into a chatterbox...with a smile on his face.

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Chapter 12: When a Child Can No Longer Speak

Chapter 12

Communication: When

a Child Can No Longer

Speak

David Brownstone, MSW, RSW

Caelyn Kaise, MHSc, SLP(C), Reg.CASLPO

Ceilidh Eaton Russell, CCLS, MSc (candidate)

Supporting a child or teenager who has a brain tumor is an incredibly important

and dicult job. And trying to help them understand and live with their changing

abilities can be overwhelming, especially when caregivers naturally struggle with

these changes themselves. e situation is also a challenge because while a child’s

physical abilities to communicate—including the ability to produce speech and

to express thoughts and feelings—can change, cognitive abilities often stay intact.

So if a child or teenager has trouble communicating because of a brain tumor,

the task of supporting them becomes even more complex.

Family members and caregivers who have been in this situation often express that

they did not know what to do or where to start, and they often felt helpless and

frustrated. But in the end they did it. With time, patience, creativity, and support,

families nd ways to communicate with their children and teenagers with brain

tumors, even though these young patients had, or have, trouble speaking.

is chapter includes “lessons learned” from talking with 14 families about their

experiences, as well as our team’s experiences working with families of children

with brain tumors. (Note: Our team only

interviewed families of patients younger than

age 13 and our examples reect this. While

the examples may not be relevant to teens, as

many issues and struggles are unique to that

age group, the communication strategies are

similar and can be adapted for teens.)

David Brownstone is a Social

Worker with the Brain Tumor

Program and an Academic

and Clinical Specialist in the

Department of Social Work at

the Hospital for Sick Children in

Toronto, Canada.

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e parents we spoke with generously shared the creative strategies and tools they

developed, the most important conversations they had, and the most important

lessons they learned. When we began to talk with these parents, our goal was to

develop a new communication tool, yet they taught us that although tools are

helpful, in the end, direct communication is more valued and helpful. Families

encouraged us to share strategies and resources with families like yours so that

others facing this stage of brain tumors will have ideas about where to start, what

to try, and know that they—and you—are not alone.

Of course every family and every child is unique, each with their own values,

philosophies, experiences, and backgrounds. Some of your family’s experiences

may be very dierent from those of the families we interviewed. However, some

of the situations they faced or the strategies they tried may be similar to yours

or helpful to you. We encourage you to think about the ideas outlined in this

chapter and to use or modify them so they work for your family and are well

suited to your child’s age and developmental stage.

Most of all, the families we talked to and the members of our team sincerely hope

that sharing this information will help you and your family feel, at the very least,

a little more prepared and supported during this dicult time.

Quick Tips

To help you focus on how to approach and enhance communication with your

child, here are a few quick tips to think about.

• Practice communication strategies before your child needs to use them.

• Practice more than one signal for “yes;” no response can be used to mean

“no.”

• Start by asking broad questions, and then ask more and more specic questions

as you get an idea as to what your child is thinking about or wanting to say.

• Use simple sentences to get to the main point. For example, ask “Are you

hungry?” instead of “Do you want something for dinner?” Remember the “KIS”

principle: “Keep It Simple.”

• Remind your child what the “yes” signal is before asking each question.

• Wait longer than usual for your child to

respond.

• If your child has a hard time responding,

repeat the question or simplify it. For

example, if you’ve asked “Are you hungry?” simplify by saying, “Hungry?”

• To make sure your child’s message is understood correctly, repeat what you think

he said. For example, “Okay, you are hungry,” or “So you’re not hungry.” is

gives your child a chance to conrm that his message was interpreted correctly.

• Be patient with yourself, your child, and the process.

• When exploring emotional issues, ensure that you understand your child’s

unique perspective rather than thinking about it only from an adult perspective.

In other words, focus on how your child is thinking and feeling, not how you

would think or feel in the same situation.

Communication

Preparing for the unexpected

It is hard to prepare for something when you don’t know what to expect. Brain

tumors aect children’s abilities in dierent ways at dierent times, but some

changes are more common than others and can be anticipated. For example,

speech often starts sounding slurred and can be dicult to understand due

to weakness or diculty coordinating the lips, tongue, and jaw. Children’s

abilities to use their arms and hands may also become compromised, making

it dicult for them to write, draw, or point.

Regardless of the kinds of diculties children with diuse intrinsic pontine

gliomas (DIPGs) have, the parents we interviewed agreed that two important

strategies helped maximize communication with them.

1. Learn and practice ways your child can communicate without speech

before your child needs to use them. is is not always easy. Children

can be reluctant to use communication strategies before they absolutely

have to, and parents and children often do not want to think about a

time when these strategies will be necessary. is reticence is natural

and understandable. However, the patience and concentration that are

needed to learn a new skill may not be present once your child’s energy

and abilities are declining.

2. Practice more than one way of

communicating without words. is

way, if some of your child’s abilities

change in an unexpected way, she

can continue to communicate using

Caelyn Kaise is a Speech-

language Pathologist with the

Brain Tumor Program at the

Hospital for Sick Children in

Toronto, Canada.

Ceilidh Eaton Russell is a Child

Life Specialist with the Max and

Beatrice Wolfe Children’s Centre

at the Temmy Latner Centre for

Palliative Care, and a Researcher

at the Hospital for Sick Children in

Toronto, Canada.

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Chapter 12: When a Child Can No Longer Speak

another familiar means. When practicing other ways to communicate,

it is often useful to nd a way to adapt a current communication tool or

technique to suit your child’s changing abilities rather than switching to

a brand new system. By adapting a strategy that children and families are

more familiar with, their experiences serve as “practice” and they may feel

more comfortable and condent in their abilities to use it.

In this chapter, we present some concrete examples of communication tools

and strategies to use with children who have a DIPG. is is in no way an

exhaustive list, but it serves as a stepping stone to understand how to maximize

communication.

Dierent ways to ask questions

Two techniques that are very useful when helping children express a wide

range of messages are:

1. Oering two clear choices.

2. Asking questions that can be answered with a “yes” or “no.”

ese techniques require you to ask clear and carefully worded questions and

will take thought and practice.

Oering two clear choices

No matter what a child’s functional ability is, he/she is likely to be able to

choose between two things, whether by pointing at or by looking at dierent

objects. It is important to clearly tell your child what the two choices are and

then ask your child to show you which one he wants.

For example: A parent can hold chocolate milk in one hand and juice in the

other. After showing them to the child and saying what is in each hand, the

parent then asks the child which one he/she would like, reminding him/her

to point or look at the drink he/she wants. Once the child has made a choice,

the parent should double-check by asking, “Do you mean that you want the

juice?” then wait for him/her to show that he/she means “Yes.”

When a child is choosing between two things that you cannot show him/her,

try asking a series of questions to nd out what he/she wants. For example:

1. “I wonder if you would rather go for a walk or take a bath?”

2. “I’ll ask you about one thing at a time, and then I’ll wait after each one

in case you want to say “yes.”

3. “So, want to go for a walk?” After asking this question, pause for at least

10 seconds.

4. If your child does not respond, say, “Okay. Want to take a bath?”

It may take your child longer than usual to make a choice, so remember to

wait for a response. If your child does not respond, here are a few things to try.

1. Ask if he/she needs you to remind him/her of the signal for “yes.”

2. Ask if he/she needs you to remind him/her, what the options are, then

wait for him/her to respond. If he/she says “yes,” repeat the series of

questions above and wait for his/her response.

3. Ask if he/she does not want either of the choices that were oered, and

wait for him/her to respond. If he/she says “yes,” try to think of other

options he/she may prefer.

Oering choices helps children feel like they have some control. Although

with this method it can take a long time to nd out what your child wants,

it is usually worth the extra eort.

Using “Yes” or “No” questions

Even when it’s very dicult for children to choose between two things,

caregivers can help them express themselves by asking questions that can be

answered with a simple “yes” or “no.” is is a technique that can be used

with a wide range of other communication tools and techniques and a method

that will come up numerous times throughout this chapter.

Children can show they mean “yes” in a range of ways, including:

• Nodding their heads.

• Giving a “thumbs up.”

• Wiggling a nger up and down.

• Raising their eyebrows.

• Looking up (like nodding with their eyes).

• Wrinkling their nose.

• Wiggling their toes or moving a foot.

**Remember to practice more than one signal for “yes!”

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Any part of the body that the child can control can be used as a signal for

“yes.” Instead of making a second signal for “no,” it is easier to assume

that if the child doesn’t say “yes,” he means “no.” is creates less confusion

about which signal to use for which word. When practicing this technique,

ask your child to choose a couple of signals, then ask him/her ve “yes” or

“no” questions that you know the answers to and make sure your answers

match his/her signals. If they match, you’re ready to start!

Some questions may have more than one meaning, so it is very important to

ask in a way that is clear and direct. For example, asking your child, “How are

you feeling?” can be confusing, because it could refer to physical or emotional

“feelings.” Instead be specic; ask “Are you sad?” or “Does your body feel

okay?” is allows your child to respond with a clear “yes” or “no.”

When there are fewer clues about what your child wants or needs, start

by asking broad questions, then ask more and more specic questions

based on your child’s responses. For example, if your child seemed upset you

could start by asking, “Is something bothering you?” If the answer is “yes,”

you can ask more specic questions one at a time until she says “yes” again.

e following is an example of a progressive series of questions.

1. “Is it something in your body that’s bothering you?”

•Ifshe says “yes,” ask, “Isityourhead?”or “Isit yourstomach?”

continuing to ask about dierent body parts until she says “yes.”

Remember to pause after each question to wait for a response.

o Once your child says “yes” about a particular body part, ask,

“Is it sore?” “Is it itchy?” or “Is it hot?” etc.

If he/she does not say “yes” to any part of the body, say “Okay, maybe it’s not

something in your body that’s bothering you. Are you feeling upset about

something?” If he/she says, “yes,” ask questions about specic feelings, such as,

“Are you sad? Are you feeling frustrated?” until he/she says “yes” to something.

If your child does not say “yes,” try asking, “Is it something you’re thinking

about?” or “Are you worried about something?”

is example illustrates that it is often easier to know what to ask when the

topic is concrete, such as physical sensations or nding out what a child

wants to do. Talking about more abstract concepts, such as emotions and

ideas can be much more complicated because there are many more possible

questions. Because of this, you will need to ask a lot more questions when

discussing these topics.

If you continue to ask questions without being able to gure out what your

child wants and he/she becomes frustrated, it is good to talk with your child

and explain in the following way.

1. “I know that you know what you want to say. is is really hard for both

of us, but I want to try to help.”

• enask,“ShouldIkeeptryingtogureoutwhatyou’rethinking

or should we take a break? I’m going to ask you that again and wait

for you to show me “yes” after the one that you want me to do.”

o en repeat these two options, pausing in between for your

child’s response.

It is especially important to be patient with the process, and with yourself

and your child, during these discussions.

Figuring out what to ask

Although interactions may feel dierent when a child has trouble speaking,

he/she is still the same person as before. Try to consider past experiences with

your child, including his/her typical behaviors, preferences and needs, to give

you clues about what he/she would want now.

Facial expressions and body language

When you recognize a familiar facial expression, it probably means the same

thing it used to mean. In addition to telling you about their feelings and

moods, a child’s face or body can also show you whether he/she is comfortable

(through a relaxed body) or uncomfortable (through a tense body or face).

Tumors may aect facial muscles for some children, making facial expressions

look dierent than they used to. However, parents often say that even with

these changes they can recognize what their child is expressing, especially

because the children’s eyes continue to show a lot of emotions.

Routines and preferences

Time of day, familiar routines and the context of a situation can oer clues

about whether your child is tired, hungry, wants to bathe, go outside, or

play. Although children may have to do these things in a dierent way than

they used to, if they are losing some of their abilities it is still helpful and

comforting for them to participate in familiar activities as frequently as

possible. inking about the situation—where you are, who’s around, and

what you are doing—will also help narrow down the questions or the needs

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the child may currently have.

We have found that while it may feel like there are a million things a child

could want or need; it is often the simplest things that the child wants. Try

to always start with basic questions, such as whether the child wants to sit

up or change position. If the child has a communication tool, check to see if

that’s what the child is asking for.

Coping with the challenges of communication

If you feel daunted, frustrated or overwhelmed, try to remember that although

this can be an incredibly dicult task, YOU CAN DO IT. In fact, you have

probably done it already, before your child learned how to speak as a baby.

Although he/she has developed intellectually since that time and now has more

complex ideas to express, remember that with your help, your child was able

to learn a new way of communicating once before and will again. Try to be

patient with yourself, keeping in mind that the diculties you may face with

this new way of communicating are caused by this enormously challenging

situation; always remember that you’re doing the best job you can. If you

need to, take breaks to manage your own stress. Young people can sense your

anxiety, stress, or frustration, so allow yourself the time to refocus and know

that this is a challenging process for any parent.

Communication Strategies

Families have shared with us a range of creative communication strategies they

have used, which fall into two categories:

1. Tools: meaning there is an actual “thing” to help the child express himself.

2. Techniques: referring to a special way of communicating without using a

physical tool.

Please note: this may be an overwhelming list of possibilities. We’ve included

these to assist you in nding what will work best in your situation; you are not

expected to use them all.

Tools

• A bell or buzzer: ese can be used to get someone’s attention if the child is

in a dierent room, or be used as a way to say “yes.”

• Paper and pencil/markers: For kids who have learned to print or write, this

is a familiar way to express their thoughts.

• Magna Doodle: Children can write messages, draw pictures, or draw an

arrow to point the Magna Doodle at what they want. Kids typically enjoy

these because they are familiar and feel like using a toy rather than a “special

device,” and because they are easy to use.

• Laptop/tablet: Children who know how to type like using laptops because

they can send emails or type messages for someone to read while they type.

ey also tend to like that they can watch movies on the same device, although

for some the laptops are too heavy.

• Keyboard: A few children have used regular keyboards that are not connected

to computers. ey press a series of letters to spell a message while someone

else watches and reads what they typed. Special keyboards that have the letters

in alphabetical order can also be used. ese tools help children express a

wide range of messages, but some people who have used the keyboards say

it can take a long time to type messages and a child can forget what letters

they have already typed. Many families create their own keyboards by clearly

writing the

alphabet in large letters on a piece of paper or cardboard for the

child to point to.

• Picture books or boards: ese can be like scrapbooks or a piece of cardboard

with photos or drawings and words, made by family and friends. Children

can point to a picture or word, or parents scroll through, pointing to one

message at a time and waiting for the child to say “yes” when they point at the

right message. Some people nd it frustrating to search for the right message,

especially when the child wants to say something that is not included in the

book or board.

• Feelings faces: A chart showing a variety of faces, including happy, sad, angry,

frustrated, lonely, bored, excited, hopeful, etc., can help children to express

themselves by pointing (or having their parents point) to the feeling they are

having. e number of faces to include depends on a child’s age and abilities;

faces can be added or taken away as a child’s needs change.

• High-tech communication devices: ese devices usually have buttons for

children to press, with each button causing a dierent message to be spoken,

allowing kids to express a range of messages. While some children like using

these, others do not, because certain devices are complicated, seem unfamiliar,

and are sometimes hard to use or learn or feel impersonal.

Tips about tools

• For kids who are able to read, include words as well as pictures or symbols in

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communication tools. Children will associate the words with the symbols so

if it later becomes dicult to read the words, they are still familiar with the

meaning of the symbols.

• Include your child in creating their communication tools (such as books,

boards, high-tech devices) as much as possible. By choosing which images will

represent dierent words, feelings, activities, etc., your child maintains some

control and will feel more connected and involved in the process. Involving

children also promotes familiarity and makes them feel more invested in

using the tools.

• As much as possible, consider your child’s individual voice. For some families

this means recording the child’s voice on a high-tech device or a voice recorder,

saying common messages so he/she can hear his/her own voice. Families who

have done this typically treasure the recording and encourage other families

to do this as early as possible. When such a recording is not possible, families

can record another child’s voice that sounds similar in age and gender. Many

parents have said that it wasn’t just about the sound of the child’s voice but

the kinds of things that he/she would have wanted to say. By including jokes,

sayings or common phrases, a child’s unique personality is able to continue

shining through in a meaningful way.

• If you are using a tool that has preset messages or pictures in it, such as a

picture book or a high tech device, your child may want to express something

that is not included in the tool. In this case, be sure to ask your child about

messages that are not in the tool. Ask, “Is it something that isn’t in here?” to

nd out if that’s the case. en you can use “yes” or “no” questions to nd

out what your child is thinking, and to decide whether or not to add that

new message to the tool.

Techniques

Most families we interviewed said they use special ways of asking questions,

such as oering two choices, asking “yes” or “no” questions, and reading their

children’s body language and facial expressions. Some families also used the

following techniques:

• Signs and signals: ey use their hands or their faces, or adapt sign language,

especially by using the rst letter of a person’s name to refer to that person.

An example of a signal would be a child holding an imaginary cup up to

their mouth to show she is thirsty.

• Pointing: Children can point to things to show what they want, such

as pointing to a window to say they want to go outside. If a child is

uncomfortable, he/she can point to the part of his/her body, or a picture of

a body, to show others where he/she feels discomfort.

• Lip reading: Some children have trouble producing sounds or words but are

still able to make the shape of words with their mouths. For children who

have trouble hearing, a few parents say that by mouthing words slowly, and

exaggerating their mouth’s movements, their children can gure out what

they are saying.

• Physical presence, touch and hugs: When it is too hard to use words,

being close to one another and sharing aection are great ways of expressing

emotions and love.

• Lists: Many parents said it was very important to keep three kinds of lists,

and to keep adding to them, including:

1. Signals, such as what the signals look like and what they mean, (i.e.,

“pointing to mouth means hungry or thirsty”).

2. Common questions that caregivers ask, things that the child frequently

asks or says, or issues or needs that the child has.

3. Clues to a child’s needs, such as body language, time of day, or anything

else that can help caregivers gure out what the child wants or needs.

ese lists may help you remember or think of what to ask, and improve

communication when someone else, who is less familiar with his communication

strategies, is caring for your child.

Tips about communication in general

• When possible, try to adapt familiar communication tools to meet a child’s

changing needs rather than introducing new tools.

• Keep talking to your child. Avoid asking questions that they can’t answer;

stick with “yes” or “no” questions, but keep including your child and asking

her opinions.

• Teach siblings how to communicate using the new tools or techniques. is

helps to encourage interaction and maintain sibling connection.

• Use communication strategies to play games with your child to improve

comfort using the strategies. Children who are able to say “yes” can play

twenty questions; children who are using a communication book can choose

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a message while others try to guess what it is. Play charades by having your

child point out one message for another person to act out.

• Try to be patient with yourself, your child, and the process. ere is no easy

way to do this. Try to stay calm, take deep breaths, and take care of yourself.

Parents and their children can often feel frustrated and helpless. In the midst

of this dicult process, one of the most important things for children to hear

is: “I know that you know what you want to say.”

Challenges

Some children are reluctant to use tools before they are needed and may feel the

tools undermine their current abilities. If a child refuses to use a certain tool, try

telling him/her that he/she does not have to use it right now but that you want

to show him/her how it works anyway. at way if you need to reintroduce it

later, it will be familiar.

While we do not want to force children to use a communication tool they don’t

want to use, if their abilities change unexpectedly and they have not already

had the chance to learn and practice communication strategies, it can be even

more challenging for them to use new techniques to express themselves. For

these reasons, we recommend that families talk about and practice a range of

communication strategies rather than focusing only on one.

Try adopting old strategies as much as possible so your child can keep using

the same approach in a slightly dierent way, rather than learning something

completely new. For example, start with a picture board with many small pictures,

and if your child’s vision starts to change, narrow down the number of pictures,

spread them out, and enlarge them so they’re easier to see. Practicing a variety of

techniques and adapting them (rather than starting something totally dierent)

are ways of helping children feel familiar with dierent communication strategies.

Sometimes you may need to communicate in the midst of a crisis situation or

while your child is distressed; these moments may be brought on by physical and/

or emotional pain that the child is feeling. It is important to know how to calm

yourself and your child so you will be able to work together and communicate

eectively to manage these situations. Practice calming techniques together on

a regular basis. Some examples are deep breathing, blowing bubbles, soothing

touch, or focusing on each other. ese techniques are helpful because when you

and your child are calm, you will be able to communicate more eectively, which

is especially important in an urgent situation.

Deciding what to try

Choosing a strategy for communicating with your child depends upon the child’s

abilities and personal preferences. Consult with your child’s team to nd out what

strategies might be the best suited to your child’s needs, abilities, and preferences.

en, considering your child’s personality, decide which ones to try. Together you

can decide which ones work best. Some children are open to using familiar tools

that feel like play, such as drawing, writing, or using a Magna Doodle. Remember

that the emphasis of communication should be on the connection between you

and your child rather than the content of the messages.

While it is often easier for a child to keep doing what is familiar rather than trying

something new, sometimes there is no choice. If a communication strategy is no

longer working, or if your child is getting too frustrated, it is time for a change!

Communication Topics

Parents we spoke with felt it was important to be able to talk about “everything:”

physical comfort, feelings, worries and “regular conversations” about friends,

jokes, hobbies, and daily activities. Some messages were more concrete—hunger,

discomfort—which are easier for children to express by pointing to a picture or

an object, or answering “yes” or “no” questions. Abstract topics such as emotions,

spirituality, and the future are more dicult to discuss, requiring caregivers to ask

more questions in order to help a child express what he/she is thinking and feeling.

Parents described some of the most important topics they addressed with their

children, and strategies they used to do so. It may seem overwhelming to think

about all of the topics or messages your child may want to express, and the

charts, lists, or strategies you could create. Remember that becoming familiar

with communication strategies will happen over time and with support from

family, friends, and your child’s team at the hospital.

e way you communicate throughout this time will be shaped by your family’s

values, belief systems, personalities, and previous experiences communicating,

especially about dicult topics. While we know sharing information and

discussing feelings helps children and families cope and support one another,

there is no “right” way to go through this experience.

Physical and health needs

Parents described important conversations they’d had with their children about

how their abilities had changed and that the changes would continue. Although

these can be dicult discussions, children cope better when their questions are

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answered than when they are left to wonder and make up their own answers.

To assist with talking with, or responding to your child’s physical needs, below

is a chart [Table: 1] outlining some issues and approaches.

Child’s Messages Parents’ Questions

Ouch/I’m in pain/Something’s

hurting.

“Is something hurting?”/“Are you in

pain?”

If “yes,” ask: “Can you show me where it

hurts?”

Point to dierent parts of your child’s

body, or to a picture of a body, or even

name dierent body parts—“Is it your

head?”/“Is it your stomach?”—and ask

your child to let you know when you’ve

said, or when you have pointed at the

part of the body where he/she feels pain.

Remind your child how to signal “yes.”

I’m uncomfortable. “Are you uncomfortable?”

If “yes,” ask (one at a time, slowly, until

your child indicates “yes”).

“Do you feel sti/numbness/itchy/dizzy/

hot/cold/weak?”

I need to move/I

need to change positions.

“Do you want to move/change posi-

tions?”

If “yes,” ask (one at a time, slowly, until

your child indicates “yes”).

“Do you want to sit up/lean back/lie

down/roll over/move over/sit somewhere

else/lie down somewhere else/go out-

side?”

I need to go to the bathroom. “Do you need to go to the bathroom?”

If “yes,” ask (one at a time, slowly, until

your child indicates “yes”).

“Do you need to use the toilet or a new

diaper/take a shower or bath/brush your

teeth/brush your hair/wash your face?”

I’m hungry. “Are you hungry?”

If “yes,” oer food choices, one at a time,

slowly, until your child indicates “yes.”

Child’s Messages Parents’ Questions

I’m thirsty. “Are you thirsty?”

If “yes,” oer various drink choices, one

at a time, slowly, until your child indi-

cates “yes.”

I need my walker/wheelchair. “Do you want your walker/wheelchair?”

Table 1: Questions and responses

Medical needs

Children we spoke with wanted to know about medical equipment, tests, and

procedures, including the use of dierent medical equipment, how it works, and

what procedures will feel like. When a procedure will be uncomfortable, people

may be afraid of upsetting children by telling them the truth. Unfortunately,

when children are caught o guard by a needle or other unpleasant things, they

do not have the chance to react and then calm down and then try to cope with the

experience before it is time for the procedure. Children may also begin to doubt

caregivers and to think that things are being kept from him even when they’re not.

Children benet from knowing what to expect—where a procedure will take

place, who will be there, what steps are involved, and what it will feel like. is

information gives kids a chance to prepare for what will happen and practice

coping strategies, such as deep breathing, blowing bubbles, holding your hand,

listening to music or a story, using guided imagery, or squeezing a stress-ball.

Children may also benet by watching a simulated procedure on a play-therapy

doll or stued animal like American Childhood Cancer Organization’s Cozy,

the “Port-a-Cat.”

When explaining medical procedures to children, it is important to be honest, to

use language that is clear and simple, and to check in with them by asking “Does

that make sense or would you like me to try to explain it in a dierent way?”

Children may also want to know why treatments are needed, how to know if

they’re working, and what happens if they don’t work. When a child nishes or

stops a certain treatment, he/she may wonder what that means, whether it is

because the disease is gone or because it can’t be cured. ese are dicult concepts

to explain, but if a child has a question, it is better to explore the answers honestly

and openly together than for a child to rely on his own imagination. ese issues

can be overwhelming for children to think about on their own; talking about

them together oers reassurance and support for the child even when there aren’t

clear-cut answers.

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It is helpful to talk to children about what kinds of information they want to be

told about their illness, treatment, and side eects, before communication gets

more dicult. at way you have an idea of what your child wants to know

about and you can continue to provide the information your child wants and

needs throughout his/her journey.

Emotions

To talk about feelings you can use charts with pictures of dierent facial expressions

or use a list of feelings. Your child can point to the face that shows how he/she feels,

or you can point and look for your child to indicate when the right answer is selected.

It is helpful to oer a wide range of feelings so your child can express his/her true

emotions, rather than settling for one that is “close but not quite right.” On the

other hand, if your child is getting overwhelmed, use a shorter list or chart with

four to eight simpler feelings such as happy, sad, scared, mad, bored, etc. Try to

use words that are familiar to your child and make sense given her age. If possible,

try to include your child in creating this list of feelings to ensure she is familiar

with all the words and that she has some control.

Strategies for talking about emotions

Ask your child if he/she feels a certain way. For example, “Are you feeling happy?”

or “You look frustrated, are you feeling that way?” is oers your child the chance

to express an emotion and to oer some control by answering “yes” or “no.”

Share how you are feeling and then ask your child whether he/she is feeling the

same way. is helps a child express his feelings and reassures him/her that others

feel that way, too. However, it is important to recognize that children may feel

dierently than the people around them; this is perfectly normal. Try to say

something like, “I’ve been feeling pretty sad and I wonder if you have, too. You

know, it’s okay to feel sad and it’s okay not to, too.”

Children need to be reassured that all of the feelings they have, no matter how

intense, unfamiliar or conicted, are natural. Let your child know that even though

these are not “easy” feelings to have, they are natural, understandable, and “okay.”

A lot of emotional messages can be conveyed through hugs and touch. Being close

and making eye contact also helps children feel more connected and comforted.

Activities

When a child’s abilities change what he/she is able to do or play with, it is helpful

to have a list of things that your child can do to choose from. Lists also help

parents so they don’t always have to remember all of the options. Some of the

most common activities that parents we interviewed said their children enjoyed

were: listening to music, watching a movie, hearing a story, going outside, playing

a game, writing to someone, making food, or visiting friends.

People and pets

Maintaining relationships with family and friends is very important for young

people. Parents and caregivers can help by giving children a way to ask to see a

special person, or to send them a message. Create a chart with names and photos

of family members, friends, and even pets, for children to point to.

Many children ask about people they know who have died, wondering where they

are now, whether they are “okay” and commenting that they miss these people. It

is natural for a child who has a serious illness to start thinking about life and death

and loved ones who have died. It can be a safe way to wonder about these things,

an indirect way for children to show you that they’re thinking about death, and a

way to start a dicult conversation. Also, when children realize their loved ones

are still remembered and loved after they’ve died, it oers them the reassurance

that they, too, will be remembered and loved after their death.

e Future and Spirituality

It is natural for children to wonder about these topics, especially as they feel their

bodies changing and sense the emotions in the people around them. It can be very

hard for children to initiate conversations, especially when they fear that talking

about these things will be upsetting for others. ey may ask questions in indirect

ways, such as asking about the death of a pet, or the death of someone else, or

general questions about what happens after you die. Because of how dicult it

can be for children to bring up these topics, it is very important to support them

when they want to have these conversations, rather than avoiding or changing

the subject.

If your child has questions about death and spirituality, try to answer his/her

questions as honestly, clearly and calmly as you can. He/she may ask you questions

you don’t have answers to. at’s okay. You can say you’re not sure, that many

people wonder about questions like that, and that it’s okay to wonder about these

things together, even without nding any answers.

In interviewing parents, some of the biggest struggles they said they faced were

about whether or not to tell a child that he/she could or would die and how to do

that. Research and our own clinical experiences suggest that children and families

benet from having open and honest conversations. Families who do this said

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they did not later regret having had these conversations. Many parents said that

even though it was so hard for them to talk about these things, after they had

spoken with their child about death or spirituality, they realized the child seemed

comforted and relieved, and that they—as parents—did as well. Whether you

decide to talk with your child about death and spirituality and how you do this

is up to you and will be a very personal decision based on your experiences and

your beliefs.

About the future

For some children, thinking about the future can include writing a will, exploring

organ donation, or planning a memorial celebration. Parents often worry that

talking about these things with their children will cause them to lose hope. On the

contrary, if a child is already thinking about these things, the opportunity to share

his/her thoughts and feelings about them with loved ones can oer tremendous

comfort and relief, a sense of control, and the opportunity to plan his/her own legacy.

You can also talk about how you will remember and honor your child at holidays,

family events, birthdays, and other special times. Some families have a special meal

or celebration, wear a special piece of clothing or jewelry, listen to a certain song

or musician, or make up their own unique rituals for these special times. Others

may plant a memorial tree or garden, hold a fundraiser, or create a scholarship

in the child’s name. Some children have their own ideas about how they want

their family to remember them, and many children want to be involved in family

discussions about this. Not only does it reassure the child that he/she will not be

forgotten but it gives him/her a clear idea of exactly how her family will remember

and feel connected to him/her.

About spirituality

Some children ask their parents questions about what happens after someone

dies, what they will do when they are in heaven, or how their families will feel

their presence. Whatever your beliefs are, you can share them with your child.

Many people don’t know what they believe, or may believe that there is nothing

after death. If this is the case for you, you can explain to your child that many

people have dierent beliefs and that you’re not sure what will happen, or that

you’re not sure whether any of them will happen; either way, ask your child what

he/she thinks, or would like to think.

Regardless of what you believe about what happens after death, you can talk with

your child about how he/she will always be part of your family even though he/she

will not be physically present. ings he/she taught others, personality traits, his/

her values, and hobbies that he/she shared with others, are all deeply meaningful

ways that his/her life will continue to impact his/her loved ones.

Caring for Your Children and Yourselves

is is a very dicult and challenging experience for parents and children.

Developing strategies to manage the impact of the ongoing loss of abilities

can be as important as developing communication strategies. is section is

meant to assist parents and caregivers in thinking about and addressing some

of these challenges.

Supporting the child with a brain tumor

Here are examples of some of the challenges and concerns that parents described

and the things that can help kids deal with them. Strategies from the previous

sections will assist in dealing with these issues.

Feeling frustrated

When a child nds that he/she can no longer do something that used to be

easy to do, or realizes that so much about his/her body or his/her life is beyond

his/her control, frustration is a natural reaction. e loss of independence or

needing help with things such as eating or going to the bathroom can be very

upsetting, especially as children realize they will not regain the ability to do those

things on their own. is kind of frustration might be expressed in dierent

ways, such as being impatient or getting angry. One way to help children cope

with these feelings is to help them nd ways to express themselves with words

added to a communication board or book, or physically using a stress ball made

out of Play-Doh

People often want to cheer kids up when they are feeling upset; sometimes they

try to distract them by talking about something fun or focusing on an activity.

But when children have these strong feelings, they need ways for their feelings

to be expressed and heard—and to know that someone else understands—before

they are ready to move beyond these emotions. It’s important to be patient and

let your child know that you will work together to gure out what he/she wants

or needs, whatever it may be.

Feeling self-conscious

As their bodies and their abilities change, it is common for children to feel less

comfortable around others. Children, particularly teenagers, are often fearful

about being seen as “dierent” or being treated “dierently” than others.

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Educating a child’s peers about his/her illness, explaining that a tumor is not

contagious and that it is the reason for his/her changing abilities, and helping

them learn useful communication techniques can be a very good way to help

them understand and relate to one another. ere may be someone at your

child’s hospital—such as a nurse, a child life specialist, or a social worker—

who can visit your child’s classroom to talk about these things. Teachers and

other school sta are often very helpful in organizing this kind of classroom

experience. On the other hand, some children feel strongly that they do not

want other people to know about their illness and would not be comfortable

having someone speak with their classmates. Sometimes it helps to talk with

your child about what he/she is afraid would happen if others found out, and

you may be able to dispel these fears and facilitate the connection.

However, if your child does not change his/her mind, it is important to respect

his/her wishes in order to avoid your child feeling embarrassed, helpless, or even

vulnerable. ere are so few things that a child in this situation can control that

deciding what information to share with others may be one of the few things

that he/she can control.

A few parents described their children feeling self-conscious about

communication. MSN and other online chat systems, email, social networking

sites, text messages, or even written letters can be great ways to help children

keep in touch with their friends without having to feel so self-conscious. Also,

if your child is comfortable with you teaching others how to use the specic

communication strategies your family has developed, with time and practice,

his/her feelings of self-consciousness may decrease.

Missing familiar people and activities

Familiarity provides so much comfort to children. When it’s possible to help children

continue to participate in these kinds of activities, even if it means participating

in a dierent way than they used to, it can be very helpful for them. On the other

hand, some children may nd that there are some things they don’t want to continue

being involved in. If this is the case for your child, try to help him explain why

he feels this way. It may be that he/she is self-conscious and afraid of how others

might treat him/her, in which case you can talk to him/her about anything that can

be done to help make the situation more comfortable or inviting. In some cases a

child may feel uncomfortable or even unsafe in dierent environments. Whatever

the situation, respecting your child’s wishes as much as possible will help him/her

feel more comfortable and safe and give him/her a sense of control.

Coping with medical experiences

Play is a great way to help children cope with dicult experiences. In times

of stress, play may be the furthest thing from our minds, but it may also be

the most valuable tool. Blowing bubbles, bringing paper and crayons to draw

or play tic-tac-toe, a deck of cards, or even a list of games such as “I Spy” or

“Twenty Questions” are all simple and useful distractions. For older children

and teenagers, think back to what has helped them before; listening to music,

playing a video game, or reading a book may be useful distraction techniques.

Guided imagery, deep breathing, and other relaxation techniques can also help

children of all ages cope with anxiety related to medical issues. Talking with

your child about what is happening, what medical procedures might feel like,

and any other questions or concerns they might have will help them better

manage these experiences.

Knowing they will be cared for

Parents highlighted that it was extremely important for their children to know

that they would be well cared for. is concept included three things.

1. Knowing that the health care team would continue to care for them. When

they know that a disease or a tumor is not curable, children may think that

means there will be no more medical care.

2. Knowing that they will still be looked after and that their pain and other

symptoms will still be managed is very important.

3. Knowing that they are not alone and that their parents and their family will

always be with them and love them “no matter what.” When children are

struggling with how they’re feeling and the ways their bodies are changing,

this may be the most valuable comfort you can oer them.

Children’s concern for others

Another common and important concern parents told us about is children’s

worries about whether their parents and their families will be okay after the child

dies. Parents said it is very important to address these concerns by letting your

child know two things: that the family will be sad and will miss the child after

he/she dies, but at the same time, the family will be alright. Families did their

best to try to ease the child’s burden of worrying about how his/her loved ones

will cope. It’s important to express one’s love for the child while acknowledging

the impact of his/her loss.

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e importance of communicating

Parents told us that they often feel helpless and frustrated that they are not able

to change the situation and protect their child from what is happening. Of course

this feeling is natural. Sometimes in an attempt to protect a child, parents avoid

talking with their child about his/her illness or letting him/her know that he/she

is going to die. Although this is done with the best intentions, it does not have

the impact parents hope for. Some of the unintended, possible consequences are:

• When children are not invited to talk about their illness, they learn from

others’ example not to raise the issue themselves. Without having someone

to talk to about their thoughts and worries, they are left to wonder on their

own, using their imaginations to answer their own questions.

• Children are very sensitive to the emotions of the people around them and

know when others are upset. ey can recognize when something is being

kept from them and can only wonder what that might be, often imagining

the worst.

• Children are more aware than anyone of the changes occurring in their own

bodies. Although they may not know what will happen in the future, they

have learned that unpredictable changes can continue to occur. If they do

not feel able to talk about their illness or the future, they are left to face

these questions and fears on their own.

With these things in mind, it is clear that protecting a child from talking

about his/her illness does not protect him/her from the dicult experience he/

she is already living. Instead of letting this fact make you feel helpless, try to

see that it actually oers you an important opportunity. You are not helpless.

Even though no one can change what is happening, there is a great deal that

you can do to help your child through this experience. As we’ve discussed in

this section, there are some very important messages that will oer your child

comfort, reassurance, and security. Make sure your child knows the following.

• Your child is not alone. You will be there to support him/her throughout

this experience.

• Your child can trust you. You can truthfully prepare him/her for things

such as medical procedures and other events so he/she feels less anxious

and surprised by these things. Your child’s health care team at the hospital

can help you gure out how to do this.

• Your child will be well cared for. You can reassure your child that you, your

family, and your child’s health care team will all be working to make sure

that he/she has what he/she needs to feel comfortable and taken care of.

• Your child will always be part of your family. You can talk about all of the

things you will remember and all of the ways that your child will continue

to have an important place in your family.

• Your family and people who know and love your child will be incredibly

sad when he/she dies, but your family members and friends will support

one another through their grief.

Although these things cannot change what is happening to your child, they can

make him/her feel supported in the knowledge that he/she will not be alone.

Nothing can take away the pain that your child and your family will struggle

with, but these important messages can oer your child support and strength

as you face what is happening, together.

Supporting siblings

As a parent, you may not only be supporting a child who has a DIPG but also

his or her siblings. ere are some issues that are common for children who

have a sibling living with a serious illness, and these can vary depending on the

age of the children. For example, many children in this situation have questions

about why this happened, worries about their own and/or their sibling’s health,

and concerns about their parents’ emotional struggles. It is also very common

for children to wonder if they are somehow to blame for a sibling’s illness and

to worry that they may also “catch” the illness. Even if a child has not expressed

these worries, it is helpful to say something like, “I just want to make sure you

know that there is nothing you could have done to make this happen and that

this is not the kind of illness you can catch from someone else.”

Siblings may also have questions about the future. e suggestions in this chapter

about how to talk with a child about his or her own illness and the future, as

discussed in the previous sections, also apply to talking with the child’s siblings.

Many of the parents we spoke with shared their suggestions about how to help

brothers and sisters.

• Make sure the siblings are able to continue spending time together at home

or in the hospital.

• Help all of your children learn how to use the new communication

strategies, as it can help children continue to interact with each other and

maintain their relationships.

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• Encourage siblings to say “hello” and “goodbye” to their sibling when they

come home and when they go out.

• Encourage interactions that help a sick child continue to feel recognized and

included in the family’s day-to-day activities despite their changing abilities.

Brothers and sisters may be reluctant or nervous about learning new

communication strategies, and may be afraid of doing it “wrong” or looking

silly if they do. Just like teaching communication strategies to a child who is

sick, it can also help to use games to teach these strategies to their siblings,

and to practice with them until they feel more comfortable using them. ey

may also need your help to understand why their brother or sister isn’t able

to talk the way they used to. Because they may not be able to see any physical

evidence of something stopping their sibling from being able to speak, some

children wonder why their brother or sister just doesn’t try harder. It helps to

explain that our brains are like computers that send signals or instructions to

all of the other parts of our body to make it work, including our arms, legs,

stomach, heart, lungs, eyes, ears, mouth, etc. When a person has a brain tumor,

it interferes with, or “mixes up,” some signals so that things don’t always work

the way they’re supposed to. is is why some children who have brain tumors

aren’t able to speak the way they used to.

Similarly, children may not know how to interact or play with their brother or

sister since their abilities have changed. ey may also believe that their sibling

doesn’t want to play with them anymore. Again, it is important to explain that

these changes are caused by the tumor rather than being the child’s choice.

en you can help your children nd new ways of playing or being together.

Healthy siblings can read stories to their brother or sister, watch movies or listen

to music together. ey can also play “for” their sibling; some examples of this

are making a beaded bracelet or building a LEGO tower by asking their sibling

what color bead or LEGO block to use next. ey can also draw a picture or

write a story based on their sibling’s ideas about what to draw or write. When

thinking about how to help children play together, consider what they used to

do together and try to nd ways to adapt those activities. Children may have

a hard time trying new things; it can be easier and more comfortable to do

what feels familiar.

Some other considerations we’ve learned about siblings are:

• Healthy siblings need opportunities to play for themselves.

• ey will need your assistance to nd a balance between feeling helpful

without taking on too much responsibility for their sibling with a brain

tumor.

• Even when they understand why their brother or sister needs the extra

attention, siblings need support to make sense of, and express, their

emotions and possible feelings of jealousy about the extra attention their

ill sibling is getting.

• Sometimes siblings are asked to be patient, helpful, and understanding for

a long time, which isn’t easy. is is a challenging experience for children

of all ages, and their frustrations can be expressed dierently at dierent

developmental stages.

• All children need to know that their needs will be met.

• Children of all ages need love and support from their parents, though how

they express this need changes at dierent ages.

• It is important to recognize and tell each child how much you appreciate all

that he or she has done throughout their sibling’s illness, including specic

examples when possible.

• Let them know that you recognize how challenging it has been and will

continue to be and encourage them to let you know when they’re struggling

and need help.

Talking with your other children about how they are feeling, helping them to

understand that all of their emotions are natural, and encouraging them to

express any questions or fears that they have is very important and benecial.

ere may be people at the hospital or at school, such as child life specialists,

social workers, counselors, or volunteers who can help support children when

their sibling is ill. ere may also be local organizations that can provide support.

Parents’ Advice for Other Parents

e parents we spoke with shared some very personal insights into their

experiences that may be helpful advice for others parents. Some of these are

reections or quotes about a parent’s outlook or important things that they

tried to keep in mind while going through this same process with their child.

About relating to children

• Know your child, their personality, interests, coping styles, and preferences

for support.

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• Have important conversations sooner rather than later. Have important

conversations about topics such as illness, life, death, your love for them,

and spirituality as early as possible. Although these can be emotionally

dicult conversations to have, they get even more dicult once children

have a harder time communicating.

• Keep communicating. When a child can no longer express themselves to

others, it can be hard to know whether or not to continue to talk to them.

Communicating through story-telling and touch (including a hug, gently

squeezing or rubbing a child’s arm) can convey love, warmth, aection,

and provide great comfort to a child.

About relating to one another as parents and as a family

Try to work together—as a couple, as parents, and as a family.

Asking questions and asking for help

• Whatever you want to know, ask. If there is anything you have wondered

or worried about, do not hesitate to ask a member of your child’s health

care team.

• Whatever you need, ask. Dierent services will be available depending on

the hospital or the community where you live. Ask a member of your child’s

health care team to help you nd resources near you.

Acknowledgements

We want to express our sincerest thank you to the families who participated

in this research and who shared their experiences and insights. ank you to

our colleagues, Dr. Eric Bouet, Dr. Ute Bartels, Cindy Van Halderen and

Dr. Tom Chau. Funding for this research and the creation of a handbook for

families and caregivers has been generously provided by B.r.a.i.n.child at www.

sickkids.ca/brainchild.

Parent Perspectives

Caleb was diagnosed with DIPG January 28th, 2010. At the time of

diagnosis his speech was slightly slurred. Within a week of starting steroids

and radiation this cleared completely until progression. In December 2010

we noticed his speech became very nasal; progression was confirmed

January 13, 2011. Steroids and a second round of radiation helped but

not completely.

In June 2011 he began having a lot of trouble with speech, to the point

that no one, other than his father, his sister and me could understand 75%

of what he was saying. Caleb was nine and a half years old at the time.

This frustrated and upset him far more than any other symptoms, including

the loss of strength in his left side and the ability to walk. He told us he

could hear himself perfectly clear and could not understand why no one

could understand him. He said that if he could hear what we heard then he

would know how to try to fix his words, but since he heard himself "clear

as a bell," he had no idea how to help us understand. This was extremely

frustrating for him.

Initially he would speak one word at a time and we would repeat what we

thought he had said until we guessed what that word was before moving

on to the next word. Caleb was very witty—a funny little man who had the

best “one-liners,” so it saddened him so much when he would try to speak

and no one understood. He told me that things are not funny when they

have to be repeated over and over. That was when he began to withdraw.

We bought a small white board that we carried everywhere we went so

he could write down whatever he wanted to say. It helped, but he missed

talking and being part of conversations. When he spent time with friends

he would become so sad because whenever he wanted to say something he

would begin to write but by the time he was done writing, his friends had

moved on to a new topic. That is when we insisted on more one-on-one visits

instead of group visits with friends and family. This helped a lot because

he didn't feel he had to compete to get his thoughts across and he didn't

lose the chance to have his point heard.

As time went on and he began losing the ability to write (some days he could,

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Chapter 12: When a Child Can No Longer Speak

and some days he couldn't) he would lose his interest in communicating and

he didn't want those around him talking or communicating either. We found

it very important to match his mood. If he was in a good mood it was okay

to laugh and talk a little, but when he wasn't we tried to keep the house

quiet and low key. Up until this point his relationship with his sister, Avery

(seven and a half years old at the time) had held strong, but once Caleb's

ability to communicate had diminished he did not want her around much

and she avoided him as well. She learned very quickly to only ask “yes or

no” questions and she would always ask if she could tell him something

instead of bombarding him with her conversation. Giving him that choice

helped him feel some sense of control. This helped with his patience and

his willingness to listen to her.

We also made up small cards with words on them so he could pick out one

or two that would help us guess what he was thinking. In the end when he

was not able to move at all we wrote the letters of the alphabet on a white

board, we would point to the letters and he would either nod or blink when

we had the right letter, then we would move on to the next letter, spelling

each word out. It was extremely slow but we only used this method when

he needed something new or out of the ordinary.

Throughout the process of Caleb losing his ability to communicate, I become

acutely aware of his needs. I learned his expressions and could usually

guess fairly accurately what he wanted or needed through them. All of this

was extremely hard for all of us to adjust to, but with these tools we were

able to keep as much fun in his days as we could.



When Ella started to lose her ability to speak, we created a picture book

with photos of all sorts of things she liked to do, needed to do, and feelings.

When we couldn't understand her speech we would pull it out and flip the

pages. She had just enough strength to point to the pictures. My favorite

was the “I Love You” picture because I missed hearing her sweet voice

say those words to me.



Warren’s speech wasn’t very good. People had a very hard time

understanding him. I had a hard time too. He would have to repeat things

a lot and he would get frustrated. Other than listening hard I didn’t know

what to do. Looking back both of us learning some simple sign language

such as drink, eat, bathroom might have helped.



Whereas in August and prior, Stella was speaking in full sentences with a

huge vocabulary, now it takes her up to 30 seconds to squeak out one word,

which is generally difficult if not impossible to comprehend.



We find it necessary to be close to him and looking directly at him to

understand his speech. He is not at all frustrated by this and patiently

repeats himself as often as necessary so that we know exactly what he

wants to tell us.



It was Monday, Nov. 29th, when our 4-year-old Julian woke me at 5 a.m. I

noticed he wasn’t nishing his sentences as he kept repeating, “Mommy, I just

wanna... I just... Mommy, I just wanna...” Crediting the early hour and perhaps

a still sleepy state, we pulled him into our bed to sleep a little longer. When he

woke again, this time vomiting, lethargic and still speaking as if confused, we

knew something was terribly wrong.

Three months after that dreaded day and diagnosis, while searching for signs

of hope on the internet, I came across a site lled with text by a father who

had lost his daughter. He detailed DIPG treatment options and what to expect

during “end of life” care. I read a passage about how most children lose the

ability to speak in the last month or so due to tumor progression or, in the

author’s daughter’s case, a “stroke-like” episode. I recall wanting to throw my

computer across the room. Julian was famous for his sweet, raspy voice and

endless chattiness. Our conversations were treasures and I could not bear the

thought of not hearing his voice let alone him not being able to tell us what he

needed or wanted.

A few weeks later, Julian did suffer a series of seizures that left his speech

slowed but intact. In his nal two weeks, he spoke less and less, but was still

able to point and nod in answer to our questions. We were fortunate in that he

still shared a few beautiful words right up until his last day.



Like many children with DIPG, Caleb was unable to speak during the final

days of his life. At first, we developed a system of communication involving

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both side to side and up and down eye movement. Then, he lost the ability

to even move his eyeballs from side to side. After that, up was “yes” and

down was “no.”

We were at home, with Caleb set up in a hospital bed in the living room. His

school principal (who had been his 5th grade teacher) contacted classmates

she knew would want to see him and established a visitation schedule. The

children were precious. They sat beside his bed and talked to him, read to

him, remembered. The memory of his best friend sitting beside him on the

bed is seared into my mind. His buddy was scared, unsure what to say, so

I was trying to help. I explained something I’d been doing and concluded

with, “but that gets on Caleb’s nerves.” Immediately, Caleb’s eyes began

moving up and down, up and down forcefully. He was clearly saying “YES

IT DOES!” What a gift that even in those final hours and with such limited

abilities, he continued to bless us with his quick wit and sense of humor.

He helped his best buddy realize that even though his body was no longer

cooperating, our Caleb was with us at that moment.

223

Chapter 13: Overcoming Research Hurdles in DIPG

Chapter 13

Overcoming Research

Hurdles in DIPG

Patricia Baxter, MD

Susan Blaney, MD

e treatment of childhood brain tumors remains a tremendous challenge for

pediatric oncologists, particularly the treatment of aggressive brain tumors such

as high-grade gliomas (e.g., anaplastic astrocytoma or glioblastoma multiforme

[GBM]). is challenge is even greater when the tumor is located in an area of

the brain that is not amenable to surgical resection, such as the hypothalamus

or brainstem (pons). e subsets of pediatric glial tumors that are located in the

brainstem are also known as brainstem gliomas (BSG), or diuse intrinsic pontine

gliomas (DIPGs). As discussed in previous chapters, the diagnosis of DIPG is most

commonly made by a radiologist after reading the magnetic resonance imaging

(MRI) scan, rather than by a pathologist after a neurosurgical procedure such as

biopsy or tumor resection.

So how do we know that DIPGs are high-grade glial tumors if there is no biopsy

or other surgical procedure to determine the tumor pathology? And because

treatment progress for many other types of cancer has been the result of laboratory

studies of human tumor tissue, how can scientists advance research on this type

of tumor and develop eective treatments for children who have a DIPG without

tissue from a biopsy or surgery? ese important questions will be addressed in

this chapter.

DIPG Research Hurdles

Physicians and scientists are optimistic that with modern scientic tools, progress

will be realized in the treatment of children

with DIPGs. Patients, parents, physicians, and

scientists must all work together to overcome

the research hurdles associated with DIPGs,

Dr. Baxter is an Assistant Professor

of Pediatrics at Texas Children’s

Cancer Center, and Baylor

College of Medicine, Houston, TX.

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Chapter 13: Overcoming Research Hurdles in DIPG

one of the most, if not the most challenging childhood tumor.

Biopsy tissue challenges

e diagnosis of a DIPG is particularly dicult for many parents to accept because

tumor biopsies with resulting pathology are not routinely performed for DIPGs in the

majority of pediatric oncology centers. Surgical resection of DIPGs is not performed

because the brainstem serves as the main roadway for all information that travels to

and from the brain. e brainstem is critical for vital functions such as breathing,

maintaining blood pressure and heart rate, along with other physiological functions

essential to life (see chapter 3). DIPGs are physically located within the brainstem,

and the tumor itself is intertwined with the non-cancerous cells that conduct these

vital life functions. ere is not a denitive border that distinguishes the tumor from

the normal brain tissue, so DIPGs cannot be surgically removed.

Several decades ago, neurosurgeons routinely performed diagnostic biopsies on

children with symptoms of a DIPG and found that these tumors were, with rare

exception, high-grade glial tumors. With the advent of improved imaging technology

and the widespread availability of MRI, it was found that a diagnosis of DIPG could

reliably be made through a history, physical examination, and MRI. As a result, the

practice of diagnostic biopsy was abandoned because of the small, but very real,

risk of severe or life-threatening complications associated with a biopsy and the fact

that past biopsy results have not changed treatment recommendations. is lack of

available tissue from biopsy specimens however, creates an enormous research hurdle

for investigators who need tumor tissue to perform essential molecular analyses of

this unique tumor.

In the future, physicians may routinely recommend biopsy for children with a

clinical and radiographic diagnosis of DIPG. Currently, this recommendation only

occurs when a child’s physician believes the potential benet of a biopsy outweighs

the potential risks, for example, if the MRI ndings are not classical for a DIPG.

In the future, the most likely situation in which biopsies would be recommended

would be if scientists were able to analyze the tumor tissue and identify a set of

tumor genes or other characteristics specic to the tumor that could suggest one

treatment may be of greater benet to a child with a DIPG than another. In this

case, a physician and parent would want the

child to receive the treatment that has a higher

likelihood of benet. Scientists make constant

advances through research that have made

such scenarios a reality for a variety of other

tumors. Our hope is that such advances will

occur sooner rather than later for DIPGs. However, this requires ongoing intensive

research by the best scientic minds and access to tumor tissue, which will be

discussed below.

Challenges associated with the tumor location

Progress has been made in the treatment of some high-grade glial tumors, particularly

those that can be surgically removed. However, progress has been slower for tumors

that cannot be surgically removed, such as DIPGs. As noted above, the location

of DIPGs deep in the brain impedes ready access by the surgeon to tumor tissue.

Tumor tissue is essential to the work of research scientists who are trying to acquire

a better understanding of the tumor’s basic biology and unlock the key for guring

out how a DIPG rst develops. is understanding is needed for the development

of better treatments for this disease. Once scientists understand the tumor’s biology,

they can develop strategies to destroy the tumor cells or to convert them to cells that

no longer behave in a malignant fashion.

Tumor cells can be destroyed in a variety of ways. However, the location of a DIPG

within the central nervous system (CNS) makes all potential treatment approaches

even more challenging, because the CNS has natural mechanisms (the Blood-

Brain-Barrier) that isolate it from other parts of the body. is isolation protects the

brain from damage or side eects associated with chemicals in the blood, including

chemotherapy. Yet this isolation also means that most anti-cancer drugs in the blood

do not get into the central nervous system to any appreciable extent. In everyday

life this isolation is good, because it protects the brain. But this isolation is a major

obstacle in the treatment of brain tumors because the target of the therapy is in the

CNS. us, researchers are developing strategies to ensure drug delivery to the tumor.

is can be accomplished by delivering a drug directly into the CNS, by making

drugs that can more readily enter the CNS, or by developing special carriers (e.g.,

nanoparticles) that can deliver the anti-cancer drug to the tumor.

Clinical trial challenges

Despite the many challenges in treating DIPGs, doctors and scientists, assisted by

patients and their families, continue to work diligently toward nding new and

more eective therapies for children with DIPGs and other brain tumors. While

progress has been slower than desired, we continue to make incremental advances

in understanding the biology of these challenging cancers. While we are working to

unlock the keys to determine what makes a DIPG develop, we are simultaneously

evaluating new drugs in clinical trials to determine whether or not they should be

used in the treatment of DIPGs.

Dr. Blaney is a Professor and

Vice Chair for Research in the

Department of Pediatrics at Texas

Children’s Cancer Center, and

Deputy Director, Baylor College

of Medicine, Houston, TX.

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Chapter 13: Overcoming Research Hurdles in DIPG

Because the survival rate for children with DIPGs is unacceptable, doctors and scientists

are constantly evaluating new drugs, biological agents, and immunotherapeutic

strategies to improve survival. e best way to evaluate new treatments is through

clinical trials. Clinical trials are a scientically rigorous way to determine the best dose

and schedules of new agents and treatment strategies, and to ultimately determine

whether a new treatment is of benet for a particular disease. As such, many patients

with aggressive cancers such as DIPGs are oered the option of a clinical trial either

at diagnosis or relapse, if a trial is available.

Local radiation to the brainstem is the standard treatment for children diagnosed

with a DIPG. Because the benets of radiation in DIPGs are temporary (typically

less than 1 year), and because there are no chemotherapy agents that have a known

benecial eect for DIPGs, many of the current clinical trials for children with a

DIPG are early phase clinical trials (Phase 1 or Phase 2) where the goals of therapy

are to: a/ nd the appropriate dose of medication to give with radiation therapy;

b/learn more about the side eects of the medications when given with radiation

therapy; and c/ nd early information about the eectiveness of a new treatment.

ere are many contributing factors associated with clinical trial participation

that create additional hurdles for DIPG research. Not all patients will qualify for

participation in clinical trials. All clinical trials are conducted using strict guidelines to

minimize the risk to patient safety. Patients must also have a physical and neurological

examination, laboratory tests, and imaging studies (scans) to determine if they are

eligible to participate in the trial. ese additional tests and the clinical trial itself

might be regarded by the family as interfering with the quality of life of their child.

Trial requirements may also result in disappointment or frustration if a child is not

eligible to participate or if no open slots are available for trial enrollment.

e decision to participate in a clinical trial, if eligible, is also a personal one. e

decision may be inuenced by the potential for benet from the treatment; the

potential side eects of the treatment; a need to travel to a new treatment facility that

is far from home; a desire to help children in the future; and other factors. When

balancing the pros and cons of participation, the family must decide what is best for

their child. is might mean that participation in a clinical trial is not the decision

that they choose to make.

Clinical trial phases and institution challenges

Clinical trials are normally divided into three phases––Phase 1, Phase 2, and Phase

3. Phase 1 trials are most frequently performed in a limited number of pediatric

oncology centers that have specially trained clinical research personnel. In North

America, the institutions that perform these studies are comprised of a small group

of institutions that have been designated by the National Cancer Institute to work

together to perform these trials. ese groups include the Children’s Oncology Group

Phase 1 and Pilot Consortium (comprising 20 pediatric treatment centers) and the

Pediatric Brain Tumor Consortium (comprising 11 pediatric treatment centers). e

formation of these consortia facilitates patient access throughout the country to a

treatment center closer to home and allows trials to be conducted more eciently.

After the optimal dose and schedule of the new therapy have been determined in

Phase 1, Phase 2 trials are conducted to evaluate whether or not the new treatment

is eective for children with DIPGs. Phase 2 trials are typically conducted by the

Children’s Oncology Group, which is comprised of more than 200 children’s oncology

treatment centers in North America. At this stage, access is more widely available

to children throughout the United States. Because the Phase I trials are conducted

at fewer sites, this might make participation dicult for many families. Traveling

distances to participate in a trial can seem overwhelming when there is no clear benet

from a Phase I trial for the participating child. Additional mobility challenges, as

well as communication issues impacting consent and assent that are common with

DIPG children make participation in clinical trials even more dicult. Delays to

clinical trial enrollment prolong the time to completion of the study and analysis of

the trial to determine the ecacy of the new therapy being tested.

Benets, risks, and accrual challenges of clinical trials

ere are benets and risks of participating in a clinical trial. is too can impact

a parent’s decision to not enroll their child into a study, leading to delays in study

accrual and research progress. Participation gives patients access to new therapies

that are promising, but the best dose is often not yet known and side eects may be

present without ultimate direct benet for the patient. However, all clinical trials lead

to information that helps future patients. e dramatic success in the treatment and

cure of other childhood cancers such as leukemia, lymphoma, Wilms tumor, and

many other types would not have occurred without the participation of patients and

physicians in clinical trials. All clinical trials in children with cancer have scientic

rationale and the potential for benet, but no guarantee of benet. is is a challenge

to families as they are faced with the decision of participating or not.

Another challenge to progress in the treatment of DIPGs is the length of time it takes

to complete a trial. DIPG is a rare tumor and it may take several years to accrue an

adequate number of patients for a trial. A drug or therapy may sound very promising

based on information about its use in other tumor types or in an individual patient,

but to determine whether or not there is an actual benet for patients with a DIPG,

there needs to be a scientic evaluation through a clinical trial. If children are treated

with new therapies at random—meaning outside of clinical trials—there is risk of

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Chapter 13: Overcoming Research Hurdles in DIPG

exposing them to serious side eects, without the benet of learning whether the

treatment is eective and safe. To be scientically valid research, there needs to be a

sucient number of patients entered into the study to determine the benet of any

therapy. Given such a small patient population, it takes time to accrue the required

number of patients in order to give denitive scientic validity to the study. is too

can be a dicult research hurdle to overcome.

In the future, we hope to have enough understanding of DIPG biology to tailor the

treatment for each individual child based on an analysis of a tissue sample (biopsy)

from his or her tumor. We do not have that knowledge today, and such knowledge

will only come from rigorous scientic studies, which includes clinical trials.

How Can the Barriers be Removed?

As already noted, many barriers exist to progress in the research and treatment

of DIPGs. Because of the tumor’s location, surgery and biopsy are generally not

performed. e resultant lack of tumor tissue from patients at diagnosis limits

researchers’ ability to understand the biology of these tumors. Scientists must

therefore make inferences from what we know about similar tumors in adults

and children in our treatment approaches, which may or may not be appropriate.

So, how can progress be realized?

Parents of pediatric cancer patients are the advocacy voice of their children. It has

been through the initiatives of parent advocates that progress has been realized in

many types of childhood cancer treatment. In the early 1970s, a group of parents

of children with cancer formed Candlelighters Childhood Cancer Foundation

(now the American Childhood Cancer Organization) and lobbied Congress for

childhood cancer research funding. eir eorts led to 1) an increase in awareness

of the devastation of childhood cancer, 2) designated pediatric oncology program

funding within the National Cancer Institute (NCI), 3) the inclusion of pediatric

oncology language in President Nixon's National Cancer Act of 1971, and 4)

the development of information and support programs within Candlelighters.

Similarly, parents of children diagnosed with DIPG have a tremendous

opportunity to make a dierence in the future outcome of this disease. A number

of families have responded by forming non-prot organizations in memory

of their children. Some of these organizations provide funding for promising

research, some oer nancial help to families, some have websites populated

with invaluable DIPG specic information, and others raise awareness of this

disease in the community and amongst national funding agencies such as the

federal government and the NCI. Individual parents have dedicated their time to

the creation and administration of online groups in an eort to provide support

and allow families to connect with one another. All of these eorts contribute to

progress toward making life better for children with DIPG.

For some parents, donation of their child’s post-mortem tumor tissue is a way to

make a dierence. is seless act provides tissue that would not otherwise be

available for research. As a result, scientists have recently been able to establish

DIPG cell lines and animal models, and to advance their understanding of the

biology of these challenging tumors. It is hoped that this progress will make it

possible to quickly develop, test and prioritize DIPG treatments for evaluation

in clinical trials. Tissue donation is perceived by many families as a way for their

child to nally be free from the ravages of DIPG, while giving hope to those

children who will follow in their path. Sandy Smith and Kimberlee Spady are

two DIPG parents who, along with others, have devoted themselves to providing

families with information regarding, and/or assistance with, the planning of

autopsy tissue donation. It is their goal to ensure that once a family has made

the decision to donate tumor tissue, they will not be burdened with the details

of arranging the donation. ey also oer support to families from the time of

diagnosis, helping with treatment information, and hoping for the best possible

outcome for each child.

Individuals and foundations are working with determination to raise much needed

funds for on-going research eorts. One way a family can make a big dierence

is to team up with an established organization or group of organizations, because

as organizations grow, they are able to make more of an impact by funding larger

research projects. Individual families and groups of families around the world

have been able to fund national and international summits for researchers. ese

forums have provided opportunities for scientists to come together to share

data and ideas. An important factor to consider when teaming up with another

organization or foundation, is whether or not the organization has a scientic

advisory board that advises the organization. is helps to ensure that the research

projects that are funded are addressing the most important issues in the eld and

are of the highest quality.

In summary, there are many ways that families can honor their children with DIPG

by helping to promote progress toward improving current treatments. It remains

clear that ongoing research is required to develop a cure for children with DIPGs.

is research requires tissue to understand the biology of DIPGs, participants in

clinical trials to evaluate new treatment approaches, increased awareness of the

devastation of this disease, and nancial support for basic science and clinical

research. Although there are hurdles and barriers related to DIPG research and

Chapter 13: Overcoming Research Hurdles in DIPG

230

treatment, they will continue to be overcome as scientists, physicians and families

work together to overcome them.

231

Chapter 14: Genomics and Proteomics in DIPG

Chapter 14

The Future of

Genomics and

Proteomics in DIPG

Mark W. Kieran, MD, PhD

e sequencing of the human genome has resulted in a revolution in biology and

medicine that oers enormous possibilities leading to an improved understanding,

diagnosis, and treatment of human diseases. ese advances have largely been

achieved in two major domains. First, the development of new technologies

that can rapidly and cheaply analyze DNA, RNA, and proteins has lead to an

explosion in our understanding of the building blocks of the cells, and how they

interact with each other through the process of growth and development. e

second major advance has occurred in the area of bioinformatics. Developments

in computational sciences have permitted the storage and analysis of the billions

of fragments of tumor data that result from these technologic advances, and

provide the opportunity to place them in the context that better approximates

complex biologic systems. us, we now have the opportunity to examine the

genome of cancer as well as begin to understand it. e goal of this chapter will

be to review the technical advances, specically genomics and proteomics, and

place these in the context of future therapeutic developments for diuse intrinsic

pontine gliomas (DIPG). ese important advances are just now being applied

to DIPG and like most other advances, will take some time before their impact

is felt in the clinical treatment of DIPG.

Genomics

In its simplest form, genomics refers to the

reading of the genetic code of cells. DNA is

the genetic material that acts as the blueprint

for making new cells as well as all of the

Dr. Mark Kieran is the Director

of Pediatric Medical Neuro-

oncology at the Dana-Farber

Cancer Institute and Children’s

Hospital, Boston, MA.

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Chapter 14: Genomics and Proteomics in DIPG

information needed to maintain the current ones. Tumors often alter their DNA

(the blueprint), and divide into multiple "daughter" cells which then inherit the same

altered DNA, leading to the propagation of the cancer. When a cell divides, the two

new cells formed are called daughter cells and when they divide, four daughter cells

will be created etc. Alterations in the DNA occur via changes in the genetic code

which is made up of four nitrogen bases identied by the letters: A (adenine), G

(guanine), T (thymine), and C (cytosine). ese 4 letters spell out all of the proteins

that need to be made (called the coding regions) as well as the intervening sequences of

DNA that contain the control regions (called the non-coding regions) that determine

when proteins are made. When an error occurs in the code of a cell, not only does it

have the potential to aect that cell, but that error is also transmitted to every new

daughter cell. us, errors can accumulate, increasing the malignant phenotype of

the tumor, as well as its resistance to therapy.

How do Mutations in the DNA Sequence Cause Cancer?

ere are generally two types of genes that can sustain mutations leading

to cancer: tumor suppressor genes and oncogenes. In normal cells, tumor

suppressors make proteins that keep cells "in check" (e.g. suppress tumors).

However, if errors in the DNA of tumor suppressor gene(s) are acquired, and

these errors destroy the function of the tumor suppressor, then tumors are no

longer suppressed, and the cell is not kept "in check" any longer. While tumor

suppressors cause cancer by their absence, oncogenes cause cancer by their

presence. Mutations occur to oncogenes that impart new abilities of the protein

to cause cancer. e alteration in the DNA of oncogenes results in a protein

that instructs cells to continuously divide, with uncontrolled proliferation.

e cell that possesses these types of mutations determines the kind of cancer

observed. When these mutations happen in blood cells for example, leukemia

results. If they happen in a brain cell of the pons, the patient is diagnosed

with a diuse pontine glioma. us, we consider cancer (tumor) a result of

the accumulation of abnormalities in the DNA of cells. e major types of

alterations of the DNA that can occur in pediatric brain stem gliomas (and all

other cancers) are described below.

Mutation: Genes contain the sequence code necessary to make proteins,

and the proteins make up all cells and tissues. Mutations in the DNA occur

such that the sequence (blueprint) for a protein has an error in it resulting in

defective functioning. In other words, mutations in the genetic code result in

no protein being produced, or a defective protein being made. Mutations may

involve alternations in only one letter of the code (point mutation), many letters

(nucleotides), or the entire gene (deletions, amplications, see below). If the

altered protein has a critical role in cell proliferation, then the rst step toward

development of a tumor has occurred.

Translocation: Translocations of the DNA occur when certain parts of the

DNA coding for a protein, break into two and rejoin at a site belonging to a

dierent protein. is can sometimes result in a new molecule that tells the

cell to do the wrong thing. For example, if the protein responsible for rapid

proliferation of immune cells during infection accidently gets linked to the gene

that makes astrocytes (the cells of the brain that hold everything in place), you

may create a new "molecule" that accidentally tells astrocytes to rapidly divide.

Deletions and amplications: Deleting or amplifying regions of the DNA is a

common way in which errors can be introduced into the genetic material of the

cell. If a piece of DNA coding for the molecules that stop cellular proliferation

is lost (deleted), then uncontrolled cell division can result. In a similar way, if

a segment of DNA that codes for the protein that makes cells start to divide is

amplied, then the cell is stimulated to proliferate and tumor growth ensues.

Truncation (partial deletion of a gene): Many genes are organized such that

one part possesses the functional part of the molecule (stop or start cell division)

while the other end possesses the control sequences. us, knocking out bits of

a gene, rather than the whole thing, can sometimes have a signicant impact on

the function of that molecule. For example, if the control region of a molecule

is lost, it may continue to activate the cell even at times when it should be in

the "o" position.

Epigenetic control of methylation and acetylation: Some cells are out of

control not as a result of some assault on the integrity of the DNA but because

a perfectly normal protein is expressed in the wrong place or at the wrong time.

For example, during early embryogenesis, the fertilized egg must rapidly divide

billions of times as the fetus grows. is is an example of normal proliferation. If

an astrocyte that has nished dividing accidently turns on the embryonic signal

for a cell that is supposed to be dividing, then it will begin to divide even in

the absence of any mutations, translocations, deletions, or amplications. e

process of abnormal expression or timing of a normal gene may be of particular

importance for pediatric cancers where the proliferation of many cell types

associated with growth and development are still active.

e eld of genomics is typically divided into two major components: structural

and functional. Advancements in the evaluation of the structural organization of

the DNA required technology that could rapidly, inexpensively and reproducibly

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Chapter 14: Genomics and Proteomics in DIPG

analyze the genetic code of both normal and abnormal tissue. is would then

allow for the identication of the mutations, translocations, amplications,

or deletions of the DNA discussed above. Improvements in this technology

are happening rapidly, and genomic analysis can now be done at both large

and small academic institutions around the world. Many of these techniques

are performed on small inert platforms (often called "chips") where millions

of reactions can be performed simultaneously. e complexity of each chip

determines how much information can be gathered from the sample being

tested. Chips are available for the study of DNA (the genetic material), RNA

(the intermediate code derived from the DNA) and proteins (the translated

end product of the RNA code into amino acids). Simply nding an alteration

in the DNA, RNA, or protein however does not prove that it is responsible

for disease. us, clinicians and scientists must map the genetic abnormalities

identied, onto the tumors ability to divide, inltrate, and escape treatment.

For example, a mutation in a protein not expressed in the tumor is unlikely

to be responsible for the tumor. us, each abnormality in the DNA, RNA,

and protein must be assessed for its active role in the tumor. Once identied,

the relevant abnormalities can then be considered for targeting with drugs or

other therapies.

Proteomics

Changes in DNA, RNA, or epigenetic events may be responsible for the abnormal

function associated with many tumors, but the analysis of the proteins themselves is

the most direct method to assess for critical changes in a cell’s function. Recall that

the purpose of DNA is to provide the code (via RNA) for all proteins. e eld of

proteomics uses a variety of techniques that allow for the separation of the thousands

of proteins in a cell, as well as the structure and function of many of these molecules.

Proteomics is usually divided into two critical phases. First is the separation of the

dierent proteins in a sample—typically achieved by their size and overall charge

(basic or acidic); and second is the identication of the dierent proteins—usually

achieved through a technique called mass spectroscopy. As with genomic analysis,

tissue is necessary for proteomics; however because many tumors shed their proteins

in the blood or cerebral spinal uid (CSF), these samples can sometimes act as

surrogates to tumor tissue. Our increasing ability to identify the location, quantity,

and activity of dierent proteins in a tumor sample has provided the pharmaceutical

industry with the targets on which tumor specic inhibitors can be developed. In

fact, a number of these drugs are already being used for a variety of dierent adult

cancers and have started testing in pediatric patients as well.

Genomics of DIPG

A primary requirement for genomic analysis of cancer, is actual tumor

material. While the biopsy of pontine gliomas was frequently performed in

the 1970s (before any of the current genomic techniques were available),

a change in national policy occurred in the 1980s for sound scientic and

clinical reasons (see chapter 19). e diagnosis of DIPG was becoming easier

to dene radiographically through CT scans in the 1970s and in particular

with MRI scans in the 1980s. Furthermore, with the very poor prognosis of

these tumors with or without biopsy, the lack of justication for a biopsy, in

which patients could experience signicant neurosurgical damage, resulted in

a moratorium on this procedure. Over the intervening 30 years, innumerable

clinical trials of radiation alone or in combination with chemotherapy,

biologic therapy, anti-angiogenic (anti blood vessel) therapy, gene therapy,

immunotherapy, etc. have been performed. None of these approaches have

signicantly altered the outcome of this disease when compared to treatment

with radiation therapy alone. Because none of these children had a biopsy, the

reason these combination therapies failed remains unknown. When biopsy

was performed, this was generally done because the tumor was atypical and

histologic assessment was needed. e majority of these atypical lesions were

discovered not to be DIPG. ese studies were important at they demonstrated

the relative safety of biopsy in this region.

Adult DIPG and animal models of pontine gliomas (not all of them are diuse

and intrinsic) are helping guide our understanding of the important genomic

changes that help maintain a tumor’s growth and resistance to therapy. Unlike

most diseases, adults rarely get DIPG and in the few reports of this disease in

these patients, the clinical course appears dierent than in children—a nding

that suggests that DIPG prefer the environment of the pediatric pons. While

it is quite easy to start tumor growth in animals for lung, breast, prostate,

or colon cancer, mice do not develop DIPG spontaneously. Fortunately, a

number of groups have been working on the development of animal models

and the rst reports of possible contenders are now available (see chapter 15).

While these models are likely to be useful in extending our understanding of

this disease, they are unlikely to provide all of the answers. As we discovered

many years ago, we have cured just about every tumor type in mice many

times over and yet those same results have often not been realized in humans.

ey may, however, become good animal models for “proof of principle

discoveries” once pediatric DIPGs are analyzed for their genomic changes.

To overcome the lack of fresh tumor material derived from the time of

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Chapter 14: Genomics and Proteomics in DIPG

diagnosis of patients with DIPG, many centers have initiated genomic

analysis of autopsy material. While these studies will provide some important

insight into the biology of these tumors, they all suer from the fact that the

molecular analyses performed post-mortem are altered by the initial treatment

of the tumor with the variety of procedures mentioned above (radiation,

chemotherapy etc.), and by the relatively limited sample size of these studies.

For example, in a study of 11 cases (9 autopsy and two newly diagnosed

DIPG), abnormal expression of PDGFRα in 4 cases and PARP1 in 3 cases

were identied. Equally important in these studies was the identication that

the genetic abnormalities in DIPG were dierent from malignant gliomas in

other parts of the brain. us, molecular proles of supratentorial malignant

gliomas cannot always be used to identify appropriate pathways for the

treatment of DIPG, which perhaps helps to explain the three decades of failed

clinical trials. ese studies also support a commonly held belief in the eld

that DIPGs are a heterogeneous population of tumors, and that one treatment

is not likely to be useful in all cases.

Another approach to the molecular classication of DIPG has used imaging.

Both MRI/MRS and PET/SPECT can identify individual markers in a tumor

without the need for biopsy. For example, an 11year old female with a large

pontine tumor demonstrated strong uptake of In-111-pentreotide, which

identies the presence of somatostatin receptors in the tumor. Similarly, PET

imaging allows for the detection of glucose metabolism in tumors and can

provide some important metabolic information in DIPG. As new pathways

in DIPG tumors are identied, the ability to follow tumor growth or response

with these types of imaging markers will likely make these modalities of greater

importance in the near future.

With significant advances in neurosurgical technique and previously

performed biopsies (in selected cases), the ability to safely biopsy brainstem

tumors is becoming better recognized. In a landmark study demonstrating

the safety of biopsy of DIPG, 24 consecutive children successfully underwent

this procedure in Paris. Not only did the patients not suer long-term

consequences of the biopsy, in two patients, a diagnosis other than a DIPG

was identied. e rapidity of improved neurosurgical techniques is now

opening the door to direct administration of therapy into the brainstem,

not just biopsy. As our improved molecular understanding of these tumors

continues, the ability to administer drugs directly into the pons will likely play

a greater role in treatment. A major regulator of cellular proliferation known

as p53, has been extensively evaluated in both newly diagnosed and autopsy

cases of DIPG, as well as other brainstem tumors. is critical regulatory gene

was abnormal in over half of the cases in two dierent studies. Unfortunately,

there are currently no drugs targeting p53. While only limited information

on the molecular phenotype of pontine gliomas is currently available, the

opportunity to change this is rapidly approaching.

We now nd ourselves at an important crossroads to the molecular classication

of DIPGs. For the last 30 years, it has been felt that the diagnosis of DIPG is

easily made by imaging and clinical evaluation. e risks of biopsy within the

pons were felt not to justify routine biopsy, and the moratorium on biopsy

was considered appropriate. Today, with improved neurosurgical techniques

and the availability of sophisticated genomic technologies that can derive

extensive data from very small biopsy samples, the tide has turned. DIPG

is not a single disease caused by a single mutation. Rather, there are a large

number of abnormal pathways that likely account for these tumors and only

by identifying them can we expect to develop the kinds of interventions that

will be successful.

In this regard, two exciting developments have recently been discussed at

national meetings but not yet published. e rst is the experience of the

French group that has expanded their biopsy program from 24 to 70 patients,

and has completed a prospective trial with an EGFR inhibitor in these patients.

A dierence in the outcome of children expressing abnormalities of the EGFR

pathway was signicantly better than in those who received the same therapy

but without the abnormality (suggesting their tumors were being driven by

something else). us, we may have the rst indications of an approach that

can begin to make small improvements in the time to progression of DIPGs.

While this may seem like a small step, if validated, it may represent the rst

time a therapy has really impacted the time to progression of this aggressive

disease.

e second important development is the initiation of a 20 institution

clinical trial within the United States run through the Dana-Farber Cancer

Institute, in which all patients with DIPG will undergo biopsy and extensive

molecular proling, and the treatment of these patients will be based upon

the expression of certain pathways in their tumors. us, rather than a single

treatment for everyone, each patient will receive a treatment designed for the

expression pattern of their specic tumor. From this trial, we will have the

opportunity to fully evaluate the molecular prole of newly diagnosed DIPG,

while at the same time, begin to adapt personalized therapy based on these

unique patient proles.

Chapter 14: Genomics and Proteomics in DIPG

238

e outcome for patients with DIPG remains poor. irty years of guessing

at treatment has not helped improve the outlook and has subjected countless

thousands of these children to toxic therapies that had no benet. With recent

advances in molecular technology and neurosurgical techniques, we are now

poised to investigate the underlying biology of DIPG—the rst step toward

rational and eective therapy.

239

Chapter 15: Animal Models for DIPGs

Chapter 15

Animal Models for

DIPGs

Oren J. Becher, MD

Diuse intrinsic pontine glioma (DIPG) is a rare tumor that arises in the pons of

children and is currently incurable. e only active therapeutic agent is radiation,

which unfortunately provides only temporary relief. Clinical trials for the past

30 years evaluating novel agents have failed to identify additional active and

eective agents against this tumor. In recent years, molecular genetic technologies

have been quite successful in identifying new molecular targets in numerous

cancers which has led to targeted drug development, and an increasing number

of promising targeted agents. e challenge is how to determine which novel

agents or combination of agents should move into clinical trials for DIPG. As

this is a rare tumor, it is impossible to test every new agent and combination of

these agents in these patients. ere are not enough patients to accomplish this

feat. An additional complexity to new drug development is that DIPG tumors

are heterogeneous and may be comprised of multiple dierent subtypes, where

each subtype may respond dierently to specic drugs.

Why Do We Need Animal Models?

One idea that scientists thought might be helpful is to develop animal models that

would allow for screening of novel agents and combinations. e results from these

animal models could be predictive of anti-tumor activity in children with DIPGs,

leading to the discovery of the most promising drugs for human DIPG trials. At

this point in time, this ideal has yet to be fully realized. ere is currently one main

obstacle that must be overcome so that

predictive animal models can be developed.

Scientists need a better understanding of the

genomic alterations that drive the growth of

human DIPGs so as to guide the development

of accurate animal models to potentially treat

Dr. Becher is an Assistant

Professor in the Departments

of Pediatrics and Pathology

at Duke University School of

Medicine, Durham, NC.

Chapter 15: Animal Models for DIPGs

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Chapter 15: Animal Models for DIPGs

it. Unfortunately, scientists do not have a good understanding of the drivers of these

tumors, although there are several research groups who are currently working on this,

and it is believed that answers to these questions are within reach.

In spite of the limited understanding of the biology of human DIPGs, there are several

animal models that have been described, although it is not clearly known if they are

predictive. In the next few paragraphs, I will review the various DIPG models that

currently exist, and the advantages and disadvantages of each.

DIPG Animal Models Available

Most of the current animal models for DIPGs are rat allograft models and only

recently a genetically engineered DIPG mouse model was developed as well.

e three main types of animal models for glioma are:

1. Allograft: Chemically induced tumors in rats that mimic DIPG.

2. Xenograft:

Human tumor from patients, transplanted into mice or rats.

3. Genetically Engineered Mouse Model/GEMM: Mice given new genes

(transgenics) that cause tumors appearing similar to DIPG, and sharing

some molecular signatures of the human tumor.

Allograft: ere are several rat glioma cell lines available, which were generated

by injecting rats with repeated dosing of chemotherapy until the rats developed

gliomas, which were then cultured and propogated. ere are currently several

rat glioma cell lines available. ree of these cells lines (C6, 9L, and T9 gliomas)

were induced by repeated injections of methylnitrosurea (MNU) to adult

rats. Two other cell lines (RG2 and F98 gliomas) were chemically induced by

administering ethylnitrosurea (ENU) to pregnant rats. In this case, the progeny

developed brain tumors that subsequently were propagated in vitro and cloned.

Both MNU and ENU are alkylating agents, which mean that they damage

DNA by adding alkyl groups to it. Most of the above mentioned rat glioma

cell lines are being used to generate brainstem gliomas by direct injection

into the brainstem of either rats of the same strain or immunodecient rats.

Depending on the number of cells injected, the cell line used, and the age of

the rats at the time of injection, the rats go on to develop brainstem tumors one

to several weeks later. A head-to-head comparison between 3 week-old and 10

week-old rats injected with the same cell line and the same number of cells into

the brainstem demonstrated that the microenvironment of young rats allows

for the formation of diuse pontine tumors, while the microenvironment of

older rats allows for the development of focal brainstem tumors. Interestingly,

there have not been many trials testing systemic chemotherapy using such

models. is is most likely due to the belief that systemic chemotherapy for

the most part does not get into the brain tumor due to the blood-brain barrier

(BBB). erefore, most of these models have been mainly used to test for CED

(convection enhanced delivery) of chemotherapy such as carboplatin. A detailed

description of CED is given in chapter 17 of this book.

Xenograft: Recently, a rat xenograft model was developed whereby adult

human glioma cell lines were implanted into 6-week old immunodecient

rats. Prior to implantation, some of the cell lines were maintained in media

with serum (these are usually grown as cells adherent to plastic); some of the

cell lines were maintained as subcutaneous xenografts (grown under the skin

of immunodecient rats); and one cell line—the GS2 cell line was maintained

as neurospheres (these are spherical colonies in suspension in media).

It is well documented that gliomas which are cultured in epidermal growth

factor (EGF) and basic broblast growth factor (bFGF), and are grown as

neurospheres, have genomic signatures that most resemble the signatures of

naturally developing (in vivo) gliomas. While an advantage of such a model is

that the tumor cells are human, the disadvantage is that adult glioma cell lines

have dierent genetic alterations than DIPGs. In addition, the in vitro culturing

step likely alters the biology of the cells even in neurosphere conditions. Lastly,

such models remove the role of the immune system in DIPG tumorigenesis.

GEMM: Genetically engineered mouse models for brain tumors have been

developed since 2000 and are a more recent addition to the animal modeling

toolbox. e advantage of such models is that the genetic alterations which

initiate and drive tumor formation are known and recapitulate the genetic

alterations present in the respective human tumors. erefore, the genetic

alterations of the respective human tumors should be determined so as to guide

the development of the genetically engineered mouse model. Such models

are helpful in determining if a particular genetic alteration can drive tumor

formation. Not all genetic alterations are equally meaningful and scientists divide

genetic alterations into “drivers” and “passengers” to imply that only certain

genetic alterations can drive tumor growth (so-called driver mutations) while

the role of other genetic alterations is less clear (so-called passenger mutations).

ere are numerous technologies that can be used to generate these mice. One

brain tumor model uses conditional knockout mice where mice that have

lost one copy of p53, PTEN, and NF-1 develop brain tumors through loss

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Chapter 15: Animal Models for DIPGs

of heterozygosity. A second system is the RCAS-tv-a system, which allows for

oncogene delivery by injection of virus producing cells into areas of interest such

as the brainstem. Normal mice do not express the receptor (called tv-a) and so

are not susceptible to infection by RCAS vectors. However, two transgenic mice

were developed that express the tv-a receptor in progenitor/stem cell of the brain

compartment: nestin tv-a mouse and GFAP tv-a mouse. (A transgenic mouse

is a mouse which integrates an additional piece of DNA in its germline called

a transgene, and so every cell in the mouse acquires this extra piece of DNA.)

Recently a genetically engineered mouse model for brainstem gliomas was

developed which recapitulates the genetic alterations of a subset of the human

disease. It was recently observed that PDGFRα is amplied in 20% to 30%

of DIPGs which means that the receptor for PDGF ligand is expressed in

high levels in a subset of DIPGs. e derived mouse model uses the retroviral

delivery system described above, whereby a virus is used to deliver oncogenes to

specic areas in the mouse brain. Tumors are generated by the over-expression

of PDGF-b in nestin positive cells which line the oor of the 4th ventricle

at postnatal day 1 to 3. Nestin positive cells are cells that express nestin,

an intermediate lament that is expressed in progenitor cells in the brain.

Overexpression of PDGF-b results in the formation of low-grade brainstem

gliomas. e addition of Ink4a-ARF null genetic alteration (which has been

described as a common alteration in human DIPGs and normally restrains

cell division), together with PDGF-b overexpression, results in the formation

of high-grade brainstem gliomas, or DIPGs, with high incidence by six weeks

of age.

Advantages of genetically engineered mouse models are that a) the genetic

alterations are clearly dened; b) the tumor forms in the right microenvironment

(the brainstem); and c) the tumor forms at the right time period (pediatric). It

is generated completely in vivo and develops de novo in the mouse. As tumors

are a complex cellular setting, it is important that this environment is as close

to reality as possible. Another advantage of the genetically engineered mouse

model is that it can be used to determine the cells-of-origin for a particular

tumor. e cells-of-origin for the recently developed DIPG mouse model were

derived from cells lining the oor of the 4th ventricle and aqueduct. However it

does not tell us with any certainty that the cells-of-origin for human DIPGs are

similar cells. One disadvantage of this animal model is that it is probable that this

genetically engineered DIPG model may be oversimplied, as human DIPGs

likely contain more genetic alterations than simply PDGF-b overexpression

and Ink4a-ARF loss. It remains to be determined whether therapeutic agents

with antitumor activity in this animal model will also be active in children

with DIPGs.

ere is no perfect animal model. Ultimately there is a need for a predictive

model of activity in the clinic. An added complexity is that the human tumors

are heterogeneous and so it is likely that we will need to classify them into

several groups based on their genetic alterations. Each subtype will then require

specic therapy and an associated specic DIPG animal model. Of note, adult

gliomas have recently been subdivided into three groups based on the genetic

alterations of the tumors.

One advantage of rat brainstem glioma models is that the rat brainstem is

larger than the mouse brainstem. As a result, it may be easier to conduct CED

preclinical studies. e disadvantage of rat allograft models are that in most cases

the genetic alterations of the tumors are not clearly dened and may change

over time. Most of the cell lines are maintained on plastic dishes that are quite

articial. In addition, as mentioned, human tumors are complex with several

cell types interacting including tumor cells and various stromal cells such as

blood vessel cells, support cells, and immune cells. erefore it is ideal for the

animal to develop the tumor within a normal immune system and with all of

the support cells being present from tumor onset.

Preclinical Testing

e question that often arises, is how much preclinical evidence is needed before a

decision is made to move a new agent into the clinic for DIPGs? ere are several

levels of preclinical evidence and I personally believe that novel agents should move

to the clinic after full preclinical testing has been done. is means that a novel

agent has been tested in cell lines; in DIPG xenograft rat models where the xenograft

originated from a DIPG tumor that has been propagated in vivo or, second best,

neurospheres; and has also been tested in genetically engineered DIPG subsets.

Depending on the therapeutic agent, some agents cannot be tested in cell lines at all

and can only be tested in vivo or in neurospheres. An example is the sonic hedgehog

pathway inhibitors, which cannot be tested in cell lines grown on plastic dishes, as

the pathway is not functional in such conditions.

Once an agent shows strong promise in preclinical testing, a decision is then made

to test it in patients with DIPGs. e rst clinical study is a phase I study which is

used to determine the correct dose to use in the clinic, as well as assess for toxicities

of the drug. Even if a drug has already been tested in adults, it will still need to be

tested in a phase I trial for children as children at times metabolize drugs dierently

Chapter 15: Animal Models for DIPGs

244

than adults. Usually phase I studies are open for children with diverse cancers but it

does not mean that a particular drug will not be active in DIPGs. Once the safety and

dosing are established in a phase I study, then a phase II trial is designed to determine

if the drug or drug combination is active against DIPGs. Phase II studies are usually

done on a selected tumor subtype. Phase III studies are large studies that are used to

conrm promising results from phase II studies (see chapter 5).

Conclusion

At this point in time, most clinicians do not believe that animal models can help

guide which therapeutic agents or combination of agents will be active in the clinic.

e burden of proof lies with the animal-modeling eld to continue to improve

the animal models so that eventually they will be predictive of activity in the clinic.

Similar to what has been done in adult gliomas, in the near future DIPGs will also

be grouped into genomic subgroups, and genetically engineered animal models will

be developed for each subtype. It is my hope that these genetically engineered DIPG

mouse models will be predictive of activity in the clinic, but it remains to be seen if

this will indeed be the case.

245

Chapter 16: Neural Stem Cells and DIPG

Chapter 16

Neural Stem Cells and

DIPG

Michelle Monje, MD, PhD

Diuse intrinsic pontine gliomas (DIPG) occur strictly in the ventral pons

and typically during a relatively specic period during mid-childhood, peaking

between ages 6 and 8. e age and location-specic nature of DIPG suggests that

the underlying pathophysiology may involve dysregulation of a developmental

process. In this context, it makes sense to approach DIPG from the vantage of

neural stem and precursor cell biology.

Normal Neural Stem Cells

Neural stem cells—cells that can renew themselves and also can make all types of

neural cells (neurons, oligodendrocytes and astrocytes), are well-recognized in the

brain and spinal cord of both children and adults. Two populations of neural stem

cells are very well studied. ese two populations reside in the hippocampus, a brain

structure important in memory function, and in what is called the subventricular

zone (i.e. just below the ventricular walls) of the lateral ventricles. It is known that, at

least in mice and rats, stem cells exist throughout the ventricular system of the brain

and spinal cord, but little attention has been paid to those in the subventricular zone

of the third and fourth ventricles. e fourth ventricle sits immediately behind the

pons. e term “neural precursor cell” includes both true stem cells and cells that

are somewhat further along the path of dierentiation but still give rise to daughter

cells. Both types of cell—stem and “precursor”

are important to developmental processes in

the brain both before and after birth.

Cancer Stem Cells

Cancer stem cells (CSCs) represent a

subpopulation of cells that can generate all

Dr. Monje is an Assistant

Professor of Neurology and

Neurological Sciences at

Stanford School of Medicine,

and Practicing Pediatric Neuro-

oncologist at Stanford Hospital,

and Lucile Packard Children’s

Hospital, Stanford, CA.

Chapter 16: Neural Stem Cells and DIPG

246

247

Chapter 16: Neural Stem Cells and DIPG

cell types found within a tumor and are thought to be responsible for tumor

growth and spread. Like normal stem cells, cancer stem cells possess the capacity

for self-renewal and multi-potency. (Multi-potent cells can make all the cell

types in a tissue. In this case the tissue is the tumor.) e rst cancer stem

cells were described in acute myeloid leukemia, and have now been shown in

many solid tumors, including many brain tumors such as glioblastoma and

ependymoma. CSCs isolated from primary brain tumors possess many of the

characteristics of normal neural stem cells, and can recapitulate the tumor in

vitro and in vivo, whereas other cell types from the tumor cannot. CSCs are thus

a small proportion of a tumor, but are solely responsible for tumor propagation.

e relationship of normal neural stem cells to cancer stem cells is somewhat

controversial, but there is an emerging consensus that many brain tumors

arise from stem or precursor cell populations in both children and adults.

Excellent examples of this point include “radial glia” cells (a type of stem cell)

giving rise to ependymoma and subventricular zone neural stem cells giving rise

to central neurocytomas. With respect to more lineage-restricted precursors,

Shh-responsive granule cell precursor cells of the cerebellum give rise to

medulloblastoma in many cases, and recent animal model data indicate that

oligodendrocyte precursors give rise to periventricular low grade gliomas in a

mouse model of platelet-derived growth factor (PDGF) overexpression. Brain

tumor stem cells exhibit many of the same marker proteins and utilize many

of the same signaling pathways as normal neural stem cells. Understanding

normal neural stem or precursor cells in the brainstem may thus shed light on

brainstem tumor pathogenesis.

What Stem Cells Need to rive—the “Stem Cell Niche”

Normal stem cell niche

Neural stem cells in the childhood and adult nervous system reside in a niche

of signaling factors, extracellular matrix composition and specialized cell types

that support neural stem cell function for that brain region. Perhaps best studied

is the stem cell niche that supports forebrain neurogenesis in the hippocampus.

is specic microenvironment necessary for stem cell production of new

neurons is referred to as the neurogenic niche. Transplantation experiments

demonstrate that neurogenesis is restricted in the postnatal brain to regions

in which it occurs naturally, namely the subventricular zone (SVZ) and the

subgranular zone (SGZ) of the hippocampus. In general, microenvironmental

determinants of neurogenesis include the presence of the trophic signals

required for progenitor cell proliferation, dierentiation and survival, and

the absence of inhibitory factors. Neural stem/precursor cells form a close

anatomical relationship with the small vessels in the neurogenic region, and this

neurovascular relationship—the so-called “vascular niche”—is believed to be

crucial not only for nutritional but also for growth factor support. Vessel cells

(endothelial cells, pericytes) and glial cells (astrocytes) all contribute to the stem

cell niche. Hippocampal astrocytes play key roles in creating and maintaining

the neurogenic niche. As noted above, many of the signaling pathways central to

prenatal neural development are conserved in postnatal neurogenesis, including

pathways called Wnt, Shh, and Notch. Additional molecules with potent pro-

neurogenic eects include broblast growth factor (FGF), vascular endothelial

growth factor (VEGF) and certain neurotransmitters. An important negative

regulator of the neurogenic microenvironment is microglial cell inammation,

particularly in disease states. Pro-inflammatory cytokines elaborated by

microglial cells in certain states of activation, including IL-6 and TNF-alpha,

inhibit neurogenesis via a specic blockade in neuronal dierentiation mediated

by Notch signaling, as well as a non-specic increase in precursor cell death.

e eects of inammatory cells on neurogenesis are complex and depend on

the microglial phenotype involved; microglia stimulated by cranial irradiation

or systemically-administered lipopolysaccaride (LPS, also known as endotoxin)

inhibit neurogenesis, while microglia stimulated by IL-4 or interferon gamma

promote neurogenesis.

Cancer stem cell (CSC) niche

Just as cancer stem cells share many properties with normal stem cells, so

the cancer stem cell niche is similar to the normal stem cell niche. e

vascular niche appears to be recapitulated in human brain tumors. Cancer

stem cells, dened molecularly by expression of the proteins CD133 and

Nestin, are localized in close proximity with tumor microvessels in human

medulloblastoma, glioblastoma, oligodendroglioma and ependymoma. e

relationship between cancer stem cells and tumor microvessels is bidirectional:

glioblastoma cells induce angiogenesis (new vessel cell growth) via VEGF

elaboration, and vascular endothelial cells supports glioblastoma cell

tumoriogenicity. Treatment of a mouse orthotopic glioblastoma model with

the VEGF blocking agent bevacizumab (Avastin) depletes CD133+ cells,

decreases tumor vascularity and reduces tumor growth rate. Accordingly,

bevacizumab has shown modest clinical ecacy in glioblastoma, at least in

adult glioblastoma of the forebrain. Highlighting the dierences between

DIPG and adult glioblastoma, bevacizumab is not ecacious for DIPG.

Important determinants of the DIPG cancer stem cell niche are yet to be

dened.

Chapter 16: Neural Stem Cells and DIPG

248

Stem Cells in DIPG

Cell of origin

Presently, intense research is underway to identify the cell type in the normal

childhood pons from which DIPGs originate. e cell type that transforms

and gives rise to DIPG could be a neural stem cell, a neural precursor cell type

(that is destined to give rise to glial cells or neuronal cells) or a dierentiated

cell type (glia or neurons). Lessons learned from other pediatric brain tumors

teach us that the most likely candidate would be a neural stem or precursor

cell. Neural stem and precursor cells are not well described in the brainstem,

but current research will soon shed light on candidate cells of origin for DIPG.

Understanding the cell of origin for DIPG is of fundamental importance to

elucidate mechanisms by which DIPG may form, and thus potential targets

for treatment.

DIPG cancer stem cell

Researchers are working to identify and characterize a cancer stem cell in DIPG.

is research requires fresh tumor samples for cell culture, and scarcity of tissue

for research has limited progress in this area until very recently. Donation

of tumor in the early post-mortem period after the loss of a child allows for

successful cell culture of both normal brain and brain tumor tissue. is

strategy can allow crucial research to be done without putting a child through

an additional procedure such as a biopsy. Identifying and studying the cancer

stem cell of DIPG may elucidate new targets for therapy that are at the core of

DIPG growth and propagation.

A few words on hematopoietic stem cell and bone marrow transplant

Hematopoietic stem cell transplant (HSCT) and bone marrow transplant are

designed to rescue the bone marrow after intensive chemotherapy or to provide

cell replacement therapy for certain genetic diseases. At present, there is no role

for either HSCT or bone marrow transplant for DIPG.

249

Chapter 17: Convection-Enhanced Delivery in DIPG

Chapter 17

Convection-Enhanced

Delivery in DIPG

Zhiping Zhou, MD, PhD

Mark M. Souweidane, MD

Diuse intrinsic pontine glioma (DIPG) is locally highly inltrative. In this

type of tumor, cancer tissue cannot be distinguished from normal brain tissue

macroscopically. is inltrative nature makes eective therapy extremely dicult,

if not impossible. To be clinically useful, a therapy must have the ability to

selectively target and kill tumor cells without signicant damage to the normal

brain tissue. Given the need for cell specicity, surgical resection and stereotactic

radiosurgery have limited utility, pose a great risk of injury and are therefore rarely

an option to consider. Conventional radiation therapy is currently employed

routinely as a palliative approach. e improvement of newer chemotherapeutic

agents’ tumor selectivity and the development of targeted therapeutic agents in

recent decades raise hopes that improved chemotherapy will lead to improved

outcome. Paralleling this development has been the promising advance in drug

delivery to the central nervous system via local delivery systems to overcome the

blood-brain barrier (BBB), one of the major hurdles in delivering drugs to the

brain.

In this chapter, we will be discussing the application of convection-enhanced

delivery (CED), also known as interstitial infusion, in the treatment of DIPG.

CED is a technique designed to deliver drugs directly into the tumor at high

concentrations. is avoids or at least greatly reduces systemic exposure to the

drug. Drugs being studied for delivery through CED include conventional

chemotherapy drugs, novel small molecule agents and macromolecules such as

therapeutic antibodies, immunotoxins, and

viral vectors, some of which would otherwise

never gain access to the brain.

Dr. Zhou is an Instructor in the

Department of Neurological

Surgery at Weill Cornell Medical

College, New York, NY.

Chapter 17: Convection-Enhanced Delivery in DIPG

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Chapter 17: Convection-Enhanced Delivery in DIPG

Blood-Brain Barrier

Chemotherapy may be administered systemically or locally. In systemic chemotherapy,

the drug is administered orally or intravenously. An important limitation of systemic

chemotherapy in the treatment of brain tumors is the existence of the blood-brain

barrier (BBB). e BBB isolates the circulating blood from cerebrospinal uid

(CSF) in the central nervous system (CNS). It occurs along cerebral capillaries and

consists of tight junctions (zona occludens) that do not exist in systemic circulation.

Endothelial cells joined by tight junctions restrict the entry of microscopic objects

(e.g., bacteria) and large or hydrophilic molecules into the CSF, while allowing

the diusion of small hydrophobic molecules (O

, certain hormones, CO

, etc.).

Typically, molecules with molecular weight greater than approximately 40kD are

unlikely to penetrate the intact barrier. For the brain’s supply of nutrients and removal

of metabolites, cells of the barrier actively transport substances such as glucose across

the barrier with specic proteins (transporters). e BBB acts eectively to protect

the brain from many common bacterial infections and some toxic substances. Yet

it presents a major challenge in delivering therapeutic agents to specic regions of

the brain for the treatment of brain tumors and other disorders. Most cancer drugs

are not able to permeate the BBB because they are polar in structure or too large in

molecular weight. Even for drugs that are able to cross the cerebral capillary bed, it

is dicult to achieve optimal concentrations due to systemic toxicity.

Another diculty in the delivery of drugs for the treatment of brain tumors is how

to direct those agents to the specic anatomic region or tumor mass to reduce the

disturbance of normal neurological functions. Several strategies have been developed

in an attempt to overcome this barrier, including: 1) the temporary disruption of

the BBB, 2) modication of drugs to enhance their ability to permeate the BBB and

3) local delivery methods such as intratumoral/intra-cavitary embedding of drug-

containing polymers or microchips, intra-arterial injection, direct injection of drugs

into the tissue or CSF in the ventricles or subarachnoid space, and CED to deliver

drugs directly into the extracellular space.

Local Delivery

Direct injection into the tumor or CSF is

one of the earliest local delivery methods

attempted. When injected into the tumor,

it relies on diusion for the drug to reach

the cancer cells not directly adjacent to the

injection site. erefore the drug has an

uneven distribution and can only reach the

tumor tissue that is a short distance from the injection site. With small molecules,

depth of distribution is often limited to several millimeters, with an exponential

decay in concentration from the point source. us, the distribution of therapeutic

concentrations of a drug is limited to a small volume of tissue around the injection

site, often with very high and sometimes toxic concentration at the center. Drugs

can also be injected directly into the CSF, and the drug is usually only able to

reach a shallow layer of the brain using this technique.

Drug-containing polymers and microchips are a more recent development and

they can be embedded at the time of surgical resection of brain tumors. As in the

case of direct injection, this method relies on diusion for the drug to spread past

the embedding site and has similar limited and uneven distribution.

Convection-Enhanced Delivery

Convection-enhanced delivery (CED) is a novel drug delivery method rst

developed by a research group directed by Edward Oldeld at the National

Institute of Neurological Disorders (NINDS) in the early 1990s. is method

was named convection-enhanced delivery because the therapeutic molecules are

distributed into the extracellular space driven by a small, persistent hydrostatic

pressure generated by an infusion pump, essentially, forced convection of a uid

containing a therapeutic agent. In contrast to diusion which depends on a

concentration gradient to distribute the molecules, the use of hydrostatic pressure

in CED allows for the distribution of a homogeneous concentration of small

and large molecules over large distances by displacing extracellular uid with the

infusate (uid infused). In practice, the agent is delivered into the parenchyma

or tumor through a microcatheter, or multiple microcatheters, inserted into the

tissue. Infusion rates typically range from 0.1-10µl/min. e distribution from

a single point source results in an elliptical to spherical distribution and spatial

distribution is in some degree dependent on the tissue type (i.e., grey matter

versus white matter). In a given tissue type, distribution volume is approximately

linear to infusion volume.

CED into brain parenchyma, both white and gray matter, has shown reproducible

large volumes of distribution with homogeneous drug concentration. Oldeld

group’s initial work showed that the concentration fall-o at the border is steep,

resulting in a potentially large benet in the delivery of cancer drugs in reducing

toxicity to surrounding normal brain tissue.

Several factors inuence the distribution volume. One key factor to achieve a

large volume of distribution is the stability of the agent in the extracellular space.

Dr. Souweidane is the Director of

Pediatric Neurological Surgery

at Weill Cornell Medical College

and Memorial Sloan-Kettering

Cancer Center. He is also

Vice Chairman and Professor

of Neurological Surgery and

Professor of Neurological

Surgery in Pediatrics at Weill

Cornell Medical College, New

York, NY.

Chapter 17: Convection-Enhanced Delivery in DIPG

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Chapter 17: Convection-Enhanced Delivery in DIPG

Lipophilic agents may be exported transvascularly through blood vessels leading

to a high eux of the drug and limited distribution. Some other drugs may be

prone to enzymatic degradation in the extracellular space. Another important

determinant for distribution of macromolecules is the surface characteristics of the

molecule and the extracellular matrix, i.e., the substances in the extracellular space

within tissues that serve various purposes, including but not limited to serving as

scaolding to hold tissues together and helping to determine the behaviors of the

cells. Binding of the molecule to the extracellular matrix or surface receptors may

limit distribution. Binding to cell surface receptors may be overcome by saturating

receptors with excess ligands. Binding of macromolecules to extracellular matrix

has been overcome with some success by co-infusion of heparin.

Size of the molecules also aects volume of distribution. Early CED studies by

Oldeld group and others suggested that 180kD, the size of immunoglobulin

G (IgG), appeared to be the largest size that could pass through the extracellular

space without the need of surface modication to the extracellular matrix.

Recently, with the help of surface modication, adeno-associated virus (AAV,

40nm) and liposomes (50-200nm) have been distributed to large volumes of brain

tissue. Surface modications used were pegylation with liposomes and heparin

co-infusion to saturate heparin sulfate proteoglycan (HSP) binding with AAV.

e volume of distribution is also aected by the retrograde movement of uid

along the outside of the catheter (backow or reux). Reux is determined by

catheter diameter, infusion rate, and tissue density among other factors. e

larger the diameter of the catheter, the greater is the backow along its outer

wall. If reux reaches a low pressure zone (necrosis or CSF space), the uid will

inadvertently be lost into these spaces. is leads to the accumulation of the drug

in these regions which may cause toxicity. Finally, increasing the infusion rate

can increase the overall volume of distribution; however, this may also increase

backow, potentially shunting uid away from the target region.

Ideally, agents delivered via CED should be contained within the target region of

brain parenchyma or tumor mass. However, there are low pressure regions in some

tumors along which infusate will ow, sometimes into ventricles or subarachnoid

space. is phenomenon is usually referred to as leakage and has often been

observed in both humans and experimental animals. One study indicates that this

can happen in 20% of CED procedures. is obvious waste of therapeutic agents

will consequently reduce the volume of distribution and drug concentration in

the planned target region. It may also cause untoward eects on normal brain

tissue. It is therefore critical to follow the ow of the infused agents. When this

happens, it might be helpful to adjust the placement of the catheter to move the

opening away from the low pressure region. It is also not known yet whether

this leakage is reversible. If reversible, pausing infusion for a period of time and

subsequently restarting the infusion could eliminate leakage.

Although the physical parameters inuencing drug distribution by CED have

not been thoroughly claried, the ability of CED to achieve high concentrations

of a therapeutic agent over large volumes of brain tissue has led to several clinical

trials in patients with neurodegenerative disorders and malignant gliomas.

erapeutic studies for malignant gliomas have focused on delivering targeted

macromolecules (monoclonal antibodies, recombinant toxins, etc.) or currently

available small molecule drugs.

Catheter Design for CED

Metal needles have been used as the infusion tool since the early studies of CED

in laboratory animals. Most of the recent clinical trials of CED in the treatment

of malignant gliomas have used ventricular catheters made of Silastic® rubber.

Ideally, a catheter for CED should be reux-free; does not adsorb therapeutic

agents to its wall, especially when expensive novel targeted agents are used; and

should have tip congurations that direct the drug to desired regions. In certain

instances, it may be required to conrm catheter placement before drug infusion

with magnetic resonance imaging (MRI) where MRI-compatible catheters are

needed.

As briey discussed above, reux negates the bulk ow of infusate in the

extracellular space that is produced by CED. In the presence of reux, an

increase in infusion volume does not produce an increase in distribution volume

accordingly. Reux causes the drug to ow into ventricular or subarachnoid

space where it may cause toxicity. While reduction in infusion rate may reduce

the chance of reux, it would be ideal to have the option of infusing at various

ow rates, i.e., up to 10µl/minute or more if possible, to achieve desired volume

of distribution in a reasonable period of time.

Simple infusion tools such as metal needles have high rates of reux. Several

groups, including Souweidane group at Weill Cornell Medical College, observed

that a step-design cannula signicantly reduces, or even eectively prevents,

backow. e group used a 22 gauge guide cannula with a 28 gauge internal

cannula, both of fused silica. e internal cannula extended beyond the end of

the guide cannula by 5 mm. e cannula set was left in place for 5 minutes before

infusion started. At ow rates as high as 8µl/minute of an

124

I-labeled monoclonal

antibody, no reux was observed on positron emission tomography (PET)

Chapter 17: Convection-Enhanced Delivery in DIPG

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255

Chapter 17: Convection-Enhanced Delivery in DIPG

imaging. Presumably the tissue surrounding the extended internal cannula sealed

o the entry tract. ere might be a threshold that this design can withstand the

pressure, but infusion rates higher than 8µl/min have not been attempted with

this tip conguration. Nevertheless this design oers an attractive improvement

over the cannula design previously used. is fused silica cannula set is not and

probably will never be approved for clinical use due to its insucient mechanical

strength. Ventricular catheters currently used in CED clinical trials have larger

diameters and would produce a higher chance of reux based on laboratory

observation of the relationship between reux and cannula diameters. Advances

in biocompatible materials such as polymers and ceramic may eventually make

small diameter MRI-compatible step-design cannulas and catheters strong enough

for clinical use.

Tip Conguration

A standard cannula only has an opening at its tip. In certain instances, such as

after radiation therapy where scars may form inside the tumor, this may not

allow for sucient ow of infusate. Considering infusates will follow the path

of least resistance, a multi-tipped cannula may provide better pressure output,

and therefore, achieve a better volume of distribution. e eectiveness of the

multi-opening conguration has been questioned by studies showing that a

multi-port catheter delivered most of the infusate through the proximal port

and thus behaved like catheters with only one port.

One research group constructed a 3-mm long porous hollow ber catheter

to increase the surface area of the brain in immediate contact with the drug

releasing area. e hollow ber has innumerous pores of 0.45µm along its

walls. is theoretically avoids clogging, which happens in certain instances.

e hollow ber catheter oers up to a threefold increase in the distribution

volume of the drug into the normal mouse brain when compared to a needle

which has a single macroscopic pore. e tiny microscopic pores do not have

the same pressure-shunting properties as the macroscopic pores do; therefore

a long length of the porous wall is eective in delivering drugs. In large animal

and human applications, it is more reasonable to have this porous hollow ber

conguration at the tip for a few millimeters to a few centimeters rather than

the entire catheter being porous. e porous wall and step design could even

be combined to reduce reux during drug administration.

In certain other instances, it may be desirable to direct the infusate preferentially

in a specic direction. Due to the pressure-shunting properties of the proximal

port on the regular multi-port cannulas, it may not be eective to direct infusate

distribution via such a tip conguration. One potential design is to construct

a catheter with independent cannulas inside. Each cannula has an opening at

a predetermined location and direction with its pressure being independently

controlled. is design will require additional engineering and testing to

determine its feasibility.

Monitoring Drug Distribution

Monitoring the distribution and concentration of an infused drug is critical for

numerous reasons. In order for the delivered therapeutic agent to be eective, in

addition to its biological eectiveness, it must be distributed within the tumor

in therapeutic concentrations. Exposure of normal tissue to the drug should

be controlled to reduce the probability of toxicity. It is also highly desirable

to monitor for possible backow and leakage so that cannula placement

can be adjusted to correct for any problems that may arise. e importance

of monitoring in vivo distribution and concentration is highlighted by the

diculty in achieving optimal therapeutic ecacy in recent clinical trials. In

the recent TGFα-PE38 study and the phase III PRECISE trial for glioblastoma

(see below), poor drug distribution was cited as one of the reasons for the

unsatisfactory ecacy results. Monitoring the distribution and concentration

of CED infusate in humans is dicult due to the fact that the majority of

therapeutic agents cannot be seen on any of the clinical imaging methods.

Nevertheless, distribution can be visualized under certain circumstances. T2-

weighted magnetic resonance (MR) images are helpful in identifying infusate

distribution in regions of relatively normal intensity, but distribution cannot

be identied with certainty when infused into already hyperintense regions,

such as in the case of DIPG.

Another choice is to use visible surrogate tracers. Gd-DTPA and

123

I-albumin

have been co-infused as surrogate tracers, viewable on T1-weighted MR and

single photon emission computed tomography (SPECT) images, respectively,

in clinical studies. e shortcomings of surrogate markers are that they are

only able to track the initial distribution accurately. Dierences in biological

activities and clearance can confound their ability to follow the volumetric

distribution of the therapeutic agent over time. Moreover, neither T2 MRI

signals nor surrogate tracers are able to provide information on the concentration

of the infused therapeutic agent. e ideal scenario is to directly image the

therapeutic compound. With calibration, the concentration of the drug can be

determined as well as the distribution. Utilizing serial imaging, clearance can

be followed over time. In an ongoing clinical trial at Memorial Sloan-Kettering

Chapter 17: Convection-Enhanced Delivery in DIPG

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257

Chapter 17: Convection-Enhanced Delivery in DIPG

Cancer Center and Weill Cornell Medical College, a therapeutic monoclonal

antibody is labeled with

124

I to treat DIPG.

124

I is a positron emitter that can

be visualized using PET imaging at a high resolution. e spatial resolution of

124

I PET is signicantly higher than that of

123

I SPECT.

124

I has an intrinsic

spatial resolution loss of only 2.3 mm. It is expected that much more detailed

information regarding the distribution and concentration of CED infusate

will be acquired. is approach of labeling a therapeutic agent with imageable

radionuclide can be applied to some other agents and applications. For some

other therapeutic agents, novel tags such as paramagnetic particles may prove

useful in labeling the drug for quantitative in vivo imaging.

Predicting and Planning CED Distribution

It is critical to dene the relationship between the volume of infusion (Vi) and

the volume of distribution (Vd) to understand the expected distribution of an

agent delivered into the brain via CED. is relationship is approximately linear

and has variable slopes depending on the anatomical site of administration as

well as the therapeutic compound. For instance, the Vd/Vi ratio is 8.2 in the

non-human primate (NHP) striatum compared to a ratio of 4.1 in cerebral white

matter for small molecules. A ratio of 8.7 was observed in the NHP brainstem

for Gd-albumin (72kD). is ratio can serve as an estimate to match tumor

volume in clinical trials.

BrainLAB AG (Feldkirchen, Germany) has developed a software package

called iPlan Flow specically for use in planning CED. e software takes data

obtained via MRI regarding brain tissue characteristics of individual patients as

input. en the software helps in determining cannula placement, calculating

the infusion parameters and predicting distribution. e plan for treatment

can be visualized in three dimensions, including the number and position of

catheters. One study retrospectively tested the ability of this software using

MR diusion tensor imaging to predict patient-specic drug distributions by

CED.

123

I-labeled albumin was co-infused as a surrogate tracer with the targeted

recombinant cytotoxin IL13-PE38QQR in patients with recurrent malignant

gliomas. e spatial distribution of

123

I-albumin was then compared with a

drug distribution simulation provided by iPlan Flow. e algorithm had a

high sensitivity and specicity in identifying catheter trajectories that resulted

in reux or leakage. e mean concordance of the volume of distribution

between the actual

123

I-albumin distribution and the simulation was 66% and

the mean maximal inplane deviation was less than 8.5 mm. e use of this

simulation algorithm was considered clinically useful in 85% of the catheters.

Even though albumin does not have a specic anity towards malignant tissue

compared to targeted agents, this simulation showed that software with the

ability to take into account characteristics of an individual patient’s anatomy

and pathophysiology is helpful in the planning of CED. iPlan Flow has yet to

be tested in CED in the brainstem.

Safety of CED in the Brainstem

e concept of using CED for DIPG is appealing given that this particular

tumor is relatively compact, has growth patterns simulating white matter

tracts, seldom metastasizes before local relapse and has no denitive therapy.

e Souweidane group rst established the feasibility of this delivery route

in the brainstem in small animals for potential clinical application in 2002.

Subsequently, the safeties of inert agents, characteristics of distribution and

toxicity of potential therapeutic agents in the brainstem of small animals and

non-human primates have been studied. is approach has also been used

safely in a small number of patients with brainstem diseases. ese studies

showed that CED does not cause clinically relevant mechanical injury to the

brainstem and this approach has a promising therapeutic application in humans.

In clinical practice, image-guided frameless stereotaxy can be utilized to target

the brainstem in children for biopsy or cannula insertion with high accuracy

and low risks of temporary or permanent morbidity. ese will help establish

CED as an accepted drug delivery method in the treatment of DIPG.

erapeutic Ecacy of CED

CED of chemotherapeutic molecules has shown considerable promise in phase

I and phase II clinical trials in patients with recurrent malignant gliomas.

However, phase III results are less encouraging. CED in the treatment of DIPG

has produced encouraging results in preclinical studies. A few phase I trials of

CED in DIPG are recruiting patients or in the planning stage.

Several factors that are critical in achieving good therapeutic ecacy require

further elucidation. The convective force used in CED facilitates drug

distribution to larger volumes of brain tissue. However, malignant gliomas may

contain areas of brosis and necrosis, especially after receiving external beam

radiation therapy, which is currently part of the standard of care. CED, as an

investigational therapy, usually is not started until the completion of radiation

therapy. e brosis and necrosis may cause chaotic pressure gradients within

the tumor and therefore an unpredictable distribution of the drug. Even within

the peritumoral margins, targeting inltrating tumor cells may be limited by the

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Chapter 17: Convection-Enhanced Delivery in DIPG

normal anisotropy of the brain tissue resulting in preferential ow of uid away

from the intended target. Furthermore, the presence of areas of disrupted BBB

either by the pathological changes or by previous treatment such as radiation

therapy may increase eux of drugs out of the CNS. A better understanding

of drug distribution will become a critical part of evaluating future studies

employing CED. Another concern is that the drugs infused in a single session

may maintain their therapeutic concentration for a period too short to be

eective before being cleared out of the target region. Once we have a better

understanding of drug distribution and clearance, other unsolved questions

including optimal catheter design and placement, infusion rate and duration,

and the benet of repeat infusions can be better addressed.

e use of targeted macromolecules allows for either intratumoral or peritumoral

treatment in malignant gliomas. Some of these agents may not be specic

enough, potentially leading to injury to normal tissue. is was seen with IL4-

PE, which initially started at a concentration of 2µg/ml. e potential benet

of targeting multiple molecules by combining dierent recombinant toxins, or

combining these agents with other chemotherapies, remains unknown. Despite

these limitations and uncertainties, signicant responses have been observed in

all of the CED clinical trials described below.

CED Clinical Trials for the Treatment of Brain Tumors

eoretically, any antineoplastic agent can be delivered through CED for the

treatment of brain tumors, including standard chemotherapeutic agents and

novel macromolecules such as monoclonal antibodies and viral vectors. One

unresolved issue is that CED, in its current form, is a surgery and typically

performed as a single session. It is unknown how long the infused drugs remain

at therapeutic concentrations after a single session of CED. Imaginatively, it

is more like a bolus dose, and predictably only a portion of the cancer cells

are killed by such a bolus dose and the remaining cancer cells will continue to

grow, ultimately resulting in failure of treatment.

For various reasons, most standard chemotherapeutic agents do not cross the

BBB in sucient amounts to have a signicant eect on the cancer. CED

of such small molecules showed that these agents have observable antitumor

responses. However, more neurological complications have been observed when

these agents were delivered via CED compared to systemic chemotherapy. ere

are eorts to improve formulations of these agents for local delivery to reduce

neurotoxicity and enhance therapeutic response. ese eorts, if successful, will

make CED of small chemotherapeutic molecules applicable on a larger scale.

More eort is focused on delivering recombinant toxins via CED in the

treatment of brain tumors. ese toxins are recombinant proteins and have

two components, a targeting moiety, typically a monoclonal antibody or a

ligand to an over-expressed cell membrane receptor, and a toxin, which can be

bacterial toxins. Bacterial toxins frequently utilized in recombinant toxins are

Pseudomonas exotoxin (PE) and Diphtheria toxin (DT). ese polypeptide toxins

have strong cytotoxicity against mammalian cells by inhibiting protein synthesis.

ey do not show selectivity in killing cancer cells over normal cells. But by

attaching them to a targeting moiety directed to cancer cells, the recombinant

toxins can become highly selective in killing cancer cells while sparing normal

cells. For this purpose, these bacterial toxins have been genetically modied

to make them easier to attach to targeting moieties. Genetic modication

also reduces the activity of these toxins to give a wider therapeutic window.

One targeting moiety widely studied for adult malignant brain tumors is

interleukin-13 (IL-13), because the IL-13 receptor is known to be over-expressed

in a high percentage of these tumors. Binding of a recombinant toxin on the cell

surface triggers internalization of the toxin, which enzymatically arrests protein

synthesis and ultimately causes cell death. Several recombinant toxins have been

utilized in clinical trials for adult malignant brain tumors delivered via CED.

ese toxins are attractive in that they have strong cell-killing capabilities and

resistance rarely develops.

Transferrin-CRM107

Several recombinant toxins have reached the stage of clinical study. e rst

cytotoxin that was used in brain cancer therapy via CED was Transferrin-

CRM107, a thioether conjugate of human transferrin and CRM107, a mutant

form of Diphtheria toxin. e compound was developed by a group led by

Richard Youle at the NINDS and is commercially available as TransMID™

from Celtic Pharma (HM, Bermuda). Transferrin-CRM107 targets tumor

cells by binding to the transferrin receptor, which is over-expressed on rapidly

dividing cells.

In a multicenter, open label phase II clinical trial, 44 adult patients received

intratumoral CED at 0.67µg/ml of Transferrin-CRM107 delivered directly into

the tumor bed. Numerous signicant clinical responses were observed. Of the

34 evaluable patients, ve had a complete response and seven a partial response.

e median survival for all 44 patients was 37 weeks. However, the tumor-

selectivity of this recombinant toxin is not high, shown by its toxicity to normal

tissues. In eight of the patients, increased cerebral edema was noticed. ose

with clinical neurotoxicity also had MRI changes suggestive of microvascular

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Chapter 17: Convection-Enhanced Delivery in DIPG

injury, perhaps related to the higher levels of transferrin receptors on normal

blood vessel walls. A phase III multicenter, randomized study in recurrent,

nonresectable glioblastoma multiforme (GBM) was opened but withdrawn

prior to patient enrollment due to the toxicity data from the phase II trial.

IL4-PE

Another recombinant toxin clinically examined is IL4-PE, which is commercially

labeled as NBI-3001 (Neurocrine, San Diego, California) and PRX321 (Protox

erapeutics, Vancouver, British Columbia, Canada). More accurately called

IL-4(38–37)-PE38KDEL, the agent uses a mutant interleukin-4 (IL-4) as the

targeting moiety and a modied Pseudomonas exotoxin as the cytotoxic eector.

A phase I study of intratumoral CED of IL4-PE started at a concentration

of 2µg/ml and was dose escalated to determine the maximum tolerated dose

(MTD). Drug-related grade 3 or 4 CNS toxicity was seen in a total of 39% of

patients in all groups, and no systemic toxicity was seen. A phase II, multicenter

randomized study of intratumoral IL4-PE followed by tumor resection between

2 and 7 days after the completion of toxin infusion enrolled a total of 30 adult

patients. e accrual was completed in 2003 and the objective clinical responses

were not as good as Transferin-CRM107. A phase II trial of CED of IL4-PE

with real-time imaging for therapy of recurrent glioblastoma (the study is

referred to as CLARITY-1) has been approved but not recruiting patients as

of November 2008, the last time the status of the trial was reported. ere are

no plans for a phase III study.

TGF-α-PE38

TGF-α-PE38 is another recombinant toxin that entered clinical phase. It

is labeled as TP-38 commercially (TEVA Pharmaceuticals, North Wales,

Pennsylvania). TGF-α-PE38 is composed of transforming growth factor-α

(TGF-α), a native epidermal growth factor receptor (EGFR) ligand, and a

38kD fragment of the Pseudomonas exotoxin. TGF-α-PE38 binds to the EGFR,

which is over-expressed in the majority of GBM and is naturally present in

many normal organs.

Moderate or better responses were recorded in several patients in clinical trials.

A phase I study of intratumoral and peritumoral infusion of TGF-α-PE38 was

performed in 20 patients with recurrent malignant glioma with a concentration

escalation of 0.025 to 0.1µg/ml. Two catheters were initially placed during

tumor resection and then a total volume of 40 ml was infused. TGF-α-PE38

was well tolerated and a MTD was not established. At the completion of the

study, four patients had no recurrence of tumor over 55 weeks after treatment.

e overall median survival for all patients being treated was 28 weeks. For

those without radiographic evidence of residual disease at the time of therapy,

the median survival was 33 weeks. One GBM patient remains alive and without

progression more than 211 weeks after CED therapy, and another GBM patient

went 198 weeks without progressive disease after a nearly complete response

to TGF-α-PE38 and remains alive more than 260 weeks from CED therapy.

In the majority of patients imaged using SPECT, infusate distributions were

signicantly inuenced by leakage and failed to produce any signicant intra-

parenchymal distribution. is highlights the importance of accurate catheter

placement and drug distribution monitoring.

A phase II multicenter randomized study was conducted in adults with

recurrent GBM. Patients were randomized into two groups treated with

peritumoral CED of 0.05 or 0.1µg/ml of TGF-α-PE38. e total volume

infused was approximately 40 ml. Post-infusion MRI changes were seen 1 to

4 months after treatment, geographically associated with the site of catheter

placement. ese changes usually resolved by 20 weeks post-treatment. ere

were no grade 3 or 4 toxicities related to TGF-α-PE38. Only 20% of patients

retained the cytotoxin within the tumors by imaging. A phase I/II clinical trial

evaluating TGF-α-PE38 in treating young patients with recurrent or progressive

supratentorial high-grade glioma was terminated prematurely. Further clinical

trials are pending resolution of issues encountered in the phase I and II trials,

with catheter placement and infusate leakage as the most important concerns.

IL13-PE38

IL13-PE38 was developed by a research group led by Waldemar Debinski

in the mid-1990s. It is a recombinant toxin consisting of human IL-13 with

PE38QQR, a 38kD fragment of the Pseudomonas exotoxin. It is labeled

commercially as Cintredekin Besudotox by NeoPharm (Lake Blu, Illinois).

High levels of the IL-13 receptor have been found in more than 90% of

glioblastoma, whereas expression of the receptor in the normal brain is not

present or at low levels. is toxin demonstrated ecacy in several preclinical

GBM models before moving into clinical study.

Intratumoral and peritumoral CED of IL13-PE38 has been investigated in four

separate phase I studies. In the largest peritumoral phase I study, a maximum

tolerated concentration of 0.5µg/ml was observed. In this four-stage study,

histological ecacy, maximum tolerated concentration and maximum infusion

time were assessed. e nal stage explored the stereotactic placement of

catheters after tumor resection to improve targeting the peritumoral brain tissue.

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Chapter 17: Convection-Enhanced Delivery in DIPG

A total of 51 patients with malignant gliomas were treated including 46 patients

with GBM. IL13-PE38 and procedure-related adverse events were primarily

limited to the CNS, including those associated with increased edema. With the

administration of steroids, all patients tolerated infusions of 40ml through 2

to 3 catheters lasting up to 6 days. e maximum tolerated concentration was

0.5µg/ml and tumor necrosis was observed at this concentration. ere were

no grade 3 or 4 adverse events associated with drug infusion at concentrations

lower than 0.5µg/ml, and no systemic toxicities were observed. Delayed

radiographic changes were observed in some patients 2 to 4 months after therapy,

which responded to steroids and may represent an inammatory response or

nonspecic activity.

e overall median survival for GBM patients was 42.7 weeks. Catheter

placement was variable in the early portion of the study, with some catheter

tips placed in CSF spaces. Catheter placement was correlated with survival. e

27 GBM patients with two or more catheters placed optimally without loss

of drug into the CSF compartment had a median survival of 55.6 weeks with

follow-up extending beyond 5 years, and 5 of these patients (18.5%) survived

beyond two years after a single treatment. ese trials showed that most of

the eective drug deliveries were achieved by infusing into the parenchyma

surrounding the gross total resection cavities rather than into the remaining

tumors themselves. ey also demonstrated that the chance of successful delivery

without reux or leakage was enhanced if the catheter tip was at least 2cm deep

from the last traverse pial surface and 5mm from the nearest non-traverse pial

or ependymal surface.

ese encouraging results led to a phase III multicenter, randomized study

(known as the PRECISE study) in patients with rst recurrent GBM. e

patients were randomized 2:1 to surgery followed by peritumoral infusion of

IL13-PE38 versus surgery and Gliadel wafer (MGI Pharma, Inc., Bloomington,

Minnesota) implant. Gliadel wafer contains carmustine (bis-chloroethyl-

nitrosourea [BCNU]) and is approved by the Food and Drug Administration

(FDA) as a standard therapy for GBM following surgical resection. Fifty-two

medical centers participated in this trial worldwide. Total enrollment was

targeted at 300 patients to demonstrate a 50% improvement in overall survival

in the experimental arm. Enrollment was completed in December 2005.

Analysis of follow-up data showed that this goal was not achieved. e median

survival of the 184 patients in the CED arm was 36.4 weeks compared to 35.3

weeks for the 92 patients in the control arm. When the dataset was restricted

to sites having enrolled more than six patients progressing to drug delivery,

the results are more encouraging. In this case, the CED arm had an overall

survival of 46.8 weeks versus 41.6 in the control arm, even though statistical

analysis showed that this cannot be said with sucient certainty. However, it

is signicant that progression-free survival was 17.7 versus 11.4 weeks in favor

of CED. e investigators believe poor drug distribution in some patients is a

major factor that adversely aected the therapeutic response. e trial implies

that a uniform method must be applied in participating centers to ensure exact

and reproducible drug delivery. Future trials will probably benet from improved

catheter placement, drug distribution and screening of expression level of IL-13

receptor chain α2 (IL-13Rα2). IL-13Rα2 is expressed specically by glioma

cells. e next generation toxin has been developed to bind the tumor-specic

IL-13Rα2 rather than the IL-13 physiological receptor, and should be studied

clinically.

131

I-chTNT-1/B mAb

131

I-chTNT-1/B mAb is an

131

I-labeled humanized murine monoclonal antibody

(mAb). It binds to a universal intracellular antigen, histone H1. Histone H1

is in the assembled DNA double strand and is exposed and accessible for

antibody binding in the necrotic core of solid tumors. is antigen provides

an abundant insoluble anchor for the mAb.

131

I emits γ rays with suciently

high energy to penetrate and kill adjacent tumor cells. From the principle of

how the drug was designed,

131

I-chTNT-1/B mAb is not as specic as those

targeting specic receptors (e.g., the EGFR or IL-13 receptors) expressed by

tumor cells, but rather delivers cytotoxic radiation to the tumor mass as well

as to tumor cells invading the surrounding tissue. “TNT” in the name of the

agent stands for “tumor necrosis therapy.”

131

I-chTNT-1/B mAb is commercially

labeled as Cotara (Peregrine Pharmaceuticals, Tustin, California). e eect of

131

I-chTNT-1/B mAb in patients with malignant gliomas was investigated in

several clinical studies. e results of two non-randomized, open-label studies

have been published: a phase I study in 12 patients with recurrent anaplastic

astrocytoma (AA) and GBM, and a phase II study in 39 patients with newly

diagnosed or recurrent malignant gliomas.

e 51 patients enrolled in the two studies included 37 recurrent GBM, eight

newly diagnosed GBM and six recurrent AA. All patients had previously

undergone radiation therapy, 42 had previously undergone at least one surgery

and 31 had a chemotherapy regimen. More than half of the patients (53%) had

a tumor volume of ≥ 30 cm

. One or two catheters with slit openings near the

closed distal end were placed with tips at or near the center of the enhancing

tumor.

131

I-chTNT-1/B mAb was infused using CED over 1 to 2 days at a

Chapter 17: Convection-Enhanced Delivery in DIPG

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Chapter 17: Convection-Enhanced Delivery in DIPG

rate of 0.18ml/h. In the rst six patients, 1.5mCi/cm

clinical target volume

(CTV) was prescribed, which was calculated to deliver a dose of 137 Gy. For

subsequent patients, the dose was based on tumor size and the prescribed activity

was 0.5 – 3.0mCi/cm

administered in 1 or 2 infusions.

e phase I study showed that more than 130 Gy could be delivered to the

tumor with 34 ± 9% dose retention at 24 hours and a biological half-life of

46 ± 16 hours. Imaging and dosimetry studies on a subset of six malignant

glioma patients in the phase II study showed that infusion of 13.2 – 71.1mCi

of activity produced a calculated absorbed dose of 55 – 135Gy.

Treatment-emergent, drug-related central nervous system adverse events

included brain edema (16%), hemiparesis (14%) and headache (14%). Most

of these were reversed by corticosteroids. Systemic adverse events were mild.

Treatment with

131

I-chTNT-1/B mAb in the phase I study resulted in three

of nine GBM patients having stable disease at 60 days, and all nine patients

with progressive disease at 90 days. e median time to progression (MTTP)

and median survival time (MST) were 8.7 and 27.3 weeks, respectively. Of the

three patients with AA, one achieved a partial response and the other two had

stable disease 90 days after treatment. e 28 recurrent GBM patients in the

phase II study had an MTTP of 8.4 weeks (historical control 8.0 weeks) and

an MST of 23 weeks (historical control 24 weeks).

e phase II study contained patients with more diverse conditions. In an eort

to “normalize” ndings in this study, ecacy data from a subset of 12 recurrent

GBM patients who received a total activity between 1.25 and 2.5mCi/cm

which was considered a therapeutic window based on ecacy versus toxicity,

were examined. e median survival for these patients was 37.9 weeks. In

addition, seven of the 28 recurrent GBM patients and one of the three recurrent

AA patients survived for more than one year. Further research is required to

determine the value of

131

I-chTNT-1/B CED in these patients.

Two other phase I trials of

131

I-chTNT-1/B CED in patients with recurrent

or relapsed GBM have been completed recently and the results have not been

published. A dose conrmation and dosimetry phase II study for GBM patients

at rst relapse is ongoing. e dose is a single 25-hour infusion of 2.5mCi/cm

CTV. Brief interim results for a subset of 14 patients were reported in October

2010 and the median overall survival was 86 weeks.

Current and Upcoming CED Clinical Trials in DIPG

ere are no completed CED clinical trials for DIPG and only a small number

of CED trials for DIPG are under way or in the planning stage. is is in

contrast to the application of CED in the treatment of adult malignant gliomas,

where a number of clinical trials have been completed as summarized above.

Institutions sponsoring CED trials for DIPG have spent signicant eorts

in studying the safety of CED into the brainstem in small and large animals,

including non-human primates.

CED of IL13-PE38 for DIPG

e NINDS is sponsoring a phase I clinical trial led by Dr. Russell Lonser,

using CED to deliver IL13-PE38QQR into DIPG [Fig. 1a, 1b]. is study

started recruiting patients in 2009 and is expected to nish in early 2013. It

is an open label dose escalation safety study. IL-13 is an immune molecule

normally occurring in the body. About 90% of malignant gliomas have high

levels of IL-13 receptors while the normal brain tissue has only a low level of

these receptors. e experimental drug, IL13-PE38QQR, which combines the

modied PE with human IL-13, has been discussed above.

is study recruits patients 3 to 17 years of age with DIPG or supratentorial

high-grade glioma that have not responded well to standard radiation therapy.

20 patients are expected to enroll in this study. e planned doses are 0.125,

0.25 and 0.5µg/ml. Safety and tolerability are the primary endpoints with

secondary endpoints including imaging changes and treatment responses.

CED of

124

I-8H9 for DIPG

Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College

are conducting a phase I clinical trial led by Dr. Mark Souweidane, using CED

to deliver

124

I-8H9 for the treatment of DIPG. is study is ongoing and

expected to be completed in 2014. is is an open label dose escalation safety

study.

124

I is a radionuclide with a half-life of 4.18 days. It emits γ rays and

positrons, both of which having energies high enough for therapeutic purposes.

Positrons will eventually be annihilated in the tissue resulting in the release of

photons that are detected in PET imaging. 8H9 is a monoclonal antibody that

binds to membrane protein B7-H3, which is expressed in high levels in most

DIPG but not by normal brain tissue. In principle, this antibody conjugated

124

I potentiates the antineoplastic eects of the radionuclide by directing

therapeutic irradiation preferentially to cancer cells.

is study recruits patients with DIPG ages 3 to 21 years old. e enrolled

Chapter 17: Convection-Enhanced Delivery in DIPG

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267

Chapter 17: Convection-Enhanced Delivery in DIPG

patients will have undergone standard external beam radiation therapy but have

not shown signs of progression. A maximum of 24 patients will be enrolled in

this phase I study. e planned doses are 0.25, 0.5, 0.75 and 1.0mCi of the

radio-antibody

124

I-8H9. Safety and tolerability are the primary endpoints.

Uniquely, this study uses PET to image drug distribution and calculate radiation

dose, which will provide invaluable information to correlate with tolerability

and therapeutic response. e usefulness of other imaging modalities in CED

planning in the brainstem will also be assessed as a secondary objective.

Future Directions

CED of therapeutic agents in the treatment of malignant brain tumors has shown

considerable promise in preclinical and some clinical studies. Future advances

will occur on two fronts: 1) the development of more eective therapeutic

agents for delivery via CED and 2) the improvement of the technique of CED.

A promising advance in the development of therapeutic agents for the

treatment of DIPG is the recent molecular characterization of this tumor.

ree groups independently discovered that the platelet-derived growth factor

receptors (PDGFR) are over-expressed in the majority of DIPG. erapeutic

agents targeting the PDGFR signal transduction pathways will be studied for

therapeutic ecacy. ese include anti-PDGFR antibodies and inhibitors of

the receptor tyrosine kinase (RTK) and downstream pathways. Another over-

expressed growth factor receptor is the EGFR. Like in the PDGFR pathway,

agents targeting the EGFR pathway include anti-EGFR antibodies and

inhibitors of the RTK and downstream pathways. e Sonic hedgehog (Shh)

pathway is over-activated in many cancers, including malignant gliomas. Its

study in DIPG is less in depth than in adult malignant gliomas. Inhibitors of

this pathway could also be potential therapeutic agents. Like in adult malignant

gliomas, IL-13Rα2 is highly expressed in DIPG therefore recombinant toxins

using IL-13 as a targeting moiety are also potentially eective therapeutic agents

for DIPG. e safety of CED of IL13-PE38QQR in the brainstem has been

investigated by the Souweidane group in preclinical studies and a clinical trial

sponsored by the NINDS is studying this agent in DIPG patients. Even though

biopsy of DIPG is far from being routine, when these targeted therapies based

on molecular proling of tumors come to clinical use, it would be ideal for the

tumor to be pre-screened for the targets that the drugs are designed for.

Increasing evidence shows that each individual tumor harbors multiple

mutations. For instance, there are on average 60 mutations per glioblastoma.

ere is no reason to believe DIPG contains a much smaller number of

Figure 1a:

Illustration demonstrating convection-enhanced delivery (CED) in the treat-

ment of diuse intrinsic pontine glioma (DIPG). An infusion cannula is inserted through

the transfrontal approach into the pons. e tip of the cannula will be at, or near the center

of the tumor. is is achieved by image-guided high-precision stereotaxy.

Figure 1b:

With the cannula in place, drugs are infused into the pons driven by a preci-

sion pump. Ideally, the drug infused area encompasses the tumor and the surrounding

inltrated area.

Chapter 17: Convection-Enhanced Delivery in DIPG

268

mutations than other malignant gliomas. Targeting one therapeutic target rarely

causes death to 100% of the cancer cells. RTK, downstream and parallel signal

transduction pathways may be regulated in complex compensatory fashions that

reduce the chance of cell death when the tumor is treated by aiming at only one

therapeutic target. erefore it is not surprising that drug resistance has been

inevitable in almost all single-drug targeted therapies. We believe it is worthwhile

to characterize defects in parallel and downstream signal transduction pathways

and devise multi-targeting therapeutic regimens based on such characterization.

On the technical front of the delivery method, there is a need for better designed

cannulas and more accurate stereotactic placement of cannulas into the tumor to

achieve optimal drug distribution. e use of computer algorithms may help in

planning the cannula placement and infusion parameters by taking into account

anatomical structures and structural changes induced by the disease and prior

treatment. Perhaps more important, imaging should accompany CED to ensure

eective drug distribution and concentration as well as to determine how long

the therapeutic agents are retained in the tumor and tumor-inltrated brain

tissue in individual patients. is requires the improvement of current imaging

techniques or the development of new imaging methods.

As discussed above, the current single session CED is more like delivering

a bolus dose. Clinically feasible methods to deliver multiple cycles of CED

or continuous CED lasting up to several weeks are desired. is will require

the development and engineering of catheters suitable for these purposes and

desirably also pumps that can be embedded and allow patients to remain

ambulatory.

CED-based therapies will continue to evolve, with a need for additional

preclinical and clinical research.

269

Chapter 18: Vaccine Treatment Strategies

Chapter 18

Vaccine Treatment

Strategies

Christopher Moertel, MD

Over the last 40 years, incredible advancements have taken place in the treatment

of childhood cancer. e overall cure rate for childhood acute lymphoblastic

leukemia is approaching 90 percent and some pediatric cancers have exceeded

that mark. New treatment strategies for medulloblastoma, a malignant brain

tumor of childhood, have increased the cure rate while managing to decrease the

dose of radiation necessary for cure. e history of cancer therapy has seen rst

advancements in surgical techniques, then radiotherapy, then chemotherapy.

Despite improvements in surgery and radiation delivery for some types of brain

tumors, the survival rates for one type of brain tumor known as glioblastoma

multiforme (GBM) has changed little over the years. The incorporation of

temozolomide in the treatment of adult GBM was heralded as a great treatment

advance, but it did little more than extend survival by about two and one half months.

Temozolomide has been used to treat children with the same tumor, but little to

no benet has been seen. Specically, children with DIPG (which looks like GBM

under the microscope) have seen no benet from the addition of temozolomide, let

alone any chemotherapy added to classical radiation therapy. Hence, the need to

keep looking for new answers to old questions. Is there any way we can nd a new

tool to treat brain tumors like GBM and its pediatric equivalent, DIPG?

Tumor Immunology to Treat Cancer

We are in a new era in which we are witnessing a great leap in the knowledge of

chemical pathways at work in cancer cells and

are now able to create designer drugs known

as targeted therapies to attack these pathways

and, hopefully disable the cancer cell. Another

novel area for cancer therapy has been the

focus on tumor immunology. e hope of

Dr. Moertel is a Professor of

Pediatrics and Clinical Director of

the Pediatric Brain Tumor Program

at the University of MN, and

Children’s Hospital in St. Paul, MN.

Chapter 18: Vaccine Treatment Strategies

270

271

Chapter 18: Vaccine Treatment Strategies

tumor immunology is built on the premise of taking advantage of the body’s own

weapons to attack foreign invaders and tumor cells. Some of the immunologic tools

in this arsenal are antibodies, immune stimulators and vaccines.

Vaccines have been used in medicine for decades to boost the body’s own immune

response to protect against invading foreign diseases, particularly infectious diseases.

In this case , the vaccine is given prior to the individual becoming severely ill with the

disease—hopefully with the result that the individual only exhibits a very mild form

of the disease or no symptoms at all. ere are currently two vaccines available which

prevent virus infections leading to the development of cancer. e rst is against

hepatitis B, a virus that can cause liver cancer. e second is against human papilloma

virus that is designed to stop specic strains of the virus leading to cervical cancer.

Tumor immunotherapy to treat childhood cancer is no longer just theory and research

taking place in the lab. A recent breakthrough in the treatment of neuroblastoma—

another dicult childhood cancer to cure, employs an antibody against the tumor

cells. One monoclonal antibody, called chimeric (Ch) 14.18 attacks a molecule

on the neuroblastoma cell surface called GD2. e body can then recognize this

antibody-tumor cell complex and attack it using its own immune system to destroy

the cancer. To enhance this immunological response from the child’s own body, the

children are also given ‘immune stimulators’ to excite their own immune system

eliminating even more antibody-tumor cells complexes. e immune stimulators

include interleukin 2 and granulocyte-macrophage colony stimulating factor (GM-

CSF). Some children can have signicant side eects, but the benet of cure far

outweighs the risks in the setting of this otherwise lethal disease. is approach has

helped saved many more children’s lives. Indeed, antibody therapy has become part

of the standard of care for treating advanced-stage neuroblastoma.

Tumor immunology to treat brain tumors

Researchers hypothesizing about the possible use of vaccines to treat brain cancer

were concerned about the established belief that the brain was “immunologically

privileged.” at is, the immune system could do little across the blood brain

barrier. However, our laboratories here at the University of Minnesota, in

addition to other labs across the country, have shown that immune system cells

and antibodies can go into the brain fairly easily. In fact, it has been shown that

malignant brain tumors can train cells called myeloid (bone marrow) derived

suppressor cells to “dumb down” the immune system. A lot has been learned

about the immune system’s relationship with the brain and the body’s ability

to mount an immune attack within brain tissue. is body of science has

encouraged many to pursue immunotherapy strategies against brain tumors.

Recently, there has been signicant energy put into vaccine therapies for brain

tumors, with GBM being the main target.

One group at Duke University has studied an antibody against a protein found in

excess on the cell surface of brain tumors called Epidermal Growth Factor Receptor

(EGFR). Indeed, about 20% of GBMs have a mutant variant of EGFR called

EGFRvIII. So if EGFR is found in abundance on tumor cells and EGFRvIII is a

unique mutation on tumor cells, why not use this as a target for a programmed

immune attack? at is what the Duke group did. First, they conducted a clinical

trial combining their EGFRvIII protein with cells from the patients’ immune

system called dendritic cells (DC) and re-injected them into the patients with newly

diagnosed GBM. is led to an overall survival rate that was better than expected.

ey then went on to do a study in partnership with MD Anderson that used their

EGFRvIII vaccine combined with KLH, a protein that excites the immune system.

None of the patients’ dendritic cells were removed and re-injected in this study and

everyone received “standard” temozolomide in addition. e results of this trial were

somewhat encouraging. Immunotherapy for brain tumors burst onto the scene and

a great deal of enthusiasm and interest was created in the brain tumor community.

Currently there is one trial open at Stanford for newly diagnosed children with

DIPG that uses an EGFRvIII vaccine. is vaccine trial was initiated after Dr. Li

and colleagues reported 50% of DIPG tumors had EGFRvIII on their cell surface.

While the Duke group was working on their specic protein-based approach,

another group in California was using a patient’s own tumor cells to make a

vaccine. Dr. Linda Liau and colleagues resected the patient’s own tumor, cultured

it in the lab and separated proteins from the surface of the tumor cells. ey

then removed cells called mononuclear cells from the patient’s circulating blood

through a process known as apheresis and separated cells called dendritic cells

(DC). e patient’s own tumor surface proteins were then combined with his

or her DCs, incubated for up to an hour, and re-injected into his or her body.

is treatment is best called an acid-eluted glioblastoma multiforme peptide-

pulsed dendritic cell vaccine. Dr. Liau’s group showed that the vaccine was safe

and, resulted in longer survival for a number of patients. is work has now

been commercialized (Northwest Biotherapeutics, Inc.) and is available to adult

patients with GBM through a phase II trial at participating centers. is therapy

is not yet available for DIPG patients.

Another group led by Dr. Hideo Okada at the University of Pittsburgh has had

signicant experience with glioma-associated antigen-derived synthetic peptides

that excite cytotoxic T cells. Okada’s work also employs dendritic cells incubated

with the peptide and given along with a substance that excites the immune

system called Poly-ICLC (polyinosinic-polycytidylic acid). is peptide strategy

Chapter 18: Vaccine Treatment Strategies

272

is available only to individuals with a specic HLA subtype, A2. Unfortunately,

HLA-A2 is present in only 45% of the population. One of Dr. Okada’s vaccine

studies conducted with Dr. Regina Jakacki, who has participated in and run a

number of DIPG clinical trials, target DIPG specically. Dr. Okada has reported

(unpublished data) that at least one vaccine patient exhibited signicant tumor

regression after initial worsening of the MRI abnormality in the brainstem.

At the University of Minnesota, we have developed a dendritic cell vaccine

based on a brain tumor initiating cell (BTIC) line called GBM6. is cell line

has surface characteristics on the cells that match the surface characteristics of

initiating cells in many types of brain tumors, including glioblastoma. e cell

line also more closely mimics the growing conditions of human brain tumors

by being grown in 5% oxygen rather than the usual room air or 20% oxygen

seen in most lab environments. While our research is still early, we are in the

midst of a phase I trial that is showing that patients with brain tumors have

immune responses to our vaccine and may have tumor regression or stabilization

without any unusual toxicity. Indeed, the stronger immune responses have been

noted in our younger patients. Based on this early data, we are going on to start

a phase I trial targeting patients with newly diagnosed DIPG using a lysate of

our GBM6 cell line and topical Imiquimod, another immune system-enhancing

agent. Initially, we will be treating adult patients with GBM so that any unusual

toxicity will be dealt with before kids are exposed to this new treatment modality.

We feel this treatment approach has three specic advantages for the DIPG

population. First, there is no need to obtain tumor tissue to create the vaccine

(a nearly impossible task in patients with DIPG). Second, the vaccine is not

HLA restricted, as is the case in most peptide-based vaccines, being available to

the entire population. ird, this new vaccine trial will not use dendritic cells.

Hence, there will be no need for apheresis and all of the diculty that entails.

e common experience among those conducting brain tumor immunotherapy

trials is that minimal residual disease is optimal at the beginning of treatment.

Because DIPG cannot be surgically removed, we will need to depend on

radiation therapy to create minimal disease. Unfortunately, this means that

immunotherapy strategies will generally not be optimal for those whose disease

has relapsed, unless caught at a very early stage.

All of this is very early and may certainly end up not providing what we and all

parents of children with DIPG ultimately desire, but the early experience with

GBM immunotherapy tells us that there is a glimmer of hope for patients with

DIPG that has not been realized with classical radiation and chemotherapy–based

approaches. At the very least, we hope that new pathways to a cure will be revealed.

273

Chapter 19: DIPG and Tissue Donations

Chapter 19

DIPG and Tissue

Donation

Cynthia Hawkins, MD, PhD

Eric Bouffet, MD

Ute Bartels, MD

Before magnetic resonance imaging (MRI) became available, surgery was usually

recommended to conrm the diagnosis of brainstem tumors including diuse

intrinsic pontine glioma (DIPG) to provide both histological and prognostic

information. However, surgery was associated with signicant morbidity and the

benet of this approach was questioned when it became evident that the MRI

scan was able to provide images that were basically diagnostic of DIPG. erefore,

since the early 1990s, the frequency of biopsy has signicantly decreased and most

DIPG children are currently treated without histological conrmation.

Although this approach is the result of a consensus, over the years there has also

been increasing awareness that progress in the management of this deadly disease

will only occur with more biological information on DIPG. In this context, several

teams have explored ways of collecting tissue material, in particular at the time

of death, from limited brain or brainstem autopsies.

Early Experiences

Autopsy

Autopsy was a standard practice for in-hospital

deaths in many institutions until the late 20th

century. Autopsies were a standard procedure

in former times. They were performed

to identify the cause of death, and the

contribution of autopsies to the understanding

of many conditions has been significant.

However, there has been a steep decline in

Dr. Hawkins is a Principal

Investigator at the Arthur and

Sonia Labatt Brain Tumour

Research Center, an Assistant

Professor at the University of

Toronto, and Neuropathologist

at the Hospital for Sick

Children, Toronto, Canada.

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Chapter 19: DIPG and Tissue Donations

autopsy rates over the last decades as, in many cases, the cause of the patient’s disease

was felt to have already been identied. A drawback to this practice, however, is that

it limits researchers' ability to study diseases at the tissue level particularly for diseases

such as DIPG, where no surgical procedures are ever undertaken. us, until recently

there has been no experience with systematic collection of brain or brainstem tissue

to advance research in DIPG. Now groups from Canada and the U.S. have reported

this experience and demonstrated the possibility to use postmortem material for

genome-wide studies and even for generating cell lines.

In the Toronto experience, the concept of autopsy was discussed by the treating neuro-

oncologist after radiation therapy, at the time of progression or later during palliative

care. Sometimes this discussion was initiated during a home visit. Explanation

included the dierent types of autopsies, in particular the possibility to restrict the

autopsy to the whole brain or to the brainstem tumor according to the family’s

preference. In cases where only the tumor was removed, a small biopsy of the frontal

normal brain was also performed. To obtain appropriate tissue, in particular RNA

(ribonucleic acid), the autopsy needs to be done relatively early following death. In

the St. Jude experience, there was minimal RNA degradation when the autopsy was

performed within 5 hours of death; however, the quality of RNA dropped signicantly

beyond that delay. Similarly the possibility to grow cell lines from tumor tissue is

strongly related to minimizing the delay between the time of death and autopsy.

Interestingly, in both the Canadian and U.S. experiences, most patients died at

home (88% and 84%, respectively). If a family or patient consented to an autopsy,

the process was carefully organized ahead of time in order to avoid any delay in the

funeral. At the time of death, a transportation service was arranged to pick up the

body and transfer it to the academic center or to a local hospital where the autopsy

was performed within hours. e autopsy itself was carefully performed in order to

avoid any visible scars, in particular in the context of viewing visitations and open

casket services, which are an important part of bereavement in the North American

culture.e body of the child was brought back to the funeral home. is organization

allowed privacy for the family and a timely funeral without delay.

e issue of the consent for post mortem tissue collection has been described in

detail in one publication from the Toronto

group. In this experience, 10 out of 21 parents

who were approached gave their approval. For

the 10 families who consented, their main

motivation was to support research and to

contribute to breakthroughs in scientific

research on DIPG to benet future children.

In this experience, 2 children (11 and 10 years old) expressed their own wish to

donate their brain for research purposes. e main reasons for declining autopsies

were ethical and/or religious reasons or related to the level of emotional distress. Only

one family felt upset by the request for brain donation. In all cases, when an autopsy

was performed, a face- to-face meeting took place between the treating physician and

the parents once the results of the autopsy were available. No parents expressed any

regret from having given consent. All expressed their hope that their child’s death

may help research and contribute to the development of new treatments.

e scientic results of the research conducted on postmortem material have been

reported since 2009 in several important publications. Researchers have been able to

identify a number of potential targets for new treatments. is work has also shown

that DIPG is not a single entity and that dierent types of treatments may be needed

according to the underlying biology of the tumor.

Stereotactic biopsies

In parallel, other teams have decided to reintroduce the concept of biopsying DIPG

at the time of presentation. e neurosurgical team from Necker Hospital in Paris

has reported on the feasibility and safety of stereotactic biopsies of patients with

newly diagnosed DIPG. In their initial report, 2 out of 24 patients presented with

a transient decit associated with the procedure. ey have subsequently reported

and updated their experience and have conrmed the safety and feasibility of DIPG

biopsy in more than 80 patients. is work has also provided new information

regarding the biology of DIPG. Interestingly, the results of studies conducted with

tissue obtained at the time of diagnosis or at autopsy (therefore after radiotherapy

in most cases) do not dier considerably.

What Have We Learned So Far About DIPG From Autopsy

Studies?

ree genomic studies have now been published on autopsy series of DIPG.

While still somewhat limited when compared to genomics studies conducted

in adult cancer, several important conclusions can be drawn from the data

available from these DIPG studies which can help in the development of future

clinical trials. First, the studies support dierences at both the copy number and

expression level that distinguish pediatric

DIPG from both adult and pediatric

glioblastoma multiforme (GBM) elsewhere

in the brain. is conrms that DIPG must

be considered as a separate biologic entity

Dr. Bouffet is the Director of the

Neuro-oncology Program and

a Senior Associate Scientist in

the Research Institute at the

Hospital for Sick Children, as well

as Professor of Pediatrics at the

University of Toronto, Canada.

Dr. Bartels is an Oncologist in

the Neuro-oncology Program at

the Hospital for Sick Children,

and Assistant Professor at the

University of Toronto, Canada.

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Chapter 19: DIPG and Tissue Donations

for the purpose of clinical trial design.

Second, receptor tyrosine kinases (RTKs) appear to be upregulated at the

genomic or expression level (or both) in the majority of pediatric DIPGs. e

most commonly amplied RTK in pediatric DIPG is PDGFRA, occurring at

the genomic level in at least 30% of DIPGs with an even larger number showing

over-expression at the RNA and protein levels. Gain of EGFR does not appear to

be a frequent event in pediatric DIPG. However, two other RTKs are reported

to be frequently gained in DIPGs: MET and IGF1R. Interestingly, in many

cases more than one RTK is amplied in the same tumor, a nding that may

have implications when using single RTK-inhibitors.

Based on their work on stereotactic biospies, the team for Necker (Paris)

has described two distinct subgroups of DIPG. e rst subgroup shows

mesenchymal and pro-angiogenic characteristics. e second subgroup displays

oligodendroglial features, and appears to be driven by PDGFRA. is later

group had a signicantly worse outcome and shorter survival expectancy. is

suggests that dierent treatment strategies may be needed as DIPGs do not

appear as a uniform disease.

Current Situation

ese experiences have generated signicant hope and enthusiasm in the DIPG

community and also amongst parents and support groups. In April 2009, the

FDA held an open public hearing specically to discuss the science and ethics

regarding pediatric DIPG biopsy in the United States. e purpose of the FDA

hearing was to address a research initiative proposed by a U.S. based children’s

hospital that wanted to biopsy newly diagnosed DIPG children to compare

similarities between their tumors and pediatric cerebral glioblastomas. Several

issues were addressed during the 2009 FDA hearing including the concern of a

number of the panel members that the risk of biopsy of DIPG was not balanced

by certain benet for the individual child. As a way to bridge this issue, several

experts suggested that an initial eort be made to evaluate port-mortem tissue.

is would alleviate concerns regarding safety of biopsy and also make more

tissue available for research purposes. Several groups (Dana Farber of Boston,

UCSF of San Francisco, the National Cancer Institute of Bethesda, the Institut

Gustave Roussy of Paris) are currently working on biopsy driven protocols. In

these protocols, the results of the biopsy will be taken into account to stratify

patients and allocate their treatment accordingly.

Concurrently, an increasing number of institutions, including Sick Children’s

Hospital in Toronto, St. Jude Children's Research Hospital, and the National

Institutes of Health (NIH), already have research procedures in place for autopsy

tissue donations from families whose children were treated under their care or

in outside institutions.

Where Do We Go From Here?

Autopsy studies have triggered a tremendous enthusiasm in the pediatric neuro-

oncology community. Several protocols have been developed or are about to

open following the publication of the rst genomic studies that have identied

potential targets. However, most protocols target one mechanism only and it

is likely that the successful management of DIPG will require combination

therapies. In this context, recent development of genetically and histologically

accurate preclinical (animal) models is critical, as this will allow the testing of

targeted therapies that may eventually be brought to the clinic. A number of

models are currently being tested that may contribute to selecting the most

appropriate agents or combinations for future clinical trials. ere is no doubt

that the coming years will see an explosion of new DIPG protocols based on

the data generated by the collection of autopsy material. Everyone hopes that,

as a result, we will observe for the rst time a dierence in the dismal outcome

of children with DIPG.

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Chapter 19: DIPG and Tissue Donations

Parent Perspectives

I know this is such a difficult thing to consider while a child is fighting, but

planning for tissue donation is not giving up in the fight. It is just one of the

many ways we can prepare for our children’s memories to endure and for their

lives to make a difference, even as we hope and plan to never reach the day.



None of Caleb’s doctors ever approached my wife or me about a donation

of Caleb’s tumor. Through reading the web blog of another family whose

son had passed away, I learned that they had donated his tumor and I

became aware of the medical value of the tumor. I would not have known

the tumor had any value, or that a doctor would want it, if I’d not stumbled

across that web page.

While we were on a routine monthly trip to the NIH, I raised the subject with

Caleb’s doctor. Caleb was still doing well, but I knew the prognosis of his

disease and I wanted to begin the discussion with his doctor. She seemed

hesitant to discuss it, but simply said that when the time was right, there were

some studies that could use the tumor and we could certainly discuss it later.

I also asked Caleb’s doctor in Houston about donating the tumor, wanting

to make sure they knew of my interest. Since my wife had not yet accepted

the possibility that Caleb could die, I did not discuss my questions with her.

When Caleb began to worsen, and it finally became clear that he would not

survive, I raised the topic with my wife. She was open to making the donation,

but wanted Caleb’s doctor to be at the hospital to receive him, and so I more

seriously pursued the topic with Caleb’s doctors at the NIH and in Houston.

They informed me that there were studies that could use his tumor, and they

would be glad to receive it. I know recent cases where parents selected the

studies and beneficiary institutions for the tumor tissue, but at the time, I

didn’t know this was possible. So we simply donated it to the hospital in

Houston where Caleb was treated, making sure our doctor at the NIH knew

of the donation and could obtain the tissue she needed for her studies as well.

I also talked with our funeral director early on. I was concerned about

Caleb having an open casket funeral, and I didn’t want to do something

that would disfigure him noticeably. Both the doctors as well as the funeral

home assured me this should not be a problem.

We signed the paperwork for the study, and there were no expenses at all

which were charged to us for either the surgery or the transportation of

Caleb’s body to the hospital for the removal of the tumor.

Caleb passed away at home, and we kept him there for a few hours afterwards.

Then, the funeral home brought him to the hospital for the removal of the

tumor. Caleb’s doctor agreed to my wife’s request and was present during

the tumor removal, to ensure he was lovingly taken care of. We did not see

Caleb again until he was embalmed and ready for viewing.He looked amazing,

and angelic. The doctors and the funeral director were right—there was

no evidence whatsoever of the tumor removal; they must have done a very

discreet incision on the back of his head (which was resting on the pillow).

He looked beautiful.

In hindsight, we would do this all over again. Knowing that Caleb might

help other children fighting the disease, even in his death, brought us some

peace. And, having the tumor removed from him was also important to us.

We wanted it gone, even if that were only possible in his death.

Five years have passed now, and there are many more options available.

Some parents have selflessly made themselves available to help others

through this experience, and I wish we would have had that help with our

decision. There are many studies, well known, which will accept tumor tissue

donations. Parents can have a say which studies benefit from the donation,

and the tumor can be divided among several studies. Every parent must

make their own decision, but for us, this was the best decision.



Probably mid-way through Mara’s diagnosis with DIPG we heard about

the need for tissue samples. For us, the decision to donate seemed easy and

quite frankly it seemed like the only way we could make a difference for

the future of this disease. To us, donating meant that if Mara were to pass

away, it would not be in vain, for perhaps someone else could live even

though she could not. Initially though, we prayed to be THE MIRACLE

and didn't want to think about crossing that bridge.

It wasn't until Mara's pediatric oncologist set up a palliative care meeting

for Mara at the end of August (approximately 1 month before her passing)

that the issue was discussed directly with them. As I recall, we were the

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Chapter 19: DIPG and Tissue Donations

ones in this meeting to bring up tissue donation. As I look back, I was a

little surprised that our medical team never mentioned it to us directly.

However, I see their wisdom in it now. What kind, compassionate doctor

can tactfully ask a parent for a tumor donation when their child is still

living and the family is still fighting? So, my husband and I brought up

the issue of having Mara's tumor donated upon her passing as well as any

other organs that could be donated.

Mara’s doctor was honored that we would suggest donation. He explained to

us that we'd have to sign a consent form and we did that at Mara's next CT

scan, which was a few weeks later. The consent form we signed was a rather

generic form. It was a form that anyone would sign to release tissue, whether

it is due to the child's passing or just a simple donation derived from a biopsy.

We made it clear at this time that we'd like samples to be sent to St. Jude and

to the NIH, as well as the researchers at Seattle Children’s Hospital. He did

communicate with us the need to have Mara transported post mortem and

taken from our home up to Seattle (about an hour away). He told us that any

cost associated with the transportation would be paid for by the hospital.

As the week continued, we realized that we should probably at least touch

base with a funeral home to let them know about our situation and that

transportation would be an issue. Bryan made this excruciating call, an act I

can never imagine doing myself. It seemed against every parental inclination

to arrange for our child's death when she had not yet passed. This phone call

occurred only 2 days before Mara left her earthly home. The funeral home

assured us that this would not be a problem. We gave hospice the funeral

home information, which worked out well because when Mara did pass away

they took care of everything. We didn't have to think about it anymore after

this phone call. It made the decision much easier in the long run.

The day Mara passed, we received a phone call from her doctor and from

our nurse practitioner telling us that the autopsy was being performed and

that the transport went smoothly. They cried with us, and thanked us. Later,

we also received a note in the mail from Mara’s doctor thanking us once

again and letting us know that in his opinion, we did everything possible to

help Mara. Reassurances like that mean the world to grief-stricken parents.

In the end, nothing about this disease is easy, nothing. I understand that

the decision to donate is most personal in nature. However, the pride in

my heart for my daughter’s offering is beyond description. For us, this was

the best decision and will allow Mara’s legacy to live on.



We had already made arrangements to donate Caleb’s tumor for research.

So, after my husband and our other boys and our friends had had some

time with Caleb's body, my husband called our oncologist to let her know of

his death and to make plans to meet her at the hospital. Our funeral home

director is our neighbor and was prepared to hear from us. He came to the

house when my husband was ready. They rode to the hospital with Caleb's

body and delivered it to our oncologist (with our friends following behind).

After my husband was sure that our oncologist had Caleb's body and was

prepared to supervise the harvesting and preservation of the tumor tissue,

he left the hospital with our friends. After the autopsy was complete, the

funeral director took Caleb's body back to the funeral home.



Our son Andrew died on December 4, 2009. We donated his tumor to his

neuro-oncologist at the NIH, and tissue was shared with Hopkins and

Children's National Medical Center.

I have been helping with DIPG and other brain tumor tissue donations

since November, 2008. As a result of tumor tissue donation over the past

few years, researchers are beginning to have an understanding of DIPG

biology which means that treatments can now actually be developed and

chosen in a scientific way. Though we do not yet have a cure for DIPG, we

are headed in the right direction. We could not say this in October 2007

when my son was diagnosed.



It was almost seven months after Ethan passed when I happened to email

his oncologist. His oncologist shared information with us that he had

received from a researcher at Texas Children’s. I wanted more information,

so I emailed the researcher directly. I wasn't sure I would hear back, but he

was very willing to share with me the progress of his research with Ethan's

tumor and the mouse model he had created with it.



I believe in miracles but I am also a realist. As we sat in the exam room

listening to the doctor tell us our daughter had a brain tumor for which

there was no real treatment much less a cure, I remember thinking I want

this thing out of her head. If we don’t get our miracle someone has to

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Chapter 19: DIPG and Tissue Donations

study this beast so no one else has to do this. I had no illusions that our

donation in and of itself would be the magic bullet for DIPG patients but

Hope was special and her life mattered. Her grey matter would be studied

and knowledge could be gained.

While I am positive that our doctor would have brought tumor donation to

our attention at the time he thought appropriate, I beat him to it. I always put

reality in the driver’s seat with hope firmly strapped into the passenger seat.

I wanted to know up front what all my options were. When he said, “Don’t go

online I will answer your every question,” I raced to the computer. I trusted

him completely but I needed to know ahead of time what potentially could

or would happen. We had conversations throughout Hope’s battle regarding

tumor donation. These conversations were always welcomed by our team

but were initiated by me. I felt compelled to be sure they understood how

important it was to me. They felt bound by compassion to be gentle with me.

As Hope appeared to be nearing the end of her life we had our most serious

conversation regarding our donation. Hope’s doctor assured us that he

would stay with Hope during the entire autopsy and made sure her “blankie”

was nearby. He asked us for permission to share her tumor with other

researchers, which we happily agreed to. We did not ask where he would

send the tumor or how it would be used as we had complete confidence

in his professional judgment. We have no regrets. Hope’s tumor is being

studied at some of the finest institutions in the country.

If I had any suggestions to give, I would suggest that doctors be upfront

with families about tumor donations and for families to understand why they

need to do so. These relationships are built out of respect and honesty. It

is unfortunate that the time line for our kids is so short that doctors really

can’t afford to wait for the “right time.” Just like a clinical trial is fully

explained as an option, so should tumor donation be explained as an end of

life option. I wish I had known more about the need for live cell lines and

what they have to offer research. While I know that Hope’s tumor, having

been frozen, is offering much to the research community, it would have

made my heart happy to know that somewhere the evil thing that took my

child’s life was alive and potentially being used for the good of our kids.



Throughout my daughter’s battle with DIPG, I constantly struggled to

balance my ultimate hope that she would somehow survive, with my

acknowledgement of the reality of the disease and the likelihood that

she would not. By nature, I am a planner. Subconsciously, I think that I

somehow believe that if I can think through all of the possible outcomes

and scenarios and plan for all contingencies, then it will be easier to deal

with whatever actually happens when the time comes. Of course, I knew

that I could never prepare for my daughter’s death.

So, it wasn’t long after my daughter’s diagnosis that I learned about

tumor tissue donation and began to think about whether it was something

I would want to do. Our daughter’s medical team did not mention it for

a long time; in fact, they didn’t mention it until very close to the end. But

long before they brought it up, we had considered it. We learned of other

families who had donated, and how comforted they were in knowing that

perhaps their child’s death was not in vain—that the donation might help

another child someday. Throughout my daughter’s battle, my husband and

I occasionally discussed the issue. He was hesitant to do it, while I thought

it would be comforting. In the end, we discussed it with our clergy, other

parents who had donated, and with a few very close friends and family. We

were reassured that it would not affect our funeral plans or how long we

would be able to stay with our daughter once she had died. We also were

told that the logistics would be handled and that it would not require any

additional burden on our part at such a difficult time.

Despite all of that, ultimately we decided that donating our daughter’s tumor

tissue was not the right decision for us or for our daughter. It was not an

easy decision by any means; but it is one with which we are comfortable and

do not regret. Throughout the course of her battle, she had participated in

four clinical trials. She had sacrificed so much already in her short life. She

went through extra weekly pokes, prods, and tests, and never complained.

She had scars from various surgeries. She took drugs that caused her side

effects but gave her no benefit. She had suffered enough. My husband and I

also struggled with the thought of picturing our daughter after the donation.

We wanted to remember her as the beautiful little girl that she was, and

not be clouded with images of her “less than whole.” While I, no doubt,

would have found great comfort in possibly helping to find a cure through

donation, that comfort may not have outweighed the emotional distress that

such a donation may have caused me and my husband. Whatever parents

decide; it will be the right answer for them and their family. But parents

should know that it is okay if they choose not to donate.



Chapter 19: DIPG and Tissue Donations

284

Our decision to donate our daughter’s tumor tissue was easy in comparison

to the other decisions we had to make at that time. We had just been dealt

the news that her tumor had progressed and we were dealing with being

removed from a clinical trial, setting up hospice care, and looking for other

treatment options. Other parents of DIPG children mentioned they would

be willing to help set up the tumor donation. I asked my husband what he

thought and he said we should go ahead with it. I agreed. I contacted the

parent/advocate who had offered to help and we began the process. Of

all the decisions we had to make at that time, we gave that one the least

amount of thought. We did not realize the positive impact it would have.

Because our daughter’s condition deteriorated so quickly, our involvement

in setting up the donation was minimal. We made important choices, such

as where the tumor would ultimately be donated, but the DIPG mom who

was helping us let us know that she could take care of the logistics if we

did not have the time. We were able to choose our level of involvement so

that we could focus on our daughter during her last days on earth.

After she passed away, we signed some paperwork and the donation was

made. The donation did not disrupt our plans for her Catholic mass and

burial. We laid our daughter to rest tumor free. We opted to have her tumor

go to Dr. Monje at Stanford. Once the donation was done, I thought that

would be it. But Dr. Monje has graciously shared her progress in research

using Bizzie’s donation. She took the time to provide us with details about

our daughter’s tumor and how she was using the tissue. Within weeks of

our donation, Dr. Monje shared with us that Bizzie’s tumor was used to

confirm an important finding in DIPG research. To know that our decision

to donate has, along with other donations, facilitated a finding that could

help develop an effective treatment for future DIPG kids is something that

honors our little girl’s memory in a way that nothing else could. No amount

of fundraising could provide the same value. While we could not help our

daughter beat cancer, we can help other kids have a chance at growing up.



Brendan knew there was no cure and that he would die from the tumor. He

also knew that donating the tumor could lead to a cure in the future. His

tumor tissue was donated to Children's Hospital and a pathology report

was shared with us. His post mortem tissue is going to be useful for future

research.

285

Chapter 20: Organ and Tissue Donation

Chapter 20

Organ and Tissue

Donation by Pediatric

Brain Tumor Patients

Angela Punnett MD, FRCPC

Some patients with brain tumors and their families may wish to explore the

potential for organ and tissue donation following an expected or unexpected death.

is is a complicated decision and it is helpful when planning to understand the

background of organ donation in the context of a cancer diagnosis; issues specic

to patients with brain tumors; the process for donation; and implications of organ

donation at the time of death.

History of Organ Donation and Cancer

ere are a signicant number of patients awaiting solid organ transplantation at

any given time and 5% to 7% of these patients will die while awaiting transplant.

Lack of consent to organ donation by the population at large is the main limiting

factor to transplantation.

It is generally accepted that individuals with a diagnosis of cancer are not eligible to

donate their organs because of the risk of transmitting cancer to the organ recipient.

is risk of transmission has been documented since the early days of solid organ

transplantation, with reports of close to half of recipients developing the donor’s

cancer, resulting in death.

However, not all cancers are equally likely to

spread, and recognizing the need to balance

pre-transplantation life-threatening conditions

with post-transplantation malignancy risk,

an International Consensus document was

written in 1997 (Council of Europe, 1997).

Dr. Punnett is an Assistant

Professor in the Department of

Pediatrics at the University of

Toronto, and Program Director

of the Pediatric Hematology

Oncology subspecialty training

program at The Hospital for Sick

Children, Toronto, Canada.

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e group of experts who crafted this document recommended consideration of

donors with primary brain tumors that very rarely spread outside of the central

nervous system (CNS).

Risk of Spread of Primary Brain Tumors

Spread of a primary brain tumor outside of the CNS, or extracranial

metastasis, has been considered unlikely because of anatomical and biological

features of the CNS itself. e CNS is a relative sanctuary with the so-call

“blood brain barrier” and has few lymphatic channels. As a brain tumor grows

it invades surrounding tissue, collapses existing blood vessels, and really has

nowhere else to go. However, studies have shown that brain tumor cells can

grow in other types of tissue and invasion of blood vessels and lymphatic

drainage has been documented.

e most important and consistent risk factor for extracranial spread is the

cell type and grade of malignancy. e tumors most likely to demonstrate

extracranial spread include ependymoma at about 6% of patients,

medulloblastoma at about 5% of patients, and glioblastoma at about 0.5%

of patients. ese numbers are based on relatively limited and older data

however, and are dicult to interpret. In addition, a number of other risk

factors for extracranial spread have been proposed, including duration of

disease, receipt of chemotherapy and/or radiation therapy, and history of

craniotomy and/or ventriculosystemic shunt.

Donor transmission of primary brain tumors

ere are a number of case reports in the literature documenting transmission

of tumors from donors with primary brain tumors to their organ recipients,

in some cases causing death. Recipients of heart, lung, or liver transplants,

were more likely to die from transmitted malignancy, as kidney transplant

recipients could be saved with chemotherapy or removal of the transplanted

kidney.

A number of transplant centers have reviewed their local experience in an

attempt to understand the risk of transmission. e resulting analysis showed

that donors with a history of a primary brain tumor accounted for 1% to

4% of all donors. Among those donors with a history of a primary brain

tumor, the risk of transmitting a tumor to an organ recipient was 0% to 3%.

Larger experience is available through mandatory reporting to national organ

transplant registries. In the United States, the United Network for Organ

Sharing (UNOS) has published its experience, which shows donors with

primary brain tumors consistently represent approximately 1% of all donors.

Out of 642 transplant recipients, 3 developed a fatal tumor from one donor

with glioblastoma multiforme (0.5% transmission rate). When comparing

survival curves for recipients of kidney and liver transplants from donors

with and without primary brain tumors, there is no dierence. Donors with

primary brain tumors represent 2.6%, 2%, and 1.5% of all donors in the

Australia/New Zealand, Czech Republic, and United Kingdom registries

respectively, with no cases of donor-derived malignancy reported.

Somewhat dierent data is available through the Israel Penn Tumor Registry,

an international, voluntary reporting registry based in the United States that

started in the very early days of transplantation. It is not possible to estimate

the incidence of transmission with this registry data, but it is possible to

look at risk factors for transmission. Among 62 organ recipients from 36

donors with primary brain tumors, 14 (23%) developed a tumor; almost

half of the donors had glioma/glioblastoma. Risk factors for transmission

from this data include the presence of ventriculosystemic shunt, extensive

craniotomy, high-grade histology, and the presence of a cerebellar lesion.

When organ donation is being considered, the local Organ Procurement

Organization (OPO) and the transplant team must consider all of this

information in the context of the patients awaiting transplantation. e

risk of transmission of a tumor from a donor with a primary brain tumor

is dicult to quantify but appears to be low, with identiable risk factors

that increase the risk. It has been recommended that potential organ

recipients be counseled around the small but denite risk of transmission

of malignancy, as well as the chance of survival if they choose to remain

on the waiting list for their needed organ. With donors considered to be

higher risk, transplant teams may exclusively request certain types of tissue

donation (for example, heart valves, cornea, bone, other), where the risk of

transmission is practically nil.

e Process of Organ and Tissue Donation

As parents of a child with a brain tumor, you may be considering organ and tissue

donation at different times during the course of your child’s illness. It is helpful

to speak with the health care team sooner rather than later in order to explore

options and the implications for your child’s care around the time of death. The

health care team will then refer your family to the local OPO and a representative

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will meet with you to discuss the donation process.

Organ donation occurs following conrmation of a donor’s death with the goal

of maintaining the organs in a healthy state until the time of transplantation. e

process of removal of the organs from the donor is called organ retrieval. With

brain death, there is conrmation of irreversible brain damage but continued

heart activity, such that the organs are still perfused, or receiving their blood

supply from their donor. Donors are maintained on articial life support until

organ retrieval occurs. Some hospitals will oer donation after cardiac death,

after careful ethical consideration. In those situations, a donor is removed from

all life support and death is conrmed by lack of heartbeat and breathing eort.

Organ retrieval occurs immediately thereafter. In either case, death must occur

in the hospital for donation to occur.

Current guidelines recommend careful review of a donor’s medical history for

the risk factors discussed above, as well as careful exploration at the time of organ

retrieval to assess for metastatic disease. e areas to assess may include sites of

previous surgery, related lymph nodes, and the shunt tract, including the chest,

abdomen, and pelvis. In the unlikely event that spread of malignancy outside

of the brain is conrmed by pathology, the transplant team will be notied

immediately and the organs retrieved will likely not be used for transplantation.

e process around tissue donation depends on the tissues to be donated and

will require discussion with the OPO representative. For cornea donation for

example, the tissue is less sensitive to lack of oxygen and retrieval can take place

hours after death. In this situation, there is more exibility for families around

the time of death.

At the time of death

Every family will have their own needs and wishes for their child at the time of

death, and organ donation may not be appropriate or possible for many families.

For those families who do want to pursue the opportunity to donate, it is

important to understand the small possibility that your gift of organs may

be denied. (is is much less likely for gifts of tissue.) It does appear that

transplant teams now have better data to appreciate how small the risk of tumor

transmission actually is, and to counsel potential organ recipients appropriately.

ere is an urgent need for organ donors worldwide and patients with primary

brain tumors and their families have developed an extraordinary legacy with

their gifts of life.

Parent Perspectives

Parents do need the option of organ donation; therefore, they need to know

the right questions to ask and when to ask them. It's so difficult because

in asking the questions we are admitting that we are going to lose our

children—something we try to condition ourselves not to think about.

When we thought we were going to lose Emma I asked about organ donation

but was told we couldn't donate. Tissue donation was possible—hence the

corneal donation. The morning she earned her wings, our palliative care

medical team was connecting with the agency and we received the news

that they would accept Emma's corneas. It was so bittersweet to hear that

decision. Emma had an amazing way of seeing the world, people and events.

And now, there are two people that will be able to see their world, through

Emma's eyes. We take comfort in knowing this, and knowing that part of

Emma lives on in this world.



Soon after Mara's passing we received a phone call from the donation

center verifying our intent to have the corneas donated. We could have

missed this phone call had it not been for others answering phones for us

at the time. Just a few weeks later, we received a letter from the donation

center indicating to us that Mara's corneas were indeed used. We cried

tears of joy knowing that a small piece of our daughter was still alive. It

made us want to find the person and gaze into their eyes. It was made clear

to us through the letter that anonymity was paramount in this situation,

however. I understand why this has to be and appreciate that we can write

an anonymous letter to the recipient telling them about Mara.



I want to start by telling everyone a story about my family. My Mom lost her

husband, son, and mother all in a car accident on Mother's Day in 1963.

It was before I was born. My mom and my two sisters lived but the others

died. My brother's name was Max. Ironically, Max was 8 years old when

he passed away, the same age as my son Ethan. Max was killed instantly

and the one thing that my mother always said when I was growing up was

that she wishes she would have been able to donate Max's organs. That

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even though it wouldn't have taken the pain away of losing him, it would

make her feel like his death had some purpose. And so when Ethan was

diagnosed with DIPG and his tumor later progressed, I felt a very strong

need to donate whatever organs, or cornea, or tumor that I could.

Like most of you, I always thought if you were a cancer patient you could

not donate your organs. In reading other children's websites I noticed that

many were donating their tumors and their corneas. So as Ethan's health

declined, I emailed his oncologist and asked him what we needed to do to

make pre-arrangements for this. At that point in time, he emailed me back

and said, “Lets cross that bridge when we get to it.”

A few weeks before Ethan passed away; we sat down with Ethan’s oncologist

and asked him again about tumor and cornea donation. He told me that as

Ethan's tumor is a glioma, they are known to not spread to other parts of

the body, i.e., the organs. He thought that Ethan may be able to donate all

of his major organs. He made some phone calls and put us in touch with

the Gift of Life Organization.

They told us that if Ethan was to be a candidate for donation, he would

have to pass away at the hospital. We had been on hospice with Ethan since

October so it would mean that the plans we had made for Ethan to pass

away peacefully at home would have to change if we wanted to donate. So

in talking with Ethan's father, he at first was not sure if he wanted to donate

but would think about it. I believed in leaving this to God, so decided that

if we were meant to donate Ethan's organs we would make it to a hospital

and he would die there. If we weren't, then he would pass away at home.

During Ethan's final days, he was in so much pain due to headaches. He

had never complained hardly ever of headaches previously, only very minor

ones. These were “over the top,” leaving him hollering in pain. Hospice

gave him morphine but it was not easing his pain. The hospice providers

kept in close touch with Ethan’s doctor and on Tuesday, he suggested we

should bring Ethan to the hospital to get his pain under control. So we

packed him up for the 1 hour 15 min ride to the hospital. The car ride up

there I rode in the back seat with him stroking his hair and forehead and

holding his hand.

When we got to the hospital, and laid him on the bed, I noticed his fingers

and toes were a bluish color. They hooked up the pulse oximeter and he only

had 10% oxygen saturation. So he was admitted to PICU and was eventually

put on a ventilator. A CT scan of his head showed that the tumor had grown

and was compressing areas of the brain that controlled breathing, but that

the brain had not herniated or hemorrhaged. The doctors told us that the

brain had been pushed upwards and that it was blocking the flow of spinal

fluid throughout the brain. This was something he could not recover from

and if taken off the ventilator he would not be able to breathe on his own.

But also that he probably would not have brain death for quite some time,

(days or weeks).

We were forced to make a decision: 1) continue to support him, knowing he

will not recover and that he is in discomfort; 2) make a decision to remove

support in his hospital room, and let him pass away as it would occur,

knowing he would not be able to donate any organs, or 3) plan to remove

life support in the operating room, with my husband and I present. They

would allow him to take his last breath and his heart to stop beating, and

then life support would be placed back on. At that point in time we would

have to leave the operating room so that the transplantable organs could

be removed (this is called a post-cardiac death transplant). If Ethan did

not pass away within a certain time frame of removing life support, then

he would be brought back to his room in the PICU, and we would be with

him until the very end, but not able to donate his organs.

There had only been four previous post-cardiac death organ donations done

at this hospital in 10 years. Ethan's case had to be brought to the Ethics

Committee to make sure it was ethical in his case. It was decided it was, so

we planned for him to be taken off the ventilator at 6:00 p.m. the following

evening in the operating room and donate his organs.

The Gift of Life Organization was able to locate one match for Ethan's

kidneys from someone who was willing to take them from a cancer patient,

and two recipients for his corneas. It was decided later that his tumor

would go to research.

So at 6:45 p.m. we were changed into scrubs and taken into the operating

room where Ethan was already prepped for surgery. They had all of the

surgical instruments covered up, and had Ethan draped with the exception

of his face and hands. His dad and stepmom stayed at one side and his

stepfather and I at the other. At 7:30 p.m. they removed the breathing tube

and we waited holding his hands for him to pass. He took several last

gasping breaths but then did not breathe again for several minutes even

though his heart was still beating. His heart would flatline but then register

Chapter 20: Organ and Tissue Donation

292

and then flatline and then register. Finally it stayed flatlined and the doctor

confirmed he had passed. We said our goodbyes and left the OR, while the

surgical team recovered the organs. Afterwards, they cleaned him up and

we were able to come and see him before leaving the hospital. He looked

very much at peace.

We had to give up the chance to have him at home for his death but I know

we made the right decision. I know in the end that Ethan would have wanted

his organs to save other lives, and I know he would have been proud of us

for making this difficult decision. It was evident when they removed the

tube that he could not breathe on his own enough to sustain his life. I think

his time to go was Tuesday evening, we just were fortunate to get two more

days with him while making preparations for his Gifts of Life. While it may

have changed where he died, we were able to see that he was at peace, and

know that someone else was able to live and see because of our sacrifice.

293

Chapter 21: Integrating Palliative Care

Chapter 21

Integrating Palliative

Care and Making

Difcult Decisions

Justin N. Baker, MD, FAAP, FAAHPM

Adam J. Tyson, MD

Javier R. Kane, MD

As you have read in prior chapters of this book, diuse intrinsic pontine glioma

(DIPG) is a serious disease. e majority of patients with DIPG and/or their

families are told that the tumor cannot be removed with surgery because of its

location. ey are also told that the tumor is rarely sensitive to chemotherapy,

and that while the tumor may decrease in size with radiation therapy, the disease

often continues to grow despite best eorts. What this means is that DIPG is

usually an incurable and progressive disease. When presented with such dicult

news, most families want their child to receive the best possible treatment for

this terrible disease, hoping that their child will beat the odds. Most families also

realize that serious illness often comes with pain and suering, and they want to

avoid this for their child as much as possible.

Parents in these circumstances often report that making decisions regarding their

child’s care is extremely dicult because it requires balancing the dual goals of

care that include cancer-directed goals and care that provides comfort-directed

goals. Parents often wonder how they can

possibly prepare for such an overwhelming

and dicult situation and how to plan for

their child’s care in such a way that hopes

for the best but allows for consideration

of all possible outcomes, thus allowing a

balanced approach to decision making.

In these dicult situations, parents must

often think about what is most important

Dr. Baker is the Director of the

Quality of Life and Palliative

Care Division, Director of

the Hematology/Oncology

Fellowship Program, and an

Attending Physician for the

Quality of Life Service at St.

Jude Children’s Research

Hospital, Memphis, TN.

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for the child and family. Based on what is happening with the tumor, available

medical treatment, and the child’s experience, the parents must decide the most

important goals in the care of their child. Families may also have important life

goals they would like to accomplish with their child. ese goals are critical and

should be taken as seriously as evaluating blood levels or assessing the side eects

of medications. Every attempt should be made to integrate these goals into the

overall plan of care for children with DIPG so as to balance the use of treatments

to ght the tumor, and the eorts of the family and the care team to preserve

comfort and the best quality of life (QOL) possible for these children.

Establishing Goals of Care and Making Dicult Decisions

Most families start treatment with the hope of attaining a cure for their child with

DIPG. Having hope is very important, as it sustains patients, families, and their

caregivers during extremely dicult times. Unfortunately, this disease makes cure

highly unlikely and in reality most therapies for DIPG are either experimental or are

only intended to prolong life. is does not mean the team will not remain hopeful

with you that a cure can be attained, but it does mean that you and your team must

hope for the best possible results while planning for all possibilities, including the

possibility that the tumor will continue to grow in size despite everyone’s best eorts.

If and when the tumor begins to grow despite the treatment, parents may know with

greater certainty that the child’s tumor is incurable. During this time it is appropriate

to continue to hope for the best possible outcome. If you come to realize that your

child has a disease that cannot be cured, it is also critical to work on deciding the

goals you would like to try to achieve while your child is alive.

You may want to think about what is most important to you and your family,

and how you would like to spend the remaining time you have with your child.

You will once again face many dicult decisions. It may be easier for you to make

decisions at this time if you think about whether or not the possible treatment

choices presented to you will help you achieve the goals you have for your child

and family. Parents report that the most dicult decisions they have to make

for their child happen at this stage and include whether or not to stop ghting

the tumor and stop cancer treatment or to

enroll their child in a phase I research trial

[Table: 1].

Goal to prolong a life of good quality—minimal morbidity

Values discussion regarding location of care and cancer-directed

treatment options:

• Phase I trial possibilities

• IV or oral cytotoxic chemotherapy with hopes of tumor response

• "Palliative" chemotherapy

Values discussion regarding priorities and life plan goals:

• Discussion with your child about DIPG progression

• Hospice enrollment

• Placement of a DNAR order

Goal to optimize comfort

Values discussion regarding priorities and life plan goals:

• Discussion with your child about progression

• Hospice enrollment

• Placement of a DNAR order

Table 1: Goals and values discussion

Parents may also choose to avoid further pain and suering caused by invasive

treatments such as breathing machines or other aggressive and potentially

uncomfortable life-sustaining treatments and have a “Do Not Attempt

Resuscitation” (DNAR) order (see questions 6 to 8 in addendum below for

more information about DNAR orders) placed in the medical record, or to

decide against certain treatments that may not help achieve the primary goals

of care. Other important decisions to consider include whether or not to enroll

their child in hospice, to speak to their child about the fact that the disease

is worsening or the possibility of death, choosing a desired location of death,

deciding whether an autopsy should be performed, and other important life

choices such as whether or not to continue going to school, traveling, or pursuing

other goals the child and family would like to achieve. While these are some

of the most dicult decisions you will ever

have to make, the specic goals of care you

have set for your child and family will help

minimize distress for your child and help

Dr. Kane is the Director,

Pediatric Hematology/Oncology

and Professor in the Department

of Pediatrics at The Children’s

Hospital at Scott and White,

and Texas A&M Health Science

Center, Temple, TX.

Dr. Tyson is a Family Medicine

Resident Physician at the Bryn

Mawr Hospital, Bryn Mawr, PA.

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Chapter 21: Integrating Palliative Care

to ensure his or her comfort.

Your Team and Individualized Care

You and your child are part of a team. In fact, you are the most important members

of this team. Your health care team is taking this journey with you, and everyone’s

desire is that you and your child should never feel alone. Your care team may not

be able to fully put themselves in your shoes, but they have likely walked through

this very dicult time with many other families and will draw on those experiences

to help you. You should encourage your medical team to be very open with their

thinking as they make recommendations to help accomplish the various goals of

care that you have for your child and family. is process may look dierent for

your family than it does for others [Fig. 1]. Discussing the individualized aspects

of care is dicult, but the better the team knows you and your child, the better

the care plan can be matched to your and your child’s needs.

Figure 1: Decision-making schematic

Most children with DIPG enroll in a research treatment plan or receive treatment

following a specic cancer treatment plan. You may be wondering how this

individualized approach to palliative care can work within the context of a research

protocol or a predesigned cancer treatment plan. Remember that these treatments

are only one aspect of the overall care plan. A care plan includes a medical plan

and a life plan, both of which should be individualized to your and your child’s

unique needs. A specic research protocol or cancer treatment plan may be a part

of the medical plan, but other aspects of the care plan can be highly individualized,

such as medications to relieve pain and other distressing symptoms. Any specic

needs that are unique to your situation, such as rehabilitation needs or spiritual

needs must also be addressed.

Communicating your needs and perspectives

Communication with your child’s physician and other members of the care team

about all of the before-mentioned issues is extremely important. As your team

(remember this means your child, family, and medical care team) starts out on

this journey together, you can facilitate better communication and understanding

by talking to the medical team as much about your child and family as possible.

Do not hesitate to bring your child’s and family’s needs to the attention of your

care team, because they cannot address your needs if they do not know what

your concerns are or what is most important to you. e better the team knows

you and your child, the better the team can make an individualized plan of care

along with you.

You may not automatically know what information is important to share. It will

be helpful for the team to be able to judge your level of understanding of the

prognosis, goals, and treatment options as treatment begins, and at other key

points in time if the illness progresses. It will also be very helpful, for example,

to hear about whom your child is, how your family is doing, and what the illness

experience has been like for each of you.

Questions to consider when talking to the team about these things are listed in

Table 2.

Category Questions to Consider

Understanding your perspective What does good quality of life mean

for you and your child?

What are you hoping for? What is

your child hoping for?

What is most important for you and

your family?

What are you most concerned about?

What is your denition of being a

good parent to your child?

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Category Questions to Consider

Information and decision making What information do you or your

child need right now?

How do you like information to be

delivered/handled?

How much does your child want to

participate in decision making and

dicult conversations?

Specic needs: symptoms What are your child’s most concerning

or distressing symptoms that interfere

with good quality of life?

Specic needs: spiritual Are you or your child experiencing

spiritual distress? Do you feel aban-

doned by God? Do you feel angry

toward God?

Specic needs: emotional Is anyone in the family experiencing

emotional distress that is interfering

with good quality of life?

Specic needs: social Are there any family needs that if

not addressed will lead to increased

distress?

Are there any sibling needs that are

currently not being addressed?

Chance for treatment success What is your family’s understanding

of your child’s chance for cure and

overall life expectancy?

Goals What are your goals for treatment?

What other goals do you have for your

family and your child?

Treatment alternatives What is your understanding of the

availability of cancer-directed treat-

ment options?

Table 2: Helpful perspectives for your child’s health care providers

Reconsider these questions from Table 2 periodically and tell the rest of the care

team of any changes. e diagnosis of a DIPG is overwhelming for all families,

and the way you look at the tumor and its impact on your child and family

is likely to change as time goes by and as symptoms resolve and/or progress.

Some key moments when most families should consider these questions include:

• at diagnosis and the beginning of treatment;

• at the end of radiation therapy;

• upon returning for the rst magnetic resonance imaging (MRI) scan

following radiation;

• when symptoms seem to be returning;

• upon conrmation that the tumor has progressed on imaging;

• as your child’s condition declines or the symptoms continue to progress,

or worsen.

Your family’s level of understanding is likely to shift during any and all of

these events and your goals of care for your child and family are also likely to

change. e medical team will not be aware of these changes unless you help

them understand your evolving thoughts and goals.

e key to establishing goals of care is open communication between you, your

child, and the primary medical team.

Some examples of goals of care are noted here:

• Cure of disease;

• Prolonging life, while having the best quality of life possible;

• Providing comfort;

• Maintaining or improving the ability to perform activities of daily

living;

• Attaining specific life goals (e.g., going to graduation, camp, wish

trip);

• Support for family and loved ones;

• Advancing medical knowledge (i.e., helping contribute to a cure);

• “Knowing we did all we could” (i.e., that we did not give up);

• “Being the best parent that I can be” (i.e., making the best decisions for

my child).

ese goals are not necessarily mutually exclusive. Many families will choose

dierent goals of care at dierent points in time, and the list above is only a

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sample of the large number of possibilities. Table 3 contains decisions you may

need to make for your child, along with possible positive and negative aspects

of these decisions.

Decision Potential Positive

Aspects

Potential Negative

Aspects

Further cancer-directed

therapy.

• Slow progression of

the tumor.

• Fulllls a need to

continue to ght

against the tumor.

• Introduces or in-

creases suering due

to side eects.

• Continued need for

medical care primar-

ily provided through

outpatient clinic or

hospital setting, so

less time to pursue

other life goals.

Enrollment in a phase I

study

• Further understand-

ing of how the

medicine works.

• Involvement in re-

search altruism; a

chance to give back.

• Closer monitoring

of clinical status.

• Fullls a need to

continue to ght

against the tumor.

• No studies may be

available.

• Introduces or in-

creases suering due

to side eects.

• Continued need for

medical care primar-

ily provided through

outpatient clinic or

hospital setting, so

less time to pursue

other life goals.

Decision Potential Positive

Aspects

Potential Negative

Aspects

Hospice enrollment • Home-based provi-

sion of care.

• Expertise in pain

and symptom man-

agement.

• Interdisciplinary

team approach to

care—availability of

chaplain, physician,

nurse, social worker,

and volunteers.

• 24/7 call coverage

for symptom-related

or other emergen-

cies.

• May be viewed by

others as “giving

up,” because hospice

is sometimes viewed

by the general

public as being for

people dying soon.

• Another team work-

ing with you and

your child; meeting

new people may

seem dicult.

• May not allow for

blood product trans-

fusions or continu-

ing cancer-directed

therapies.

Placement of a DNAR

order

• Tells all team mem-

bers that benets of

aggressive resusci-

tation eorts are

outweighed by the

suering such ef-

forts may inict.

• Focuses the nal

moments on com-

fort and mourning.

• Can be changed/re-

versed at any point

in time.

• May be viewed as

“giving up,” or not

doing everything

possible.

• Because it is a piece

of paper, it may not

be followed unless

presented to medical

personnel when the

patient is actively

dying.

• Can be a statement

of acceptance that

the end result will

likely be death.

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Decision Potential Positive

Aspects

Potential Negative

Aspects

Aggressive symptom

control

• Decreasing symp-

toms allows one

to focus on other

important aspects of

life and the things

that can be enjoyed.

• Helps decrease suf-

fering.

• May cause drowsi-

ness or sleep.

• Certain pain

medications may

cause unintended

consequences (e.g.,

signicant constipa-

tion) if not treated

properly.

Location of death: home • Allows the child

to be in a familiar

environment.

• Limited interrup-

tions (e.g., no nurse

taking vitals con-

stantly, noisy alarms

going o, doctors

being paged over-

head).

• Ease of access for

friends and family

(no visitor hours).

• May decrease costs.

• May feel less sup-

ported (i.e., we tend

to look to hospitals

or clinics for medi-

cal support instead

of having it deliv-

ered in the home).

• Limited gatekeepers

(e.g., hospital sta

and nurses who can

help control who

has access to family/

patient).

Location of death:

hospital

• May allow sta to

help control visitors

(keeping visits to a

minimum).

• Continual access

to nursing sta and

physicians at the

bedside.

• Noisy with many

interruptions.

• An unfamiliar envi-

ronment.

• Limited and con-

ned space.

• May increase costs.

Decision Potential Positive

Aspects

Potential Negative

Aspects

Speaking to my child

about death and dying

• Allows you to ad-

dress/relieve the

fears and concerns

your child may not

express without be-

ing invited to share.

• May provide a sense

of closeness and un-

derstanding between

you and your child

during this process.

• May relieve your

child to know that

you will be okay and

will be able to cope.

• Dicult emotion-

ally.

• Takes time.

• Requires facing the

fears of saying “the

wrong thing.”

Table 3: Specic decisions, along with positive and negative aspects of each decision

Pediatric Palliative Care

Children with DIPG often benet from palliative care. Palliative care is specialized

health care designed to relieve suering and provide the best possible quality of life

for people facing the pain, symptoms, and stresses of serious illness. If your child has

DIPG you may decide that having access to palliative care resources is the right option.

Palliative care aims to promote healing and increase the quality of life throughout

a child and family’s journey through serious illness. e aims of pediatric palliative

care are not limited to a disease process (e.g., DIPG), but rather become helpful

for improving quality of life, maintaining dignity, and attending to the suering

of seriously ill or dying children in ways that are appropriate to their upbringing,

culture, and community.

Pediatric palliative care promotes a team approach to care focused on addressing the

patient’s and family’s needs and on providing the highest quality of care. is care

should help with dicult decision making and care planning; attend to suering

from physical or psychological symptoms; address social, emotional, and spiritual

needs; improve communication and coordination of services; be a point of continuity

no matter where the child is receiving care; provide the highest quality hospice and

end-of-life care; and address grief and bereavement issues.

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Hence, palliative care is about giving the child the best quality of life possible,

regardless of whether or not the child is receiving cancer treatment. In this regard,

a child with DIPG may have access to palliative care services provided by members

of the primary oncology care team while he or she receives cancer-directed therapy.

Adding pediatric palliative care resources and principles into the overall plan of

care helps the primary care team and your child and family work together, with the

ultimate goal of providing the best possible treatment for the disease while creating

the most comfort and best quality of life. In your hospital, your primary care team

may also be able to consult with a specialized pediatric palliative care team to help

you and your child achieve the best quality of life possible.

Addendum

e following section provides some specic examples of some frequently asked

questions and possible decisions.

1. What are some of the things you want to consider in making dicult decisions?

Every decision and situation is unique. However, some things that parents think

about include:

• What your child wants;

• Care team recommendations;

• Your personal feelings, such as how to be a good parent;

• Faith/beliefs;

• How the decision aects the family.

Some reasons children give for making the dicult choices they make include:

• Avoiding treatment that will make them feel worse;

• Specic life goals (e.g., going to graduation, prom, camp, wish trip);

• Pursuing comfort when cure is no longer an option;

• Pursuing specic care-directed goals, including not wanting to continue therapy;

• Seeing how other patients around them have suered.

2. Who can help me make these decisions?

Your child’s primary medical team is generally looked to for the most support. Many

families also ask for help from other health care sta, family, friends, and spiritual

leaders. Also, other families you have come to know through the DIPG journey

with your child may have helpful insights. It will be important to recognize that

these decisions are understandably very dicult, and because they are so dicult,

it is important to realize when you need help making them. You may need help

in getting information or talking with others who have more experience with this

process. Any time you realize that you need help making these decisions, ask your

clinical team for assistance. Ongoing communication is crucial in every aspect of

this process. Recalling your specic goals of care will be helpful in directing these

decisions. Once you have identied those goals, share them with your team regularly

so they can maintain your goals as they suggest a course of treatment for your child.

Depending on your child’s age and situation, it may be appropriate to discuss these

decisions with your child. He or she may bring insight and revelation that the team

can draw on when making decisions. If you have doubts about whether or not to

discuss these decisions with your child, ask for help in determining whether or not

it would be right or helpful.

3. What kinds of decisions will I be making?

Some decisions, in general terms, are centered on whether or not to:

• Enroll in phase I or II experimental clinical therapies, which do not have a

curative goal but may oer more quality time for the patient;

• Try treatment to prolong life (e.g., radiation, chemotherapy, surgery);

• Pursue aggressive symptom control for improved quality of life;

• Create a DNAR order for your child;

• Choose the location of your child’s death;

• Speak with your child about death and dying.

4. How can I help the medical team help my child?

Many times the treatment decision and plan are based on specic goals of care as

established by you and your child. ese goals may be as simple as “aggressively treat

pain,” or as complex as “I want my child to be able to perform normal activities for

a child his/her age.” Presenting these goals clearly to the medical sta needs to be a

top priority. ese goals should be agreed upon by you, your child, and your child’s

primary care team. From these goals, a particular care plan can be established.

e medical sta will never know your child as well as you do. You must continue

to be his or her strongest advocate. is cannot be over-emphasized. You are very

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likely to be more in tune with your child’s needs than anyone else, so you must be

his or her advocate. Any time you think there is something dierent the team should

be doing, share it with them. Any time you think your child is suering or could be

doing better, tell the team. Ongoing communication is the key.

5. Where should my child receive the remainder of his or her care?

Your child will continue to receive medical care to ght against pain and other

symptoms, no matter where you decide to receive care. Choosing to continue

receiving cancer-directed therapies on a study may limit your location options (e.g.,

your ability to return home or be close to home). is must be considered in the

context of overall goals of care. If being at home is important to your child and family,

plan ahead and organize a team of providers who are your best allies—work toward

this transition before an emergency or crisis arises that might hinder or completely

prevent you from going home (e.g., your child being in the intensive care unit on

a ventilator). Every eort will be made to help coordinate your child’s and family’s

goals of care throughout the treatment course.

6. What is a “Do Not Attempt Resuscitation Order” (DNAR) and should I have

my doctor place a DNAR order on my child’s chart?

A DNAR order is a request to allow a natural death for your child rather than

performing cardiopulmonary resuscitation (CPR) if your child’s heart stops or if he

or she stops breathing. You and your child’s primary medical team will consider such

an order in light of the goals of care for your child. It is best to make this decision

when the goals of care are changing, rather than during a time of crisis. If you decide

a DNAR is best for your child, the order is put in your child’s medical record by your

primary medical team. A DNAR order is most appropriate when using medicines,

procedures, or machines to restart your child’s heart or breathing are unlikely to

benet your child or when such measures may actually be harmful. is decision is

usually the case when the DIPG has started to grow again and your child’s physical

decline is due to the growth of the tumor.

As patients go home to receive care, many of them have an out-of-hospital DNAR

in place. It is best to plan for these events in advance, because unless given other

instructions, medical sta (i.e., hospital sta or emergency medical sta) will attempt

to resuscitate all patients whose hearts have stopped or who have stopped breathing.

7. Can I change my mind about the DNAR order for my child?

Yes, you can change your mind about the DNAR order. Feel free to discuss changing

or canceling the DNAR order with hospital or medical sta at any time. ese

decisions should again be considered in view of the goals of care for your child and

can be reversed at any point in time. Children are treated on a case-by-case basis,

and all types of treatment can be given, whether or not a DNAR order is in place.

e condition of your child and the agreed upon goals of care will determine the

clinical decision making for your child.

8. is is a very dicult decision; how do most parents decide?

Most children who have died from DIPG had a DNAR order in place at the time

of their death. Some parents know early on in treatment what they will decide about

a DNAR; others prefer to speak with their family, friends, their child’s pediatrician,

other parents of children with cancer, or their ill child, when possible. is is a very

dicult decision and it should be made with the goals of care for your child in mind

and with the help of your primary medical team. Your primary team can help you

look at all the options from dierent perspectives to help you make the best decision

with/for your child and your family.

9. How much do I tell my child?

Every situation is dierent and the level of understanding for children varies greatly.

ere is no right or wrong answer to this question. You know your child best, and

over the course of your child’s illness you have learned how much your child wants

to know and how your child handles information. Children as young as 9 or 10

years old, or even younger in some cases, understand complex situations and can

help in making dicult end-of-life decisions. Some families regret not speaking to

their child about these issues, especially if they feel their child knows or wants to

discuss such topics further. Studies have shown that parents who have discussed

death and dying with their child do not report any regrets about doing so. On the

other hand, some parents who did not discuss these issues with their children report

wishing they had done so.

10. What if I change my mind about the decision I have already made?

As time goes by it may be very appropriate to change your mind, or it may be

important to stay the course. If you want to change your decision or shift the focus of

care, the medical sta will do their best to support that decision. e rst thing that

will likely occur is to suggest a revisiting of the goals of care. From these goals, you

can decide as a team the best way to proceed. It is always important to consider all

aspects of these decisions and ask if these decisions will lead to more harm than good.

11. What if I want to pursue "complementary and alternative medicine" (CAM) or

other non-standard therapies such as herbs, nutritional and vitamin supplements,

acupuncture etc.?

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Parent Perspectives

The following, are stories written by parents of children with DIPG. Some

of the stories may be emotionally difficult to read. As editor, I felt they were

important to include in the book in order to help you gain what I hope will

be a balance of perspectives, through the experiences of other parents who

have endured this stage of the journey. My intent is to provide you with

information that you can discuss ahead of time with your health care team,

and assist you with making decisions that are appropiate for your child.

Ruth I. Hoffman, MPH



No one's path with DIPG is the same, and the only thing you can strive for

is that you don't regret any of the decisions you've made.



We have been extremely lucky to be connected to an excellent palliative

care doctor who visits us weekly at home and gives us an incredible amount

of information and support. Although Stella is not receiving treatment,

she receives morphine on a daily basis to eliminate the pain in her head,

PEG flakes to counteract constipation, Zofran for nausea, and Ativan for

seizures. So far we have been able to give her all her medications orally…

mostly hidden in ice cream!

When we decided against treatment, doctors told us to expect Stella to live

3 to 4 months maximum. We are 8 months into the diagnosis, and Stella is

still with us. She has seen her brother being born, lived through Halloween,

Christmas, New Year's, Valentine's Day, etc. She still smiles on a daily

basis, and although she is declining, the decline is slow and often stalled.



We have been open and honest with Andrew about his situation.

Conversations regarding dying and Heaven have become fairly common

over the past couple of months. When you are dealing with cancer, especially

one with such a dismal prognosis, there is already a sense of isolation. We

have not lost hope, but we do understand the reality of what we are facing.

And we do not want to isolate Andrew further by making him feel that he

Talk openly with your child’s doctor and care team about this option. Often these

therapies have not been studied for their potential benet or harm to your child. If

the therapy is not seen as harmful, and you feel strongly about pursuing a particular

option(s), the team can try to watch for possible side eects and cross reactions with

other medications your child may be receiving.

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cannot talk to his own family about the things that are on his heart. When a

child—or anyone—expresses his feelings, we do not help by making light of

those feelings or attempting to explain away those feelings. When Andrew says

he doesn’t want to die, we can honestly respond, “We don’t want you to die.”



Bryce was told that first week that other children who had had this kind

of tumor had not survived. My husband and I decided at this point that

if we were going to ask him to go through all of this treatment, then we

were going to have to be hopeful, even knowing what we knew, and after

researching on my own, I knew that the doctors were right. We decided

that we were going to follow Bryce’s lead, and so we asked his care team

to not talk about dying until Bryce wanted to know about it. That meant

informing every doctor who saw him that we were choosing this path before

they spoke to Bryce. How could we ask him to do all of these treatments

and still know that he would probably not survive?

It wasn’t until the end of June that he finally asked us about his future.

Children do things in such an uncanny way. He and I were at the gas station

when he finally asked. (We had some of our best talks in the car.) He said,

“Mom, what is going to happen now?” I asked what he meant, even though

I already knew where he was going with it. “Now that I’m done treatment.

What if it comes back?” So, at that point I reminded him about what we

had been told—that radiation could not be done in the same spot for a few

years; that they did not have any chemotherapy that was working for this

kind of tumor; and that surgery was not an option either. With tears in his

eyes, he responded with, “You mean they are just going to let me die?”

My response was, “I hope not Bryce. We will have to see if something new

comes along, but for whatever comes our way, we are going to just try to

enjoy every single day.” Next, he said, “Mom, go pump the gas.”

As Bryce began to feel worse, it was then that we started to talk about

dying. It would often be that Bryce chose to speak to me about it. He began

asking questions about things like: Would he be here for his birthday in

December? Would he be here for Christmas? Would he be here for his

cousin’s birthday next summer? My response would always be, “I hope

so Bryce.” I tried to be as honest as possible, and also let him know how

much I loved him at the same time.

He continued to go to school right up until December 19th. And on

December 20th he fell at home. We contacted the hospital because over

the weekend we were seeing a decline in his speech, abilities, and mental

capacity. An MRI was scheduled for Dec. 23rd. His oncologist called with

the results on December 24th to confirm what we already knew. The tumor

had progressed. At that time, she indicated that once the tumor progressed,

that it would more than likely be swift. So she referred Bryce to hospice

care and we signed papers for Care at Home. Life at that point felt like

it was spiraling out of control for all of us. Over the Christmas holidays,

Bryce progressed from walking on his own, to a walker, to a wheelchair, to

spending most of his time in bed as his ability to walk and move declined.

We decided at that point that our daughter would only go to school for half

a day. She needed the normalcy of going to school, but we felt that she also

needed some time at home with Bryce, without visitors. It was one of the

best things that we did, and it allowed her to feel like she was part of his

daily care. She would often crawl into bed with him and we would hear

them talking away. This was a stressful time for her too, and she was full

of questions about what was happening to him. We tried not to give her too

much information at once, or to let her know more than she needed to hear

at the time, because we felt that it would frighten her. But we always felt

that we needed to answer her questions clearly and honestly. We watched

her grow up in the process of watching her brother’s decline and throughout

his palliative care. It was almost as if she felt that she became the older

sibling throughout the process. She knew as much as we did by the end

because she even felt comfortable asking the nurses who came into our

house what was happening. I look back, and now feel that this is honestly

how she learned to cope with losing him too.

Talking about dying would pop up at the oddest moments, and catch me

off guard. I would make a point of stopping whatever I was doing because

I was afraid that he would not ask again, and I wanted him to have the

answers. One day he asked if his head was going to just explode. It became

very important then that we discuss what was going to happen medically.

As Bryce became unable to walk, the questions changed to what happens

after one dies and whether or not he would still be sick. He asked, “Will I

be able to walk in heaven?” I took this as some kind of acceptance of his

fate, and tried to follow his lead.

In reflection, we did make one mistake. One day, when Bryce referred to

the day when his head would explode because the tumor would not have

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anywhere else to grow, it became very important to explain medically

about what would happen to him. None of us had really asked the BIG

question—we were afraid of the answer. I mentioned to him that eventually

he would just become tired and that his body would begin to shut down

and that that would be when he would be dying. He began having trouble

sleeping. We finally figured out, with help from our palliative care team,

that he was afraid to sleep because he thought that he was going to die in

his sleep. Obviously not a good choice of words to explain what was going

to happen to him.

One of the most difficult things about watching Bryce go through this was

that as his tumor progressed, he became more anxious, and had more pain.

As this happened, Bryce began talking of dying more freely. Every morning,

because his mental capacity and memory became affected, he would wake

up and yell out “I’m scared!” We would ask him what he was scared about.

He would say “I don’t remember what you told me about heaven!” So we

would spend time every morning reminding him of what our family believes

happens when someone dies. And we began having to give him Ativan for

his anxiety. He then began asking us to put his hands together every night,

so that he could say his prayers.

About two weeks before Bryce’s passing, he was in pain and very anxious

and he actually looked at me, and asked me if I would kill him. I thought

I was going to die myself with heartbreak. But I looked at him, held his

hands very tightly, and said “Bryce, I know that you are frustrated, and

angry with what is happening to you, and that you can’t find the right words

to tell us how scary and awful this is. When you are ready to go because

you are tired of fighting, I want you to know that it’s okay. I love you with

every breath that I take and every beat of my heart, but I can’t kill you—it’s

illegal.” And he laughed, but I knew that he was serious. I feel that that was

the day that he honestly tried to show us that he accepted what was coming.

Talk about dying changed into making us promise that he would be buried

near his grandparents or by the pond at the cemetery, and into making us

promise to go there to visit him every day. He was afraid of being forgotten,

which is apparently normal for most teenagers.



I had been diagnosed with colon cancer in late June and was scheduled to

have the cancer resected on July 13th. So, the plan was that I would have

surgery in the morning and as soon as I came out of recovery, my husband

and Caleb would drive to Memphis so Caleb could start treatment the next

day. Caleb snuggled up in bed with me for a while before they hit the road

and then they were off.

Caleb began declining rapidly during the drive. By the time they got to

Memphis at about midnight, my husband was worried that Caleb wouldn't

be able to qualify for the study. He was declining quickly. By the next

morning, the only concern became whether they'd be able make the hour

trip home before he died. He was declining quickly and obviously could

not be treated. My husband and I discussed it and decided we would take

the risk. We wanted him to be home.

As we left the hospital, Caleb was in a wheelchair. His breathing was

more labored and he'd just been placed on oxygen that day. We arrived

home and the hospice nurse and equipment was there and ready to be put

in place. The guy who brought the hospital bed had quite a time getting it

put together. He made the comment that it was an old bed and so heavy. He

had no idea why he'd been required to bring it for Caleb. Our nurse told

us that she has a 10 year old son and she knew that if her son was dying

at home, the whole entire family would want to be piled in bed with him.

She wanted to make sure to get us the strongest and biggest bed she could

so that we could all pile in whenever we wanted. I carry that memory with

me as an example of the blessings so many people gave us along the way.

So, Caleb was set up in the living room. We had an open door policy.

Friends and family were welcome to come and stay as long as they liked.

Some of our closest friends were with us the entire time. Some of Caleb's

closest friends came and just sat by his bed for hours. By this time, Caleb

could only communicate by moving his eyes up and down. Even the side-

to-side movement was gone. I will never forget that I was sitting on his

bed, talking with his best friend Samuel, and Caleb managed to make a

joke by moving his eyes up and down during our conversation! Caleb's 5th

grade teacher came by to check on him often, and we asked her to contact

any of his classmates who would like to spend some time with him and let

them know they were welcome to come and visit. So, we had many children

come through our home to spend time with Caleb over the next two days.

By the following morning, Caleb was not very responsive and did not really

interact with anyone. The home health aide came mid-morning to check

on him and she and my husband gave Caleb a bath. My husband noticed

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that Caleb’s breathing changed and knew the end was near. He called our

other boys in to be with Caleb and the friends who were here went into

another room. Caleb peacefully took his last breath with his brothers and

daddy holding him in their arms.



Our hospice care was subpar, at best. We felt that our highly recommended

hospice staff was not adequately trained to deal with children, especially

children with this type of brain tumor. We also felt the staff was lacking

in compassion, the ability to read parents, and deliver the proper care to

our son. Sadly, we did not get the privilege of time to adequately research

hospice care, so we trusted our medical staff and their recommendation.

I wish I could say our Connor passed away peacefully, but after my many

urges that he was still suffering, I was simply dismissed. The end was even

more horrific and it really hurts to talk about it. We had a hospice nurse

trying to get an oxygen tank for his much labored breathing (which we

had been requesting for days). After suffering for a long time, he died.

Our hospice nurse, who was on the phone at the time trying to secure an

oxygen tank, simply said, in a calm manner, "No, never mind, we no longer

need it…the patient has expired." Really? My sweet, precious little boy has

"expired" to you? I will never forget those final moments and have to say

the hospice staff was unbelievably unprofessional and lacked compassion

in our situation.



It has been 22 days since my son's passing and we still haven't had a

response from a hospice bereavement counselor.



When I had time, I would send an email or call a friend telling them about

the conversations I was having with my kids. I didn’t know if I was saying the

right thing and I wanted a counselor to help me navigate these land mines.

I have a couple of friends in the counseling profession so I knew I could

trust their perspective. St. Jude offered professional counseling through

the child life specialist or the social worker if I needed more support for

myself or my kids.

I learned that giving my kids the opportunity to talk about what was in

their heart gave them the freedom to heal and move in and out of the stages

of grief just like I moved through these stages. Children have immature

ways of handling emotions and if I can help my kids by listening without

criticizing or interrupting and asking questions, then it makes them feel

loved and safe, and they are able to handle their grief until a professional

counseling environment can be offered.



Scan results confirmed our growing fears. Julian’s doctors braced us with

the news that the “relentless” disease had taken over and that we had less

than a month left with our sweet boy. Turns out, we only had five days.

Barely five years old, we spared Julian unnecessary fear and anxiety, and

never really explained that we would soon have to say good-bye. Wonderful

hospice nurses and doctors coached us on comfort care and what to expect

as the end drew near. We, intent on keeping Julian happy and at ease,

surrounded him with his favorite toys, books, movies, music and most

importantly, his favorite people.

In his final moments, we assured him over and over that it was ok to go, that

he was safe and loved and that we would be ok too. I held him in my arms,

and my husband held us both in his, and together we ushered our child out

of this world, just as we had ushered him in. Julian, ever the generous of

heart, left us with one final gift just moments after he passed. He wore on

his beautiful face the most serene, almost blissful expression, in which he

seemed to be telling us, “We did it. I’m in a wonderful place now. And you

guys aren’t even going to believe how good this gets!”



Liam passed away at home in my arms with his daddy and siblings

whispering their “I love You's” in his ear, and with his extended family in

the rooms nearby. Nearly 14 months after his diagnosis he finally won his

peace. He is a magical boy and dearly, dearly missed.



Mara passed away after a 12-hour intense struggle, at 8:12 a.m. on

September 22nd. Both sets of grandparents, 2 aunts, her siblings and

Bryan and I were all nearby when Mara slipped away. Our hospice nurse

arrived very soon after Mara’s passing (Hospice nurses had been in and

out throughout the course of the night) and started making preparations.

I began the process of getting my little girl ready for nearly the last time.

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When the moment was right (probably an hour after she passed) I began

to bathe her, dress her, and do her hair. Grandma helped Natalie (Mara's

younger sister) pick out the right nail polish for her fingernails. We put

on just the right dress and picked out her favorite jewelry. We took some

precious pictures of the kids' hands together. This time with her was so

very painful, yet it was peaceful. It was excruciating but sacred. I would

not have traded this precious time for anything. The funeral home came at

approximately 10:00 a.m. to pick up Mara. We held a family prayer and

then Bryan carried his baby girl for the last time to the van (rather than

use a stretcher) in a final act of love and compassion.

Looking back, there are moments when I wished I had perhaps one more

hour with Mara's body before they took her away. However, things were

beginning to happen to her body (blood was starting to pool—something

we were told is very normal) and I'm not sure that I'd like to witness every

detail of nature taking its course. We did everything we could have done.

We did have the privilege of dressing her at the funeral home 4 days later

before her viewing. It was nice knowing that we'd have one more chance

to see her alone. Sure, it was not the same but in some ways Mara looked

more beautiful at the funeral home than she did at our home. I don't think

as a mom that I realized how sick Mara truly was. That probably sounds

silly, how could I not know, right? But I just think that we kept picking up

and moving forward so many times that I didn't absorb completely what

was happening. It wasn't until I looked back at pictures of her last days

that I could see how sick she was. At the time, I just saw my perfect angel

without any imperfections. Even to this day when I think of memories with

Mara, I think of her running and playing…not lying on the couch with a

feeding tube in her nose.



Our oncologist was brutally honest, which we appreciated to no end. But

even when things were stable, they kept reminding us, "It will come back;

it’s just a matter of time." We wanted to celebrate the small things, even if it

was just for a couple of hours, but were usually crushed before leaving the

hospital room. This is after getting “good" news, i.e. stable tumor. We all

know it is "coming back," but do the doctors really need to constantly drill

it in? Trust me no parent EVER forgets that this tumor usually comes back.



Imagine that you had a cherubic, mischievous, energetic and moody two

year old with flashing blue eyes, a brilliant smile and curly red hair.

Imagine that each morning she got you up at 5:15 am by standing up in

her crib and shouting, "Maaamaaa, I'm awaaaake! Maaamaaa, where are

you??" Imagine if when you went into her room she threw both her arms up

towards you in a great big hug and chattered her way into the living room,

telling you she wanted Cheerios for breakfast…with banana…and milk…

and when is Auntie Heather coming…and can we paint now…and watch

Caillou. Imagine if when you tried to get her dressed in the morning, she

ran away from you laughing, no matter how exasperated you got. Imagine

if she insisted on picking out her own clothes and you let her, rather than

fight about it. Imagine if she could sing the entire theme song to "Golden

Girls," could go down the slide on her own, could pee on the potty, catch

a ball, dance and chase her friends. Imagine when you step off the subway

after work and walk into her daycare room, all the kids turn to look at who

has entered the room, and when she sees you she flashes the most brilliant

smile and comes running with her arms up, saying "Mama! Mama! Mama!"

Imagine if no matter how many times she had a tantrum and demanded

things from you and exhausted you, she ended each night with a snuggle and

a kiss and you breathed in the smell of her curls and felt warm happiness

all over. Imagine if you could never love anything as much as you loved

your first born child, your dream come true, your daughter.

Now imagine it’s 9 months later. Imagine she is lying next to you in your

bed. She can't walk. She can't use her arms or hands. She can't hold her

head up. She can't see the television. She can't tell you she loves you.

She can't hug you. She is lying in the bed sound asleep, but coughing on

her own saliva, which she is starting to choke on because she can barely

swallow. Imagine she was dying and there was nothing you could do to

change it. Imagine if you knew that one day soon you would never get to

see her again. Never see her smile, feel her hand slip into yours, kiss her

warm cheek, feel her sigh into your chest.

That is the simple reality of what we are living with. And it's hard. No matter

how many good things happen to us, no matter how much we believe in a

bright future for ourselves and a time of healing, we are being tortured. No

matter how well or easily we manage to get through the days, to talk with

our friends, to laugh and joke and even fight sometimes, we are broken

inside. It's a very strange way to live. We need to not focus only on what

we are losing, but on all we have gained, but despair creeps in nonetheless.

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

It is never the same in progress…always the same in result. It is the cessation

of the brain signal to breathe that causes the death of each child. That

time can come swiftly as with my daughter Savannah…4 1/2 months from

diagnosis with absolutely no slowing of symptom progression…or it can

move more slowly like in so many kids. I hate it…I hate it!



I think I've said before that despite the large groups of people who surround

us, sometimes grief feels incredibly lonely. One of the realizations I've made

this past week, is that there never seems to be a good time to cry. All these

people come in and out of our house and they bring hugs and kind words

and delicious foods and generosity and beautiful friendships, but no one

ever comes in and just cries. I guess it's human nature to want to avoid

being sad in front of one another, but I feel like crying all of the time and

it's difficult to find the “right time" to do it. You can't do it when you're out

walking on the street…you shouldn't really do it when you have company…

it upsets our daughter if you cry in front of her. The only safe spaces left

are at night when the darkness blankets my room and I fall asleep with hot

tears pooling at my neck, or behind my dad's house on a small swing that

lies hidden from sight.

This is the saddest thing in the world, but no one wants to cry with me. I

understand it on some level, but sometimes it makes me feel as though no

one else is sad, or they are able to push it out of their minds. I am jealous.

I wish I could also ignore the grief, but to me it's palatable in the air we

breathe day in and day out within the white walls of our house.

I wonder if the issue is that we live in such a superficial culture that often

seems uncomfortable with true depths of feelings, in particular grief. I feel

there is a certain amount of intolerance of acute sorrow and intense mental

anguish that makes up the bulk of my life right now. Sorrow is something to

be medicated, as I'm doing right now, or something to be divided into five

recognizable stages that I can read about, label and rate my growth with.

Grief is too complex an emotion to be ignored, pushed away, or forgotten

about. I have been grieving my daughter since June 24th and have learned

that for me to grieve is to let sorrow and tears invade my soul so that it

permeates my pores like a heavy perfume. I am always stunned that no one

else can see and smell the sadness that is so obvious to me.

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Chapter 22: Journey of Sadness and Hopes

Chapter 22

Journey of Sadness

and Hopes: A Letter to

Parents

Tammy I. Kang, MD, MSCE

Chris Feudtner, MD, PhD, MPH

Dear Reader,

As this book draws to a close, following many pages lled with information

about the diagnosis, prognosis, scientic advances, and emerging treatment

options for diuse intrinsic pontine glioma (DIPG), what can we add that would

be worthwhile to parents? Is there anything we can say that would help in this

journey of sadness and hopes?

After wondering and worrying about these questions, we thought that the best

place to start would be to tell you, from the bottom of our hearts, that we wish

your child did not have this cancer. We wish that you did not have to embark

upon this journey. We wish that we knew with certainty what your questions and

concerns were, that we understood what you might nd potentially helpful. And

we wish that we knew you, so that we could say all of this face-to-face.

We decided that the best way to proceed was to write the nal entry for this

book as though we were writing a letter to distant friends who had asked for our

thoughts and suggestions. us we write with the hope that some of what follows

may be of help to your child, to your family,

to you. At the same time, we know that no

single conversation, no single approach,

can work for everyone; so if our ideas aren’t

working for you, please put this aside and

accept our apologies.

Dr. Kang is the Medical Director

of the Pediatric Advanced Care

Team at Children’s Hospital

of Philadelphia, and Assistant

Professor of Pediatrics at the

Perelman School of Medicine at

the University of Pennsylvania,

Philadelphia, PA.

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e Breadth of Hopes

If we were able to sit down and talk, we might ask a question that we often pose

to parents as a way to start a conversation. Given your child’s situation, what are

you hoping for? ere are many answers to this question, and none of them are

wrong. We encourage parents to relay as many hopes as they have. is takes time.

Some hopes may feel much more important than others. When working with this

question, at this point, the goal is to get all the hopes to surface and to set them

out in front of us, as though spread upon a table, so that they can be discussed.

Indeed, some of our patients want to do this. Once, a cheerful, bright-eyed

11-year-old girl, meeting her oncologist for the rst time said, “Before you start

asking me a lot of questions, you should know a few things. I know I have a

brain tumor called an intra-pontine glioma. I know most people can’t be cured

of this and that I have had a lot of problems because of it, more than most. I was

in the hospital for a long time and didn’t like it much. I already had radiation

and am excited to move here because it will be easier here for my mom.” As if

this wasn’t already remarkable enough, she nished by saying, “I hope for lots of

things, some of them maybe I can have, and some I can’t. Even though I know my

cancer probably won’t go away, there are still things I want, like I would really like

to be able to get rid of this trach and g-tube before I die. I want to go to school

and, no oense, I’m sure you’re really nice and everything, but I would rather

not see you too much.” Remarkable. In one conversation this patient illustrated,

and illuminated what we have learned over decades—that inherent within us,

no matter how dicult the circumstances, we harbor hope. Not a singular hope,

but many hopes.

Hope for the best

One of these hopes can always be—and, in our conversations with parents, often

is—to hope for the very best. ese hopes take many forms, and are often the

rst thing that parents mention when asked about their hopes. Some of these

hopes are as large as life, or even larger.

I hope that the cancer goes away. I hope

that the treatment cures this awful disease.

I hope that this is all a bad dream. I hope

for a miracle. Parents also have other hopes

which, in some situations, may seem quite

small in comparison; but to those who

hope such hopes, they brim with life. I

hope to go home. I hope my child gets this

tracheostomy and gastrostomy tube out. I hope to celebrate my child’s birthday.

I hope to see my child with those whom I love and who love my child. Hoping

for something that may not happen does not mean you “don’t get it” or have

unrealistic expectations. For many parents, these hopes are one clear way they

show their love and devotion for their children. And while we cannot say for sure

for you, for many parents, there are other hopes as well.

Hope against the worst

Hopes can also be shields of sorts against the potential worst. We cannot begin

to imagine the emotions that have entered your life. Parents have shared with

us their intense, painful feelings of fear, anger, desperation, and sadness. Hopes

swirl aloft in these wild winds. ey do not tame the feelings, but they can help

to ride them out. Some hopes will be that certain events do not happen. Other

hopes will be that, if those events do happen, plans will be in place to assure that

the child is well cared for, as protected as possible, comfortable and not afraid.

Modifying the old adage, hope for the best and plan for the worst so that you

can hope that the true worst does not happen. Although dicult to discuss these

fears, mentioning them to health care providers and asking, “What would we do

if this happened?” can start the process of making these plans tangible, forging a

clearer pathway toward the hope that the worst will be prevented. Although the

hope that arises to counter these fears may seem grim, this type of hope is full of

deep commitment and resolve.

Everyday hopes

When the diagnosis of DIPG enters the lives of many families, for a time life

may seem to stop, to be put on hold, consumed by the chaos and emotions

surrounding the diagnosis and coordinating and coping with the early stages of

complex medical care. How can life resume? ere is no single right answer, and

every potential answer is dicult; yet one recurring answer we hear from parents

is this: one small everyday hope at a time. Start by hoping to simply take a deep

breath and let it out. en hope to get outside and see the sun straight overhead

or the rst stars at dusk. Parents have told us that even seemingly insignicant

things like running a short errand without worrying about not being at their

child’s side, or being able to attend to another child without feelings of guilt, is

something to hope for in a day. Name these hopes to yourself and to others, and

then work toward them. One small hope at a time can make a large dierence.

Ask for help if needed and accept the help that is oered.

Dr. Feudtner is an Attending

Physician and Director of

Research of the Pediatric

Advanced Care Team at

the Children’s Hospital of

Philadelphia, and Associate

Professor of Pediatrics at the

Perelman School of Medicine at

the University of Pennsylvania,

Philadelphia, PA.

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Hopes to be a good parent

Many parents we have spoken to wonder—and worry—about what they need

to do in order to be, in their own view, a good parent for their child with serious

illness. is is usually not a topic of conversation that comes up spontaneously,

arising only when we ask whether parents think about this, and then they often

say words to the eect of “yes…all the time.” Cast upon a journey that no parent

ever anticipates, and none are prepared for, parents often have told no one about

these furtive thoughts, which arise from confronting the uncharted enormity of

this disease and the inevitable doubts and confusions. Our hope when broaching

this topic is simply to be a companion and help to dispel some of the loneliness

that accompanies these private worries. What do I need to do? Am I doing the

right thing? Am I doing enough? Again, there are no right or wrong answers.

We nd that parents usually can name a few things that they feel that they must

do for their child, and hope fervently that they can do these things. Our job, as

we see it, is to gain an appreciation of what these things are, help the parents to

achieve what they are hoping to do, and oer feedback and reassurance that they

are indeed doing them.

Hopes for health care providers

“Given your child’s situation, what are you hoping for?” Sometime during the

days or week after receiving the news that their child has a DIPG, when the

initial shock of the news has started to lift, this question should be routinely

posed to parents. Yet typically, medical providers don’t ask. Is it because they

are sure they already know the answer? Because they cannot bring themselves to

imagine with this family what hope might look like in even the most dicult of

circumstances? Or is it because they are afraid of not being able to aid in making

those hopes a reality?

Quite often physicians assume—or, more blatantly, assert—that parents have

only the capacity for one hope: hope for cure, the hope for a miracle. In this

regard, physicians and other health care providers are not alone. Studies of the

social construct of hope as portrayed by print media suggest that the public

dialogue in the newspapers and magazines around hope for patients with advanced

cancer conveys the message that only one legitimate hope exists for persons with

cancer—hope for a cure.

What are the origins of this notion that, when given a diagnosis of advanced

cancer, hope becomes a singular entity? Perhaps this concept is just a self-reassuring

shared myth, consoling all of us, who do not have to confront cancer personally,

that one need only hope for cure. Perhaps this notion is a way to push aside

the health care provider’s own feelings of failing their patients and families. Or

perhaps this is an optimistic—and thus eective—way to market and advertise

medical innovations.

Whatever the origins, this notion is a conceptual straightjacket, causing us to

underestimate a parent’s ability to harbor, frame, and hold hope while still being

grounded in reality. Certainly parents have voiced that what is important to

them is honest communication with their child’s medical providers about their

child’s medical issues, regardless of prognosis. Health care providers may need to

be encouraged that one of the most valuable things they can give to patients and

parents is permission to hope—and that they themselves can hope to participate

in the care of a patient and family, oering to help in ways that extend beyond

the physical or biological treatment of disease, all in the pursuit of hopes.

Completing a Circle of Hopes

Not all of the aspects of hope outlined in this chapter may come readily to you

or your child or your family. And some aspects may not be what you need. What

is right, hope-wise, is what is right for you and your child. In the profusion of

what you hope for, your hopes are intertwined with your values, your loved ones

and your goals. Take a look, from time to time, at what your hopes have become,

building your hopes until you can envision your child, your family, and yourself

surrounded by a protective circle of hopes, 360 degrees of commitment and

compassion, capable of moving forward with purpose.

We started by asking whether there was anything that we could do that would be

helpful, and here at the end we still worry that our words may not have suced

to bring clarity of thought or comfort of feeling to you. Yet we, too, live in hope,

as we all must, and hope that you have found something of value in this letter,

something within you or around you that can help carry you, your family, and

your child forward with hope.

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Parent Perspectives

Julian was diagnosed with an atypical brainstem glioma because of the

way his tumor was growing up and out of his brainstem. We clung to the

hope that this tumor would prove “atypical” in its behavior and that he

could be an exception to the grim statistics.

Another brain tumor parent asked me, “How do you walk the line between

accepting the reality of this and staying hopeful?” It was the internal

struggle we faced every day. Walking the tight rope between fear and

optimism, we found balance by taking it practically one hour at a time,

savoring the small, beautiful moments and committing to the task of keeping

him feeling safe and loved.

Early on, a friend and pastor made me tell him the prognosis. He said,

“You need to be honest with me before I can help you.” It was the first time

I said it aloud, “Typically patients have less than a year.”

His advice that followed stuck with me throughout our 7-month battle.

He said, “You need to prepare your heart, but make no plans to lose.”

Encouraging us to stay hopeful, he continued, “You will not start planning

the funeral. You find him the best care you can, and you will not stop

searching for a breakthrough.”



Keep your head where your feet are was my motto. You can spend your

time searching the world over for a wonder cure or treatment, but if you

use your time wisely you will quickly see what is important. Assign that

role to someone else. Keep in mind your priorities and don’t lose sight of

quality over quantity. Don’t ever lose hope but please put reality in the

driver’s seat so that you don’t miss out on one single happy moment with

your child. Ask for your miracle but some part of you must come to terms

with the “what if you don’t get it” part. Don’t think you are giving up if you

decide to end treatment or follow a different path. You are never going to

give up. You are always going to do what you think is best for your child.



It was at the end of radiation that we did another good thing. We were

asked, and agreed, to meet with the pediatric palliative care nurse, before

going home. I can say that I was in complete dread of meeting Bryce’s

palliative care nurse, because she was going to tell us all the terrible

things that we couldn’t and didn’t want to even imagine yet, including

how and when Bryce would die. I wasn’t ready for it, didn’t want to hear

it. The day that my husband and I met with her I was physically sick. We

walked in, and the first thing that she asked us was to tell her about Bryce,

which threw me off kilter. She didn’t want to know about his symptoms like

every other person we had encountered. She wanted to know about him as

a person, and as a child. She wanted to know what his interests were, and

about our family. After being submerged in the cancer world and on “a

mission” to treat him, this was somewhat shocking, and even refreshing.

She then looked at us and asked if we knew what palliative care was all

about. We said yes, it was about dying. She said, yes, that was part of

it, but it was also about so much more. She looked at us and told us that

palliative care was about choosing to LIVE, for as long as possible, and

in the best manner possible with the time that is left. It was about making

each day a choice to live, not about waiting to die. And at that moment

we made a choice. We decided that we would do just that. We would go

home and LIVE Bryce’s days with him, and make those days everything

that they could be—and it became our new mission. Our hope changed.

We knew there was no cure, but we also knew that our hope became about

making whatever days we had left with our son be good ones. Those days

would have to be so good that for him, and for us, and for his sister there

would be no regrets.

Once we were home, we contacted hospice right away. We were trying to

find a connection at home for Bryce and for our family that was local. We

all started to see the social work team there. It was one of the good things

that we did. Bryce met with the social worker every couple of weeks. She

suggested that they work on a scrapbook together, one page every session,

about Bryce’s life. So we would get fancy papers and pictures ready for

the theme of the week, and during their sessions, they would talk—alone.

It was nice for Bryce to have someone to talk to who was not a family

member, and to have someone to tell how he really felt about what was

happening, without being afraid of hurting anyone at home. They worked

on the scrapbook for almost 6 months.

Over that summer and into the fall many wonderful things happened.

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Bryce got his “Wish” for a camper from Make-a-Wish Foundation. We

camped and traveled. He spent time with his friends, and he did his

best to be a regular kid. He continued to have double vision, so some

activities were no longer possible, but he was determined and found ways

to compensate. His balance generally improved, so he still rode his bike.

As dirt-biking was too fast, much to the dismay of his doctors, we got

him a four wheeler, which he was allowed to ride on flat fields with his

friends. This was probably his most prized possession that summer. For

the most part it was a good summer, when he felt good.

He never really wanted to discuss his illness except on the days when he

wasn’t feeling well. He even started high school. He attended two classes in

the morning. He went to the gym with special permission in the afternoon

with his dad, and we got him a personal trainer. This really helped to

keep his strength and balance up, too. He continued to hang around the

arena, skated when he felt up to it, and even coached his own team with

his father. He always amazed us with how hard he fought to be a regular

kid every single day. He wouldn’t accept any less from the rest of us either.

Not only were we on a mission to help Bryce no matter where this journey

took our family, but we were also dealing with the reality of losing a

child. And you do what you have to do to help your child, no matter

what—because that’s what he expected of us. There were many days when

I would just want to crawl into bed and never get up again. We were

already grieving and he was still here. But he would say, “Mom, go take

a shower, you look like crap.” And I remember crying one day all the way

home from the hospital, and cuddling with him when we got home that

night. He was accepting of me being sad, but then, he suddenly looked at

me, and said “Mom, you can cry today, but you can’t cry tomorrow.” I

asked why not. He said, “Because I just need you to be mom every day.”

And that was when I decided that no matter what happened, if my son

was going to have to do this, that I would be present every step of the

way. What choice was there? He needed us to be.

It was at this point that we decided that we needed to fill in a booklet

that was given to us about what Bryce wanted for end-of-life care. As

Bryce’s progression developed, his speech became quite affected, so we

were glad to have this booklet full of answers to help us to make sure that

his wishes were being met. It also helped for planning his celebration of

life thereafter.

As Bryce lost his gross motor ability to hold up his head and to sit, we

found the right wheelchair for him so that we could still do things with

him. He wanted to go for a walk around the block one day. We had to

wait until all visitors left, because they thought it was a terrible idea

taking him out. It was unsafe, he would get sick, they argued. But that

was what he wanted. These adventures took 2 to 3 hours from start to

finish. He wanted his snowsuit on because it had snowed. So we did that.

We went for a walk, and he wanted us to lay him in the snow. So we did.

He wanted to lie in bed with his hockey skates on, so he did. He wanted

to hold his skateboard in bed, so he did. He wanted a remote control car,

so we searched the earth and found it in Australia. He got it with a lot of

help. He wanted to go to Walmart for an F150 dinky car. So we did. One

of the biggest adventures was that Bryce wanted to go and watch his sister

play hockey. It was her first hockey tournament. The arena where she was

playing did not “support” a viewing area for individuals in wheelchairs,

so, with the help of Earth Angels, 6 police officers came out to lift Bryce

and his wheelchair up a flight of 25 stairs to the viewing area. He watched

his sister play, and at the end of the game he said, “You forgot to tuck in

one side of your jersey, Bailey.” Those officers came back an hour later

to lift him back down. Another day former NHL player Bobby Orr showed

up at our house to visit.

I have to say that as a parent, and not a health care professional, it was

the scariest thing that we will ever experience, but we could only have

survived it because of the communication and support that we received

from the healthcare team. You see, for the entire 361 days that Bryce

fought this cancer, we were supported. We were able to talk to people who

could help us and explain things to us, so that we could in turn explain it

to Bryce and his sister, and ultimately live through what was happening.

Everyone was only a phone call away, or a visit away. Once in Care at

Home, Bryce’s care team continued to support us by calling us regularly

in the evenings. This meant so much to us, because this would be when

we felt that much more separated from medical staff and when truthfully

after dealing all day, we were most vulnerable and scared of what was

to come. What if it happened at night?

I can tell you that now, 20 months later, I still feel that we did what

was right for our Bryce and for our family. All of the decisions and

conversations that we had were right for us. We have no regrets that we

didn’t get to talk about things, or that we didn’t get to spend time doing

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the things that Bryce chose to do, or that he didn’t LIVE every single day

that he was given. That is not to say that we do not miss our boy every

second of every day, or that our life will ever be the same without him.

We said what we needed to say, and did what he needed us to do. In the

meantime, we LIVE as he showed us how to—with hope for a cure, much

courage to get through our days, strength in making good decisions, and

with the peace of knowing that we will one day be together again.



As I look back on this journey, my advice to parents that may have a

newly diagnosed child with DIPG is to not give up. There are survivors

of this—not many. It is crucial, in my opinion, to send out your child’s

scans to doctors that know this tumor. Join the DIPG yahoo group online

for a list of exceptional doctors with expertise in DIPG, for other families

that have gone through this and are in the battle, for the most up-to-date

treatment options from around the world, for clinical trial information, for

alternatives that others have tried, and for understanding. Please know

there are people that will help you and will listen and will understand.

Finally know that as the parent you will make the right decisions for your

child in this very difficult journey.



Things were as normal as they could be with all the appointments and the

anxiety of knowing that this reprieve was probably going to be a short-

lived gift. Although we held out hope that Miguel would be the one to

beat this, we were realistic. We were able to enjoy him fully for 18 months

from diagnosis. It wasn't easy, especially when progression occurred

almost one year from diagnosis, just like the doctors said it would. While

he was able to compensate for many of the symptoms prior to diagnosis,

after progression, things changed one by one: loss of mobility, difficulty

swallowing, loss of speech, and the loss of fine motor skills to name a few.

Although the deterioration was difficult to watch and endure, Miguel's

short life has made a profound impact in many lives. Miguel is a precious

yet rare gift and it is an honor to be his grandma—always.



“Honey, I am scared Johnny is going to die too. Right now, I don’t know

if he will or not, but I do know he isn’t going to die today. So each day I

have with him, I am going to love him and make it as special as possible.

Does that sound like a good plan?” At this point, we were both crying.

Through our tears, a small smile came to her face and we headed back

up to the room to check on the one boy we couldn’t stop thinking about.

We had been at St. Jude for about three weeks. We had a routine of

radiation, chemotherapy and clinics. We were beginning to accept that

Johnny had cancer, and although there was no cure, we were given more

time with him, and we all wanted more time. One afternoon, we were in

the truck driving back to the Ronald McDonald House. Johnny’s stomach

was upset and he was lying down in the back. Johnny speaks up from the

back, “Mom, am I going to die?” I felt the stabbing dagger of pain once

again. My son knew he was going to die and no one needed to tell him,

but he needed to talk.

Since I had already talked with my daughter, I knew how I would respond.

I went on to ask more questions from him and then closed the conversation

by telling him his feelings were normal and good, his dad and I felt the

same way, there were some things we can’t control and don’t have the

answers to, how much we love him and how special we will make the time

we do have with him. We were taking life one day at a time. We had no

guarantees about tomorrow, but today we were living it for all it was worth.

The questions from my other children continued, “It’s not fair. Why did

he get sick? What did we do wrong? We are good people. I mean we do

some bad things but not really bad. Why is God punishing us?” I didn’t

know what to say. Having questions about faith and spiritual matters is

normal. The intensity of this pain is going to bring to the surface questions

that most people can go a lifetime without addressing. One option is to

ignore or avoid my child’s questions. A second option is to seek out the

answers and wrestle with the questions. Option one gives immediate

relief but the questions will resurface throughout their life because they

go unresolved and unanswered. Option two is a more difficult path, but

when the wrestling is over and the tension is resolved my other children

will be able to move through their grief in a healthy pattern.

So, this was my reply. “I don’t know why God is allowing this to happen

to us. This is what I do know. I know all the stories of people helping us.

I know dad’s friends from his childhood live in Memphis and have a house

so you kids can stay here with us. Most families have to live apart from

each other all this time. I know that grandpa and grandma have the time

to live here with you, so that dad and I can take care of Johnny. I know

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dad’s work is letting him stay here the whole time Johnny is at St. Jude

and still paying him so we don’t lose our house. I know our neighbors are

mowing our grass and taking care of the dog. I know people are sending

you kids gifts and cards. I know that every time we turn around someone

is doing something special for us, and a lot of those people don’t even

know us because we just moved to Arkansas three months ago. I know

these things mean something."

I could not offer many answers to my son that day. I still cannot offer

many answers. But my answer offered hope to him. Hope that there are

good things in the face of tragedy. Living one day at a time, hope was

enough to calm my child’s heart.



In the days that followed his diagnosis we would tell Liam he had cancer.

We felt it was incredibly important to tell him the truth, to use that word.

As hard as it was, we wanted him to know he could always trust us to be

honest with him going forward.

We called family and close friends. We had family bring our other three

children to the hospital. We told our kids that Liam had brain cancer and

that they could not take it out but that we were going to do everything we

could to make it smaller. Liam's neuro-oncologist allowed the kids to visit

Liam very briefly. Liam's identical twin brother asked his doctor what

would happen if the medicine didn't work. The doctor reassured him that

they had lots of things they could try to help Liam feel his best. We felt

grateful for this small offering of hope.



I would have liked to have a group of individuals to talk to about our

daughter's specific tumor type during her treatment. We were following

another DIPG child’s story and were very inspired at how long he was able

to live after treatment. We never gave up hope and we always believed that

something would come up to save our daughter. We never really thought

she would really die from this even though that's what they told us.



Things are changing for our kids, for your child. There are viable

alternatives to current steroids and new therapies on the horizon. I know

that there is always hope.



We have found it incredibly helpful to hear from other parents that have

lost a child. Their advice is always so heartfelt and honest. The only

advice we can come up with at the moment is to listen to your own heart

and make decisions based on your knowledge of your child, individual

circumstances and personal convictions. Grieving is such a personal

journey, and the patience you need to have with yourself is infinite. No

one's path with DIPG is the same, and the only thing you can strive for is

that you don't regret any of the decisions you've made. We think the best

way to do this is to trust your instincts and be at peace with the journey

as much as possible.

Stella is many things. As was evident early, she is a force to be reckoned

with. She is inquisitive. She is intelligent. She is hilarious. More than

anything else, Stella is her aptly given middle name: Stella is “Joy.” Stella

proves that cancer can't take away everything...her smile is our lifeline!



Aimee asked me last night if I thought we would ever be happy again.

It's an interesting question. It's not that we haven't felt happiness these

last 8 1/2 months; it's just that all happiness is tinged with a pervasive

sadness as well. I had to think for a while before answering, because the

truth is I have no idea if I will ever feel true happiness again. I think

we will definitely have many moments in the future of being happy. But

feeling happy? I think they are two different things. My best guess is

that each joyful moment will come with a small shadow of wishing that

our daughter was there to experience it as well. Every family vacation

and holiday, every accomplishment in our lives, every celebration (big

or small) that she should have been there for. I imagine that eventually

the shadow around your heart just becomes who you are and happiness

and sadness cease to exist as separate entities and your new norm is to

just accept that happiness and sadness are not mutually exclusive, but

intertwined in one another—bitter and sweet.

What is keeping us moving forward right now, even when our hearts are

completely broken, is watching how our daughter has chosen to live her

short life. How she treats each day as a new adventure, pushes herself

both physically and mentally to ensure that she accomplishes what she

wants on that particular day. Sometimes it's something big—painting

Chapter 22: Journey of Sadness and Hopes

332

with her mouth and visiting the pigs at the farm. And sometimes it's just

being able to mouth the words "ice cream," and then napping most of the

day. But she is always true to herself, and even though things are hard

for her, she ignores the barriers of DIPG and chooses to forge her own

path. Most importantly, she believes that when life gives you a hundred

reasons to cry, you need to find a thousand reasons to smile…And in my

own smiles, I have become familiar with the bittersweet taste of getting

to parent my precious daughter—the best experience in the world, but

like a spring day that is much, much, too short.

333

Appendix A: Medications Form

Appendix A

Medications Form

Appendix A: Medications Form

334

Appendix A: Medications

Name of

Medication and Strength

Instructions/Dose

(Include all

details, dose, and times)

Purpose Prescribing

Doctor

Ex: Tylenol liquid

(acetaminophen)

160 mg/5 ml

Takes 3 ml every 4 hours by mouth

as needed

For fever or pain Dr. Smith

It is strongly recommended that you take any medication that your child is receiving at home to each doctor or hospital visit.

e medications will be reviewed and any changes can be made at that time.

335

Appendix B: Glossary of Terms

Appendix B

Glossary of Terms

e following terms were referenced by the authors throughout the book. ey

are listed here to provide additional information to assist with understanding.

Accessible: Tumors that can be approached using a surgical procedure.

Active Immunization: is is the kind of vaccine we are most used to. e

MMR, inuenza, DPT, and Polio vaccines all depend on active immunization by

presenting an antigen to the immune system and inducing an immune response

and long-lasting central memory.

Adaptive Immunization: is comes into play when the innate immune system

is evaded and an invader (a pathogen or cancer cell) gains a foothold. e adaptive

response recognizes these invaders and enables the immune system to mount

a stronger response each time they are encountered. is response involves all

branches of the immune system, both B cells and T cells, working together in

balance. e adaptive response can be trained through dendritic cell vaccine

strategies.

Adjuvant Chemotherapy: Administering chemotherapy after the primary tumor

has been treated by some other method, for example after radiation.

Adoptive Immunization: e transfer of mature circulating lymphocytes to

treat certain diseases.

Anaplastic Astrocytoma: A synonym used interchangeably for WHO grade 3

astrocytoma (glioma).

Angiogenesis Inhibitor: An agent that inhibits the growth of new blood vessels.

Apraxia: Inability to perform activities such as making gestures, speaking in spite

of the person’s willingness to do so; inability of the brain to correctly communicate

instructions to the body.

Astrocyte: One of two types of glial cells in the central nervous system that help

support the neural cells. e other type of glial cell is called an oligodendrocyte.

Appendix B: Glossary of Terms

336

337

Appendix B: Glossary of Terms

Astrocytoma: A tumor developed from the glial type of cell called an astrocyte.

ese tumors are oftentimes further described by location or appearance under

the microscope. e microscopy appearance can be into one of 4 grades using

the World Health Organization classication.

Ataxia: Uncoordinated and clumsy appearing walk that is associated with balance

issues.

B Lymphocytes: Cells in the immune system responsible for the humoral immune

response. at is the production of antibodies that attack foreign antigens (like

bacteria) or tumor associated antigens.

Blood-Brain Barrier (BBB): Protective barrier separating circulating blood from

the brain's extracellular uid thereby preventing substances in the blood from

entering into the brain. e BBB is created through tight junctions around the

capillaries of the linings of the blood vessels of the brain.

Brainstem Glioma: e broadest term to describe all histologic grades of glial

tumors that are located in any part of the brainstem (pons, medulla, tectum

and cervicomedullary junction). Brainstem gliomas can always be classied

more specically by particular location (e.g. pontine glioma, tectal glioma,

cervicomedullary glioma) and by certain descriptive terms (e.g. diuse, focal,

intrinsic, exophytic and extrinsic).

Biopsy: Surgical procedure to remove a sample of tumor tissue to establish

diagnosis. Tissue can be further utilized to determine specic molecular analysis

for research purposes as well as potentially used to develop personalized treatment

plans.

Cerebellar Ataxia: Loss of muscle coordination brought on by a lesion in the

cerebellum.

Cerebral Spinal Fluid (CSF): Clear, colorless uid that circulates around and

inside the brain and spinal cord.

Contrast Enhancement: Use of an agent administered to a patient prior to an

MRI scan to increase the visibility between the tumor and surrounding tissue.

Computerized Tomography (CT) Scan: A medical imaging procedure using

x-ray technology from a series of dierent x-ray angles, which are then processed

through computer technology to create cross-sectional images of bones and soft

tissue including the brain; also referred to as CAT scan.

Cranial Nerves: Twelve pairs of nerves originating in the brain, and often included

in the designation of central nervous system (brain, spinal cord, and cranial nerves.)

Cytoarchitecture: e typical arrangement of cells within a particular tissue or

organ.

Cytotoxic: Toxic to cells. Any agent or process that kills cells.

Cytotoxic T Cells: T lymphocyte cells that directly induce the death of tumor

cells or virus-infected cells; also known as killer T cells.

Daughter Cell: Cell(s) that result from cell division. Daughter cells are genetically

identical to the originating parent cell.

Dendritic Cell: ese cells are unique to mammals and function to capture

foreign invaders (antigens) and present them to the immune system. Activated

dendritic cells from the nose, lungs, or skin migrate to the lymph nodes to tell

B and T cells what to do.

De Novo: New—for example a de novo mutation is a new genetic mutation.

Diuse: An adjective that can be used to describe an inltrative nature of a

tumor as opposed to focal tumors which are more conned or circumscribed.

Diuse tumors are usually a higher histological grade (3 or 4) but can be low

grade. Except in the cases of leptomeningeal spread or gliomatosis cerebri, diuse

is also intrinsic. ese tumors cannot be removed as they are like "sand in grass"

or "pepper in Jello" i.e. being too dicult to remove the tumor without severely

disturbing the normal tissue of the pons.

Diuse Brainstem Glioma: is is an inltrative tumor of glial origin located

anywhere in the brainstem. Approximately 80% of these tumors will be in the

pons. us most, but not all, diuse brainstem gliomas can be more specically

called diuse pontine gliomas or diuse intrinsic pontine gliomas.

Diuse Pontine Glioma: A glioma (usually an astrocytoma) located in the pons

which intermingles and inltrates normal pontine tissue. Synonyms include

diuse intrinsic pontine glioma or diuse inltrative pontine glioma.

Diuse Intrinsic Pontine Glioma (DIPG): A glioma (usually an astrocytoma)

located in the pons which intermingles and inltrates normal pontine tissue.

Synonyms include: diuse pontine glioma or diuse inltrative pontine glioma.

Diplopia: Double vision

Dorsal Exophytic Pontine Glioma: Tumor that grows from subependymal glial

tissue out into the 4th ventricle; typically presents with hydrocephalus.

Dysarthria: Speech disorder resulting from defects in the central or peripheral

Appendix B: Glossary of Terms

338

339

Appendix B: Glossary of Terms

motor nerves leading to an impairment of neural transmission to the muscles

involved in speech. Can include impairment to all processes involved in the

production of speech including respiration, phonation, and articulation.

Dysphasia: Loss or impairment of the ability to speak, read, or write; understand

or interpret speech or written language.

Edema: Excess bodily uid leading to swelling.

Embryo’s Yolk Sac Endoderm: e germ layer that lines the yolk sac.

Endoscopic ird Ventriculostomy (ETV): Surgical procedure in which an

opening is created in the oor of the third ventricle using an endoscope through

a burr hole. is allows for the cerebrospinal uid to ow directly into the basal

cistern, thereby used as a means to treat obstructive hydrocephalus.

Extrinsic: An adjective to describe a tumor that is located on the outside.

Exophytic: An adjective to describe a tumor that is growing out of the brainstem—

like the top part of an iceberg sticking out of the water.

Focal: An adjective used to describe a tumor that is well dened and does not

seem to intertwine with normal tissue. Focal brainstem gliomas are usually

histologically grade 1 (also called pilocytic astrocytoma).

Glial Cell: One of the supportive cells in the central nervous system. ese can

be either astrocytes or oligodendrocytes.

Glioma: A tumor arising from glial cells, either astrocytes or oligodendrocytes.

If one can dierentiate the cell line from which the tumor derived from, then it

may be called by a more specic name, i.e. an astrocytoma, oligodendroglioma or

a mixed tumor. Dierent adjectives can be applied to the term glioma to convey

a more descriptive, specic understanding of the tumor.

Glioblastoma Multiforme (GBM): A synonym used interchangeably for WHO

grade 4 astrocytoma (glioma).

Helper T Cells: T lymphocyte cells that help the immune system recognize what

to attack.

Hemiparesis: Muscle weakness on one side of the body.

Hirsutism: Abnormal hair growth on face and body.

Histologic: A term referring to the classication of tissue based on microscopic

examination. With gliomas, there are 4 grades based on the WHO classication.

Hydrocephalus: Excess uid in the brain resulting from a blockage of the CSF

pathways.

Hyperphagia: Abnormal increased appetite for food.

Hypoxic Cells: Cells that are deprived of oxygen.

Hypoxic Cell Sensitizers: Compounds that selectively sensitize hypoxic tumor

cells to the eects of radiation.

Immunohistochemical: Pertains to an assay used in research analysis that shows

specic antigens in tissues through the use of uorescent markers.

Inltrative: An adjective used to describe a tumor that is intermixed with normal

tissue. A synonym for diuse.

Intrathecal: An area sometimes used to administer drugs, which is located in

the space under the arachnoid membrane that covers the brain and spinal cord.

Intratumoral: An area within a tumor.

Intraventricular: An area located within a ventricle of the brain.

Intrinsic: An adjective used to describe that a tumor is located on the inside.

In Vitro: A preclinical study or experiment done within a test tube or laboratory

dish.

In Vivo: A study, medical test, or procedure that is done on a living organism,

such as a laboratory animal or human.

Lumbar Puncture (LP): Insertion of a needle into the subarachnoid space of

the spine to either administer drugs or to withdraw a sample of CSF for biopsy;

also referred to as spinal tap.

mAB: Monoclonal antibody.

Magnetic Resonance Imaging (MRI) Scan: Medical imaging technique that uses

magnetic eld and radio waves to generate computer imaging data; produces high

contrast images of the soft tissue of the body with useful application to the brain.

Malignant: Another term meaning cancerous.

Memory B Cells: e cells that most childhood immunizations depend on.

Memory cells are created from activated B cells the rst time an antigen is

encountered (like a tetanus vaccine). When one encounters the same antigen again

(like stepping on a rusty nail), even years later, the memory B lymphocyte cells

Appendix B: Glossary of Terms

340

341

Appendix B: Glossary of Terms

will respond quickly to create an immune response before things get out of hand.

Memory T Cells: Experienced lymphocyte T cells that have previously

encountered virally infected cells or tumor cells. ey are more eective than

naïve T cells are when encountering an immune target for the second time, i.e.

they hit harder and faster. Memory T cells are divided into central memory and

eector memory subtypes.

Mitotic Cycle: e transferring of the parent cell genome through cell division

into two identical daughter cells.

Necrosis: e death of living cells or tissue(s) due to disease, injury, loss of blood

supply, radiation or chemical agents.

Neoadjuvant: Induction therapy that is given to a patient prior to the main

treatment; can include chemotherapy, radiotherapy, hormone therapy. e goal

is to reduce the size of the tumor prior to the radical therapy.

Neoadjuvant Chemotherapy: Administration of chemotherapy in order to

decrease the tumor burden prior to treatment by other modalities such as radiation.

Neurospheres: A free-oating (non-adherent) in vitro spherical cluster of neural

stem cells.

Neurotoxicity: A damaging eect on the nerves or nervous tissue.

Passive Immunization: Fetuses acquire antibody from the mother via the placenta

of breast milk and are more able to cope with specic infections during the rst

weeks of life. Articial passive immunity can be used to treat transplant rejection,

rabies or tetanus.

Peritumoral: Area around the margins of a tumor.

Peritumoral Edema: Swelling around a tumor.

Pilocytic Astrocytoma: e lowest histologic grade of tumor. When in the

brainstem these tumors tend to be more conned and less inltrative. ey

possibly could be operable. ese are WHO grade 1 astrocytomas.

Plasma B Cells: Large B lymphocyte cells that have been exposed to a specic

immune target and make lots of antibodies against it.

Pons: A specic area of the brainstem located below the midbrain and above the

medulla which is connected to the cerebellum through the cerebellar peduncles.

Pontine: An adjective used to describe the specic location as being in the pons.

Pontine Glioma: A tumor of glial origin which is located in the pons.

Progenitor Cell: Cell that is an early oshoot of a stem cell but one that is more

dierentiated than a stem cell.

Radiation Necrosis: e death of living cells or tissue(s) caused by radiation.

Radioresistant: Tumors that do not respond well to conventional radiation

therapy.

Radiosensitive: Tumors that do respond to conventional radiation therapy.

Ras Protein: A protein involved in signal transmission within cells which typically

promotes normal cell division. Abnormal ras, caused by gene mutation(s) results

in increased cell division leading to cell proliferation.

Resect: Surgically remove.

Spiral CT Scan: CT scan technology using a helical/360 degree capture of the

x-ray image which results in increased resolution, also referred to as a helical CT.

Stem Cell: Master cell that is undierentiated within the human body, capable

of growing into any one of more than 200 cell types, allowing them to replace

defective or lost cells/tissues in patients with disease or defects.

Stereotactic: Surgery or radiation therapy that is directed by 3D scanning device

to enhance procedure accuracy.

Sublethal Radiation Damage: Radiation that damages but does not kill the

tumor cell.

Suppressor T Cells: T lymphocyte cells that maintain immune tolerance so we

don’t attack ourselves or overly respond to everything we come in contact with;

also known as Regulatory T Cells (Treg).

Teratogen: Drug that can disturb the development of an embryo or fetus.

T Lymphocytes: Cells within the immune system which are responsible for the

cell-mediated immune response.

Tumor Necrosis: Death of tumor tissue.

Tumor Vasculature: Arrangement of blood vessels within tumors; vascular-

targeted therapies are being studied to destroy the blood supply to cancer cells

within tumors.

Ventricle: A small cavity located within the brain.

Appendix B: Glossary of Terms

342

WHO Grading of Glial Tumors: e World Health Organization has criteria in

categorizing glial tumors by the way they appear under the microscope. ose that

appear closer to normal cells are lower grade (1 or 2) and are generally considered

less aggressive. ose that look more abnormal are higher grades (3 or 4) and are

typically considered more aggressive.

Grade 1-pilocytic astrocytoma

Grade 2- brillary astrocytoma

Grade 3- Anaplastic Astrocytoma

Grade 4- Glioblastoma Multiforme

e number grade and the corresponding terms are considered synonymous and

used interchangeably.

343

Appendix C: Resources

Appendix C

Resources

Many resources exist for families of children with diuse intrinsic pontine

glioma. is appendix contains a sampling of some especially helpful books,

organizations, videotapes, and websites.

Books

General

Keene, Nancy. Chemo, Craziness, and Comfort: My Book About Childhood Cancer. American

Childhood Cancer Organization, 2002. Provides clear explanations and practical

advice for children ages 6 to 12 with cancer. Warm and funny illustrations, by Trevor

Romain, help the child (and parents) make sense of cancer and its treatment. Free

to children with cancer.

Dodd, Michael. Oliver's Story, For 'Sibs' of Kids with Cancer. American Childhood Cancer

Organization, 2004. A practical book written to celebrate the ways in which siblings

of children with cancer can help during this time of family crisis. Free to families of

children with cancer. Available in English and Spanish.

Homan, Ruth I. Along the Way. American Childhood Cancer Organization, 2010. is coil-

bound journal provides a place for contact information for doctors, school and other

caregivers essential to caring for the child with cancer. It also includes information

about clinical trials, informed consent, medical terminology, blood counts as well as

forms to log the child's temperature and out-of-pocket expenditures. An extensive

journal section is also included. Free to families of children with cancer.

Homan, Ruth I. Cozy Cares Journal. American Childhood Cancer Organization, 2010.

is 122 page journal includes illustrations by Trevor Romain. e drawings of Cozy

the 'Port-a-Cat' include hand gestures such as 'high ve,' 'ok,' and 'thumbs up' to

encourage the child to draw strength from within themselves as well as those around

them. Writing prompts throughout the book help the child cope during their diagnosis

and express their thoughts and feelings during this dicult time. Examples of writing

prompts include: I am special because ...; When I'm bored in the hospital my family

and I ...; When I'm feeling sad it helps to ... etc. Free to children with cancer.

Romain, Trevor. Lift Me Up. American Childhood Cancer Organization, 2008. is 24

page book with inspirational text is lled with wonderful illustrations to color. Free

to children with cancer.

Grief in school

Gliko-Braden, Majel. Grief Comes to Class: A Teacher’s Guide. Centering Corporation, 1531

N. Saddle Creek Rd., Omaha, NE 68104. (402) 553-1200. Comprehensive guide

to grief in the classroom. Includes chapters on grief responses, the bereaved student,

teen grief, developmental changes, sample letter to parents, and sample teacher/parent

344

Appendix C: Resources

345

Appendix C: Resources

conferences. Also available on Amazon.com

e Compassionate Friends. Suggestions for Teachers and School Counselors. P.O. Box 3696,

Oak Brook, IL 60522. (630) 990-0010.

Romain, Trevor. What on Earth Do You Do When Someone Dies? Minneapolis, MN: Free

Spirit Publishing, 1999. Warm, honest words and beautiful illlustrations help children

understand and cope with grief.

Harvey, Diane. Why the Snowman Melts. Sandstone Publishing Saint George, UT, 2010.

rough the story of the melting snowman, young children gain understanding of

change and loss.

Brown, Laurie Krasny and Brown, Marc. When Dinosaurs Die: A Guide to Understanding

Death. Little Brown and Company, New York, NY, 1996. For children ages 5 to 8

years. Direct answers to children's questions about death such as "Why does someone

die?" Available through Amazon.com.

Wilhelm, Hans. I'll Always Love You. Crown Publishers, 1985. e loving story of a little

boy and his love and loss of his dog Ele. Available on Amazon.com.

Heckert, Connie. Dribbles. Clarion Books, New York, NY, 1994. For ages 5 to 8. is

picture book addresses death as told by three household cats living with an aging

owner and aging feline. Available on Amazon.com.

Grootman, Marilyn. When a Friend Dies: A Book for Teens about Grieving and Healing. Free

Spirit Publishing, Minneapolis, MN, 1994. Practical guide for teens that addresses

and validates emotions associated with death such as guilt, fear, anger and confusion.

Wolfelt, Alan. Healing a Child's Grieving Heart: 100 Practical Ideas for Families, Friends and

Caregivers. Companion Press, Ft. Collins, CO, 2001. Practical guide that provides

suggestions on how to help those who are grieving by oering sensitive responses

to "what to say and do" and "what not to say and do." Available on Amazon.com.

Hearing loss

Poitras Tucker, Bonnie. IDEA Advocacy for Children Who Are Deaf or Hard of Hearing: A

Question and Answer Book for Parents and Professionals. Singular Publishing Group,

1997.

IEP school advocacy

Siegel, Lawrence. e Complete IEP Guide: How to Advocate for Your Special Ed Child.

Harbor House Law Press, 2001. Spells out the IEP process for families and includes

helpful sample letters and forms.

Anderson, Winifred, Stephen Chitwood, and Deidre Hayden. Negotiating the Special

Education Maze: A Guide for Parents and Teachers. 3rd ed. Bethesda, Maryland:

Woodbine House, 1997. Excellent, well-organized text clearly explains the step-by-

step process necessary to obtain help for your child.

Susan Gorn, Editor. Special Education Dictionary. LRP Publications, 1997. (215) 784-0860.

Wright, Peter, and Wright, Pamela. Wrightslaw: Special Education Law. Harteld, VA:

Harbor House Law Press, 1999. Text of key laws and regulations.

Wright, Peter, and Wright, Pamela. Wrightslaw: From Emotions to Advocacy: e Special

Education Survival Guide. Harteld, VA: Harbor House Law Press, 2001. Full of

information on special education law, advocacy tactics, and IEP tips.

Speech and language

McAleer Hamaguchi, Patricia. Childhood Speech, Language and Listening Problems: What

Every Parent Should Know. John Wiley & Sons Inc., 1995.

Schoenbrodt, Lisa, ed. Children with Traumatic Brain Injury: A Parent’s Guide. Woodbine

House, 2003.

Schwartz, Sue, and Joan E. Heller Miller. e New Language of Toys: Teaching Communication

Skills to Special-Needs Children. Rockville, MD: Woodbine House, 1996.

Videotapes

Paul and the Dragon. Powerful 25 minute video created to help children, siblings and

friends understand the world of childhood cancer in a safe way, with humor but also

with truth. rough watching Paul’s battle with his dragon, the child with cancer will

understand that scary things will happen to them as they ght their "cancer-dragon."

ey will learn that the doctors, nurses and even the blue "medication-men" and

purple "chemo-blobs" are there to help them beat their cancer. Available through the

American Childhood Cancer Organization. http://www.acco.org

Why, Charlie Brown, Why? Tender story of a classmate who develops leukemia. Available as

a book or videotape. For video availability, call the Leukemia and Lymphoma Society,

(800) 955-4572 (4LSA).

Cancervive Back to School Kit. A comprehensive package of materials developed to assist

children and adolescents re-entering the school setting. e kit contains a “Teachers

Guide for Kids with Cancer” and two award-winning documentary videos: “Emily’s

Story: Back to School After Cancer” and “Making the Grade: Back to School

After Cancer for Teens.” http://www.cancersourcekids.com/parents/schoolintro.

cfm?usertypeid=3

Drying eir Tears. Produced by CARTI. For information, call (800) 482-8561. Video and

manual to help counselors, teachers, and other professionals help children deal with

the grief, fear, confusion and anger that occur after the death of a loved one. Has three

segments: one about training facilitators, one for children ages 5 to 8, and one for ages

9 to teens. Each section includes interviews with children and video from children’s

workshops. http://www.hopkinschildrens.org/tpl_rlinks_nobanner.aspx?id=828

Back to School: Teens Prepare for School Re-entry. Produced by Starbright Videos with

Attitude, call (800) 315-2580. Teens who have been there share their stories and

advice on how to get back into the groove of school. Also discusses how teens can

get the extra help they may need to make returning to school a successful experience.

http://www.starbright.org

Organizations

ACCO would like to acknowledge the many non-prot organizations that have been

founded in memory of children diagnosed with DIPG. It is because of the work of so many

of these organizations that DIPG has received increased awareness as well as heightened

research interest. e following is a list of organizations that support DIPG research

and/or provide resources to families on a national basis, whether nancial, emotional, or

informational. It is provided as a starting point to assist families, and is not to be regarded

as a comprehensive list.

346

Appendix C: Resources

347

Appendix C: Resources

Air Care Alliance

Email: [email protected]

(888) 260-9707

http://www.aircareall.org

e Air Care Alliance promotes, and provides public benet ying through facilitation of

ights for health, compassion and community service. ese groups do not y patients or

supplies when insurance or other funds can provide commercial transport via air ambulance,

charter or airline. e public benet ying volunteers y when nancial need or other

special circumstances mean a compelling human need would go unfullled.

American Childhood Cancer Organization®

10920 Connecticut Ave. Suite A

Kensington, MD 20895

(855) 858-2226

http://www.acco.org

Founded in 1970, ACCO has more than 70,000 members. Some of the free services

provided by ACCO include a toll-free information phoneline, an e-bulletin, childhood

cancer books to help children with cancer and their families, diagnosis kits, local support

group aliates, and national advocacy.

American Speech-Language-Hearing Association

2200 Research Blvd.

Rockville, MD 20850

(800) 638-8255; TTY: (301) 296-5650

http://www.asha.org

ASHA’s mission is to ensure that all people with speech, language and hearing disorders

have access to quality services to help them communicate eectively. Canadian organization

can be found at http://www.caslpa.ca

Believe in Tomorrow Children's Foundation

6601 Frederick Road

Baltimore, MD 21228

(800) 933-5470

http://www.believeintomorrow.org

e Believe in Tomorrow Children's Foundation provides hospital and respite housing

services to critically ill children and their families.

Brain Tumor Foundation of Canada

620 Colborne Street, Suite 301

London, ON N6B 3R9

(800) 265-5106; 519-642-7755

http://www.braintumour.ca

e Brain Tumor Foundation of Canada provides up-to-date brain tumor information

materials, educational events and support groups. Important brain tumor research is

supported through annual grants, a fellowship and the brain tumor tissue bank.

Childhood Brain Tumor Foundation

20312 Watkins Meadow Drive

Germantown, MD 20876

(877) 217-4166

http://www.childhoodbraintumor.org

Founded in 1994, the Childhood Brain Tumor Foundation funds scientic and clinical

research for pediatric brain tumors, and sponsors educational conferences.

Children's Brain Tumor Foundation (CBTF)

274 Madison Ave. Suite 1004

New York, NY 10016

(866) 228-HOPE

http://www.cbtf.org

Founded in 1988, the CBTF provides information, support and advocacy to children with

brain tumors and their families. ey fund scientic research leading to better treatments

and cures of pediatric brain tumors, as well as research leading to improved quality of life.

Compassionate Friends

900 Jorie Blvd. Suite 78

Oak Brook, IL 60523

(877) 969-0010

http://www.compassionatefriends.org

Compassionate Friends provides personal comfort, hope and support through local chapters

for bereaved family members experiencing the death of a child.

Just One More Day

1853 Surrey Court

Viera, FL 32955

(321) 698-8538

http://www.justonemoreday.org

Just One More Day is committed to providing information and support for families

aected by diuse intrinsic pontine glioma, promoting awareness, and funding research

leading to a cure.

Kids v Cancer

4646 Hawthorne Lane

Washington, DC 20016

(646) 361-3590

http://www.kidsvcancer.org

Kids v Cancer is committed to the creation of legislative initiatives leading to pediatric

cancer drug development, as well as the parent-led eort to making autopsy tissue donations

more widely available for research.

Make-A-Wish Foundation®of America

4742 N. 24th Street, Suite 400

Phoenix, AZ 85016

(800) 722-9474

http://www.wish.org

Founded in 1980, the Make-A-Wish Foundation has enriched the lives of children with

life-threatening medical conditions, and their families, through their wish-granting program.

National Association of Hospital Hospitality Houses (NAHHH)

P.O. Box 1439

Gresham, OR 97030

(800) 542-9730

http://www.nahhh.org

348

Appendix C: Resources

349

Appendix C: Resources

NAHHH is a nation-wide association of 200 non-prot organizations that provide lodging

and support services to patients and their families who are receiving medical treatment far

from their home communities.

Pediatric Brain Tumor Foundation

302 Ridgeeld Court

Asheville, NC 28806

(800) 253-6530

http://www.pbtfus.org

e PBTF, founded in 1991, provides education and emotional support for children with

brain tumors and their families. ey seek to nd the cause and cure for childhood brain

tumors by supporting medical research and increasing public awareness of childhood brain

tumors.

Reections of Grace Foundation

P.O. Box 298

Irwin, PA 15642

Email: contact@reectionsofgrace.org

http://www.reectionsofgrace.org

Reections of Grace Foundation is dedicated to providing nancial, emotional and

educational support for children and families ghting pediatric brain tumors; and funding

the search for a cure for DIPG and other forms of pediatric brain tumors.

Smiles for Sophie Forever Foundation

31722 Leeward Court

Avon Lake, OH 44012

Email: info@smilesforsophieforever.org

http://www.smilesforsophieforever.org

Smiles for Sophie Forever is dedicated to providing nancial support to families burdened

by pediatric brain tumors, as well as increasing global awareness of the devastation of

pediatric brain tumors.

SuperSibs!

660 N. First Bank Drive

Palatine, IL 60067

(888) 417-4704

http://www.supersibs.org

SuperSibs' mission is to support, honor and recognize brothers and sisters of children

with cancer. ey provide numerous “Advocacy and Support” services, including journals

for siblings, guides, scholarships and a monitored teen chat internet room. SuperSibs also

sponsors “Surprise and Delight” services such as special sibling activities and giveaways for

siblings ages 4 to 18. Services are provided free of charge.

e Cure Starts Now Foundation

10280 Chester Road

Cincinnati, OH 45215

(513) 772-4888

http://www.thecurestartsnow.org

e Cure Starts Now Foundation ghts for the cure for children with brainstem glioma

through public awareness and media campaigns, as well as the funding of research leading

to new treatments for DIPG.

Online Support Groups

ACOR, e Association of Cancer Online Resources, Inc.

http://www.acor.org

ACOR oers access to mailing lists that provide support, information, and community to everyone

aected by cancer and related disorders. It hosts numerous pediatric cancer discussion groups.

American Childhood Cancer Organization's Inpire Online Community

http://www.inspire.com/groups/american-childhood-cancer-organization

ACCO's Inspire online commmunity connects patients, families, friends and caregivers.

It provides a platform for support and inspiration from diagnosis, through treatment and

beyond. Discussion topics include: newly diagnosed; treatment; emotional support for

children with cancer, siblings, parents and caregivers; nancial and insurance issues, and

more.

Apraxia-Kids Mailing List

Listserv@Listserv.syr.edu

http://www.apraxia-kids.org

is website and mailing list covers oral motor apraxia and related disabilities. To subscribe,

send an email with the message “subscribe apraxia-kids FirstName LastName.”

Cerebellar Mutism Brain Tumor Listserv Yahoogroup

http://health.groups.yahoo.com/group/cerebellarmutism

Listserv providing online support for parents and caregivers of children who suer from

cerebellar mutism and posterior fossa syndrome after brain tumor surgery/resection.

DIPG Listserv Yahoogroup

http://health.groups.yahoo.com/group/dipg

is group is primarily for parents of children diagnosed with diuse intrinsic pontine

glioma (DIPG). e membership includes parents who are in all stages of the DIPG journey.

Educating Brain Tumor Kids

http://groups.yahoo.com/group/EducatingBTKids

A group with links and les dealing with neuropsychological testing, school re-entry, school

options, late eects etc. ere is an associated listserv with archives.

Home Schooling Special Needs Children

http://groups.yahoo.com/group/special-needs-homeschool

is group supports parents who choose to home school their children with special needs.

Most members have medically fragile children dealing with challenges in speech, motor

development and learning disabilities and home school full time or part of the time.

Hydrocephalus (HYCEPH_L)

http://neurosurgery.mgh.harvard.edu/pedi/hyceph-l.htm

is list is open to all people interested in hydrocephalus.

IEP Guide and Listserv Yahoogroup

http://groups.yahoo.com/group/IEP_guide

350

Appendix C: Resources

351

Appendix C: Resources

is is a very large listserv that oers special education support and has a free IEP guidebook.

Pediatric Brain Tumor Angels Listserv Yahoogroup

http://health.groups.yahoo.com/group/PBTAngels

Listserv providing online support for parents and caregivers who are facing end of life issues

with a child who has a brain tumor and extended support for parents of children who have

died after battling a brain tumor.

Pediatric Brain Tumor Facial Paralysis Listserv Yahoogroup

http://health.groups.yahoo.com/group/PBTFacialParalysis

Listserv providing online support for parents and caregivers to gain information and support

regarding facial nerve paralysis after surgery for pediatric brain tumor surgery/resection.

Pediatric Brain Tumor Listserv Yahoogroup

www.yahoogroups.com/group/pediatricbraintumors

Listserv providing information and online support for parents and caregivers of children

diagnosed with pediatric brain tumors including: astrocytoma, atypical teratoid/

rhabdoid, glioblastoma multiforme, pleomorphic xanthoastrocytoma, craniopharyngioma,

diuse intrinsic pontine glioma, gangliocytoma, ganglioglioma, germinoma, glioma,

medulloblastoma, metastatic brain tumor, neurocytoma, oligodendroglioma, juvenile

pilocytic astrocytoma, pineocytoma, pineoblastoma, PNET, primitive neuroectodermal

tumor, teratoma, and ependymoma.

Websites

Bandaids and Blackboards-When Chronic Illness Goes to School

http://www.lehman.cuny.edu/faculty/jeitas/bandaides/contkids.html

Wonderful, fun and informative website about ill children and school.

CaringBridge

http://www.caringbridge.org

Free, personal and private websites to help families experiencing a health crisis connect

with family and friends.

Children's Hospice and Palliative Care Coalition

http://www.childrenshospice.org/coalition

Children’s Hospice & Palliative Care Coalition is a social movement led by children’s

hospitals, hospices, home health and grassroots agencies and individuals to improve care

for children with life-threatening conditions and their families.

Children's Oncology Camping Association International

http://www.cocai.org

Website listing the more than 65 children's oncology camps located across the U.S. as well

as camps for children with cancer in Canada, New Zealand and Europe.

Children's Oncology Group

http://www.childrensoncologygroup.org

e Children's Oncology Group (COG) unites more than 7,500 experts in over 200

children's hospitals, universities and cancer centers into a global team dedicated to working

towards a cure for all children with cancer. Includes a list of all COG treatment centers.

Clinical Trials.gov

http://www.clinicaltrials.gov

Clinical Trials.gov is a registry and results database of federally and privately supported

clinical trials conducted in the U.S. and around the world.

DIPG Collaborative

http://dipg.org

DIPG Collaborative provides information on numerous foundations whose mission is to

support DIPG research and support children and families diagnosed with DIPG.

DIPG Registry

http://dipgregistry.org

Comprehensive website dedicated solely to DIPG. Divided into two portals, one for patients

and their families, and one for medical professionals. Information includes upcoming

conferences, DIPG research studies, available clinical trials, registry enrollment form, up-

to-date information on the diagnosis and treatment of DIPG as well as contact information

for DIPG specialists in Canada, U.S., Australia and Europe, providing second opinions.

iCANcer Electronic Medical Record

http://itunes.apple.com/us/app/icancer/id389815342?mt=8

Personal electronic medical record created for iPhone, iPod, and/or iPad app that stores

diagnosis, treatment and health care provider information. is app manages medical

information including current and past medications, side eects, lab results (graphed over

time), and it organizes and syncs doctor's appointments, and conveniently exports medical

information to an email format for easy communication to a health care provider prior

to an appointment.

Monkey In My Chair

http://www.monkeyinmychair.org

Monkey In My Chair is a program for preschool and elementary aged children who are

away from school because of a cancer diagnosis. Each child is provided with a "monkey

kit" which includes a teacher's guide and classroom book, a backpack and a big stued

monkey that takes the child's place when he/she is unable to be in school.

Pediatric Brain Tumor Consortium (PBTC)

http://www.pbtc.org

e PBTC is a multidisciplinary cooperative research organization devoted to the study

of correlative tumor biology and new therapies for primary CNS tumors of childhood.

Pediatric Preclinical Testing Initiative

http://pptiohsu.blogspot.com/2011/12/open-science-forum-dipg-preclinical.html

Research blogspot including postings on the Rapid Preclinical Development of Targeted

erapy Combinations for DIPG.

Autopsy tissue and organ donation

Oregon Health and Science University CCURE-FAST

352

Appendix C: Resources

353

Appendix C: Resources

http://www.ohsu.edu/xd/health/services/doernbecher/research-education/research/pape-

family-pediatric-research-institute/ccure-fast.cfm

A helpful site to assist families with information about tumor tissue donation. Includes

dowloadable information on tumor banking, Q&A about legacy gifting, religion and tumor

banking, as well as guidelines for medical professionals.

U.S. Government Information on Organ and Tissue Donation and Transplantation

http://www.organdonor.gov

Comprehensive website dedicated to providing information on organ and tissue donation

and transplantation, including statistics, information on how to become an organ donor,

legislation, associated research and grant opportunities.

Trillium Gift of Life Network

http://www.giftoife.on.ca/en/organandtissuedonation

Website to assist Canadian families with information about organ and tissue donation.

Behavior

Behavior Problems of Children who have undergone Treatment for Brain Tumors

http://www.childhoodbraintumor.org/index.php?option=com_content&view=articl

e&id=59:behavior-problems-in-children-who-have-undergone-treatment-for-brain-

tumors&catid=38:late-eects-a

Cerebellar mutism

Cerebellar Mutism and Posterior Fossa Syndrome

http://groups.yahoo.com/group/cerebellarmutism

ere is an annotated bibliography from a medline search on cerebellar mutism, a

bibliography on radiation and cognitive eects and several articles from a speech pathologist.

Disabilities

Council of Educators for Students with Disabilities, Inc. (CESDI)

http://www.504idea.org/Council_Of_Educators/Welcome.html

CESDI provides Section 504 and special education training and resources to educators.

Protection and Advocacy

http://www.disabilityrightsca.org

Group that works to advance the human and legal rights of people with disabilities. Website

includes a page on assistive technologies.

Pacer Center Parent Advocacy Coalition for Educational Rights

http://www.pacer.org

A national coalition of parents working for educational rights.

Family Village: A Global Community of Disability Resources

http://www.familyvillage.wisc.edu

A huge site that provides informational resources on specic diagnoses, communication

connections, adaptive products and technology, adaptive recreational activities, education,

health issues, disability-related media and literature.

Distance learning

Talia Seidman Foundation

http://www.taliaseidman.com

An organization dedicated to using technology to bring hospitalized and homebound

chronically ill children back into the classroom.

Hearing impairment

Hard of Hearing & Deaf Students: Resource Guide to Support Classroom Teachers

http://www.bced.gov.bc.ca/specialed/hearimpair/intro.htm

Homeschooling

A to Z’s Cool Homeschooling

http://www.gomilpitas.com/homeschooling

Huge site with information on introduction to home schooling, curricula, home schooling

laws, support groups, methods, and philosophies.

National Home Education Network

http://www.homeschool-curriculum-and-support.com/national-home-education-network.html

A source for home schooling information, support group listings, home school news, and

related resources.

Nonverbal learning disabilities

Nonverbal Learning Disabilities

http://www.nldontheweb.org

A comprehensive site on nonverbal learning disabilities.

Siblings

SuperSibs

http://www.supersibs.org

A national program dedicated to the interests of brothers and sisters of children with cancer.

Includes online activities for children at http://supersibs.org/the-sib-spot/index.html.

Siblings of People with Disabilities

http://www.iidc.indiana.edu/index.php?pageId=2458

A list of books and videos that help siblings of people with disabilites.

Special education law

Consortium for Appropriate Dispute Resolution in Special Education (CADRE)

http://www.directionservice.org/cadre

CADRE provides support and materials that can help parents and educators implement

354

Appendix C: Resources

the mediation requirements under IDEA 97.

Department of Education Information about IDEA

http://idea.ed.gov

Comprehensive information about the Individuals with Disabilities Education Act.

Wrights Special Education Law

http://www.wrightslaw.com

is extensive and well organized site is probably the best place to start to gather information

on special education law. Includes sections on advocacy, law, books and other resources.

Educational Rights/Educational Law

http://edlaw.org/wordpress

is site provides publications and services for attorneys, advocates and parents who need

to know about educational law, including a section that deals with transportation.

Americans with Disabilities Act Homepage

http://www.usdoj.gov/crt/ada/adahom1.htm

National Information Center for Children and Youth with Disabilities

http://www.nichcy.org

Includes helpful resource sheets for every state.

Speech and language

IntelliTools

http://www.intellitools.com

is rm has a great catalog of assistive technology and communication devices.

Sports

Disabled Sports USA

http://www.dsusafw.org

An organization that gives people with physical, neuromuscular and developmental

impairments the opportunity to participate in a variety of activities including water/snow

skiing, camping, and whitewater rafting. Adaptive equipment information available.

American Hippotherapy Association

http://www.americanequestrian.com/hippotherapy.htm

Hippotherapy is therapeutic riding for those with motor disturbances.

North American Riding for the Handicapped

http://www.narha.org

An organization that promotes the benets of horseback riding for those with physical,

emotional or learning disabilities.

355

Appendix D: Research Articles

Appendix D

Research Articles

e following journal articles were referenced by the authors in specic chapters

throughout the book. ey are listed here to provide direction for additional

reading for those individuals who wish to delve deeper into a specic topic.