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Understanding
Childhood
Non-Hodgkin
Lymphoma
A Guide for
Patients,
Survivors
and
Loved Ones
First Edition
Understanding
Childhood Non-Hodgkin
Lymphoma
A Guide for Patients, Survivors and Loved Ones
First Edition
This guide is an educational resource compiled by the Lymphoma Research
Foundation providing general information on childhood non-Hodgkin
lymphoma. Publication of this information is not intended to take the
place of medical care or the advice of your physician. Patients are strongly
encouraged to talk to their physician for complete information on how
their disease should be treated and followed. Before starting treatment,
patients should discuss the potential benefits and side effects of cancer
therapy with their physician.
National Headquarters
115 Broadway, 13th Floor
New York, NY 10006
(212) 349-2910 phone
(212) 349-2886 fax
Helpline:(800) 500-9976
Helpline@lymphoma.org
Website: lymphoma.org
Email: LRF@lymphoma.org
This project is supported through Cooperative Agreement Number 1U58DP001110 from the
Centers for Disease Control and Prevention. Its contents are solely the responsibility of the
authors and do not necessarily represent the official views of the Centers for Disease Control
and Prevention.
© 2010 Lymphoma Research Foundation
Information contained herein is the property of the Lymphoma Research Foundation (LRF).
Any portion may be reprinted or reproduced provided that LRF is acknowledged to be the author.
ACKNOWLEDGMENTS
The Lymphoma Research Foundation wishes to acknowledge those individuals listed
below who have given generously of their time and expertise. We thank them for their
contributions, editorial wisdom and advice, which have truly enhanced this publication. Without their dedication and efforts this publication would not have been
possible. We hope those in the lymphoma community will now be better informed
and have a better understanding of their illness because of the gracious efforts of those
involved in the planning and execution of this comprehensive disease guide.
Editorial Board
Laura J. Eisenberg, BSN, MN, ARNP, Seattle Children’s
Anna R. Franklin, MD, MD Anderson Cancer Center
Melanie Goldish, SuperSibs!
Rebecca H. Johnson, MD, Seattle Children’s
Barbara L. Jones, PhD, University of Texas at Austin School of Social Work
Jennifer Mills, LMSW, MPH, New York University School of Social Work
Sandi Ring, MS, CCLS, SuperSibs!
Stuart E. Siegal, MD, Childrens Hospital Los Angeles
James Testaverde, BS, Lymphoma Research Foundation
Brian Tomlinson, MPA, BSW, Lymphoma Research Foundation
Tim Walker, MA, National Marrow Donor Program
ii Understanding Childhood Non-Hodgkin Lymphoma
Table of Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Chapter 1
Cancer Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Lymphoma Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Non-Hodgkin Lymphoma Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Common Types of Childhood Non-Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . .
The Causes of Non-Hodgkin Lymphoma in Children . . . . . . . . . . . . . . . . . . . . . . .
3
3
6
7
9
Chapter 2
Diagnosing Childhood Non-Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . .
Use of Conscious Sedation When Performing Diagnostic Tests . . . . . . . . . . . . .
Common Diagnostic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
11
12
15
Chapter 3
Childhood Cancer Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Unique Features of Childhood Cancer Clinical Trials . . . . . . . . . . . . . . . . . . . . . .
Enrolling Children in Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Understanding the Clinical Trial Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Use of a Placebo in Phase III Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
17
18
20
21
Chapter 4
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
What Happens If Relapse Occurs? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
23
27
27
Chapter 5
Supportive Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Side Effects of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Chapter 6
Coping with Childhood Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
What Children Need and Hope For After a Lymphoma Diagnosis . . . . . . . . . . . .
Emotional Coping for Parents, Adult Family Members and Friends . . . . . . . . . .
Support for Siblings of Children with Lymphoma . . . . . . . . . . . . . . . . . . . . . . . .
41
41
43
44
Chapter 7
Long-Term and Late Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Glossary of Medical Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Childhood Cancer Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Young Adult Cancer Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
About the Lymphoma Research Foundation . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Donate Now . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Understanding Childhood Non-Hodgkin Lymphoma iii
Please refer to our website for additional
and updated information.
lymphoma.org
iv Understanding Childhood Non-Hodgkin Lymphoma
Introduction
This guide is designed for parents and loved ones of children and
teens diagnosed with non-Hodgkin lymphoma (NHL) below the
age of 18. If you are looking for resources on adults diagnosed with
lymphoma, please refer to the Lymphoma Research Foundation’s
comprehensive guides on adult lymphomas (www.lymphoma.org/
aboutlymphoma). If you are looking for resources on children
diagnosed with Hodgkin lymphoma, please visit the Leukemia
and Lymphoma Society’s website (www.lls.org.).
Since the 1970’s research has led to significant improvements in
outcome for children with NHL. With appropriate medical therapy,
childhood NHLs are curable for over 80 percent of patients. Recent
data suggests cure rates as high as 90 percent to 95 percent, depending
on the type of tumor. Even for those children who develop recurrent
disease, cures can often be achieved. It is important to remember that
childhood NHLs are very different from other types of cancer in this
respect. Furthermore, childhood cancers, as a group, have better
outcomes than adult cancers. Because of the significant differences
that exist between adult NHL and childhood NHL, it is crucial to
find a designated pediatric cancer center for advice and treatment
and to use childhood-specific NHL information for reference.
This guide is divided into seven chapters. The material provides
an overview of lymphoma and discusses: the different subtypes of
lymphoma most common among children and teens, how lymphoma
is diagnosed, the importance of clinical trials, available treatment
options, supportive care issues, how to cope with the diagnosis, and
the long-term and late effects that result from lymphoma treatments.
Understanding Childhood Non-Hodgkin Lymphoma 1
Please refer to our website for additional
and updated information.
lymphoma.org
2 Understanding Childhood Non-Hodgkin Lymphoma
1
Chapter 1
Cancer Overview
This chapter will present a broad overview of cancer and, more
specifically, non-Hodgkin lymphoma. Childhood lymphomas are
divided into two categories: Hodgkin lymphoma (HL) and nonHodgkin lymphoma (NHL). This chapter will focus exclusively
on describing the biology of NHL in childhood.
Cancer Overview
The human body is composed of millions of cells that grow and
divide in an orderly fashion to support thousands of biological
functions. Cells divide routinely to replace cells that are damaged
or dying. Cancer results from an uncontrolled growth and spread of
abnormal cells. Cancer cells develop when there is damage to the cell’s
DNA (the hereditary material found in every cell). This damage can
be caused by an inherited genetic abnormality and/or exposure to
something in the environment, such as smoking. The body’s immune
system usually destroys damaged cells, but sometimes these abnormal
cells evade the body’s defenses and grow uncontrollably, eventually
forming a cancerous tumor.
Lymphoma Overview
Lymphoma, a type of blood cancer, is more common in adults than
in children. Approximately 98 percent of all NHLs occur in adults,
with only 1.7 percent occurring in those under the age of 20. In
children, lymphoma is the third most common cancer. Lymphoma
usually develops when a genetic error, or mutation, occurs within
a lymphocyte (a white blood cell), causing the abnormal lymphocyte
to duplicate faster, or live longer, than a normal lymphocyte. Cancerous
lymphocytes can travel to many parts of the body, through the blood
stream and the lymphatic system, and form tumors.
Understanding Childhood Non-Hodgkin Lymphoma 3
Anatomy of the Immune System
The immune system is the body’s defense against outside invaders.
Tonsils
and
adenoids
Lymph nodes
Thymus
Lymph nodes
Lymph nodes
(epitrochlear)
Spleen
Peyer’s
patches
(inside the
abdomen)
Appendix
Bone
marrow
Lymph nodes
Lymphatic vessels
4 Understanding Childhood Non-Hodgkin Lymphoma
1
Immune System Invaders
Many of these invaders come from outside the body. The immune system is the
body’s defense. It acts like a shield to detect and defeat these invaders.
Bacteria
Viruses
Parasites
Fungi
Pollution
Toxins
How Cancer Forms Inside the body
Sometimes the threat comes from within the body. Cancer occurs when
abnormal cells cannot be controlled and continue to grow and multiply.
Abnormal
Cells Evade the
Immune System
Abnormal
Cells Multiply
(Cancer)
Tumors May Form
(Groups of
Abnormal Cells)
Understanding Childhood Non-Hodgkin Lymphoma 5
The Lymphatic System
The lymphatic system is a circulatory system made up of a series of
thin tubes called lymph vessels, which branch out like blood vessels
into all tissues of the body. Lymph vessels carry lymph, a fluid that
contains lymphocytes. Within this vast network of vessels are groups
of small, bean-shaped organs called lymph nodes. Thousands of
lymph nodes are found throughout the body, including the neck,
armpits, groin and elbows. Lymph fluid flows through lymph
nodes and specialized lymph tissues, such as the spleen, tonsils, bone
marrow and thymus gland. Lymph nodes filter lymph fluid, removing
bacteria, viruses and other foreign substances from the body.
How Lymphocytes Work
Lymphocytes, a type of white blood cell, are made in the bone marrow,
spleen and lymph nodes, and circulate in the blood and lymph vessels.
There are two main types of lymphocytes: B-lymphocytes and
T-lymphocytes. Each type of lymphocyte plays a role in helping the
body fight infections.
Non-Hodgkin Lymphoma Overview
The two main forms of lymphoma are Hodgkin lymphoma and
non-Hodgkin lymphoma (NHL). The World Health Organization
has identified six types of Hodgkin lymphoma and 61 types of NHL.
Although the various types of NHL have some things in common,
such as their lymphatic origin, they differ in their appearance under
the microscope, the proteins found on the surface of the cancer cells,
their growth patterns and their impact on the body. Different forms
of NHL require different therapies.
Non-Hodgkin lymphoma has grown from being a relatively uncommon disease to being the fifth most common cancer in the United
States, nearly doubling in incidence since the early 1970s. According
to the American Cancer Society, over 65,000 new cases of NHL are
diagnosed annually in the United States.
6 Understanding Childhood Non-Hodgkin Lymphoma
1
Non-Hodgkin lymphoma is divided into two major groups: B-cell
lymphomas and T-cell lymphomas. B-cell lymphomas develop from
abnormal B-lymphocytes (“B” because B-lymphocytes come from the
bone marrow) and account for 85 percent of all NHLs. T-cell lymphomas develop from abnormal T-lymphocytes (“T” because normally
T-lymphocytes spend part of their lifespan in the thymus gland, a
small organ in the chest) and account for the remaining 15 percent
of NHLs.
Common Types of Childhood Non-Hodgkin Lymphoma
There are many different types of NHL. Correctly identifying or
diagnosing the type of lymphoma a child has is critical because an
accurate diagnosis allows the physician to select the most appropriate
treatment for the child. (Diagnostic tests are described in Chapter 2.)
Childhood NHLs can be broadly divided into four categories:
1. Lymphoblastic Lymphoma
Lymphoblastic lymphoma is a type of NHL. However, this disease
is often treated using protocols originally developed for a specific
type of leukemia (a different form of blood cancer), called acute
lymphoblastic leukemia. The survival rate for children with advanced
stage lymphoblastic lymphoma is 60 percent to 80 percent.
2. Mature B-cell NHL
Burkitt Lymphoma
Burkitt lymphoma is an aggressive B-cell NHL that occurs in children
and young adults far more commonly than in older adults. It accounts
for approximately 50 percent of childhood NHL in the United States.
There are three main types of Burkitt lymphoma: sporadic, endemic
and immunodeficiency-related disease. While sporadic Burkitt
lymphoma occurs throughout most of the world, endemic Burkitt
lymphoma is found mostly in Africa, with the vast majority of cases
associated with the Epstein-Barr virus (EBV). Immunodeficiencyrelated Burkitt lymphoma is diagnosed most often in people with
Understanding Childhood Non-Hodgkin Lymphoma 7
Common Types of Childhood Non-Hodgkin Lymphoma
Childhood NHL
Lymphoblastic
Lymphoma
Mature B-Cell
Lymphoma
Diffuse Large BCell Lymphoma
(DLBCL)
Anaplastic Large
Cell Lymphoma
(ALCL)
Other Rare
Subtypes:
(PTCL/NK)
Burkitt
Lymphoma
congenital immunodeficiency or those infected with HIV. Common
sites of disease include the jaw, central nervous system, bone marrow,
bowel, kidneys, ovaries and testes.
Burkitt lymphoma is considered one of the fastest growing cancers—the
number of tumor cells doubles every 24 hours. Despite its fast growth,
this type of lymphoma is often very responsive to chemotherapy. This is
because the faster a tumor cell divides the more likely it is to be killed
by treatment. Therefore, the treatments are usually very intense, with
only a short time interval between courses of chemotherapy, so that
tumors do not re-grow. The overall survival rate for children diagnosed
with Burkitt lymphoma in the United States is 90 percent.
Diffuse Large B-cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most common form
of NHL in adults, but it is relatively rare in children. The disease is an
aggressive (fast-growing) lymphoma and can arise in the lymph nodes
or outside of the lymphatic system. It may be localized or generalized
(spread throughout the body). Despite being an aggressive lymphoma,
DLBCL is usually curable. Survival rates are extremely high for
children diagnosed with DLBCL.
8 Understanding Childhood Non-Hodgkin Lymphoma
1
3. Anaplastic Large Cell Lymphoma
Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell
lymphoma comprising 10 percent to 30 percent of all lymphomas
in children and 3 percent of all lymphomas in adults. It is the most
common T-cell malignancy in children. Anaplastic large-cell
lymphoma can appear in the skin or in other organs throughout the
body, also known as systemic ALCL. Patients with systemic ALCL
are divided into two groups, depending on the expression of a protein
called anaplastic lymphoma kinase (ALK). The prognosis is different
based on whether a patient is ALK positive (expresses the protein)
or ALK negative (does not express the protein). While both subtypes
are treated with chemotherapy, ALK positive disease often responds
permanently to chemotherapy, putting most patients in long-term
remission or cure. A larger percentage of patients with ALK negative
ALCL will relapse and potentially require more aggressive chemotherapy.
4. Other Rare Subtypes
Other rare subtypes of childhood NHL exist. For more information
on these rare subtypes, consult a physician specializing in pediatric
lymphomas.
The Causes of Non-Hodgkin Lymphoma in Children
Although the exact causes of NHL remain unknown, some common
factors appear to have an impact on risk. The disease is more common
among people with depressed immune systems and those exposed
to environmental carcinogens, pesticides, herbicides, viruses and
certain bacteria.
The risk for developing lymphoma may be higher in individuals who:
•have a family history of NHL
•are immune-deficient due to either an inherited immunodeficiency
(such as common variable immunodeficiency or autoimmune
lymphoproliferative syndrome, also known as ALPS) or an infection
(such as human T-lymphotropic virus type 1, also known as
HTLV-1, or HIV/AIDS)
Understanding Childhood Non-Hodgkin Lymphoma 9
•have received an organ transplant
•have been exposed to chemicals such as pesticides, fertilizers or
organic solvents for a long period
•have been infected with viruses such as Epstein-Barr (which causes
mononucleosis), which is associated with Burkitt lymphoma
It is important to note that having one or more of these risk factors
does not mean a person will develop NHL. In fact, most people with
risk factors never develop the disease, and most of those diagnosed
with lymphoma have never been exposed to clearly identifiable risk
factors. While researchers do not know why NHL develops, they do
know that it cannot be caused by injury or caught from someone
who has the disease.
Please refer to our website for additional
and updated information.
lymphoma.org
10 Understanding Childhood Non-Hodgkin Lymphoma
2
Chapter 2
Diagnosing Childhood NHL
Determining what type of lymphoma a patient has and where it is
located in the body is important information for both the physician
and the patient. An accurate diagnosis of childhood non-Hodgkin
lymphoma (NHL) requires a number of tests. Physicians may use some
or all of the following tests as well as the patient’s medical history
and results from the physical examination to assess the best course of
treatment: (1) blood tests, (2) biopsy, (3) imaging tests, (4) bone marrow
examination and (5) lumbar puncture. Why these tests are needed and
how they are performed will be described in this chapter.
Use of Conscious Sedation When Performing
Diagnostic Tests
Some of the tests described below can be painful, including biopsies,
bone marrow biopsies and lumbar punctures (note that blood work
does not involve pain beyond a needle prick). To prevent children from
suffering, some physicians use a technique called “conscious sedation.”
Conscious sedation drugs create an altered state of consciousness, like
sleeping lightly, to minimize pain and discomfort. During conscious
sedation, a patient can usually speak and respond to verbal cues.
Patients that are given these drugs usually experience a brief period
of amnesia, erasing any memory of the procedure. Parents should
note that these drugs are administered only by physicians with
specific training in conscious sedation. Pediatricians, oncologists
or anesthesiologists may perform the sedation. These healthcare
professionals carefully monitor breathing and vital signs throughout
the procedure. Children undergoing conscious sedation will never
be left unmonitored.
Understanding Childhood Non-Hodgkin Lymphoma 11
What You Should Know If Your Child
Receives Conscious Sedation
Planning for Conscious Sedation
•Children should not eat anything several hours before receiving conscious
sedation. The exact number of hours varies by institution. Your child’s oncologist
will inform you of the instructions.
What to Expect After Conscious Sedation
•Your child will not remember anything from the procedures.
•Most children wake up quickly, and recovery from conscious sedation is fairly rapid.
Most children recover in one hour or less.
•Children can resume eating immediately after conscious sedation.
Common Diagnostic Tests
Blood Tests
A complete blood count (CBC) may be performed to determine
whether different types of blood cells, including red blood cells, white
blood cells and platelets, are normal in number and appearance when
viewed under the microscope. Abnormalities in these blood cells may
be the first sign of lymphoma.
Various blood tests may also be performed to determine whether
lymphoma is affecting certain tissues or organs, such as the liver or
kidneys, or to identify specific substances circulating in the blood that
may help physicians select the most appropriate treatment option. For
example, levels of the enzyme lactate dehydrogenase (LDH) and/or the
protein beta (2) microglobulin (B2M) are commonly measured because
higher levels of either or both suggest that the lymphoma may be more
aggressive, indicating that a more intensive treatment may be needed.
Biopsy
A biopsy is a procedure in which a piece of tissue from an area of
suspected disease is removed from the body and examined under a
12 Understanding Childhood Non-Hodgkin Lymphoma
microscope in order to determine which type of cancer the patient
has. The type of biopsy performed often depends on the location of
the lymphoma.
Excisional Biopsy
During an excisional biopsy, an entire lymph node or a large portion
of it is surgically removed. This technique is often preferred because
attempting to make a diagnosis from a small tissue specimen may
lead to errors in diagnosis and sub-optimal therapy. Surgery may be
necessary to obtain a sufficient sample of the tumor for examination.
Needle Biopsy
When tumors or lymph nodes are in locations that are difficult to
biopsy (e.g., deep in the chest or abdomen), a needle biopsy (also
called a core biopsy) may be performed. For this type of biopsy, a
needle is inserted into a lymph node suspected of being cancerous
and a small tissue sample is removed.
Fine Needle Aspirate
A fine needle aspirate (FNA) uses a very small gauge needle to collect
a sample of cells from a cancerous lymph node. Such needle biopsies
are more often used to confirm a relapse rather than an initial diagnosis
because they generally do not produce sufficient tissue to establish a
precise diagnosis.
After a biopsy is performed, the sample is examined by a pathologist
(a physician who studies tissues and cells to identify diseases) who
develops a report. The oncologist uses this report along with results
from other tests to confirm the diagnosis. However, if the pathologist’s
interpretation of the biopsy is uncertain, the report should be reviewed
by a hematopathologist (a pathologist who focuses on the identification of hematologic malignancies).
Bone Marrow Biopsy
Lymphoma is often found in the bone marrow, a material found
within bones, which contains cells that develop into red blood cells,
Understanding Childhood Non-Hodgkin Lymphoma 13
2
white blood cells and platelets. To determine whether lymphoma is
present in the bone marrow, a physician will insert a hollow needle
into an area of the pelvic bone and extract a small tissue sample.
The sample is then studied for signs of lymphoma by a pathologist.
Lumbar Puncture
NHL can sometimes spread to the nervous system. When this happens,
the fluid present around the spinal cord and the brain (cerebrospinal
fluid) may be abnormal and contain cancer cells. To determine whether
this has occurred, the physician may recommend a test called a spinal
tap or a lumbar puncture, in which a thin needle is inserted into the
lower back. A small sample of fluid is then removed, and the cerebrospinal fluid is examined for chemical content and abnormal cells.
Imaging Tests
Physicians will often order imaging tests that provide pictures of areas
inside the body. Most of these tests are painless. Some young children
will be sedated if they are not able to lie completely still for the scans.
Several types of imaging procedures may be needed to help best
evaluate lymphoma, including the following:
X-rays
X-rays use radiation to take pictures of areas inside the body. For
children with NHL, a chest X-ray is the most common type of X-ray.
CT (computerized axial tomography) Scan
A CT scan takes X-rays from different angles around the body.
The pictures obtained are then combined using a computer to give a
detailed image. People with NHL often have CT scans of the neck,
chest, abdomen and pelvis. These tests are useful in determining how
many lymph nodes are involved, how large they are and whether
internal organs are affected by the disease.
14 Understanding Childhood Non-Hodgkin Lymphoma
MRI (magnetic resonance imaging)
An MRI is similar to a CT scan, but uses magnets and radiofrequency
waves instead of X-rays. An MRI can provide important information
about tissues and organs, particularly the nervous system, which is
not available from other imaging techniques. Because this testing
technique creates clear images of the bones, brain and spinal cord,
an MRI may be ordered to see whether the lymphoma has spread
in these areas.
PET (positron emission tomography) Scan
PET scans have largely replaced gallium scans (in which radioactive
gallium was injected into the body) in many cancer centers, because
the technique is more convenient and more sensitive. This test evaluates
NHL activity in all parts of the body. To perform the test, a radioactive substance is first injected into the body. A positron camera is then
used to detect the radioactivity and produce cross-sectional images
of the body. Unlike gallium scans, which are used primarily to detect
response to treatment, PET scans are useful for both determining
how much disease is present (staging) and how well it is responding
to treatment. While CT scans show the size of a lymph node, gallium
and PET scans show if the lymph node is active (still has disease).
Today, CT and PET scans are often being combined into one test
(CT/PET).
Ultrasound Exam
An ultrasound utilizes high-energy sound waves to create an
image called a sonogram. This technique can be used for examining
the abdomen.
Staging
Childhood NHL is divided into four stages, based on how far the
disease has spread in the body. Staging the disease helps physicians
predict outcome (prognosis) and determine the most appropriate
treatment approach.
Understanding Childhood Non-Hodgkin Lymphoma 15
2
Staging
Stage
Description
IThe lymphoma is found in one group of lymph nodes or
one area outside the lymph nodes. To be identified as
Stage I, the lymphoma cannot appear in the abdomen or
mediastinum (the area between the lungs).
IIThe lymphoma is found in: (1) one group of lymph nodes
and lymph nodes nearby; (2) two or more areas on
the same side of the diaphragm; or (3) the stomach or
intestines, but can be completely removed through surgery.
IIIThe lymphoma is found: (1) on both sides of the diaphragm;
(2) in the chest; (3) in the abdomen, but cannot be
completely removed through surgery; or (4) near the spine.
IVThe lymphoma is found in the: (1) bone marrow;
(2) brain; or (3) cerebrospinal fluid.
Childhood NHL may also be categorized and treated according to the
ABC grouping system. The number of chemotherapy cycles administered may differ by group.
•Group A: Tumors that can be completely removed.
•Group B: Tumors occurring in the chest or abdomen that cannot
be surgically removed.
•Group C: Tumors occurring in the bone, bone marrow, brain or
other location outside of the lymphatic system.
16 Understanding Childhood Non-Hodgkin Lymphoma
Chapter 3
Childhood Cancer Clinical Trials
Clinical trials are research studies designed by physicians and
researchers to answer questions about new treatments or new ways
of using existing treatments. The majority of children with cancer are
treated in clinical trials. Over the past several decades, high clinical
trial enrollment has led to rapid increases in the survival rates of
children and teens with cancer. This chapter will discuss the unique
features of childhood cancer clinical trials, describe the process of
enrolling children in clinical trials, provide an overview of clinical
trials and identify resources for more information.
Unique Features of Childhood Cancer Clinical Trials
Today, over 80 percent of children diagnosed with cancer will be
cured. This is a stark contrast to 50 years ago, when few children
survived childhood cancer. Several strategic decisions within the
scientific community led to this rapid increase in survival rates,
including the following:
•Collaboration: Progress in research only occurs when adequate
numbers of patients are enrolled in clinical trials. For example,
because childhood cancers are so rare, if one institution tried to
enroll the relatively small number of patients with Burkitt
lymphoma into a trial it would take decades before enough patients
could be enrolled. Therefore, to make significant advances in the
understanding and treatment of childhood cancers more quickly,
the decision was made to establish strong clinical trial collaborations
across institutions and countries.
•Design: Clinical trials for children are based on what physicians and
researchers know to be the “gold standard” of care for a particular
subtype. Therefore, each clinical trial is designed to improve on the
Understanding Childhood Non-Hodgkin Lymphoma 17
3
best therapies that modern medicine currently has to offer.
Improvements may include how to give smaller doses or how to
maximize effectiveness by adding an additional drug to an already
effective regimen.
•Consistency of Treatment: Due to the collaboration described
above, the majority of children with the same type of non-Hodgkin
lymphoma (NHL) will receive the same treatment regimen. For
example, a child diagnosed with DLBCL in Kansas will likely receive
the same treatment as a child diagnosed with DLBCL in Washington.
When all children with lymphoma are treated as a group, researchers
can learn things more quickly.
Children’s Oncology Group Trials
The success of the strategies listed above serves as the foundation
for how children diagnosed with lymphoma are treated today. The
Children’s Oncology Group (COG) consists of 5,000 childhood
cancer experts from more than 200 institutions throughout the United
States. COG designs, implements and evaluates the large-scale clinical
trials conducted with children diagnosed with cancer today. Therefore,
it is very likely that a child diagnosed with lymphoma will be treated
on a protocol (term used to describe the details of a research study)
designed by COG.
It is important to note that COG trials for lymphoma often continue
for five to ten years after they are initiated. Therefore, it is likely that
the majority of children treated within a specific time period will
receive the same treatment.
Enrolling Children in Clinical Trials
Pediatric hematologists/oncologists will discuss the details of the
specific trial and why it is most appropriate for the patient. Once
the physician has explained the details of the trial, the parent(s) will
be asked to give “informed consent” for their child to be “enrolled”
in the study. These details will include:
18 Understanding Childhood Non-Hodgkin Lymphoma
•Name of the trial
•Drugs used in the trial
3
•Schedule of treatment
•What to expect during treatment
•Long-term effects of treatment
For children under the age of 18 years, parents must provide consent
for treatment. At some institutions, children over the age of 14 must
also consent to receiving treatment. This also applies to children as
young as seven at some institutions.
It is important to remember that hundreds of physicians from around
the country come together to design each trial and participants are
carefully monitored while enrolled. Every trial must be approved by
institutional review boards (IRBs) to ensure that the trial is ethical
and that patients are kept safe.
Clinical Trial Process
Diagnostic Tests
Conducted and
Evaluated
Physician Evaluates
Which Clinical Trial
is Most Appropriate
Children are Closely
Monitored
Throughout Treatment
Treatment Begins
Physician Discusses
Details of Clinical
Trial with Parents
(process known as
“informed consent”)
Parents Consent on
Behalf of Their
Children
Understanding Childhood Non-Hodgkin Lymphoma 19
Understanding the Clinical Trial Process
There are hundreds of NHL clinical trials now underway in hospitals,
cancer centers and physicians’ offices around the country. The
government, pharmaceutical and biotechnology companies, universities
and physician groups often sponsor clinical trials. However, in
childhood lymphoma trials, the majority are coordinated through
the COG, as described above.
Clinical Trial Phases
Clinical trials are divided into three phases, as described below.
Phase I
Phase I studies (first in human studies) are designed to assess the
maximum tolerated dose (MTD), frequency of treatment and overall
safety of the drug in a small number of patients.
Phase II
Once the therapy dose is determined and shown to be safe in a phase I
trial, it is then ready to be tested in a phase II study. Phase II studies
aim to establish whether the therapies have any evidence of effectiveness
in a larger group of patients with a particular type of cancer (e.g.,
Burkitt lymphoma).
Phase II studies might be used to generate preliminary data on a
drug or to confirm data to obtain United States Food and Drug
Administration (FDA) approval. Phase II studies also investigate
whether a therapy already approved for one type of disease is
effective treatment for another.
Phase III
Phase III trials are performed to determine whether the treatments
developed in phase I and II studies are better than what is currently
considered the “standard of care” for a specific disease. Phase III studies
often require a large number of patients. Once a patient elects to enroll
in a phase III study, he or she is assigned to one of two groups in a
process called “randomization.” In randomization, a computer assigns
20 Understanding Childhood Non-Hodgkin Lymphoma
the treatment the patient is to receive. One group receives the standard
therapy and the other group receives the experimental treatment. It is
important to remember that this randomization process is done so that
each treatment arm will have patients with similar characteristics and
be free of bias. The randomization in phase III trials allows researchers
to determine whether or not the new treatment is more effective or less
toxic than the standard of care.
Use of a Placebo in Phase III Trials
A placebo, or sugar pill, is an inactive ingredient that is used is some
types of clinical trials to ensure that the test results are unbiased. It is
important to note that clinical trial participants will never receive a
placebo in a phase III trial if standard therapy exists. Patients would
only potentially receive a placebo if there were no standard therapies
to test against. Placebo-controlled trials are never done in a manner
to deny patients an effective therapy. In trials that include placebo
medications for some patients, all patients are notified in advance
about the possibility of receiving a placebo.
The Cost of Being in a Clinical Trial
Clinical trials are very expensive undertakings for the study sponsor.
In children’s cancer the sponsor is usually the Children’s Oncology
Group (i.e., funded by the federal government). Patient costs vary
depending on the study, who is sponsoring the trial, what portion
of the trial-related expenses the sponsor will cover and the patient’s
health insurance coverage. Some health insurance and managed
healthcare providers will pay for the basic medical procedures
associated with the trial, such as lab tests, scans and hospitalization
when required, while others may define clinical trials as “experimental”
or “investigational” and not cover some of the routine costs, such as
physician visits, tests or treatments. The costs vary depending on the
study and the health plan. Medicare provides coverage for patient
care associated with government-sponsored clinical trials.
Understanding Childhood Non-Hodgkin Lymphoma 21
3
If a patient is taking part in a National Cancer Institute (NCI)
trial being conducted at the National Institutes of Health (NIH) in
Bethesda, Maryland, the NCI will pay for the study drug and the
costs related to the study. A stipend for travel, food and lodging is
also provided. Some cancer centers provide financial assistance or
discounted rates for room and board and have special research units
that will pay for study-related costs. Some organizations provide
financial assistance for treatment-related expenses.
Parents or patients should ask the physician what clinical trials
would be most appropriate. Here are some additional ways to find
information:
•Contact the Lymphoma Helpline at the Lymphoma Research
Foundation at (800) 500-9976 to request a clinical trial search.
•Cancer centers in your area may also have information about trials.
•Coalition of Cancer Cooperative Groups (CancerTrialsHelp.org).
•NIH websites (Cancer.gov and Clinicaltrials.gov).
Please refer to our website for additional
and updated information.
lymphoma.org
22 Understanding Childhood Non-Hodgkin Lymphoma
Chapter 4
Treatment
Treatment options for children with non-Hodgkin lymphoma (NHL)
are quite different from those used to treat adults with NHL. The most
common treatment option for children with NHL is chemotherapy.
As described in the previous chapter, because of the rarity of childhood
cancers, most children diagnosed at any given point in time are treated
in a similar manner on a specific clinical trial (also known as a
“protocol”). This chapter will discuss information parents need
to know about common childhood NHL chemotherapy regimens,
including how it is given and what to expect. Other treatment options
will be presented.
Chemotherapy
Chemotherapy (“chemo”) is treatment with drugs (as opposed to
radiation, for example).
Combining Chemotherapy Drugs
Chemotherapy for NHL often consists of giving several drugs together
(combination chemotherapy) in a defined way (schedule), called a
treatment regimen. Drug combinations are used because different
medications damage or kill cancer cells in different ways, making them
more vulnerable to the treatment. Combining chemotherapy drugs
provides a more effective way to kill tumor cells, because using the
drugs together greatly augments the impact of each drug (called
synergism). In addition, when some drugs are added together in lower
doses, it helps reduce the likelihood of side effects without reducing
the overall amount of effective chemotherapy. For example, the
combination of three drugs (cyclophosphamide, vincristine, and
prednisone) is referred to as COP. This combination uses drugs that
are given in somewhat less toxic amounts while sustaining a full or
Understanding Childhood Non-Hodgkin Lymphoma 23
4
augmented (synergistic) capacity to destroy NHL. Another reason
for combination chemotherapy is to prevent the emergence of
drug resistance.
Chemotherapy Cycles
Chemotherapy is usually given in cycles in which each treatment
is followed by a period of rest and recovery. Together, each period
of treatment and non-treatment is called a “chemotherapy cycle.”
Clinical trials have determined how often chemotherapy should
be given to kill the most tumor cells while minimizing side effects.
However, timing may vary depending on the specific treatment. Most
childhood chemotherapy cycles are given every three to four weeks.
Also, most regimens include frequent vincristine (Oncovin) as well
as oral steroids within the three week cycles.
Chemotherapy Cycles
Most children present
with symptoms and
advanced disease
Draw blood on
initial visit
Scans
Child allowed to go
home and come to
clinic for chemotherapy
(goal: maintain as
much normalcy
as possible)
Admitted to hospital
and given initial
chemotherapy
24 Understanding Childhood Non-Hodgkin Lymphoma
How Chemotherapy Is Given
Depending on the regimen, chemotherapy may be administered in pill
form, as an injection or as an intravenous drip. For patients receiving
intravenous drugs (ones that are given through a vein) for multiple
cycles, an intravenous catheter may be inserted to make it easier to
give drugs. Catheters may be left in place temporarily or permanently.
There are several types of implanted catheters, which are inserted
using a minor surgical procedure. One type, called a Hickman-Broviac
catheter, consists of one to three tubes inserted through the chest wall
into a vein. Six to twelve inches of tubing remain outside the skin. The
main advantage of this type of catheter is that blood tests can be drawn
and drugs given without having to pierce the skin. Disadvantages
include: (1) the possibility of infection if the catheter is exposed to any
bacteria found on a needle during a blood draw or if the catheter is
not cared for properly, and (2) the tubes on the outside of the body
make it more obvious that a catheter is in place. Patients with catheters
will receive specific instructions from their healthcare team regarding
proper care and cleaning.
Where Chemotherapy is Given
Some chemotherapy is given in the hospital (referred to as in-patient)
and some is given on an out-patient basis where the child lives at home
and comes to a clinic to receive the treatment. The goal is to maintain
as much normalcy as possible in the lives of children living with NHL.
Common Types of Chemotherapy Regimens Used to
Treat Childhood NHL
The most common types of chemotherapy regimens currently used
to treat childhood NHL are presented in the table on the next page.
It is important to remember that today’s science is moving very fast.
Therefore the chart in this chapter may not be entirely comprehensive
or accurate depending on when this information is being read (i.e.,
please refer to the date of print of this publication). Parents should
speak to their child’s oncologist to see if any trials have closed or if
any new trials have opened.
Understanding Childhood Non-Hodgkin Lymphoma 25
4
Lymphoma
Subtype
Protocol Name
Drugs Used
Lymphoblastic
lymphoma
1.Berlin-FrankfurtMunster (BFM) Study
1.BFM Study
• Vincristine
• Corticosteroids
• Anthracyclines
• L-asparaginase
• 6-thioguanine
2.COPG A5971:
A randomized Phase
III study for the
treatment of newly
diagnosed
disseminated
lymphoblastic
lymphoma or
localized
lymphoblastic
lymphoma
2.COPG A5971
• Vincristine
• Daunorubicin
• L-asparaginase
• Cytarabine
• Methotrexate
• Prednisone
• 6-Mercaptopurine
• Cyclophosphamide
• Thioguanine
• Doxorubicin
• Dexamethasone
1.Berlin-FrankfurtMunster (BFM) Study
1.BFM Study
• Vincristine
• Corticosteroids
• Anthracyclines
• L-asparaginase
• 6-thioguanine
2.French LMB
2.French LMB (COPAD
or COPAD-M)
• Cyclophosphamide
• Vincristine
• Prednisone
• Methotrexate
• Doxorubicin
• Hydrocortisone
• Cytarabine
• Leucovorin
Anaplastic
large cell
lymphoma
Treatment protocols
may vary by institution.
One potential
combination:
• Vincristine
• Doxorubicin
• Methotrexate
• Prednisone
• 6-Mercaptopurine
Rare Subtypes
Treatment protocols
may vary by institution.
Diffuse large
B-cell
lymphoma
and
Burkitt
lymphoma
26 Understanding Childhood Non-Hodgkin Lymphoma
Details
No Children’s Oncology
Group (COG) clinical
trials were open at the
time of this guide’s
printing.
COG recently completed
a pilot study
incorporating rituximab
(Rituxan) into the LMB
backbone.
Treatment can range
from 24 months to
several years.
Discuss treatment
options with physician.
Radiation
Radiation is not a common treatment option for children with NHL.
Most subtypes of NHL seen in children are “chemo-sensitive,” which
means they respond well to chemotherapy and do not require radiation.
What Happens If Relapse Occurs?
Secondary Therapies
Every parent’s concern during their child’s treatment is “what happens
if this treatment does not work?” This is a very normal fear, and one
that is shared by most people who care for someone undergoing cancer
treatment. The fact is that the large majority of children diagnosed with
NHL today will be cured by the first treatment regimen they are given.
If a child does not respond to the first treatment regimen they receive,
their disease may be considered “refractory” (resistant to treatment).
A “relapse” (sometimes called a recurrence) is when a child’s disease
returns after treatment. Most relapses happen shortly after treatment,
decreasing in frequency as time passes after the completion of therapy.
If a relapse is going to occur in a child with B-cell NHL, it will generally
happen within the first 18 months. If a relapse is going to occur in a
child with T-cell NHL, it will generally happen early. However, there are
some children who may experience a recurrence three to four years later.
Close monitoring and early identification of relapse is important.
All patients will be carefully watched for five years following diagnosis. Parents whose child experiences a relapse or refractory diagnosis
should not lose hope. Complete remission may still be achieved
following a diagnosis of relapsed or refractory lymphoma.
The type of treatment used for children who relapse or have refractory disease depends on two factors: (1) the disease type (e.g., Burkitt,
anaplastic large cell lymphoma) and (2) stage. Treatments used after
the first treatment (also known as primary treatment) are often
referred to as “second line” or “secondary” treatments. These treatments are described on the following pages.
Understanding Childhood Non-Hodgkin Lymphoma 27
4
Chemotherapy Plus Rituximab (Rituxan)
For children with B-cell NHL, most secondary treatment options
include a combination of chemotherapies plus rituximab (Rituxan),
which is a monoclonal antibody—a drug that selectively targets
specific cancerous B-cells within the body. A commonly used
secondary treatment option is RICE, which includes rituximab
(Rituxan) plus a combination of chemotherapies (ifosfamide,
carboplatin, etoposide).
Rituximab (Rituxan) was the first monoclonal antibody approved for
cancer therapy by the United States Food and Drug Administration
(FDA) as a single agent in the treatment of relapsed or refractory
adult lymphoma patients with CD20 positive, B-cell non-Hodgkin
lymphoma. This drug was subsequently approved for additional
indications by the FDA. It has not yet been approved for use in
children, but may be used to treat relapsed or refractory disease
in children with NHL.
Stem Cell Transplantation
Current Perspectives on Transplantation in Children with NHL
Physicians may consider stem cell transplants as a treatment option
for children who have relapsed or refractory NHL. Factors affecting
the success of transplants include: (1) type of disease and (2) disease
status. One of the largest transplant-specific studies to date examined
the records of 182 relapsed or refractory NHL patients who had
received either an autologous (using a child’s own stem cells) or
allogeneic (using cells from a sibling or unrelated donor). The study
found no difference between autologous and allogeneic transplantation
for children with Burkitt, DLBCL or ALCL. Therefore, autologous
transplants are more commonly used than allogeneic to treat these
three diseases. Some debate exists regarding which transplant is most
effective for lymphoblastic lymphoma and currently, either type may
be used, depending on an individual’s specific situation.
28 Understanding Childhood Non-Hodgkin Lymphoma
Understanding Transplantation
Bone marrow transplants are now called stem cell transplants because
they use three types of blood-forming stem cells:
•Bone marrow
•Peripheral (circulating) blood (also called peripheral blood stem
cells or PBSC)
•Cells collected from an umbilical cord after a baby is born
A transplant using any one of these cells can replace a child’s damaged
marrow with healthy blood-forming cells, resulting in a new blood
and immune system. With these new cells working in the child’s bone
marrow (the spongy material found inside our bones) the marrow can
once again form healthy:
•Red blood cells, which carry oxygen to all parts of the body
•White blood cells, which fight infections
•Platelets, which control bleeding by helping blood to clot
To get the child’s body ready for a transplant, he/she will receive
chemotherapy and/or radiation. This will destroy or suppress the
immune system. Physicians call this a preparative regimen, or conditioning. The new stem cells grow in the body, and take over the
blood-forming machinery in the marrow.
Because a transplant places great strain on a patient’s body, it is not
an option for everyone. Among the things to consider are age, medical
history, cancer stage, current medical condition and response to
previous therapy. In some patients, a reduced-intensity conditioning
regimen can be used, which lowers the strain on the body.
There are two types of stem cell transplants: allogeneic, in which
patients receive stem cells from another person, and autologous,
in which patients receive their own cells.
Understanding Childhood Non-Hodgkin Lymphoma 29
4
•Autologous Transplantation: In this procedure, a patient’s own stem
cells are removed—while the patient is in remission—and frozen.
When it is time for the transplant, the patient will receive very
high-dose chemotherapy and/or radiation, after which the thawed
stem cells are re-infused back into the patient’s body. The cells go
into the bloodstream, where they make their way to the bone
marrow where they belong.
•Allogeneic Transplantation: In allogeneic transplantation, a donor’s
stem cells are used. Finding a compatible donor is important because
the body will reject stem cells if they are too different from the
patient’s own cells. The new cells may also react against the patient’s
body, a condition called graft-versus-host disease (GVHD). However,
allogeneic transplants have one important potential advantage: the
donor’s immune cells can destroy any lymphoma cells in the body
not killed by the conditioning regimen.
Very sensitive tests are used to see if someone is a suitable transplant
donor. The best candidates are siblings, but there is only a one in four
chance that a sibling will be a close enough match for a transplant.
If no family members are a match, a search for an unrelated donor
(or a cord blood unit) in a large registry of volunteers can be initiated.
For more information on transplantation, please visit the National
Marrow Donor Program’s website at marrow.org.
30 Understanding Childhood Non-Hodgkin Lymphoma
How Transplants Are Done
Transplants are performed in four steps:
Step 1: Collecting stem cells
Stem cells are collected (harvested) in one of three ways:
• Bone Marrow - To harvest bone marrow, physicians use a hollow needle inserted
into the hip bone. This is done in an operating room and the donor receives general
anesthesia. Once the marrow is harvested, it is either quickly transported to the
waiting patient receiving an allogeneic transplant or frozen until needed for an
autologous transplant.
• Peripheral Blood Stem Cells (PBSC) - The second, and now more common way
to collect stem cells from an adult, is by harvesting PBSCs from the blood. In this
case, the donor takes a drug called a growth factor that causes the stem cells in the
marrow to move into the peripheral blood. The stem cells are then removed from the
donor’s blood using a process called apheresis. Blood is taken from a vein in one of
the donor’s arms and passes through an apheresis machine, which separates out
the stem cells. The rest of the blood, minus the stem cells, is returned to the donor
through a different vein. This is done while the donor (in an allogeneic transplant)
or patient (in an autologous transplant) is awake.
• Cord Blood - Cord blood is collected at birth from a newborn’s umbilical cord. After
the delivery is complete, trained technicians pierce the base of the cord with a sterile
needle and drain the blood into a collection bag. The cord blood cells are then
processed, tested and frozen until needed for a patient.
Step 2: Processing or preserving stem cells
In autologous transplants, marrow and PBSC collections are frozen for later re-infusion.
In allogeneic transplants, cells undergo minimal processing and are given to the
waiting patient as soon as possible. Cord blood cells (almost exclusively used in
allogeneic transplants) are shipped frozen to the patient’s hospital, where they are
kept until the patient is conditioned and ready to receive them.
Step 3: Pre-transplant conditioning
Before receiving the cells, patients are conditioned with chemotherapy and/or
radiation. High-dose conditioning is always used in autologous transplants. In
allogeneic transplants, the type and dose of the conditioning depends on the stage
and type of disease, whether it is a recurrence and the condition of the patient.
Step 4: Infusing the stem cells
When the patient is ready, the stem cells are infused into the patient’s bloodstream
through a needle inserted into a vein in one arm. The infused cells travel through the
bloodstream, pass through the bones and implant themselves in the marrow. There,
they slowly begin to make healthy new blood cells. Over time, the marrow produces
enough healthy cells to completely restore the patient’s blood and immune system.
Until these new cells are created, patients are more susceptible to infections.
Understanding Childhood Non-Hodgkin Lymphoma 31
4
Novel Therapies
It is an exciting time in lymphoma drug development. Now, more
than ever before, drugs are being approved by the United States
Food and Drug Administration (FDA) to treat lymphoma in
adults. Many of the new drug approvals are not chemotherapy
agents, but rather attack the lymphoma using novel techniques.
The differences in biology between children and adults make it
difficult to rely on data from drugs investigated only with adult
populations. Therefore, studies are now underway to examine
many of the novel therapies (already approved and those still
under investigation) specifically with children. Some trials
specifically designed for adults will lower their minimum age
limit to sometimes include children over the age of 12, as well.
The following chart describes some of these treatment options.
It is critical to remember that today’s science is moving very fast.
Therefore, the charts in this chapter may not be entirely comprehensive or accurate depending on when this information is being
read. Some treatments may be found to be ineffective. Others
may advance to the front-line setting. Please check with the
Lymphoma Research Foundation or your physician for additional
information and recent updates.
32 Understanding Childhood Non-Hodgkin Lymphoma
Agent
Predominant Mechanism
of Action
Comments
Monoclonal Antibodies
Rituximab
(Rituxan)
CD20 monoclonal antibody
Approved for B-cell NHL in adults;
under investigation in children
Epratuzumab
CD22 monoclonal antibody
Ongoing clinical trials in adults
with NHL and children with acute
lymphoblastic leukemia (ALL)
SGN-35
CD30 monoclonal antibody
Ongoing separate clinical trials
in adults and children
Nelarabine
Nucleoside analog
Ongoing clinical trials in adults
and children with lymphoblastic
lymphoma
Clofarabine
Deoxyadenosine analog
Clinical trials completed as well
as ongoing in children and adults
with acute lymphoblastic leukemia
(ALL) and acute myelogenous
leukemia (AML)
Forodesine
hydrochloride
Purine nucleotide phosphorylase
inhibitor
Phase I study complete in children
with T-cell cancers; being studied
in other B-and T-cell NHLs
Bortezomib
(Velcade)
Proteasome inhibitor
Approved for relapsed/refractory
mantle cell lymphoma in adults;
under investigation in children
Other
* For more information on any of the drugs included in this chart, visit lymphoma.org/booklets
to read the Understanding Non-Hodgkin Lymphoma: A Guide for Patients, Survivors and Loved
Ones or call the Lymphoma Research Foundation at (800) 500-9976.
Understanding Childhood Non-Hodgkin Lymphoma 33
4
Please refer to our website for additional
and updated information.
lymphoma.org
34 Understanding Childhood Non-Hodgkin Lymphoma
Chapter 5
Supportive Care
Children with non-Hodgkin lymphoma (NHL) may have side effects,
also called toxicity, from the cancer treatment they receive. Fortunately,
there are many effective ways to make them more tolerable. Parents
and patients should ask their healthcare team about possible
treatment side effects and inform the physician if the patient
experiences any. In many cases, side effects can be lessened with
medications or lifestyle changes. This chapter discusses some of the
more common treatment-related side effects and how they are treated.
Side Effects of Treatment
Some of the most common side effects of NHL treatment are described
below, along with strategies for minimizing their affect on children.
Decreased Blood Cell Production
Red blood cells, white blood cells and platelets are constantly being
produced in the bone marrow. Both chemotherapy and chemoimmunotherapy treatment may temporarily interfere with the ability
of the bone marrow to produce adequate numbers of blood cells.
When this occurs, it is called myelosuppression.
Anemia is the term used when myelosuppression causes a reduction
in the number of red blood cells. Anemia can cause people to feel very
tired, get headaches and have shortness of breath. Mild or moderate
anemia is common with many chemotherapy regimens, and treatment
with red blood cell transfusions may be necessary, depending on the
degree of anemia.
Neutropenia is the term used when myelosuppression causes a decrease
in neutrophils—the primary type of white blood cells found in the
blood. Because neutrophils play a very important role in fighting
Understanding Childhood Non-Hodgkin Lymphoma 35
5
infection, a low count increases a patient’s risk for developing a
serious or even life-threatening infection that may require hospitalization or antibiotic therapy. If the absolute neutrophil count (ANC) is
too low, the chemotherapy dosage may need to be reduced or treatment may be delayed rather than risk infection. The first sign of
infection may include fevers, chills or a general “unwell” appearance.
To prevent and control neutropenia, physicians will check patients’
white blood cell and neutrophil counts before and during each
chemotherapy cycle. When neutropenia threatens a patient’s ability
to receive the planned dose of chemotherapy, drugs such as filgrastim
(Neupogen), pegfilgrastim (Neulasta) or sargramostim (Leukine) can
be given after chemotherapy to reduce the duration and severity of
neutropenia. These drugs can sometimes cause bone pain. By keeping
the white blood count from dipping too low, these medications can
help keep chemotherapy doses on schedule.
Thrombocytopenia is the term used when myelosuppression depletes
the number of platelets in the blood. Platelets help start the clotting
process when bleeding occurs. If platelet counts are low, patients
may bruise easily. A low platelet count may also cause prolonged
or excessive bleeding from cuts, nose bleeds, bleeding from the gums
or bleeding without a previous injury. A platelet transfusion may
be needed in some cases.
Mucositis (Mouth Sores)
The membranes of the mouth may become red, sore or irritated
during chemotherapy, which is referred to as mucositis. Infections of
the mouth and throat caused by viruses, bacteria or fungi may also
occur. If throat soreness occurs, the healthcare provider will examine
the throat and may do a swab (called a culture) to check for infection.
If an infection is present, several medications are available to treat it.
Pain medication may be recommended if it becomes difficult to eat or
drink, and occasionally a child will need to receive intravenous fluids
to stay hydrated while the sores heal.
36 Understanding Childhood Non-Hodgkin Lymphoma
Nausea or Vomiting
Chemotherapy can cause nausea or vomiting. Fortunately, advances
over the last few decades have made it much easier to prevent
nausea. Drugs that prevent vomiting (called antiemetics) commonly
used with children undergoing chemotherapy include:
•Aprepitant (Emend) (for children over 10 years of age)
•Benadryl
5
•Granisetron (Kytril)
•Lorazepam (Ativan)
•Metoclopramide (Reglan)
•Ondansetron (Zofran)
•Promethazine (Phenergan)
•Scopolamine patch (for children over 10 years of age)
Because nausea is more easily prevented than controlled, physicians
will likely prescribe one of the above medications before chemotherapy to prevent nausea from occurring at all. In most cases, these
drugs can partially or completely prevent nausea and vomiting.
Treatment-Induced Diabetes
Sometimes the steroids that are given as part of the chemotherapy
regimen can cause treatment-induced diabetes. This means that
during treatment, some children may develop temporary diabetes.
This happens most often to children who are pre-diabetic, though
children with no risk factors for developing diabetes may also be
affected. Treatment-induced diabetes occurs because the steroids
affect the body’s ability to handle sugar. If frequent urination occurs
or the child is unusually thirsty, the physician will check the child’s
blood sugar levels.
Most treatment-induced diabetes can be managed by decreasing the
amount of sugar and carbohydrates the child eats and drinks, for
example, eliminating soda and fruit juice. Insulin may be given if
Understanding Childhood Non-Hodgkin Lymphoma 37
limiting sugar intake does not work. It is important to note that the vast
majority of children who experience treatment-induced diabetes will
return to their normal blood sugar levels once the steroids have ended.
This means that if a child had to receive insulin, the child may be able
to stop taking insulin shortly after the steroid treatment has stopped.
Treatment-Induced Hypertension
Hypertension (high blood pressure) can occur in children with
NHL while they are receiving treatment. The steroids given in most
treatment regimens cause the body to hold onto salt, which results
in water retention and extra fluid in the bloodstream. The causes of
hypertension include:
•Lymphoma in the kidneys
•Hyperuricemia, which is a build up of uric acid in the kidneys that
can cause the kidneys to become blocked. A drug called allopurinol
(Zyloprim) may be given to treat hyperuricemia.
Infection
Most children with NHL will be at an increased risk for getting
infections while they are receiving chemotherapy. The immune system
does not work as well as it does in a healthy person, making it easier
for viruses, fungi and bacteria to invade the body. Infections may
happen from the following:
•Exposure to people with colds or flu
•Bacteria that normally live in our bodies enter the blood stream
from sores in the mouth or along the gut
•Bacteria can enter the body from a cut in the skin
•Bacteria that enter the bloodstream from a Hickman catheter, PICC
line or through the skin after accessing a Port-a-Cath
•Complications following a viral illness, such as pneumonia
38 Understanding Childhood Non-Hodgkin Lymphoma
Infections can happen suddenly, and can be very serious. Most
children will develop a fever or chills with a serious infection. It is
important to call your child’s health care provider immediately and
report any signs of infection. Most infections can be treated effectively
with antibiotics, either in the hospital or as an outpatient, if treatment
is started promptly.
Constipation
Vincristine (Oncovin) is a chemotherapy drug frequently used in the
treatment of NHL. Vincristine (Oncovin) can affect the nerves that
line the inside of the colon, resulting in the colon’s inability to contract
and push stool along, leading to constipation. It is important to drink
extra fluids, remain active and increase dietary fiber to help prevent
constipation. It may be necessary to take a stool softener such as
colace, or a laxative such as miralax.
Cardiac Issues
Anthracycline drugs, such as doxorubicin (Adriamycin), can damage
the heart. The impact on the heart is usually not clinically significant
until a specific amount of the drug has been given. However, some
children are more sensitive to anthracycline drugs and experience
problems at a lower dose. Therefore, children will be carefully
monitored during and after treatment with echocardiograms or
radionuclide scans. The goal is to identify signs that the drugs
may be affecting the heart before the problem becomes severe.
Occasionally, the dose of anthracycline may need to be reduced
or held off.
Cardiac muscle failure can occur, but only in a small number of
children. Rarely does anthracycline cause heart arrhythmias (changes
in the heart rhythm). If this does occur, the drug can be stopped or
anti-arrhythmic drugs can be administered. The drug dexrazoxane
(Zinecard) may also be given along with anthracycline drugs to
protect the heart.
Understanding Childhood Non-Hodgkin Lymphoma 39
5
Please refer to our website for additional
and updated information.
lymphoma.org
40 Understanding Childhood Non-Hodgkin Lymphoma
Chapter 6
Coping with Childhood Lymphoma
Lymphoma not only affects the child, but also the child’s siblings,
friends, parents and extended family. This chapter will discuss the
common experiences of children with lymphoma and ways parents
can help both the child and their siblings cope with the diagnosis.
Strategies for acknowledging and alleviating challenges as a parent
caring for a child with lymphoma will also be presented.
What Children Need and Hope For After a
Lymphoma Diagnosis
Unless they have had experiences with cancer, children may not
immediately know the meaning of the words “cancer” or “lymphoma.”
Therefore, at first, they may not be as scared or worried about the
words or diagnosis itself. Often, it is the reactions of adults around
them that inform their response, making them feel safe or scared.
Strategies for sharing information about their diagnosis may vary by
age. Keeping messages hopeful and grounded in simple facts can help
the child feel safe. Numerous resources exist to help parents with this
communication. (To find some available resources, refer to the
Resource chapter of this guide).
Practical Aspects of Lymphoma from the Eyes of a Child
Practical Medical Concerns
Children may be more concerned about the practical rather than
theoretical issues (e.g., what will having cancer today mean for me
10 years from now). Common questions running through the mind
of a child with cancer include:
•Will this hurt?
•Am I going to be alone?
•Is it going to be scary?
Understanding Childhood Non-Hodgkin Lymphoma 41
6
Establishing ways to reinforce their safety and letting them know
that they will not be alone will help. For example, in preparation for
receiving chemotherapy, explain to the child what to expect, including
the physical and practical pieces. Describe what they will feel during
and after chemotherapy. Make it clear that every step will be taken
to minimize pain or the “ouchies.” Children do not like surprises.
Tell them details such as:
•What will happen first, second, third, etc.
•Who will be in the room when they get specific tests/procedures
•Mom and/or dad will be there the whole time
The more they can be prepared for what to expect, the better. When
they are not told, they may be concerned that adults are lying to them
and lose trust in future medical situations. Children can often tell
when adults are being honest or trying to hide things. Tell them that
the physician and adults will be honest with them. Work with the
child to identify how much information they like to receive before
each procedure and how involved they would like to be in their own
treatment. Some children want everything explained to them step by
step, while others may just want to “get it over with.”
The Benefit of Routine
It is a common reaction for parents of children with cancer to want
to relax rules and routines for their sick child and well siblings. This
sometimes helps temporarily minimize guilt for the parent and stress
on the child. However, developmentally, children thrive with structure
and routines. It makes them feel safe because they are able to anticipate
what to do, how to do it and what is expected of them. Suspending
rules and routines may make the child concerned that they are much
sicker than everyone is telling them. Reasonable changes to help the
child feel more comfortable if they become nauseous, fatigued, etc.
can help, but extreme changes should be made with caution.
42 Understanding Childhood Non-Hodgkin Lymphoma
Social Workers and Child Life Specialists
Social workers and child life specialists are skilled at helping parents
with children affected by cancer. They are there to serve as partners
for parents during and after lymphoma treatment. Numerous books,
web-based resources and tools exist to help parents communicate
with their children about cancer, as well as ways for them to cope.
Speaking with a social worker or child life specialist can help save
time because they have access to the most appropriate resources for
families, based on the child’s age and other specific needs.
Emotional Coping for Parents, Adult Family Members
and Friends
As a parent of a child with cancer, it is completely understandable and
reasonable to be sad and scared. The following specific strategies may
help parents and children at the same time:
•Children sense what their parent is feeling. Therefore, it is best to
be honest and say something like, “Yes, Mommy is worried, but
that is okay. Here is what we are going to do (lay out a plan).” This
acknowledges what the child instinctually senses and also quickly
makes them feel secure and that the parent is in control.
•Emotional breakdowns and feeling overwhelmed may happen
frequently or come on all at once for a parent. The important thing
to do is to find a suitable outlet or source of support to help. Rely
on friends and family members for emotional support. This will help
ensure that when the parent interacts with their child they are not
overwhelmed with their own emotions and are fully supportive
and nurturing.
Coping with Guilt
Parents often believe that they can protect their children from everything.
This feeling is natural and expected. It is critical to recognize that
feeling frustrated, tired and guilty is inevitable. The causes of lymphoma
are not known, so nothing anyone “did” caused the disease. Childhood
cancers in general are very rare and out of the ordinary experiences of
Understanding Childhood Non-Hodgkin Lymphoma 43
6
parenthood. However, due to recent treatment advances, the large
majority of children will survive their lymphoma diagnosis and grow
into healthy adults. Furthermore, research shows that many childhood
cancer survivors experience something referred to as “post-traumatic
growth,” and report that their lives were positively impacted by their
cancer experience. For example, teenagers often say that they quickly
realized what is important in life, as compared to their cancer-free
peers. Many of the positive aspects occur years later. Parents are
encouraged to engage children in conversations about their experience
as they are going through it so that they are supported in the present
and prepared for the future. While parents are actively supporting their
children through lymphoma treatment, they need to do their best to
also be compassionate to themselves. Ask for and receive practical
support from friends, neighbors and healthcare providers. Talk to
a social worker and ask for resources.
Support for Siblings of Children with Lymphoma
Childhood lymphoma affects more than the child diagnosed. Fear,
sadness and extra tasks enter the daily lives of family members and
friends. Brothers and sisters of the child diagnosed with lymphoma
are uniquely impacted. Siblings of sick children may feel neglected,
angry, sad, scared, like their needs do not matter and are often forced
to grow up quicker than normal. Parents should remain aware of all
children in the family and look out for changes in behavior.
One unique resource for siblings of children with cancer is a nationwide non-profit organization called SuperSibs!. The organization is
dedicated to ensuring that the brothers and sisters of children with
cancer are honored, supported and recognized. They do this by
providing free, ongoing comfort and care support to children between
the ages of 4 and 18, who reside in the United States and Canada,
and who have (or have had) a brother or sister with cancer. (See the
44 Understanding Childhood Non-Hodgkin Lymphoma
Resource section of this guide for contact information.) In addition
to this direct support, SuperSibs! works with hospitals, clinics and
organizations across the country to provide the most effective tools
and resources so that sibling awareness and support can be a part of
the help that families receive from their medical, social and emotional
support staff.
A few strategies may help siblings better cope with their brother or
sister’s cancer:
•Try to assess the child’s awareness of cancer and what it is. Simply
ask, “Have you heard of cancer? What do you know about it?”
Aim to deliver age-appropriate descriptions. Numerous resources
exist to help parents do this.
•Spend one-on-one time with the well sibling(s). Do an activity of
their choice that opens up the possibility for talking about how they
are doing. Siblings of children with lymphoma may quickly diminish
their needs to “accommodate” their sibling’s needs. Therefore, it is
critical that you ask them about their day, their dreams and what
they would like to do. Listening is even more important than asking.
Take in what your child says and ask more questions.
•Gently ask hospital staff and other people to refer to the sibling by
their name, as opposed to “the patient’s brother or sister.” This will
help remind them that their identity matters too.
•Siblings often take on extra responsibility. Be careful of asking
the sibling to do more than they should at their age. For example,
babysitting younger siblings may not be appropriate before a certain
age. This should not change even with a sick child.
•Ask siblings if they want to be involved. If the answer is yes, then
find ways they can contribute. Being in charge of daily communication
with family, for example, may help the sibling feel connected, but
not overburdened.
Understanding Childhood Non-Hodgkin Lymphoma 45
6
Talking to Siblings About Cancer By Age
Ages 2-5
For this age group it is very important to keep things very simple.
One example for explaining lymphoma: “Tommy’s blood is very sick. The doctors are going
to give him some medicine to help his blood get better. Sometimes Tommy will have to get
his medicine at the hospital and sometimes Tommy will take the medicine at home. The
doctors are going to do everything they can to make Tommy’s blood get better.”
Kids this age just want to be close to their parents. It is important to help your kids feel
connected.
Some suggestions include:
• Record several of the child’s favorite books and songs on tape for them to listen to and
hear your voice.
• Make picture frames together and put a picture of yourself inside.
• Make a blanket together or pick one out together and identify it as the item that can
“HUG” you while mom and dad have to be away.
Ages 6-10
For this school age group, you can use the actual words.
One example for explaining lymphoma: “Tommy has cancer. Have you ever heard that word
before? There are different kinds of cancer and Tommy has a kind called lymphoma. That
means the cancer is in his lymphatic system, which helps the body fight off infections and
germs. The doctors are going to give Tommy a very strong medicine called chemotherapy.
You can call it “chemo” for short. The chemo will help to make the lymphoma go away.”
(Re-iterating): “The doctors and nurses are going to do everything they can to make the
lymphoma go away.”
Questions to Spark Conversation:
• What do you know about lymphoma or cancer?
• Do you think someone did something “bad” to cause lymphoma or cancer? (That’s not
what causes cancer!)
• Do you think you can catch cancer from someone else? (No, it’s not “catchy!”)
• How is your life different now?
• What is the biggest change in your life?
• What do you want/need from us grownups?
• How do you know you are loved?
46 Understanding Childhood Non-Hodgkin Lymphoma
AGES 11 - 18
Start with the basics and elaborate, depending on how much information your teen
wants to hear. Some want a lot of information, some want to read it themselves and
some want it kept to only what they NEED to know.
Questions to Spark Conversation:
• What do you know about lymphoma or cancer?
• Do you think cancer is contagious? (It’s not!)
• Do you think cancer is caused by something that someone did? (It’s not!)
• How is your life different now?
• What additional things do you have to do at home now?
• What do you want/need from us, your parents?
• What do you want/need from your friends?
• What do you want/need from school?
The information from this section was adapted from the
SuperSibs! new parent toolkit. If you have not received a new
parent toolkit, contact SuperSibs! at 866-444-SIBS(7427) or
supersibs.org.
Understanding Childhood Non-Hodgkin Lymphoma 47
6
Please refer to our website for additional
and updated information.
lymphoma.org
48 Understanding Childhood Non-Hodgkin Lymphoma
Chapter 7
Long-Term and Late Effects
Survival rates for children with lymphoma are extremely high,
resulting in a growing number of childhood lymphoma survivors.
Some of these survivors are at risk of developing treatment-related
health problems that could occur months, or even years, following
their last treatment.
Lymphoma treatments are designed to destroy cancer cells. However,
some of these treatments unintentionally damage healthy cells in the
process. This damage can effect the development and proper functioning of various tissues and organs and could result in the development
of secondary cancers later in life.
Most childhood lymphoma survivors do not develop treatmentrelated health problems. For those who do, the effects are generally
mild. However, a limited number of childhood lymphoma survivors
may experience severe or chronic effects.
There are several factors that can affect the risk of developing
treatment-related health problems, including:
•The type and amount of treatment the child receives
•The age at which the child is treated
•What area of the body is treated
•The child’s gender
•The child’s overall health
Treatment-related health problems are placed into two categories.
Those that continue for months or years following treatment are
called “long-term effects” and those that do not appear until months
or years after treatment are called “late effects.”
Understanding Childhood Non-Hodgkin Lymphoma 49
7
Long-term and late effects vary by treatment. Some treatments may:
•Cause cognitive impairment, such as difficulties learning, problem
solving and concentrating
•Affect the proper functioning of organs, such as the lungs, kidneys,
liver, thyroid and spleen
•Damage the digestive, musculoskeletal and central nervous systems
•Affect the reproductive system, resulting in the delay of puberty,
low sperm count, irregular periods, ovarian failure, premature
menopause and infertility
•Cause damage to the heart
•Result in the development of secondary cancers, such as breast and
thyroid cancer
The following are examples of some common therapies and their
potential long-term or late effects:
•Anthracyclines: Anthracyclines, a form of chemotherapy, may
increase the risk of developing heart damage and heart failure.
Examples of anthracyclines include doxorubicin (Adriamycin)
and daunorubicin (Daunomycin).
•Alkylating agents: Alkylating agents, a form of chemotherapy, may
increase the risk of developing heart failure and acute myelogenous
leukemia (AML). A commonly used alkylating agent includes
cyclophosphamide (Cytoxan) and ifosfamide (Ifex).
•Radiation: Radiation to the head and neck may cause vision or
hearing problems and could affect the thyroid. Radiation to the
chest and abdomen could impair the heart (with severe cases
resulting in heart failure) and lungs, and could increase the risk
of developing breast and thyroid cancer.
50 Understanding Childhood Non-Hodgkin Lymphoma
Due to the various medical conditions that can result from treatment,
it is important that parents discuss the potential risks of all treatment
options with their child’s oncologist before treatment. Once a treatment is completed, parents and the child’s oncologist should create a
“follow-up care plan” that:
•Provides a treatment summary, which includes information such as
age and date of diagnosis, staging, the types of chemotherapy drugs
administered, and response to treatment.
•Indicates the type and frequency of medical tests that a survivor
should routinely undergo over their lifespan.
This follow-up care plan should be written and provided to the parent
upon completion of treatment. As children grow up and move around,
this document will serve as a history for their primary care physician.
The follow-up care plan also ensures that any late effects will be
diagnosed and treated as early as possible.
Childhood lymphoma survivors should receive regular medical exams
from a physician who is familiar with their medical history as well as
the treatments they have received. Survivors and their caregivers are
encouraged to keep copies of all medical records and test results as
well as information on the types, amounts and duration of all treatments received. This documentation will be important for keeping
track of, and treating, any late effects resulting from treatment.
Scientific investigators are constantly testing new treatments and
varying amounts of old treatments in hopes of reducing the long-term
and late effects of lymphoma treatment or eliminating them altogether. Because greater numbers of children with lymphomas are
now surviving for many decades following cancer treatment, new
discoveries about the late effects of cancer are frequently being made.
Guidelines are periodically updated to reflect this new information.
Understanding Childhood Non-Hodgkin Lymphoma 51
7
The Children’s Oncology Group has created a document for physicians, which provides recommendations for managing the late effects
of treatment, entitled Long-Term Follow-Up Guidelines for Survivors
of Childhood, Adolescent and Young Adult Cancers. To view the
document, visit survivorshipguidelines.org
Resources
Please refer to our website for additional
and updated information.
lymphoma.org
52 Understanding Childhood Non-Hodgkin Lymphoma
Glossary of Medical Terms
Absolute neutrophil count (ANC): A measurement of the number
of mature neutrophils (a type of white blood cell) that are available for
fighting infection. A low ANC increases the risk for infection.
Advanced disease: Disease that has spread to multiple locations.
Aggressive lymphomas: Lymphomas that are fast growing and generally
need to be treated immediately. Also called intermediate-grade or
high-grade lymphomas.
Allogeneic transplant: A procedure in which a patient receives bone
marrow or stem cells donated by another person.
Alopecia: Hair loss. Alopecia from chemotherapy is almost always
temporary; hair grows back when therapy is finished.
Anemia: A shortage of red blood cells, causing weakness and fatigue.
Angiogenesis: The process of developing new blood vessels.
Antiangiogenesis therapies: Drugs that prevent tumors from developing
new blood vessels, thereby stopping or limiting tumor growth.
Antibody: A substance made by B-lymphocytes that reacts with antigens on
toxins, bacteria and some cancer cells and either kills or marks them for
removal.
Antiemetic: A drug that reduces or prevents nausea and vomiting.
Antigen: Identifying proteins located on the surface of all cells. The
immune system uses antigens to determine whether cells are a necessary
part of the body or need to be destroyed.
Apheresis: The part of the stem cell transplantation procedure in which
stem cells are removed from the blood.
Autologous transplant: A type of bone marrow or stem cell transplantation in which a patient receives his or her own cells.
Beta (2) microglobulin (B2M): A protein found in the blood. Higher levels
of B2M suggest that the lymphoma may be more aggressive.
ChildhoodLymphoma
Lymphoma 53
UnderstandingUnderstanding
Childhood Non-Hodgkin
Biologic therapy: Treatment that uses or stimulates the immune system
or other body systems to fight infection and disease.
Biopsy: Removal of a small piece of tissue for evaluation under
a microscope.
Bone marrow: Spongy material found inside the bones containing stem
cells that develop into three types of cells: red blood cells that deliver
oxygen to the body and take away carbon dioxide; white blood cells that
protect the body from infection; and platelets that help the blood to clot.
Bulky tumor: A large tumor, usually greater than five, seven or ten
centimeters.
Cancer: Abnormal cell growth that cannot be controlled by the body’s
natural defenses. Cancerous cells can grow and eventually form tumors.
Catheter (intravenous access): A device that is temporarily or permanently
put into a vein that makes it easier to give medications.
Cerebrospinal fluid: Fluid that is present around the spine and brain. It may
be examined to determine if NHL has spread to these parts of the body.
Chemotherapy: Treatment with drugs to stop the growth of rapidly
dividing cancer cells, including lymphoma cells.
Chemotherapy cycle: Term used to describe the process in which chemotherapy is given, followed by a period of rest in which the body
is allowed to recover.
Chemotherapy regimen: Combinations of anticancer drugs given at
a certain dose in a specific sequence according to a strict schedule.
Clinical trial: A research study in which a new treatment is given to
patients to determine whether it is safe, more effective or less toxic than
current therapies.
Combination chemotherapy: Several drugs given together to increase
response rate of certain tumors.
54 Understanding
UnderstandingChildhood
ChildhoodLymphoma
Non-Hodgkin Lymphoma
54
Complete remission (CR): Term used when all signs of the disease have
disappeared after treatment. About LRF
**Insert
from other booklets**
CT or CAT (computerized axial tomography) scan: This imaging test
provides a series of detailed pictures of inside the body using an X-ray
machine linked to a computer.
Cure: There are no signs or symptoms of lymphoma, and a significant
period of time (usually defined by years) has passed during which there
are no relapses.
Decreased blood cell production: A decrease in the production of red
blood cells, white blood cells and platelets that may occur as a side effect
of cancer or cancer therapies. Also called myelosuppression.
Diaphragm: The muscle below the lungs and heart that separates the
abdomen from the chest.
Disease progression: The term used if the disease worsens despite
treatment (also called treatment failure).
DNA: Abbreviation for deoxyribonucleic acid, an essential component
of genes.
Dose intensity: A term used to describe giving the highest possible doses
of drugs over a specific period of time with acceptable side effects.
Durable remission: When a complete response lasts for years.
Dysgeusia: When familiar foods taste differently.
Echocardiogram: Use of ultrasound to examine the heart. It is ordered
when potential cardiotoxic chemotherapy is used.
Etiology: The study of the causes of a disease.
Extranodal disease: NHL that has spread outside the lymphatic system.
Fatigue: A decreased capacity for activity that is often accompanied by
feelings of weariness, sleepiness or irritability.
Understanding Childhood Non-Hodgkin Lymphoma 55
Gallium (radioisotope) scan: When injected into the body, radioactive
gallium is a chemical that collects in some tumors. The body is then
scanned to see whether the gallium has collected in a tumor.
Generalized disease: A cancer that has spread throughout the body.
Genes: The basic building blocks of heredity that are present in all cells.
Genes are comprised of DNA and other materials.
Gene therapy: Therapy approaches that alter the genetic structure of
tumor cells, making them more susceptible to either the immune system
or chemotherapy drugs.
Grade: A method of classifying a tumor on the basis of how aggressively
it is growing.
Graft versus host disease (GVHD): Occurs when a donor’s bone marrow
(graft) recognizes the recipient of the marrow (the host) as foreign. In
response, the immune cells in the donor marrow attack the foreign cells
in the host.
Harvesting: A procedure in which stem cells are obtained from the blood
or bone marrow for use in repopulating the body’s cells after high-dose
chemotherapy.
Hematologist: A physician who specializes in treating diseases of the
blood and blood-forming tissues.
Histology: The study of tissue characteristics that may lead to identifying
a specific type of tumor.
Hodgkin lymphoma: One of the two major types of lymphoma that begin
in the lymph nodes and tissues of the lymphatic system. All other
lymphomas are classified as non-Hodgkin lymphomas. Hodgkin lymphoma has a characteristic cell, the Reed-Sternberg cell, seen by the
pathologist under the microscope when looking at the tissue from
the biopsy.
Hypogeusia: When the flavors of foods are not as strong as normal.
56 Understanding
UnderstandingChildhood
ChildhoodLymphoma
Non-Hodgkin Lymphoma
Hypothyroidism: A condition in which there is lower than normal
production of thyroid hormone. Low thyroid levels can lead to a variety
of effects, including mild weight gain, dry skin, fatigue and sleepiness.
Idiotype: A unique “fingerprint” portion of an antibody present on the
surface of B-cells.
Idiotype vaccine: A lymphoma vaccine that is custom-made to attack
an individual patient’s lymphoma and contains idiotype (unique) tumor
material and an immune stimulant.
Immune system: One of the body’s defense mechanisms. All lymphomas
are diseases of the immune system.
Immunological tests: Blood tests that detect the presence of diagnostic
proteins or antigens on a tumor.
Immunotherapy: See biologic therapy.
Improvement: This term is used if a tumor shrinks following therapy
but is still more than one-half of its original size.
Indolent lymphoma: Lymphoma that is slow growing and has few
symptoms. Also called low-grade lymphoma.
Lactate dehydrogenase (LDH): An enzyme found in the blood. Higher
levels of LDH suggest that the lymphoma may be more aggressive.
Laparoscopy: Passing a tube through the abdominal wall to obtain a
small sample of tissue for examination under the microscope.
Leukemia: Disease generally characterized by the overproduction of
abnormal or immature white blood cells that circulate or are present
in the blood.
Leukopenia: A shortage of white blood cells, resulting in the inability
to fight infecting organisms such as bacteria, fungi and viruses.
Localized disease: A cancer that is only present in a limited part of the
body, for example, the neck or armpits.
Understanding Childhood Non-Hodgkin Lymphoma 57
Local therapy: A therapy that only affects a small area.
Low-grade lymphoma: Lymphoma that grows slowly and has few
symptoms. Also called indolent lymphoma.
Lymph: The watery fluid in the lymph system that contains white blood
cells (lymphocytes).
Lymph nodes: Small bean-shaped glands located in the small vessels
of the lymphatic system. There are thousands of lymph nodes located
throughout the body, with clusters of them in the neck, under the arms,
the chest, abdomen and groin. Lymph nodes filter lymph fluid, trapping
and destroying potentially harmful bacteria and viruses.
Lymphatic system: The channels, tissues and organs that store and carry
lymphocytes that fight infection and other diseases.
Lymphocyte: A type of white blood cell. Lymphocytes, carried along
by the lymph fluid, are part of the immune system and fight infection.
Lymphoma: A malignant disease that begins in the lymph nodes,
organs and tissues of the lymphatic system (immune system). Hodgkin
lymphoma is one type of lymphoma; the other major type is called
non-Hodgkin lymphoma. There are approximately 61 types of non-Hodgkin lymphoma.
Malignant: Cancerous—a malignant tumor is a cancerous tumor.
Medical oncologist: A physician who specializes in the use of chemotherapy,
hormone therapy and many other types of biologic therapies to treat cancer.
Memory cells: Memory cells are types of B-lymphocytes and
T-lymphocytes. After a foreign invader or unwanted cell has been
destroyed, surviving B- and T-lymphocytes develop into specialized
memory cells that remain on watch and can provide protection if the
invader is encountered in the future.
58 Understanding
UnderstandingCLL/SLL
Childhood Non-Hodgkin Lymphoma
Metastasize: To spread to other organs of the body. Cancer may spread
from its primary site to other sites or organs.
Monoclonal antibodies: Biologic therapies that act specifically against
a particular antigen. Scientists can produce large amounts of antibody
that can be directed to a single target (or antigen) on the cell’s surface.
Monoclonal antibodies have been developed to help combat specific
cancers, including some forms of non-Hodgkin lymphoma.
MRI (magnetic resonance imaging): MRI uses magnets and radio
frequency waves to produce images of inside the body. MRIs can provide
information about tissues and organs that is not available from other
imaging techniques.
Mucositis: Inflammation of the lining of tissues and organs. In the mouth,
it is characterized by sores or inflammation.
Myelosuppresion: A reduction in the bone marrow’s ability to make red
blood cells, white blood cells and platelets.
Neutropenia: An abnormally low level of neutrophils (the white blood
cells responsible for fighting bacterial infections).
Neutrophils: The primary type of white blood cells found in the blood
that fight bacteria, etc.
Non-bulky tumor: A small tumor, usually less than five centimeters
(approximately two inches)
Non-Hodgkin lymphoma (NHL): A group of several closely related
cancers that arise from the lymphatic system. Although the different types
of NHL have some things in common, they differ in what the cancer cell
looks like under a microscope, how the cells grow and how the tumor
affects the body.
Oncologist: A physician who specializes in treating cancer. Some specialize
in chemotherapy (medical oncologists), radiotherapy (radiation oncologists) or surgery (surgical oncologists).
Understanding Childhood Non-Hodgkin Lymphoma 59
Palliation: Treatment that is given to remove or relieve symptoms.
Para-aortic: The area close to the aorta. The aorta is the largest vessel in
the body and rises from the heart.
Partial remission (PR): The term used when a cancer has shrunk in size by
at least half but has not totally disappeared. The cancer can still be
detected, and other treatments may be recommended.
Pathologist: A physician who specializes in studying disease through
microscopic evaluation of body tissues and organs. Any tissue suspected
of being cancerous must first be examined by a pathologist to confirm the
diagnosis.
PCR (polymerase chain reaction): A molecular test that can identify small
amounts of genetic material. This test is done if looking for minimal
residual disease.
Performance status: A term used to describe a person’s ability to follow
a typical lifestyle.
Peripheral neuropathy: Damage to the nerves. This condition can
be caused by some drugs and is usually characterized by tingling and
weakness or numbness in the extremities.
PET (positron emission tomography) scan: A type of test that may
be used instead of gallium scans to identify areas in the body that are
affected by non-Hodgkin lymphoma. This test evaluates metabolic activity
in different parts of the body using a radioisotope.
Plasma cell: A mature B-cell that makes antibodies—these antibodies help
the body destroy or remove toxins, bacteria and some cancer cells.
Primary therapy: The first therapy given after a diagnosis of cancer.
Prognosis: The likely outcome of a disease, including the chance
of recovery.
60 Understanding Childhood Non-Hodgkin Lymphoma
Pulmonary function test: A procedure for determining the capacity
of the lungs to exchange oxygen and carbon dioxide efficiently.
Radiation field: The part of the body that receives radiation therapy.
Radiation oncologist: A physician who specializes in treating cancer
with radiation.
Radiation therapy: The use of radiation beams (X-rays) to treat a cancer.
High doses of high-energy radiation beams carefully focused on a tumor
will kill cancer cells. Radiation therapy (with or without chemotherapy)
is used to treat certain lymphomas.
Radioimmunotherapy: A therapy that is prepared by attaching a radioactive isotope to a monoclonal antibody.
Radionuclide tests: Tests that use radioactive substances to help evaluate
the function of tissues.
Refractory disease: A cancer that is resistant to treatment.
Regimen: A specific combination of drugs (chemotherapy), their doses
and their schedules of administration. A regimen may also include
radiotherapy.
Relapse: The return of cancer after treatment. Lymphoma may recur
in the area where it first started, or it may occur in another place.
Remission: The absence of disease. A patient is considered in remission
when the lymphoma has been treated and tumors have diminished by
at least 50 percent (partial) or have totally disappeared (complete).
Remission does not necessarily mean cure. Patients with intermediate or
aggressive lymphomas must achieve a complete remission and maintain it
for a period of time, usually five or more years, before there is consideration of cure. Patients with low-grade tumors are usually not considered
cured because the disease can reappear even with a long remission of
many years. Patients may have a complete or partial remission.
Understanding Childhood Non-Hodgkin Lymphoma 61
Risk factors: Factors that may increase the chance that a person will
develop NHL. It is important to note that most people with risk factors
never develop lymphoma, and many who are diagnosed have no identifiable risk factors.
Salvage therapy: Therapy that is given if the primary therapy is not
successful or if the disease disappears and then comes back.
Spleen: An organ on the left side of the upper abdomen, near the stomach.
A key component of the lymphatic system, the spleen produces and
stores lymphocytes and releases them when required as part of the body’s
response to infections and other stimuli. The spleen may store blood and
remove old blood cells from circulation.
Stable disease: The disease does not get better or worse following therapy.
Stage: The extent of cancer in the body, including whether the disease has
spread from the original site to other body parts.
Standard therapy: The most widely used primary therapy.
Synergism: The term used when two or more drugs given together provide
a better anti-cancer effect than expected from the additive effects from the
medications alone.
Systemic symptoms: Symptoms that affect the entire body. Examples of
these include fever, night sweats and weight loss.
Thrombocytopenia: A shortage of platelets in the blood, which reduces
the ability of the blood to clot.
Thymus gland: A gland located behind the sternum (breastbone)
that enhances the reproduction and development of lymphocytes.
T-lymphocytes are processed in the thymus.
Toxicities: The unwanted side effects of cancer therapies, such as a
decrease in blood cells, nausea and vomiting, and hair loss.
62 Understanding Childhood Non-Hodgkin Lymphoma
Tumor: An abnormal mass or swelling of tissue. Tumors may occur
anywhere in the body. A tumor may be benign (non-cancerous) or
malignant (cancerous).
Vaccine: A substance or group of substances meant to cause the immune
system to respond. A vaccine can help the body recognize and destroy
cancer cells. Lymphoma vaccines often combine cancer antigens with
a substance to stimulate the patient’s own natural defenses to fight the
disease. These vaccines in lymphoma are custom-made for each patient,
using a sample of tumor obtained from the patient’s lymph nodes.
VEGF (Vascular Endothelial Growth Factor): One of a number of
substances that stimulate angiogenesis, blood vessel formation—a process
necessary for tumor growth.
Watchful waiting: An approach in which no immediate medical, surgical
or radiation therapy is given. Patients are followed closely to make sure
the cancer does not progress. Watchful waiting is an appropriate option
for some patients with indolent (slow-growing) non-Hodgkin lymphoma.
Xerostomia: A temporary reduction in the production of saliva or
“dry mouth.”
X-ray: Radiation that is used in low doses to provide images of the inside
of the body and in high doses to treat cancer.
Understanding Childhood Non-Hodgkin Lymphoma 63
Please refer to our website for additional
and updated information.
lymphoma.org
64 Understanding Childhood Non-Hodgkin Lymphoma
Resources
Childhood Cancer Resources
Candlelighters Childhood Cancer Foundation (CCCF)
(800) 366-2223
candlelighters.org
CCCF is a national non-profit organization whose mission is to
educate, support, serve and advocate for families whose children have
been diagnosed with cancer, survivors of childhood cancer, and the
professionals who care for them.
Children’s Cancer Association (CCA)
(503) 244-3141
childrenscancerassociation.org
The Children’s Cancer Association is a one-of-a-kind nonprofit
organization bringing support, resources, award-winning programs
and above all, joy to seriously ill kids/teens and their families in
Oregon, SW Washington and nationally.
CureSearch
(800) 458-6223
curesearch.org
CureSearch unites the world’s largest childhood cancer research
organization, the Children’s Oncology Group, and the National
Childhood Cancer Foundation to cure childhood cancer. CureSearch
also provides advocacy, public education, referrals and clinical
trial information.
Understanding Childhood Non-Hodgkin Lymphoma 65
National Children’s Cancer Society (NCCS)
(314) 241-1600
children-cancer.org
The NCCS provides financial assistance, advocacy, emotional support
and education to families who have children diagnosed with cancer. Pediatric Oncology Resource Center
acor.org/ped-onc
The Pediatric Oncology Resource Center provides a website by
parents of children with cancer for parents of children with cancer. This website offers patient-friendly resources as well as links to
various support groups.
Special Love, Inc.
(888) 930-2707
speciallove.org
Special Love, Inc. sponsors Camp Fantastic and 19 other events for
children with cancer and their families in the Mid-Atlantic region.
Starlight Children’s Foundation
(800) 315-2580
starlight.org
Starlight Children’s Foundation is an international non-profit
organization dedicated to improving the quality of life for seriously
ill children and their families through a variety of in-hospital and
outpatient programs and services. 66 Understanding Childhood Non-Hodgkin Lymphoma
SuperSibs!
(866) 444-SIBS (7427)
supersibs.org
SuperSibs! provides services free of charge to honor, support and
recognize brothers and sisters of children, teens and young adults
with cancer.
Young Adult Cancer Resources
Camp Mak-A-Dream
(406) 549-5987
campdream.org
Camp Mak-A-Dream is a medically supervised, cost-free Montana
experience, in an intimate community setting, for children, young
adults and families affected by cancer.
Lance Armstrong Foundation LIVESTRONG Young Adult Alliance
(866) 673-7205
livestrong.org/yaa
The LIVESTRONG Young Adult Alliance is a coalition of organizations with the goal to improve the survival rates and quality of life for
young adults with cancer between the ages of 15 and 40. This website
provides access to the websites of all member organizations.
Lymphoma Research Foundation
(800) 500-9976
lymphoma.org/youngadults
The Lymphoma Research Foundation offers a wide array of webcasts
and podcasts for individuals affected by lymphoma in their teens, 20s
and 30s, including topics specifically designed to help friends and family.
Understanding Childhood Non-Hodgkin Lymphoma 67
Planet Cancer
planetcancer.org
Planet Cancer’s website is a 24 hour, 7 days a week online community
providing peer support, information and humor for young adult
cancer patients and survivors.
Teens Living with Cancer
teenslivingwithcancer.org
TLC focuses on teen issues, presents information about cancer and
treatment written at teens’ level of interest, provides opportunities
to interact with other teens living with cancer and offers links to
relevant sites. Ulman Cancer Fund for Young Adults
(888) 393-3863
ulmanfund.org
Ulman Cancer Fund focuses on how cancer affects young adults.
The Ulman Cancer Fund offers scholarships, community grants,
advocacy services and a guidebook.
68 Understanding Childhood Non-Hodgkin Lymphoma
About the Lymphoma
Research Foundation
The Lymphoma Research Foundation (LRF) is the nation’s largest
lymphoma-focused nonprofit health organization devoted exclusively
to funding lymphoma research and providing patients and healthcare
professionals with the most current information on the disease. The
Foundation’s mission is to eradicate lymphoma and serve those touched
by this disease.
The Lymphoma Research Foundation was formed in 2001 with
the merger of the Cure For Lymphoma Foundation (CFL) and the
Lymphoma Research Foundation of America (LRFA). Both organizations were founded by lymphoma advocates who wanted to turn a
life-altering diagnosis into a positive experience for others with the
disease. Ellen Glesby Cohen founded LRFA in Los Angeles in 1991.
Until her death in 2000, Ellen was a tireless champion for patients and
their families who created new education and support programs and
served as a staunch advocate for improved government legislation. Jerry
and Barbara Freundlich founded CFL in 1994 in New York City. Jerry
is a long-term survivor of non-Hodgkin lymphoma.
Resources for Patients, Survivors and Loved Ones
Receiving a diagnosis of lymphoma can be challenging. Whether you
or someone you love is newly diagnosed or a long-term survivor,
understanding the latest medical information and accessing appropriate
support services may help. The Lymphoma Research Foundation offers
a wide array of programs and support services to assist you from the
point of diagnosis through long-term survivorship.
Understanding Childhood Non-Hodgkin Lymphoma 69
Patient Services and Support
Lymphoma Helpline and Clinical Trials Information Service
Through this phone and email service, trained staff members are
available to answer your questions and provide individual support
to you and your loved ones. Services are available in any language.
Lymphoma Support Network (LSN)
This national one-to-one peer support program matches lymphoma
patients or caregivers with volunteers who have had similar
lymphoma-related experiences.
Lymphoma Newsline
Lymphoma-related news can be distributed to you directly through
this free electronic news services. Sign up by clicking on the “register”
icon on LRF’s homepage at lymphoma.org.
In-Person Patient Education Programs
North American Educational Forum on Lymphoma
This two-day national forum is held annually and provides critical
information about the latest in lymphoma research, making the best
decisions about treatment options and patient support issues.
Lymphoma Workshop: Understanding Lymphoma Basics
and Current Treatment Options
These regional, full-day educational programs provide the latest
information about lymphoma, current treatment options and patient
support issues.
Multimedia Programs
Because LRF understands that information about lymphoma
continually changes throughout the year, the ongoing production of
webcasts, podcasts and teleconferences enable you to access the latest
information on specific topics anywhere, anytime.
70 Understanding Childhood Non-Hodgkin Lymphoma
Webcasts
Webcast programs offer you the opportunity to navigate through
a synchronized audio and slide presentation.
Podcasts
Podcasts (video format) can be viewed on LRF’s website.
Teleconferences
Teleconferences are hour-long interactive telephone programs that
provide an opportunity to learn more about lymphoma, treatments
and promising research from leading lymphoma experts. These are
conducted live, and the archived version is available after the program.
Publications
Patient Guides
In addition to this publication, LRF also produces Understanding
Non-Hodgkin Lymphoma: A Guide for Patients, Survivors and Loved
Ones, Understanding Hodgkin Lymphoma: A Guide for Patients,
Survivors and Loved Ones, and Understanding CLL/SLL: A Guide
for Patients, Survivors and Loved Ones.
Fact Sheets
Fact sheets with the latest disease- and treatment-specific information
are available in either hard copy or in PDF on LRF’s website. New
topics are added on a regular basis; check to see if the topic you are
looking for is available.
Newsletters
To keep you abreast of LRF research and news in the wider
lymphoma community, you can sign up to receive any of LRF’s
regular newsletters either electronically or via mail.
Any of LRF’s publications may be ordered by visiting lymphoma.org.
Individual and bulk copies are available free of charge.
Understanding Childhood Non-Hodgkin Lymphoma 71
How to Access Programs and Services
Many of the aforementioned programs are available on LRF’s website
at lymphoma.org. For additional information about these resources,
call (800) 500-9976 or email us at helpline@lymphoma.org.
If you would like to order additional copies of Understanding Childhood
Non-Hodgkin Lymphoma: A Guide for Patients, Survivors and Loved
Ones, please call (800) 500-9976 or visit lymphoma.org.
72 Understanding Childhood Non-Hodgkin Lymphoma
How to Get Involved and Give BACK
Take Action to Make a Difference
The LRF Advocacy Program is a network of people and programs
dedicated to increasing awareness and support for the lymphoma
community. The Advocacy Program focuses on taking action on
laws, policies and positions that affect every lymphoma patient and
survivor. By contacting elected officials via phone calls, email and
letters in support of these priorities, local advocates help LRF to make
lymphoma a national health priority. To become involved, visit
lymphoma.org/advocacy.
Start or Join a Local Chapter
Chapter volunteers work tirelessly to educate people about lymphoma,
conduct outreach, raise funds for research and participate in public
policy and advocacy initiatives. To learn more about a chapter in
your area or how to start one, please visit lymphoma.org/chapters.
Raise Funds and Awareness
Raise funds and awareness by participating in a variety of events being
held across the country such as Lymphomathon walks, bike rides, golf
tournaments, galas, lunches, young professional social events and
much more! Visit lymphoma.org/events for more information.
Join Team LRF
Team LRF is a program through which people across the country raise
much-needed funds and awareness for lymphoma research through
sporting events such as marathons, half marathons, triathlons, hiking
adventures, bowling tournaments, soccer matches, bike rides, lacrosse
tournaments, paddling events, dance-a-thons, spin-a-thons, yoga-athons and much more. Join Team LRF in an existing LRF-partnered
event in your area, or join Team LRF Teammates Across the Country
if you wish to raise funds by starting your own event or by
participating in an event in which LRF does not have official charity
entries. For more information, visit lymphoma.org/teamlrf.
Understanding Childhood Non-Hodgkin Lymphoma 73
Please refer to our website for additional
and updated information.
lymphoma.org
74 Understanding Childhood Non-Hodgkin Lymphoma
Donate Now
The Lymphoma Research Foundation (LRF) is a nonprofit health
organization with 501(c)(3) status. If you would like to support LRF,
your generous gift will help us move closer to finding a cure, while helping
those affected by the disease.
Three easy ways to give:
Website: lymphoma.org/donatenow
Call: (800) 235-6848
Mail: Cut out this form and mail it to Lymphoma Research Foundation,
115 Broadway, 13th Floor, New York, New York 10006
or
FAX
Fax: (212) 349-2886
Amount of donation $
Make checks payable to the Lymphoma Research Foundation.
Charge my n Amex n Visa n MasterCard
Credit Card #
Exp. Date
Name
Address
City
State
Telephone (day)
(evening)
Zip Code
Email address
Understanding Childhood Non-Hodgkin Lymphoma 75
Please refer to our website for additional
and updated information.
lymphoma.org
76 Understanding Childhood Non-Hodgkin Lymphoma
Understanding Non-Hodgkin Lymphoma 77
This project is supported through Cooperative Agreement Number
1U58DP001110 from the Centers for Disease Control and Prevention.
Its contents are solely the responsibility of the authors and do not
necessarily represent the official views of the Centers for Disease
Control and Prevention.