Childhood Non-Hodgkin Lymphoma

Transcription

1 Understanding Childhood Non-Hodgkin Lymphoma A Guide for Patients, Survivors and Loved Ones First Edition

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3 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 (212) phone (212) fax Helpline: (800) Helpline@lymphoma.org Website: lymphoma.org LRF@lymphoma.org This project is supported through Cooperative Agreement Number 1U58DP 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 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.

4 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

5 Table of Contents Introduction....1 Chapter 1 Cancer Overview... 3 Lymphoma Overview... 3 Non-Hodgkin Lymphoma Overview... 6 Common Types of Childhood Non-Hodgkin Lymphoma The Causes of Non-Hodgkin Lymphoma in Children... 9 Chapter 2 Diagnosing Childhood Non-Hodgkin Lymphoma Use of Conscious Sedation When Performing Diagnostic Tests Common Diagnostic Tests Staging 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 Chapter 4 Treatment Chemotherapy Radiation What Happens If Relapse Occurs? Chapter 5 Supportive Care Side Effects of Treatment 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 Chapter 7 Long-Term and Late Effects Glossary of Medical Terms Resources Childhood Cancer Resources Young Adult Cancer Resources About the Lymphoma Research Foundation Donate Now Understanding Childhood Non-Hodgkin Lymphoma iii

6 Please refer to our website for additional and updated information. lymphoma.org iv Understanding Childhood Non-Hodgkin Lymphoma

7 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 ( aboutlymphoma). If you are looking for resources on children diagnosed with Hodgkin lymphoma, please visit the Leukemia and Lymphoma Society s website ( 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

8 Please refer to our website for additional and updated information. lymphoma.org 2 Understanding Childhood Non-Hodgkin Lymphoma

9 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 non- Hodgkin 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

10 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 Appendix Peyer s patches (inside the abdomen) Bone marrow Lymph nodes Lymphatic vessels 4 Understanding Childhood Non-Hodgkin Lymphoma

11 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

12 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

13 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

14 Common Types of Childhood Non-Hodgkin Lymphoma Childhood NHL Lymphoblastic Lymphoma Mature B-Cell Lymphoma Anaplastic Large Cell Lymphoma (ALCL) Other Rare Subtypes: (PTCL/NK) Diffuse Large B- Cell Lymphoma (DLBCL) 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

15 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

16 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

17 Chapter 2 Diagnosing Childhood NHL 2 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

18 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

19 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. 2 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

20 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

21 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. 2 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

22 Stage Description Staging I II III IV The 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). The 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. The 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. The 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

23 Chapter 3 Childhood Cancer Clinical Trials 3 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

24 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

25 Name of the trial Drugs used in the trial Schedule of treatment What to expect during treatment 3 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 Physician Discusses Details of Clinical Trial with Parents (process known as informed consent ) Children are Closely Monitored Throughout Treatment Treatment Begins Parents Consent on Behalf of Their Children Understanding Childhood Non-Hodgkin Lymphoma 19

26 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

27 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. 3 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

28 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) 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

29 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. 4 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

30 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

31 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. 4 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

32 Lymphoma Protocol Name Drugs Used Details Subtype Lymphoblastic lymphoma 1. Berlin-Frankfurt- Munster (BFM) Study 1. BFM Study Vincristine Corticosteroids Anthracyclines L-asparaginase 6-thioguanine No Children s Oncology Group (COG) clinical trials were open at the time of this guide s printing. 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 Diffuse large B-cell lymphoma and Burkitt lymphoma 1. Berlin-Frankfurt- Munster (BFM) Study 1. BFM Study Vincristine Corticosteroids Anthracyclines L-asparaginase 6-thioguanine COG recently completed a pilot study incorporating rituximab (Rituxan) into the LMB backbone. 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 Treatment can range from 24 months to several years. Rare Subtypes Treatment protocols may vary by institution. Discuss treatment options with physician. 26 Understanding Childhood Non-Hodgkin Lymphoma

33 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? 4 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

34 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

35 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) 4 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

36 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

37 Transplants are performed in four steps: How Transplants Are Done 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. 4 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