3
The Trajectory of Childhood Cancer Care

In recognition of the toll its late effects have on health, cancer is increasingly being viewed as a chronic disease. This chapter first describes the entire spectrum of care for childhood cancer from diagnosis and treatment to later stages, including surveillance, rehabilitation, palliation, and end-of-life care. The chapter then provides a brief overview of the treatment of childhood cancer. Childhood cancers are a diverse set of diseases and the treatment of different types of cancer varies considerably, and within each type of cancer, the intensity and approach used may vary. For this reason, there is no clear map between a particular type of cancer and late effects. Instead, the specifics of disease and treatment dictate the likelihood of late effects. Chapter 4 explores the implications of treatment for later health and quality of life.

PHASES OF CARE

Diagnostic Evaluation

The symptoms related to childhood cancer that prompt parents to seek care are often non-specific in nature and may be similar to those of the flu or other common ailments. While symptoms may prompt parents to seek evaluation, a suspicion of cancer sometimes emerges during a routine well-child care visit. Because symptoms may mimic other common pediatric problems and because childhood cancers are rare, the correct diagnosis may be delayed. Diagnosis often begins with the primary care provider’s physi-



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3 The Trajectory of Childhood Cancer Care In recognition of the toll its late effects have on health, cancer is increasingly being viewed as a chronic disease. This chapter first describes the entire spectrum of care for childhood cancer from diagnosis and treatment to later stages, including surveillance, rehabilitation, palliation, and end-of-life care. The chapter then provides a brief overview of the treatment of childhood cancer. Childhood cancers are a diverse set of diseases and the treatment of different types of cancer varies considerably, and within each type of cancer, the intensity and approach used may vary. For this reason, there is no clear map between a particular type of cancer and late effects. Instead, the specifics of disease and treatment dictate the likelihood of late effects. Chapter 4 explores the implications of treatment for later health and quality of life. PHASES OF CARE Diagnostic Evaluation The symptoms related to childhood cancer that prompt parents to seek care are often non-specific in nature and may be similar to those of the flu or other common ailments. While symptoms may prompt parents to seek evaluation, a suspicion of cancer sometimes emerges during a routine well-child care visit. Because symptoms may mimic other common pediatric problems and because childhood cancers are rare, the correct diagnosis may be delayed. Diagnosis often begins with the primary care provider’s physi-

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cal examination and laboratory studies and later involve pediatric oncologists, radiologists, surgeons, and pathologists who may conduct surgical biopsies, laboratory and pathological studies, imaging tests (e.g., computed tomographic scans, magnetic resonance imaging scans), and assessments of family history. Primary and Adjuvant Treatment The treatment of childhood cancers is complex, involving the consideration of many factors, including characteristics of the cancer (e.g., its type, site, stage, and histology) and of the child (e.g., his or her age, presence of symptoms, and general health). In general, most children with cancer are treated using chemotherapy, surgery, radiation therapy, or a combination of two or more of these modalities. Although there are exceptions, childhood cancers tend to respond well to chemotherapy because they involve fast-growing cells, the target of most forms of chemotherapy. Many of the gains in childhood cancer survival have come through the development of combination chemotherapies (use of multiple agents) and multimodality therapy (the application of different types of treatment). While there are some accepted standard forms of therapy, an estimated 60 percent of children treated for cancer participate in clinical trials, which may involve variations in standard treatment, new combinations of agents, variations in doses of chemotherapy or radiation, use of alternate methods of administration, or entirely new approaches to therapy (e.g., immunotherapy). As information regarding late effects of treatment has emerged, therapies for childhood cancer have been informed and modified. There has, for example, been a reduction of dose or an elimination of the craniospinal radiation used to treat children with leukemia in an effort to reduce the risk of treatment-related adverse events such as growth and cognitive deficits. Since the introduction of more aggressive chemotherapies in the 1980s, however, other late effects such as damage to the heart, kidney, and hearing have been noted. Primary Care Children treated for cancer generally maintain their relationship with their primary care pediatrician for preventive care, health maintenance, and acute care. Following primary treatment for cancer, children resume care with their pediatrician, family practitioner, or internist. Their primary care provider must acquire information from the cancer care team on cancer treatment exposures, possible late effects, and guidance on appropriate follow-up care.

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Posttreatment Surveillance and Follow-Up Care The follow-up phase of care is the time after completion of the initial course of therapy. Children and young adults may be monitored by their pediatric oncologist following treatment for 3 years or more, depending on the disease, age of the patient, and other factors. Follow-up by pediatric oncologists typically focuses on checking for recurrence. More extensive follow-up might be offered by the treating oncologist or take place through a referral to a comprehensive clinic. Comprehensive follow-up care includes assessment of short- and long-term complications and sequelae of cancer therapies, detection of recurrent and secondary cancers, counseling about behaviors such as smoking to prevent secondary cancers, assessment of psychosocial adjustment and quality of life, and treatment for any identified late effects. Lifelong follow-up is often necessary to identify problems following cancer treatment. Such care may be provided in the context of a special late-effects clinic or become an integral part of primary care; however, evidence suggests that follow-up care is not routinely provided (see Chapter 5). Treatment of Recurrent Cancer Cancer may recur in the same part of the body where it was found originally (local recurrence), or it may reappear in a more distant part of the body (metastasis). The type of treatment that is selected for a recurring cancer depends on the specific type of cancer, its size, how it behaves biologically, and what previous therapy was given. Recurrent cancers can be cured, but the likelihood of cure is usually far lower than it is for the initial treatment of cancer. If childhood cancer recurs, it usually does so in the first few years following treatment. Late effects are predictably more frequent and severe in survivors treated for relapse. Psychosocial Assessment and Supportive Care The diagnosis of cancer in a child constitutes a family crisis—normal daily life is disrupted, and shock, disbelief, and grief may interfere with parents’ ability to cope with new information and the need to make decisions. Children may be fearful and in pain, and may react with unusual behavior and moods. Families may benefit from the services of psychologists, social workers, and oncology nurses as they attempt to cope with the diagnosis and subsequent treatment. As patients and their families complete primary treatment, sources of continued support may include community-based parent self-help organizations (e.g., Candlelighters Childhood Cancer Foundation), cancer survivor day celebrations, oncology camps,

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Box 3.1 Complementary and Alternative Medicine Many children with cancer use at least one form of complementary or alternative medicine (CAM) to treat their disease or cope with the side effects of conventional medicine. According to a recent population-based survey in western Washington State, where insurance companies are required by law to cover licensed alternative providers, nearly three-quarters of families of children 18 and younger being treated for cancer reported using CAM. The CAM therapies reported most often were dietary supplements, followed by alternative providers, and specifically, naturopathic doctors and massage therapists. None of the parents reported using alternative medicine instead of conventional care. Parents who were dissatisfied with their child’s doctor were nine times more likely to use CAM than satisfied parents. Although parents rarely forego standard therapy in favor of CAM for their children with cancer, those that do have been prosecuted for failing to obtain standard care. Providers are advised to ask parents and children of CAM use. Given the evident widespread use of CAM, research is needed to assess its potential risks and benefits. Some herbs have been shown to increase the risk of heart and kidney problems, while certain vitamins may reduce the effectiveness of chemotherapy. CAM should be held to the same standards of efficacy, safety, and reimbursement as traditional medicine. and family retreats. Cancer survivors benefit from information about late effects, health insurance, family planning (including genetic counseling), and educational and vocational issues. Those with persistent distress and adjustment difficulties may need counseling and/or peer support (Cella and Tross, 1986; Roberts et al., 1997). Rehabilitative Services An array of rehabilitative services may be needed following primary treatment, including physical and occupational therapy, speech and language therapy, and supportive services available at schools. Palliative Care Therapy intended specifically to relieve symptoms, ease distress, provide comfort, and in other ways improve the quality of life of someone with cancer is an important part of quality cancer care, but unfortunately is often not adequately provided (Institute of Medicine, 2001). This care may be referred to as palliative care, supportive care, or comfort care, and is important at any stage of cancer care management.

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End-of-Life Care One-fourth of children newly diagnosed with cancer can expect to die of their disease within 5 years, making death and end-of-life care important issues that must be addressed. In 2000, an estimated 2,300 children and young adults died of cancer. End-of-life care is diverse and can include the management of physical or emotional symptoms and limitations of function, provision of pain relief and palliation to improve or maintain the quality of remaining life, family respite, social support, and bereavement support. Hospice care is an approach to care during the final stages of life, but hospices generally have little experience with children (Institute of Medicine, 2001). TREATMENT OF CHILDHOOD CANCER Treatment has changed greatly over the years, with greater reliance on combinations of modes of therapy (i.e., chemotherapy, radiation, surgery) and regimens of progressively reduced chronic toxicity (e.g., reductions in radiation dose), which are intended to minimize the likelihood of late effects. Typically, a child treated in the 1960s and 1970s would receive more radiation and chemotherapy with alkylating agents than a child treated in the late 1990s. Neurologic and reproductive late effects, growth retardation, and second cancers were associated with these treatment regimens. This older cohort of survivors, now approaching middle age, is at greater risk of late effects of treatment than those treated more recently. New types of chemotherapy introduced in the 1980s (e.g., daunomycin, doxorubicin, platinum compounds, ifosfamide) are used aggressively. While they have improved survival, they have also contributed to a new constellation of late effects (e.g., damage to the heart, kidney, and hearing). Most children with cancer are exposed to a combination of two or three therapies. According to evidence from a large cohort of 5-year survivors of childhood cancer diagnosed between 1970 and 1986 (the Childhood Cancer Survivor Study [CCSS]), 44 percent had been treated by a combination of chemotherapy, radiation, and surgery (Table 3.1) (Robison et al., 2002). The treatment of many cancers involves a unique set of therapies that can lead to a signature constellation of late effects. Many chemotherapeutic agents are used in the treatment of childhood cancer. Table 3.2 shows the agents most frequently used to treat a cohort of 5-year cancer survivors diagnosed between 1970 and 1986 and followed up as part of the Childhood Cancer Survivor Study (Robison et al., 2002). At that time, the most commonly administered chemotherapeutic agents were dactinomycin, cyclophosphamide, doxorubicin, L-asparaginase, 6-mercaptopurine, methotrexate, prednisone, and vincristine.

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TABLE 3.1 Treatment Experience of the Childhood Cancer Survivor Study Cohort (n = 20,276) Treatment modality Percent • Any chemotherapy 79 • Any radiation 68 • Any surgery 83 One therapy only • Chemotherapy only 6 • Surgery only 8 • Radiation only <1 Two therapies • Chemotherapy + surgery 18 • Chemotherapy + radiation 11 • Radiation + surgery 13 Three therapies • Chemotherapy + radiation + surgery 44   SOURCE: Robison et al., 2002. What follows is a brief and simplified overview of common approaches to cancer treatment, many of which have implications for subsequent late effects.1 Information on the epidemiology of childhood cancer can be found in Chapter 2. Leukemias Primary treatment for acute lymphoblastic leukemia (ALL) involves combination chemotherapy. However, no single standard regimen exists, as proper treatment is based on the patient’s prognosis, which is determined by cytogenetic, immunologic, and molecular information. There are generally four phases of treatment: Remission induction therapy uses chemotherapy to eliminate as many of the leukemia cells as possible to cause the cancer to go into remission. Central nervous system (CNS) prophylaxis involves intrathecal (che 1   For more information about treatment of childhood cancers see the National Cancer Insitute’s PDQ® Cancer Information Summaries at http://www.cancer.gov/cancerinfo/pdq/treatment/.

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motherapy injected into the spinal canal) and/or high-dose systemic chemotherapy to eliminate leukemia cells present in the brain and spinal fluid, even if no cancer has been detected there by routine testing. For this purpose, radiation therapy to the brain may be added to chemotherapy in special circumstances. Radiation to the brain is generally not used for children under age 2. The third phase of treatment, consolidation or intensification therapy, begins once a child goes into remission and there are no more signs of leukemia. Consolidation therapy involves high-dose chemotherapy in an attempt to eliminate any remaining leukemia cells. Maintenance therapy uses chemotherapy for two or more years to attempt to continue destruction of residual leukemia and to effect a cure. Bone marrow transplantation is used for children with ALL under special poor-risk situations, when conventional treatment fails or as part of clinical trials. The primary treatment for acute myeloid leukemia (AML) is chemotherapy, sometimes followed by bone marrow transplantation. Radiotherapy is an important component for the most successful marrow transplant regimens for this disease. Biological therapy (e.g., immunotherapy) is being evaluated in clinical trials. Treatment for AML usually involves induction and consolidation as described above, sometimes followed by an intensification phase (another course of chemotherapy). Therapy may also involve CNS prophylaxis and radiation to the brain. Central Nervous System and Miscellaneous Intracranial and Intraspinal Neoplasms Treatment for brain tumors usually consists of a combination of surgery, radiation, and chemotherapy. In some cases, bone marrow transplantation and peripheral blood stem cell transplants are also used. The specific location of the tumor in the brain, e.g., whether there is involvement of vital centers, usually determines how extensive or life-threatening the treatment is. Determinants of therapy include the tumor’s classification (origin of the tumor cells), grade (degree of malignancy), and stage (extent of tumor spread). Nearly complete removal of the tumor is often possible with surgery, but complete removal of all gross and microscopic cancer is rare. Radiation therapy and/or chemotherapy usually follow surgery if the tumor cannot be completely removed. Clinical trials are evaluating radiation therapy given in several small doses per day (hyperfractionated radiation therapy). Other trials are testing ways to decrease or delay radiation therapy, especially for younger children. Researchers are also studying whether chemotherapy can be used as a means of delaying, modifying or

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TABLE 3.2 Chemotherapeutic Agent Use (percent) Among CCSS Participants, by Diagnosis Agent Total (n = 12,455) Leukemia (n = 4,215) CNS (n = 1,642) Bleomycin 6 <1 <1 Carmustine (BCNU) 4 5 3 Cisplatin 6 <1 10 Cyclophosphamide-PO 8 10 1 Cyclophosphamide-IV 40 48 7 Cytarabine-IV/IM 18 43 6 Cytarabine-IT 14 36 <1 Cytarabine-SQ 4 11 0 Dacarbazine (DTIC) 5 <1 2 Dactinomycin 20 2 2 Daunorubicin 13 33 <1 Dexamethasone 8 14 8 Doxorubicin 32 31 1 Etoposide (VP16)-IV 7 12 3 Hydroxyurea 4 4 8 Ifosfamide 1 1 1 L-Asparaginase 31 85 <1 Lomustine (CCNU) 4 <1 17 Mechlorethamine (N Mustard) 6 <1 3 Mercaptopurine (6-MP) 31 86 <1 Methotrexate-PO 28 72 1 Methotrexate-IV 22 40 1 Methotrexate-IM 4 10 0 Methotrexate-IT 36 89 2 Prednisone 47 93 10 Procarbazine 10 <1 14 Teniposide (VM-26) 5 11 1 Thioguanine 9 22 2 Vinblastine 5 1 <1 Vincristine 72 96 23 NOTE: PO = per os (by mouth); IV = intravenous; IM = intramuscular; IT = intrathecal; SQ = subcutaneous. Limited to participants with complete abstraction of medical records. eliminating the need for radiation therapy in younger patients, as well as prior to or during radiation therapy. Lymphomas and Other Reticuloendothelial Neoplasms The main treatment for non-Hodgkin’s lymphoma is chemotherapy (systemic and intrathecal). Radiation therapy is rarely used for the primary

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HD (n = 1,685) NHL (n = 908) Kidney (n = 1,068) Neuroblastoma (n = 823) Soft tissue sarcoma (n = 1,079) Bone cancer (n = 1,035) 22 6 <1 <1 4 25 3 20 0 <1 1 2 1 2 2 13 10 27 1 5 <1 27 17 10 22 84 8 43 56 64 2 31 <1 2 1 1 <1 22 <1 <1 4 <1 <1 7 0 0 0 0 16 <1 <1 20 8 4 <1 3 98 2 71 52 0 29 <1 <1 <1 <1 3 8 1 2 4 9 25 32 42 27 44 82 3 5 3 2 7 6 <1 20 0 1 <1 <1 <1 1 2 1 4 6 0 32 0 0 0 0 10 4 0 <1 <1 <1 39 2 <1 4 1 1 <1 29 0 0 <1 0 <1 41 0 0 <1 1 1 42 0 1 6 51 0 4 0 0 <1 <1 <1 75 <1 1 4 1 51 87 1 2 2 2 62 2 0 1 <1 <1 <1 5 <1 10 1 <1 <1 25 <1 0 0 0 30 3 1 1 1 1 55 90 91 37 73 65 Only commonly used agents are listed (greater than 5 percent use in any diagnostic group). SOURCE: Adapted from Robison et al., 2002. treatment of non-Hodgkin’s lymphoma. The most common treatments for Hodgkin’s disease are radiation therapy and/or chemotherapy, but treatment may depend on the stage of the cancer and whether the child has reached full growth. Lymphomas can start in almost any part of the body and the cancer can spread to almost any organ or tissue in the body, including the liver, bone marrow, and the spleen. Treatment depends on the stage of the disease, its location, histology, and whether symptoms are

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present. Bone marrow transplantation is rarely used as a primary therapy for lymphoma, but is being tested in clinical trials for certain patients. Carcinomas and Other Malignant Epithelial Neoplasms Treatment of thyroid cancer may involve surgery (e.g., a partial or complete removal of the thyroid), radiation therapy, hormone therapy, and/or chemotherapy. Surgery is the primary treatment of all stages of melanoma, but treatment may also involve chemotherapy, radiation therapy, or biological therapy. Germ Cell, Trophoblastic, and Other Gonadal Neoplasms The standard approach for childhood germ cell tumors is complete surgical excision of the tumor combined with chemotherapy. Soft Tissue Sarcomas Treatment of rhabdomyosarcoma, the most common soft tissue tumor among children under age 15, depends on tumor size, location, and how far and where the cancer has spread. All children with rhabdomyosarcoma are treated with chemotherapy. Surgery is a common treatment for rhabdomyosarcoma, sometimes in combination with chemotherapy and radiation therapy. Malignant Bone Tumors Surgery is a common treatment for osteosarcoma. Sometimes all or part of an arm or leg may be amputated to maximize the likelihood that all of the cancer is eliminated. In some patients with osteosarcoma that has not spread beyond the bone, limb-sparing surgery can be performed without a recurrence of the cancer. The cancer can be excised without amputation, and artificial devices or bones from other places in the body can be used to replace the bone that was removed. Chemotherapy is usually administered before and/or following surgery (adjuvant chemotherapy). Ewing’s sarcoma, another common tumor of childhood, may be treated by a combination of surgery, chemotherapy, and radiation. Another treatment option is myeloablative therapy with stem cell support. Myeloablative therapy is a very intense regimen of chemotherapy that intentionally destroys most of the bone marrow cells, which are then restored by an infusion of the patient’s own stem cells, or cells from a donor.

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Sympathetic and Allied Nervous System Tumors Treatment options for neuroblastoma are related to age at diagnosis, tumor location, stage of disease, regional lymph node involvement, and tumor biology. Four types of treatment are used, often in combination— surgery, radiation therapy, chemotherapy, and bone marrow transplantation. Renal Tumors Choice of treatment for Wilms’ tumor depends on the tumor’s size, stage, histology and the child’s age and general health. The treatment of Wilms’ tumor usually involves surgery to remove the cancer followed by chemotherapy. Other regimens may also include radiotherapy. Retinoblastoma Therapeutic approaches to retinoblastoma depend on the extent of the disease within the eye, whether the disease is in one or both eyes, and whether the disease has spread beyond the eye. Treatment options include enucleation (surgery to remove the eye); radiation therapy; cryotherapy (the use of extreme cold to destroy cancer cells); photocoagulation (the use of laser light to destroy blood vessels that supply nutrients to the tumor); thermotherapy (the use of heat to destroy cancer cells); and chemotherapy. Pediatric oncologists have modified treatment to improve survival, to preserve vision and cosmetic appearance, and to reduce second cancers. Chemotherapy is used to shrink tumors so that they can be treated focally, thereby avoiding enucleation or radiation in at least 50 percent of eyes (Friedman et al., 2000). Children who have hereditary retinoblastoma may also be at risk of developing a tumor in the brain while they are being treated for the eye tumor. This is called trilateral retinoblastoma, and patients should be periodically monitored for the possible development of this rare condition during and after treatment. Hepatic Tumors Surgery, chemotherapy, radiation therapy, and liver transplantation are all used to treat childhood liver cancers. Surgery may be used to take out the cancer and surrounding tissue. Chemotherapy may be administered before surgery to help reduce the size of the liver cancer and it may be administered after surgery to eliminate any remaining cancer cells. Systemic or direct infusion chemotherapy (drugs injected directly into the blood vessels that go into the liver) may also be administered. Sometimes a

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treatment called chemo-embolization is used to treat childhood liver cancer. This involves injecting chemotherapy drugs into the main artery of the liver with substances that slow or stop tumor growth. SUMMARY AND CONCLUSIONS The trajectory of care for children with cancer spans diagnosis and treatment to later stages, including surveillance, rehabilitation, palliation, and end-of-life care. This report focuses on what happens after treatment, and in particular on the care related to late effects of cancer and its treatment. Childhood cancers are a diverse set of diseases and the treatment of each type of cancer varies considerably; and within each type of cancer, the intensity and approach used may vary depending on the child’s age, general health, and characteristics of the cancer. Because late effects arise following an interaction between the individual with cancer, the cancer, and the specifics of treatment, there is no clear map between a particular type of cancer or a specific treatment and an expected spectrum of late effects. Each factor must be considered in anticipating outcomes. Understanding late effects is further complicated by the constant evolution of treatments; they are, in effect, a moving target. While these aspects pose challenges to researchers and clinicians, patterns of late effects have emerged and their recognition has contributed to an appreciation of cancer as a chronic disease. REFERENCES Cella DF, Tross S. 1986. Psychological adjustment to survival from Hodgkin’s disease. J Consult Clin Psychol 54(5):616-22. Friedman DL, Himelstein B, Shields CL, Shields JA, Needle M, Miller D, Bunin GR, Meadows AT. 2000. Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol 18(1):12-7. Institute of Medicine. 2001. Improving Palliative Care for Cancer. Washington, DC: National Academy Press. Kemper KJ, Wornham WL. 2002. Complementary and Alternative Therapies in Pediatric Oncology. Pizzo PA, Poplack DG (eds). Principles and Practice of Pediatric Oncology. 4th ed. Philadelphia: Lippincott Williams and Wilkins. Pp. 1529-1540. Neuhouser ML, Patterson RE, Schwartz SM, Hedderson MM, Bowen DJ, Standish LJ. 2001. Use of alternative medicine by children with cancer in Washington State. Prev Med 33(5):347-54. Roberts CS, Severinsen C, Carraway C, Clark D, Freeman M, Daniel P. 1997. Life changes and problems experienced by young adults with cancer. Journal of Psychosocial Oncology 15(1):15-25. Robison LL, Mertens AC, Boice JD, Breslow NE, Donaldson SS, Green DM, Li FP, Meadows AT, Mulvihill JJ, Neglia JP, Nesbit ME, Packer RJ, Potter JD, Sklar CA, Smith MA, Stovall M, Strong LC, Yasui Y, Zeltzer LK. 2002. Study design and cohort characteristics of the Childhood Cancer Survivor Study: a multi-institutional collaborative project. Med Pediatr Oncol 38(4):229-39.