APPENDIX A

Types of Childhood Cancer

Childhood cancers are classified primarily by histology into 12 major categories using the International Classification of Childhood Cancers. The distribution of the most common types of childhood cancers (incidence and mortality, under age 20) are shown in Figures 1 and 2, respectively.

The major categories of childhood cancer are described below (Ries et al., 2002).

Leukemias

Description: The leukemias are the most common childhood cancers, accounting for 26 percent of cancers occurring before age 20. The two main types of childhood leukemia are acute lymphoblastic leukemia (ALL), accounting for about three-fourths of leukemias, and acute myeloid leukemia (AML), accounting for most of the remainder. ALL is a malignancy of lymphoid cells, a type of white blood cells found primarily in blood, bone marrow, lymph nodes, the spleen, the liver, and the thymus. AML is a malignancy of the granulocyte family of white blood cells, found mainly in blood and bone marrow.

Treatment and Survival: Treatment for ALL generally consists of discrete phases of therapy that span 2.5 to 3.5 years. These phases include remission induction, consolidation (including preemptive central nervous system [CNS] treatment), intensification therapy, and maintenance therapy. Remission is successfully induced in approximately 98 percent of children with ALL. Depending on the risk category of the leukemia, at least three drugs are used for remission induction therapy administered over 4 weeks: vincristine (Oncovin), L-asparaginase, and a glucocorticoid (prednisone or dexamethasone). CNS preventive therapy historically included cranial radiation, but due to its long-term deleterious effects, therapy now relies primarily on intrathecal (into the spinal fluid) chemotherapy with methotrexate, or cytarabine, and in select patients, with the addition of systemic high-dose chemotherapy. Intensification therapy utilizes a number of chemotherapeutic drugs that may include daunorubicin or doxorubicin, vincristine, L-asparaginase, a glucocorticoid, cyclophosphamide, cytarabine, thioguanine, and etoposide. Maintenance therapy lasts approximately 3 years and relies primarily on oral methotrexate and 6-mercaptopurine, with monthly administration of vincristine and a glucocorticoid, as well as intrathecal injections of methotrexate with or without cytosine arabinoside and hydrocortisone every 3 months (Smith, 2002). Five-year relative sur-



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Making Better Drugs for Children with Cancer APPENDIX A Types of Childhood Cancer Childhood cancers are classified primarily by histology into 12 major categories using the International Classification of Childhood Cancers. The distribution of the most common types of childhood cancers (incidence and mortality, under age 20) are shown in Figures 1 and 2, respectively. The major categories of childhood cancer are described below (Ries et al., 2002). Leukemias Description: The leukemias are the most common childhood cancers, accounting for 26 percent of cancers occurring before age 20. The two main types of childhood leukemia are acute lymphoblastic leukemia (ALL), accounting for about three-fourths of leukemias, and acute myeloid leukemia (AML), accounting for most of the remainder. ALL is a malignancy of lymphoid cells, a type of white blood cells found primarily in blood, bone marrow, lymph nodes, the spleen, the liver, and the thymus. AML is a malignancy of the granulocyte family of white blood cells, found mainly in blood and bone marrow. Treatment and Survival: Treatment for ALL generally consists of discrete phases of therapy that span 2.5 to 3.5 years. These phases include remission induction, consolidation (including preemptive central nervous system [CNS] treatment), intensification therapy, and maintenance therapy. Remission is successfully induced in approximately 98 percent of children with ALL. Depending on the risk category of the leukemia, at least three drugs are used for remission induction therapy administered over 4 weeks: vincristine (Oncovin), L-asparaginase, and a glucocorticoid (prednisone or dexamethasone). CNS preventive therapy historically included cranial radiation, but due to its long-term deleterious effects, therapy now relies primarily on intrathecal (into the spinal fluid) chemotherapy with methotrexate, or cytarabine, and in select patients, with the addition of systemic high-dose chemotherapy. Intensification therapy utilizes a number of chemotherapeutic drugs that may include daunorubicin or doxorubicin, vincristine, L-asparaginase, a glucocorticoid, cyclophosphamide, cytarabine, thioguanine, and etoposide. Maintenance therapy lasts approximately 3 years and relies primarily on oral methotrexate and 6-mercaptopurine, with monthly administration of vincristine and a glucocorticoid, as well as intrathecal injections of methotrexate with or without cytosine arabinoside and hydrocortisone every 3 months (Smith, 2002). Five-year relative sur-

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Making Better Drugs for Children with Cancer vival5 for children with ALL diagnosed in the 1990s was more than 80 percent, up from about 50 percent for children diagnosed in the 1970s (U.S. Cancer Statistics Working Group, 2004). AML is treated with a number of cytotoxic drugs, but therapy relies primarily on cytarabine and an anthracycline, daunorubicin, or idarubicin. Additional drugs may include etoposide, cyclophosphamide (or other alkylating agents), mitoxantrone, and thioguanine. Therapy is significantly more intensive than for ALL, and results in prolonged periods of myelosuppression with a concomitant high risk of infection. Bone marrow transplantation is used in certain cases. Survival is poorer than for ALL, at 45 to 50 percent 5-year survival. Survival, however, has improved since the 1970s, when the corresponding figure was about 15 percent. The exception to this intensive treatment paradigm is acute promyelocytic leukemia (APL), a subtype of AML that relies on differentiation therapy with retinoic acid in addition to chemotherapy, with significantly better outcomes. Central Nervous System Tumors and Miscellaneous Intracranial and Intraspinal Neoplasms Description: CNS tumors make up the second largest category of neoplasms in children, accounting for 17 percent of cancers in people under age 20. More than half of all CNS malignancies in children and adolescents are gliomas or astrocytomas (tumors that arise from star-shaped brain cells called astroctyes). Other common pediatric brain tumors include medullo-blastomas (fast-growing tumors located most commonly in the cerebellum), brainstem gliomas, ependymomas, and optic nerve gliomas. Treatment and Survival: Treatment for CNS tumors can include surgery, chemotherapy, and radiation therapy. Surgical resection is the most widely used approach for a lower grade astrocytoma, which is the most common pediatric brain tumor (Bumol and Watanabe, 2001; Reis et al., 2001). Other CNS tumors require radiation therapy as a mainstay of treatment. Because significant growth and neurologic development problems have been associated with cranial irradiation therapy, the role of chemotherapy in delaying or avoiding radiation therapy is currently being studied (Phillips et al., 1998; Butte et al., 2000; Lightcap et al., 2000). Chemotherapy in conjunction with surgery and radiation is increasingly being used for a number of pediatric CNS tumors. 5   The relative survival rate reflects only deaths from cancer. It is calculated by adjusting the survival rate to remove all causes of death except cancer.

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Making Better Drugs for Children with Cancer The prognosis for different types of CNS and brain tumors varies tremendously, but overall 5-year relative survival rates are above 70 percent for children diagnosed in the 1990s, up from about 55 percent for those diagnosed in the 1970s. Children with brainstem gliomas, glioblastoma multiforme, and tumors that have spread throughout the CNS continue to fare poorly despite aggressive treatment. Neuroblastoma and Other Sympathetic Nervous System Tumors Description: Cancers in this category account for 5 percent of childhood cancers (under age 20) and are among the most common cancers diagnosed in the first year of life. Neuroblastoma, the most common extracranial solid tumor of childhood, accounts for virtually all cases under age 1. Neuroblastoma is a solid tumor that may begin in nerve tissue in the neck, chest, abdomen, or pelvis, but usually originates in the abdomen in the adrenal gland. In contrast to central nervous system malignancies, survival is highest among infants under 1 year of age, and declines with increasing age. Treatment and Survival: Treatment ranges from observation only in infants with a distinct subtype of neuroblastoma, to aggressive therapy with surgery, radiation therapy, chemotherapy, and stem-cell transplantation for older children. Overall, the 5-year relative survival for children with sympathetic and allied nervous system tumors has improved, but older children with disseminated disease continue to fare poorly. Lymphomas and Other Reticuloendothelial Neoplasms Description: Lymphomas (cancers of the lymphatic system) and other reticuloendothelial neoplasms account for 15 percent of childhood cancers (under age 20), and are divided into two broad diagnostic categories: Hodgkin’s and non-Hodgkin’s lymphoma (NHL). Non-Hodgkin’s lymphoma includes lymphoblastic lymphoma (usually a T-cell lymphoma similar to childhood ALL), Burkitt’s and Burkitt’s-like lymphomas, diffuse large B-cell lymphomas, and anaplastic large-cell lymphomas. Treatment and Survival: Treatment of Hodgkin’s lymphoma differs significantly from treatment of NHL, and usually includes chemotherapy, radiation therapy, or both. Treatment for Hodgkin’s lymphoma has evolved to rely less on radiation therapy because of long-term side effects, and more on cytotoxic chemotherapy. Treatment for lymphoblastic lymphoma parallels ALL therapy, though it is generally of shorter duration. For other types of NHL, treatment relies on combination chemotherapy, including both systemic chemotherapy and intrathecal chemotherapy. Treatment of Burkitt’s

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Making Better Drugs for Children with Cancer lymphoma uses dose-intensive chemotherapy, relying primarily on cyclophosphamide and high-dose methotrexate administered over a 4- to 6-month period along with intrathecal therapy. The 5-year relative survival rate for Hodgkin’s disease has risen to more than 95 percent for children diagnosed in the 1990s, compared with about 80 percent in the 1970s. For NHL, 5-year relative survival is about 80 percent for 1990s diagnoses, a major increase from the 1970s, when survival was about 45 percent. Soft-Tissue Sarcomas Description: Soft-tissue sarcomas account for about 6 percent of childhood cancers (under age 20). Rhabdomyosarcoma, a malignant disease of muscle, is the most common soft-tissue tumor among children younger than age 15. Other sarcomas are more common among older teenagers. Treatment and Survival: Surgery is the mainstay of treatment of the soft-tissue sarcomas. For rhabdomyosarcoma, chemotherapy is required and includes, at a minimum, the combination of vincristine and actinomycin-D. In most cases radiation therapy is also required. The 5-year relative survival rate for soft-tissue sarcomas is about 72 percent for teenagers diagnosed in the 1990s, up from about 60 percent in the 1970s. Malignant Bone Tumors Description: Malignant bone tumors account for 6 percent of childhood cancers (under age 20). Osteosarcoma is the most common cancer in this category, which in children often occurs in the bones surrounding the knee. Ewing’s sarcoma and the related peripheral primitive neuroectodermal tumor is a rare cancer that arises in bone or soft tissue and usually occurs during adolescence. Treatment and Survival: Surgery is essential to the treatment of osteosarcoma. Chemotherapy regimens for localized and metastatic osteosarcoma currently include combinations of high-dose methotrexate, doxorubicin, and cisplatin (Hollingshead et al., 1995; Pearce, 1995; Connors, 1996; Von Hoff, 1998; Houghton et al., 1998; Eisenhauer, 1998; Kerbel, 1998/99). Ewing’s sarcoma utilizes surgery and/or radiation for local tumor control. Chemotherapy regimens include vincristine, doxorubicin, cyclophosphamide, etoposide, and ifosfamide. Five-year relative survival rates have improved substantially over time,

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Making Better Drugs for Children with Cancer to 60 to 70 percent for children diagnosed in the late 1990s. Outcomes for children with metastatic disease remain poor. Renal Tumors Description: Renal tumors account for 4 percent of childhood cancers (under age 20). Wilms’ tumors account for more than 90 percent of malignancies of the kidney among children and adolescents, usually affecting those younger than age 5. Treatment and Survival: Wilms’ tumor therapy is based on the stage of disease. Surgical removal of the affected kidney is required. Treatment also includes chemotherapy and in select cases radiation. Five-year relative survival rates have improved for Wilms’ tumor from about 80 percent in the 1970s to better than 90 percent in the late 1990s. Current treatment efforts are aimed at minimizing long-term effects, and improving the outcome for the less common non-Wilms’ renal tumors. Retinoblastoma Description and Survival: Accounting for 2 percent of childhood cancers, retinoblastoma is a rare tumor involving the retina of the eye, or sometimes the pineal gland. Five-year relative survival is about 94 percent and has not changed over the past two decades. Treatment advances have been targeting preservation of vision. Germ Cell, Trophoblastic, and Other Gonadal Neoplasms Description and Survival: This category accounts for 7 percent of childhood cancers (under age 20), occurring commonly in teenagers. Germ cell tumors develop from testicular or ovarian cells. The 5-year relative survival for testicular cancers in teenage boys was about 90 percent for those diagnosed in the 1990s, up from about 55 percent in the 1970s. The figures for teenage girls with ovarian cancer are 94 percent in the 1990s and 70 percent in the 1970s.