Several large studies have examined the incidence and spectrum of second malignant neoplasms (SMNs) in childhood cancer survivors, in whom the cumulative risk at 20 years posttreatment varies from 3% to 10% and is three to 20 times greater than that expected in the general population. The magnitude of risk and the type of second cancers substantially differ according to the primary malignancy; the type, dose, and combinations of therapy received; and the presence of genetic predispositions.[1] A number of treatment-related risk factors have been identified. Notably, radiation therapy is associated with the development of solid tumors as well as leukemia. This risk appears to be highest when exposure occurs at a young age, and increases with total dose of radiation and time interval following irradiation for solid tumors.[1-3] Alkylating agents, platinums, and topoisomerase II inhibitors are associated with the development of leukemia.[2-13] Epipodophyllotoxins are known to increase the risk for secondary leukemia, and anthracyclines may also increase this risk after treatment for solid tumors.[14] The more commonly reported second cancers in childhood cancer survivors are breast, thyroid and bone cancers, and therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML). T-MDS/AML has been associated with specific chemotherapeutic agents, such as alkylating agents and topoisomerase II inhibitors.[3,6] A dose-dependent relationship is noted with alkylating agents, which typically cause t-MDS/AML after latencies of 5 to 10 years. Cytogenetic abnormalities in the alkylating agent-associated t-MDS/AML characteristically involve chromosomes 5 or 7. T-MDS/AML associated with exposure to topoisomerase II inhibitors classically has a shorter latency, no preceding dysplastic phase, and cytogenetic abnormalities involving chromosome 11q23. While the risk of solid tumors continues to climb with increasing follow-up, the risk for t-MDS/AML plateaus after 5 to 10 years.[14]

In an analysis of SMN in the Childhood Cancer Survival Study (CCSS), which excluded patients with retinoblastoma, the standardized incidence ratio (SIR) was 6.4, with a 20-year incidence of 3.2% and an absolute excess risk of 1.88 malignancies per 1,000 years of patient follow-up. Risk of SMN was elevated for all primary childhood cancer diagnoses, with the lowest SIR reported for non-Hodgkin lymphoma (3.2) and the highest for Hodgkin lymphoma (9.7). Risk was elevated for secondary leukemia, lymphoma, central nervous system tumors, soft tissue and bone sarcomas, melanoma, and breast and thyroid cancer, with the lowest SIR reported for lymphoma (1.5) and the higher SIRs reported for breast cancer (16.2) and bone sarcoma (19.1). In multivariate analyses adjusted for radiation exposures, SMNs were independently associated with female sex, younger age at diagnosis of childhood cancer, childhood cancer diagnosis of Hodgkin lymphoma, or soft tissue sarcoma and exposure to alkylating agents.[2] The CCSS has also reported an association between gene polymorphisms in glutathione-S-transferase M1 (GSTM1), glutathione-S-transferase T1 (GSTT1), and XRCC1, and susceptibility to radiation therapy-related SMNs in childhood Hodgkin lymphoma survivors.[15] The risk of leukemia appears to plateau at 10 to 15 years posttherapy, while the risk of second solid malignancies rises with ongoing follow-up, with a lifetime risk still unknown.[2,3,12] The complexity of risk factors associated with secondary malignancies is illustrated by a recent report on secondary sarcomas in childhood cancer survivors, in whom risk was increased by radiation therapy, higher doses of anthracyclines or alkylating agents, a history of other secondary neoplasms, and a primary diagnosis of sarcoma.[16]

Several studies have examined the risk of SMNs in survivors of Hodgkin lymphoma, in whom the incidence of secondary breast and thyroid cancer is particularly high.[17] Survivors of Hodgkin lymphoma are also at increased risk of second leukemia, sarcoma, melanoma, and lung, thyroid, and gastrointestinal cancer. Female patients treated with mantle radiation for Hodgkin lymphoma before age 30 years are at a significantly higher risk of developing radiation-related breast cancer, in comparison with those treated in their adult years. Female survivors of Hodgkin lymphoma may also be an increased risk for non-breast secondary malignancies.[1,18] Although these data suggest an increased risk in female survivors, even after accounting for breast cancer, other studies exist that do not demonstrate this association. This variation in data illustrates the complexities of analysis that relate to population selection and differences in therapy administered. While the gender effect is not consistent among studies, diagnosis at younger age and therapy for relapsed disease are uniformly associated with increased risk.[2-5,8,9,12,19-22]

Several studies have reported an association between the treatment of neuroblastoma and the development of SMNs. Survivors of neuroblastoma treated with alkylating agents, topoisomerase II inhibitors, (131)I-metaiodobenzylguanidine [(131)I-MIBG], platinums, and/or radiation have an increased risk of developing secondary leukemias, bone marrow disorders (e.g., myelodysplastic syndrome), as well as some solid tumors (e.g., breast cancer and thyroid cancer).[2,23-27] Patients who undergo bone marrow transplantation have a risk of developing SMNs, especially solid tumors. This increased risk has been observed even 20 years posttransplant.[28]

Until more is learned about the pathophysiology of SMNs and the interindividual variation in susceptibility, targeted preventive strategies are limited. For the future, children who received radiation or chemotherapeutic agents with known carcinogenic effects should be so informed and should be seen regularly by a health care provider who is familiar with their treatment and risks and who can evaluate early signs and symptoms appropriately.

Genetic Predisposition to Cancer

Patients may be at risk of SMNs by virtue of a cancer predisposition syndrome, which also placed them at risk for their primary cancer. This limited population should be targeted for education, counseling, and extraordinary surveillance because of their genetic predisposition to cancer.[29] This includes children with the genetic form of retinoblastoma. In these individuals, the SMN risk approaches 50% at 50 years from treatment if they received external-beam radiation therapy, and 25% at 50 years from treatment without previous radiation therapy treatment.[30,31] Data from the Netherlands demonstrate the spectrum of second malignancies that can occur in this setting, notably epithelial cancers (lung, bladder, and breast) in addition to the known occurrence of sarcomas. In this report, the cumulative incidence of any second malignancy 40 years after treatment for retinoblastoma approached 30%.[32] Neurofibromatosis also increases the risk of additional neoplasms, some not associated with therapy.[33,34] Breast cancer at an early age, sarcoma, and other cancers can be expected in children with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome.[35,36] Since hepatoblastoma and fibromas have been associated with familial polyposis coli, children with those tumors should be examined for the polyposis gene (APC) and screened for colon cancer, as appropriate.[37,38]

Full understanding of the pathogenesis of SMNs requires further study of the additive risks or protective effects in treated patients conferred by environmental exposures, dietary influences, and viral exposures. Genetic studies, including the investigation of polymorphisms in genes encoding for xenobiotic metabolizing and DNA-repair enzymes, may provide valuable information on genotype-environment interactions and interindividual susceptibility. Children’s Oncology Group studies of Hodgkin disease are addressing such issues.[39]

References

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