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As the population of cancer survivors has increased and continues to age, the occurrence of second cancers has risen dramatically—from 9% of all cancer diagnoses in 1975–1979 to 19% in 2005–2009. The Childhood Cancer Survivor Study, a cohort of more than 14,000 childhood cancer survivors with detailed exposure data and long-term follow-up, has substantially contributed to our understanding of the roles of radiotherapy and chemotherapy in second cancer occurrence. In particular, dose-related risks have been demonstrated for second cancers of the breast, thyroid, central nervous system, gastrointestinal tract, and sarcomas following radiation. Cytotoxic chemotherapy—which has long been known to be leukemogenic—also appears to contribute to risk for a range of other second cancer types. Individuals who develop a second cancer are at particularly high risk for developing additional second cancers. A genome-wide association study of survivors of Hodgkin lymphoma who received radiotherapy identified a locus on chromosome 6q21 as being associated with second cancer risk, demonstrating that recent advances in genomics are likely to prove invaluable for elucidating the contribution of genetic susceptibility to second cancer etiology. Among adults, risk of second cancers varies substantially by type of first and second cancer, patient age, and prevalence of second cancer risk factors, including primary cancer treatments, environmental and lifestyle exposures, and genetic susceptibility. Further research is needed to quantify second cancer risks associated with specific etiologic factors and to identify the patients at highest risk of developing a second cancer to target prevention and screening efforts.

The Rising Incidence of Second Cancers: Patterns of Occurrence and Identification of Risk Factors for Children and Adults