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Changes in chemotherapy protocols have influenced the risk and rate of secondary malignancies in high-risk populations. The alkylating agents, topoisomerase inhibitors, and anthracycline agents pose the highest risk of initiating carcinogenesis. Normal cells that are especially sensitive to chemotherapy and most likely to begin carcinogenesis include those of the bone marrow, hair follicles, and the epithelial cells of the gastrointestinal tract. Thus, the development of secondary hematologic cancers such as leukemia and lymphoma pose the greatest risk to adult and childhood cancer survivors. Lifelong surveillance is recommended.