The number of patients with multiple primary cancers is increasing so that second malignant neoplasms now represent approximately 16%, or 1 in 6 cancers reported to the Surveillance, Epidemiology, and End Results (SEER) Program. While some second malignant neoplasms are treatment-related, others are due to genetic susceptibility, lifestyle and environmental exposures, or a combination of factors, according to a review article in a special series on adult cancer survivorship in the Journal of Clinical Oncology.
”The growing number of patients with second (and higher-order) cancers mandates that we also further probe etiologic influences and genetic variants that heighten risk, and that we better define high-risk groups for targeted preventive and interventional clinical strategies,” the authors wrote.
Both radiotherapy and chemotherapy have been associated with second malignant neoplasms. “Hallmarks of radiotherapy-associated cancers include a long latency period of at least 5 to 10 years and a tendency to arise within or at the edges of prior treatment fields,” the authors stated. This could affect survivors of Hodgkin lymphoma and cancers of the testes, breast, cervix, and prostate.
Chemotherapy with alkylating agents has been associated with increased risk of acute leukemia and solid tumors, including lung cancer, gastrointestinal cancer, sarcoma, and bladder cancer. Topoisomerase II inhibitors and rituximab (Rituxan) have also been associated with increased risk of second malignant neoplasms.
“Cancer survivors with a family history of cancer may be at above average risk of [a second malignant neoplasm],” the authors wrote. “Individuals with a family history suggestive of a cancer family syndrome (eg, autosomal dominant inheritance, early onset cancer, and clustering of cancer types) may be candidates for genetic testing and should be referred for genetic counseling.” If a germ-line mutation in a cancer-causing gene is identified in a cancer survivor, that individual may be eligible for high-risk screening and prevention strategies.
The variability of effects of radiotherapy and chemotherapy on individual patients “points to an important role of genetic susceptibility,” the authors stated. “Although much of this research is not yet ready for routine clinical application, oncologists should be aware of a few key points,” the authors noted. For example, patients with “genetic mutations in highly penetrant genes such as RB (associated with retinoblastoma) or TP53 (associated with Li-Fraumeni syndrome) would be well-advised to avoid radiotherapy, if possible, because of the high rate of [second malignant neoplasms] in irradiated tissues,” the authors stated.
“Genes associated with an increased risk of therapy-related [second malignant neoplasms] have also been related to drug metabolism (such as glutathione transferase [eg, GSTP1]) or the repair of DNA damage (such as mismatch repair gene MLH1),” they continued. “Although genetic changes (polymorphisms) in these low-penetrance genes have been associated with increased risks of therapy-related [second malignant neoplasms], to the best of our knowledge, identification of these genetic alterations in individual patients has not yet resulted in changes in clinical management.”
Environment and Lifestyle
Along with therapy-related considerations and genetic susceptibility, the third group of factors associated with increased risk of second malignant neoplasms relates to shared environmental and lifestyle influences, such as smoking, excess drinking of alcohol, and dietary patterns.
“In terms of absolute excess risk, tobacco- and alcohol-related cancer sites are estimated to account for more than 35% of all subsequent malignancies,” the authors stated. While there are few data on the interaction of risk factors and the development of second malignant neoplasms, based on reports to date, “it is synergistic relationships between lifestyle decisions (such as tobacco use) and treatment that may be associated with the highest risks of [second malignant neoplasms],” the authors added.
Several risk reduction strategies were proposed in the report. These include evaluating the second malignant neoplasm risk for any cancer survivor, taking into account family history, cancer treatment, and environmental factors such as obesity and smoking. The authors include accompanying tables to suggest how patients might be categorized as average, moderate, or high risk for second malignant neoplasms.
“In general, all cancer survivors should follow applicable national guidelines for cancer screening, such as those provided by the American Cancer Society (ACS), American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), and the U.S. Preventive Services Task Force (USPSTF),” the authors continued. In addition, they highlighted randomized controlled data for consideration in the prevention of second malignant neoplasms. These include data from observational studies showing that intentional weight loss and physical activity have been associated with reductions in cancer risk.
Wood ME, et al: J Clin Oncol 30:3734-3745, 2012.