Purpose Testicular cancer (TC) treatment increases risk of subsequent malignant neoplasms (SMNs). It is unknown whether changes in TC treatment over time have affected SMN risk. Methods Solid SMN risk was evaluated in a multicenter cohort comprising 5,848 1-year survivors treated for TC before age 50 years between 1976 and 2007. SMN incidence was compared with cancer incidence in the general population. Treatment-specific risks were assessed using multivariable regression in a case-cohort design. Results After a median follow-up of 14.1 years, 350 solid SMNs were observed, translating into a 1.8-fold (95% CI, 1.6-2.0) increased risk compared with general population rates. Solid SMN risk was increased in patients with seminoma and those with nonseminoma (standardized incidence ratio, 1.52 and 2.21, respectively). Patients with nonseminoma experienced increased risk of SMNs of the thyroid, lung, stomach, pancreas, colon, and bladder and of melanoma and soft tissue sarcoma, whereas those with seminoma experienced increased risk of SMNs of the small intestine, pancreas, and urinary bladder. The 25-year cumulative incidence of solid SMNs was 10.3% (95% CI, 9.0% to 11.6%). In multivariable analysis, platinum-based chemotherapy was associated with increased risk of a solid SMN (hazard ratio [HR], 2.40; 95% CI, 1.58 to 3.62), colorectal SMN (HR, 3.85; 95% CI, 1.67 to 8.92), and noncolorectal GI SMN (HR, 5.00; 95% CI, 2.28 to 10.95). Receipt of platinum 400 to 499 and ≥ 500 mg/m increased solid SMN risk compared with surgery only (HR, 2.43; 95% CI, 1.40 to 4.23 and HR, 2.42; 95% CI, 1.50 to 3.90, respectively), whereas risk was not significantly increased with lower doses (HR, 1.75; 95% CI, 0.90 to 3.43). The HR of a GI SMN increased by 53% (95% CI, 26% to 80%) per 100 mg/m of platinum-containing chemotherapy. The HR of an infradiaphragmatic SMN increased by 8% per Gray of radiation dose administered (95% CI, 6% to 9%; P < .001). Conclusion Radiotherapy and platinum-containing chemotherapy are associated with increased solid SMN risk, specifically with GI SMNs.

BACKGROUND: Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era. METHODS: In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, causespecific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis. RESULTS: With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m 2 platinum dose administered (P trend < .001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure. CONCLUSIONS: Platinum-containing chemotherapy is associated with a dosedependent increase in the risk of SMN mortality. Cancer 2020;126:628-639.

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