Risk of Solid Cancer After Treatment of Testicular Germ Cell Cancer in the Platinum Era

Abstract

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.

Platinum exposure and cause‐specific mortality among patients with testicular cancer

“…Because few patients with seminoma nowadays undergo para‐aortic radiation and radiation doses for these patients are also generally lower (<26 Gy), radiation‐associated pancreatic cancer mortality will likely decrease in the near future. On the other hand, we recently reported that platinum‐containing chemotherapy may also increase pancreatic cancer risk …”

“…Previous studies have shown that radiotherapy is associated with increased morbidity and mortality from second malignant neoplasms (SMNs) . A recent study from our group observed that chemotherapy was associated with SMN incidence as well . Chemotherapy has been associated with increased cardiovascular disease (CVD) morbidity and excess CVD mortality, but the data are less consistent.…”

Smoking, age, nodal disease, T stage, p16 status, and risk of distant metastases in patients with squamous cell cancer of the oropharynx

“…Overall, for those patients whose deaths were not related to the study cancer, there were 22 more deaths in the concurrent cisplatin arm; this suggested that the excess non–study‐related cancer death rate was 11% (22 excess deaths divided by the 202 patients randomized to the concurrent arm). It is possible that in the HPV‐positive population with relatively good long‐term survival, the late mortality of concurrent cisplatin may outweigh its relatively modest gains in distant control.…”

Testicular Cancer Survivorship

“…RT for TC is associated with significant risks of leukemia 18 and solid cancers. [19][20][21][22] In an international populationbased study of 18,576 TCS, 18 abdominal and pelvic RT were associated with a significant 3-fold risk of leukemia (n522; median latency, 5 years). In another international population-based investigation of 40,576 10-year TCS, 20 SMN risks in locations typically within infradiaphragmatic RT fields were significantly higher (relative risk [RR], 2.7; n5212) compared with unexposed sites (RR, 1.6), and remained elevated for .35 years.…”

“…Another analytic study 22 of 5-year TCS ; stage I/II and III/IV disease: 95.7% and 4.3%, respectively) reported a significant 5.9-fold risk of stomach cancer (n587), with .20-fold risks (P trend ,.001) associated with gastric radiation doses of $50 Gy (8 cases vs 6 controls) vs ,10 Gy (15 cases vs 49 controls). A multicenter hospital-based study by Groot et al 21 reported that the hazard ratio (HR) of an infradiaphragmatic SMN increased by 8% per Gy of radiation dose administered (P,.001) compared with TCS who received no para-aortic RT. Groot et al 21 reported that TCS had a lower risk of SMN after para-aortic radiation than after dog-leg radiation in a multivariable Cox analysis; however, this same study 21 did not show a decline in solid SMN risk in patients treated in 1996 through 2007 compared with those treated in earlier decades, likely attributable to the relatively small number of patients with nonseminoma TC in the former period given high-dose RT, which is no longer used as primary treatment of nonseminoma.…”