Testicular cancer in the cisplatin era: Causes of death and mortality rates in a population-based cohort.
Authors: Hellesnes Ragnhild , Myklebust Tor Åge , Fossa Sophie D. , Bremnes Roy M. , Karlsdottir Asa , Kvammen Oivind , Tandstad Torgrim , Wilsgaard Tom , Negaard Helene F. S. , Haugnes Hege Sagstuen Sagstuen 
Published: June 2021

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Background: Previous studies have reported an increased risk of premature mortality in testicular cancer (TC) survivors, probably associated with previous platinum-based chemotherapy (PBCT) or radiotherapy (RT). However, complete data regarding PBCT cycles are lacking in available literature. Using complete TC treatment data, this population-based cohort study aimed to investigate non-TC mortality in relation to TC treatment. Methods: Overall, 5,707 men diagnosed with TC 1980-2009 were included, identified from the Cancer Registry of Norway. Clinical parameters and treatment data were abstracted from medical records and linked with the Norwegian Cause of Death Registry. Causes of death were classified by the European Shortlist. Standardized mortality ratios (SMRs) were calculated to compare the cause-specific mortality in the cohort to an age-matched general population. Age-adjusted hazard ratios (HRs) were estimated to evaluate the impact of number of PBCT cycles on non-TC mortality. Results: During a median follow-up of 18.7 years, 665 (12%) men were registered with non-TC death. The overall excess non-TC mortality was 23% (SMR 1.23, 95% CI 1.14-1.33) compared with the general population, with increased risks after PBCT (SMR 1.23, 95% CI 1.06-1.42) and RT (SMR 1.28, 95% CI 1.15-1.43), but not after surgery (SMR 0.95, 95% CI 0.79-1.14). SMRs increased significantly with increasing follow-up time ≥10 years, and the overall risk of non-TC death reached a maximum after ≥30 years follow-up (SMR 1.64, 95% CI 1.31-2.06). The most important cause of death was non-TC second cancer with an overall SMR of 1.53 (95% CI 1.35-1.73). Increased risks appeared after PBCT (SMR 1.43, 95% CI 1.12-1.83) and RT (SMR 1.59, 95% CI 1.34-1.89). Treatment with PBCT was associated with significantly 1.69-6.78-fold increased SMRs for cancers of the oral cavity/pharynx, esophagus, lung, bladder, and leukemia. After RT, significantly 3.02- 4.91-fold increased SMRs emerged for cancers of the oral cavity/pharynx, stomach, liver, pancreas and bladder. Non-cancer mortality was also increased by 15% (SMR 1.15, 95% CI 1.04-1.27), and excesses appeared after PBCT (1.23, 95% CI 1.03-1.47) and RT (SMR 1.17, 95% CI 1.01-1.34). Importantly, we report excess suicides after PBCT (SMR 1.65, 95% CI 1.01-2.69). Long-term overall cardiovascular mortality was not increased in the study cohort nor according to treatment modality. Compared with surgery, the overall non-TC mortality was increased after 4 (HR 1.41, 95% CI 1.00-1.98) and >4 (HR 2.03, 95% CI 1.24-3.33) PBCT cycles after >10 years of follow-up. Conclusions: TC treatment with PBCT or RT is associated with significantly increased long-term non-TC mortality, with non-TC second cancer being the most important cause of death. Significantly elevated risks for non-TC mortality emerged after ≥4 PBCT cycles after >10 years of follow-up.