Introduction: We aimed to investigate the effect of radiotherapy (RT) in contemporary patients treated with radical prostatectomy (RP) compared to RP alone for non-metastatic prostate cancer (PCa) on the incidence of second primary cancers (SPCs). Methods: Within the Surveillance, Epidemiology, and End Results database (2004-2015), we identified patients with PCa as the only or first primary cancer, who underwent RP and RT or RP alone. Cumulative incidence plots and multivariable Cox regression models tested for SPC rate differences according to treatment type: RP and RT vs. RP alone. Subgroup analyses focused on pelvic, primary pelvic, and non-pelvic SPCs, as well as on late SPCs (>5 years after PCa diagnosis). Results: Of 152 161 patients, 7.1% (n=10 870) received RP and RT. Overall, 6.6 vs. 5.0% developed SPCs after RP and RT vs. RP alone, respectively (p<0.001). Cumulative incidence rates at 10 years after PCa diagnosis for RP and RT vs. RP were 12.0 vs. 8.7% (p<0.001), 2.0 vs. 1.2% (p<0.001), 2.1 vs. 1.3% (p<0.001), and 9.9 vs. 7.4% (p<0.001) for overall SPCs, primary pelvic SPCs, overall pelvic SPCs, and non-pelvic SPCs, respectively. Multivariable Cox regression models revealed an increased risk after RP and RT vs. RP alone for overall (hazard ratio [HR] 1.2; p<0.001), primary pelvic (HR 1.5; p<0.01), pelvic (HR1.4; p<0.001), non-pelvic (HR1.1; p<0.01), late overall (HR 1.2; p=0.01), and late non-pelvic SPCs (HR1.2; p=0.03). Conclusions: RP with RT was associated with moderately increased risk of SPCs compared to RP alone. This observation should be thoroughly discussed at informed consent and considered during followup.
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