Assessment of Second Primary Cancer Risk Among Men Receiving Primary Radiotherapy vs Surgery for the Treatment of Prostate Cancer

Importance: Shared decision-making is an important part of the treatment selection process among patients with prostate cancer. Updated information is needed regarding the long-term incidence and risk of second primary cancer after radiotherapy vs nonradiotherapy treatments, which may help to inform discussions of risks and benefits for men diagnosed with prostate cancer. Objective: To assess the current incidence and risk of developing a second primary cancer after receipt of radiotherapy vs nonradiotherapy treatments for prostate cancer. Design, Setting, and Participants: This retrospective cohort study used the Veterans Affairs Corporate Data Warehouse to identify 154 514 male veterans 18 years and older who had localized prostate cancer (tumor stages T1-T3) diagnosed between January 1, 2000, and December 31, 2015, and no cancer history. A total of 10 628 patients were excluded because of (1) incomplete treatment information for the year after diagnosis, (2) receipt of both radiotherapy and a surgical procedure in the year after diagnosis, (3) receipt of radiotherapy more than 1 year after diagnosis, (4) occurrence of second primary cancer or death within 1 year or less after diagnosis, (5) prostate-specific antigen value greater than 99 ng/mL within 6 months before diagnosis, or (6) no recorded Veterans Health Administration service after diagnosis. The remaining 143 886 patients included in the study had a median (IQR) follow-up of 9 (6-13) years. Data were analyzed from May 1, 2021, to May 22, 2022. Main Outcomes and Measures: Diagnosis of a second primary cancer more than 1 year after prostate cancer diagnosis. Results: Among 143 886 male veterans (median IQR age, 65 60-71 years) with localized prostate cancer, 750 (0.5%) were American Indian or Alaska Native, 389 (0.3%) were Asian, 37 796 (26.3%) were Black or African American, 933 (0.6%) were Native Hawaiian or other Pacific Islander, 91 091 (63.3%) were White, and 12 927 (9.0%) were of unknown race; 7299 patients (5.1%) were Hispanic or Latino, 128 796 (89.5%) were not Hispanic or Latino, and 7791 (5.4%) were of unknown ethnicity. A total of 52 886 patients (36.8%) received primary radiotherapy, and 91 000 (63.2%) did not. A second primary cancer more than 1 year after prostate cancer diagnosis was present in 4257 patients (3.0%), comprising 1955 patients (3.7%) in the radiotherapy cohort and 2302 patients (2.5%) in the nonradiotherapy cohort. In the multivariable analyses, patients in the radiotherapy cohort had a higher risk of second primary cancer compared with those in the nonradiotherapy cohort at years 1 to 5 after diagnosis (hazard ratio HR, 1.24; 95% CI, 1.13-1.37; P < .001), with higher adjusted HRs in the subsequent 15 years (years 5-10: 1.50 95% CI, 1.36-1.65; P < .001; years 10-15: 1.59 95% CI, 1.37-1.84; P < .001; years 15-20: 1.47 [95% CI, 1.08-2.01; P = .02). Conclusions and Relevance: In this cohort study, patients with prostate cancer who received radiotherapy were more likely to develop a second primary cancer than patients who did not receive radiotherapy, with increased risk over time. Although the incidence and risk of developing a second primary cancer were low, it is important to discuss the risk with patients during shared decision-making about prostate cancer treatment options.