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.