Evaluating risk for second primary cancers by radiotherapy technique in prostate cancer survivors.
Authors: Pithadia Kishan , Advani Pragati G. , Schonfeld Sara J , Withrow Diana , Bekelman Justin E. , Citrin Deborah E. , Berrington de González Amy , Morton Lindsay M. 
Published: June 2022

12005 Background: Radiotherapy-related adverse effects such as the development of subsequent neoplasms cause significant morbidity among prostate cancer survivors. Advances in radiotherapy techniques, including intensity-modulated radiation therapy (IMRT) and proton beam radiotherapy (PBRT), have aimed to reduce exposure to adjacent healthy tissues to reduce adverse effects. Initial reports based on small sample sizes and limited follow up (through 2011) have suggested reduced risks for subsequent colon and rectal cancers following IMRT compared to 3D conformal radiotherapy (CRT) for prostate cancer patients, but not for subsequent bladder cancer. We sought to extend previous reports with larger sample size and longer follow up. Methods: We conducted a retrospective cohort study within the linked database of Surveillance, Epidemiology and End Results (SEER) cancer registries and Medicare claims. The cohort included men diagnosed with first primary non-metastatic prostate cancer at ages 66-84 during 2002-2011; received initial IMRT, PBRT, or CRT; and survived without developing a second primary cancer ≥5 years after diagnosis (follow up through 2016). Cox regression models estimated risks of second primary solid tumors after IMRT and PBRT vs CRT, adjusting for age at prostate cancer diagnosis, tumor grade, race, Charlson comorbidity score, and receipt of initial prostate cancer therapy. Results: The cohort (median follow-up = 8.4 years) included 51,020 patients, of whom 19,536 received CRT alone, 29,868 received IMRT without PBRT, and 1,616 received PBRT. Compared to patients who received CRT (n = 1,348, 7.0%), both IMRT (n = 1,289, 4.3%; hazard ratio [HR] = 0.87; 95% confidence interval [CI], 0.80-0.95) and PBRT (n = 83, 5.1%; HR = 0.77; 95% CI 0.62-0.97) showed a decrease in risk of developing any second solid malignancy. In analyses by second cancer type, risks of colon cancer (HR = 0.70; 95%CI, 0.52-0.94) and bladder cancer (HR = 0.79; 95%CI, 0.65-0.97) were significantly lower after IMRT than CRT, whereas no association was observed for anorectal cancers (HR = 1.00; 95%CI, 0.65-1.53). Further investigation by time since prostate cancer diagnosis revealed a time-dependent decrease after IMRT compared to CRT in risk for bladder cancer (HRs = 0.94, 0.87, 0.61 for 5-7.4, 7.5-9.9, and 10+ years respectively) and anorectal cancer (HRs = 1.22, 0.97, 0.78), whereas the opposite trend was observed for colon cancer (HRs = 0.70, 0.68, 1.05). Conclusions: In this large cohort with increased follow-up time compared with previous reports, we observed reduced risk of colon and bladder cancer with IMRT overall, as well as time-dependent patterns for bladder and anorectal cancer that were consistent with improved tumor targeting. Further research is needed with larger sample sizes to evaluate long-term effects after PBRT. Our study supports the value of quantifying adverse effects as radiotherapy techniques evolve.