Association between radiation therapy for primary endometrial cancer and risk of second primary malignancies: a retrospective cohort study

Our objective was to evaluate the association of adjuvant radiation therapy (RT) to subsequent second primary malignancies (SPMs) in endometrial cancer survivors. Patients with endometrial cancer as their first malignancy were identified from 8 registries of the Surveillance, Epidemiology, and End Results (SEER) database. SPMs were defined as any type of primary malignancy that occurred more than 12 months after the diagnosis of endometrial cancer. Fine-Gray competing risk regression and Poisson regression were used to evaluate the radiotherapy-associated risk (RR) for SPMs. The Kaplan-Meier method was applied to assess the survival outcomes of endometrial cancer patients. Of 62,108 endometrial cancer patients,16,846 patients (27.12%) were in the RT group, and 45,262 patients (72.88%) were in the no-RT group. During the 30-year follow-up period, the cumulative incidence of SPMs was 20.9% and 19.7% in each group, respectively. In both multivariable competing risk regression analysis and Poisson regression analysis, adjuvant RT was found to be associated with a higher risk of developing colon and rectum cancer (adjusted hazard ratio (HR), 1.29; 95% confidence interval (CI), 1.12-1.50; P < 0.001; adjusted RR, 1.29; 95% CI, 1.11-1.49; P < 0.001), lung and bronchus cancer (adjusted HR, 1.27; 95% CI, 1.08-1.50; P = 0.004; adjusted RR, 1.26; 95% CI, 1.07-1.49; P = 0.005), vulva cancer (adjusted HR, 1.72; 95% CI, 1.04-2.85; P = 0.036; adjusted RR, 1.74; 95% CI, 1.03-2.88; P = 0.035), urinary bladder cancer (adjusted HR, 1.86; 95% CI, 1.41-2.46; P < 0.001; adjusted RR, 1.85; 95% CI, 1.40-2.44; P < 0.001), and non-Hodgkin lymphoma (adjusted HR, 1.37; 95% CI, 1.06-1.77; P = 0.016; adjusted RR, 1.37; 95% CI, 1.05-1.76; P = 0.017). However, a slightly decreased risk of breast cancer was observed in patients who underwent adjuvant RT (adjusted HR, 0.89; 95% CI, 0.80-0.98; P = 0.021; adjusted RR, 0.88; 95% CI, 0.80-0.98; P = 0.020). The RR for colon and rectum cancer decreased with age and elevated with increasing latency since endometrial cancer diagnosis, and the RR for urinary bladder cancer showed a similar tendency with latency. SPMs can significantly impair the survival outcomes of primary endometrial cancer survivors. Our findings suggest that adjuvant RT for endometrial cancer patients increases the risk of non-Hodgkin lymphoma and several types of solid cancer. Long-term surveillance of these patients should be recommended for detecting SPMs.