This study investigated the long-term probability of developing a second cancer in a large pooled cohort of patients treated with surgery with or without radiotherapy (RT).All second cancers diagnosed in patients included in the TME, PORTEC-1, and PORTEC-2 trials were analyzed. In the TME trial, patients with rectal cancer (n = 1,530) were randomly allocated to preoperative external-beam RT (EBRT; 25 Gy in five fractions) or no RT. In the PORTEC trials, patients with endometrial cancer were randomly assigned to postoperative EBRT (46 Gy in 2-Gy fractions) versus no RT (PORTEC-1; n = 714) or EBRT versus vaginal brachytherapy (VBT; PORTEC-2; n = 427).A total of 2,554 patients were analyzed (median follow-up, 13.0 years; range 1.8 to 21.2 years). No differences were found in second cancer probability between patients who were treated without RT (10- and 15-year rates, 15.8% and 26.5%, respectively) and those treated with EBRT (10- and 15-year rates, 15.4% and 25.6%, respectively) or VBT (10-year rate, 14.9%). In the individual trials, no significant differences were found between treatment arms. All cancer survivors had a higher risk of developing a second cancer compared with an age- and sex-matched general population. The standardized incidence ratio for any second cancer was 2.98 (95% CI, 2.82 to 3.14).In this pooled trial cohort of > 2,500 patients with pelvic cancers, those who underwent EBRT or VBT had no higher probability of developing a second cancer than patients who were treated with surgery alone. However, patients with rectal or endometrial cancer had an increased probability of developing a second cancer compared with the general population.? 2014 by American Society of Clinical Oncology.