Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: Results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years.

3516 Background: CAO/ARO/AIO-94 was published in 2004 with a median follow-up of 46 months (Sauer et al., N Engl J Med 2004). This trial established preoperative CRT as standard treatment for rectal cancer based on an improved local control rate at 5 years, however, no survival benefit could be shown. We here report results with a median follow-up of 134 months. METHODS We randomly assigned 823 patients with stage II or III rectal cancer to preoperative CRT (50.4 Gy) with 5-FU (1 g/msq/days 1-5, 29-33), surgery, and adjuvant 5-FU (500 mg/msq/days 1-5, 4 cycles), or the same schedule applied postoperatively. The study was designed to have 80% power to detect a difference of 10% in the 5-year overall survival as primary endpoint. Secondary endpoints included the cumulative incidence of local and distant relapses and disease-free survival. RESULTS Of 823 patients, 404 and 395 were randomized to preoperative and postoperative CRT, respectively; 24 were ineligible, and 38 requested a change in treatment group. Thus, 406 patients received preoperative CRT, 393 were treated in the postoperative arm. As of 12/2010, updated data for life and tumor status were available for 791 and 783 of 799 eligible patients, respectively. Overall survival at 10 years was 59.9 years (95% CI, 55.0-64.8%) in the preoperative arm, and 59.5% (95% CI, 54.6-64.4%) in the postoperative arm (p=0.86, log-rank test, according to intention to treat). The 10-year cumulative incidence of local relapse after macroscopically complete resection was 5.7% (95% CI, 3.2-8.2%) and 10.4% (95% CI, 7.1-13.4%) in the pre- and postoperative arms, respectively (p=0.009, log-rank test, according to actual treatment). No significant differences were detected for 10-year cumulative incidence of distant metastases (25.5% both, p=0.88) and DFS. CONCLUSIONS There is a persisting significant improvement of pre- vs. postoperative CRT on local control, however, no effect on overall survival. Integrating more effective systemic treatment into the combined modality treatment has been adopted in trial CAO/ARO/AIO-04 to possibly reduce distant metastases and improve survival.