Dose-escalated versus Standard Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: 9-year Results of a Randomized Phase 2 Trial.

Abstract

To compare the safety and efficacy of preoperative simultaneous integrated boost chemoradiotherapy (SIB-CRT) versus standard chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). This prospective, randomized phase II trial (NCT02195141) enrolled patients with stage II/III rectal adenocarcinoma. Patients were randomly assigned (1:1) to CRT (50 Gy/25 fx to pelvis) or SIB-CRT (50 Gy/25 fx to the pelvis with SIB of 56 Gy to PGTV and 60 Gy to lateral metastatic nodes if present). Radical surgery was planned 6-8 weeks after chemoradiotherapy. The primary endpoint was pathological complete response (pCR) rate; secondary endpoints were disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), local control (LC), cancer-specific survival (CSS) and toxicity. From August 2013 to February 2015, 106 patients were enrolled: 55 in the SIB-CRT group and 51 in the CRT group. Acute grade 3 toxicity occurred in 14.5% (SIB-CRT) and 19.6% (CRT) of patients, primarily manifested as radiation dermatitis. Curative treatment (radical surgery or watch-and-wait) was achieved in 89.1% (49/55) of SIB-CRT patients and 78.4% (40/51) of CRT patients (P=0.135). After a median follow-up of 116.6 months, the SIB-CRT group showed superior 9-year outcomes in the intention-to-treat (ITT) population: DFS (70.8% vs 47.4%; HR 0.46, P=0.013), OS (74.3% vs 48.9%; HR 0.43, P=0.008), MFS (70.8% vs 47.2%; HR 0.48, P=0.017), LC (87.1% vs 70.1%; HR 0.40, P=0.038) and CSS (77.4% vs 57.2%; P=0.027). Similar benefits were observed in the curative treatment cohort. The pCR rates were comparable (15.2% vs 18.4%; P=0.695). Exploratory subgroup analysis showed that the survival benefit of SIB-CRT was statistically significant in patients who did not receive perioperative chemotherapy (9-year DFS: 70.8%; HR=0.343, P = .014), whereas no additional benefit was observed in those receiving chemotherapy. Dose escalation through SIB during neoadjuvant chemoradiotherapy translates into superior long-term survival outcomes. Despite comparable pCR rates, the intensified control of both local disease and micrometastases by SIB-CRT, coupled with its significant superiority within the chemotherapy-naive subgroup, likely contributed to these robust results. These findings establish dose escalation as a potent strategy for optimizing long-term cure in the modern management of LARC, particularly in chemotherapy-ineligible patients.