To determine whether LARC with negative mesorectal fascia (MRF) predicted by magnetic resonance imaging (MRI) can be excluded from preoperative radiotherapy treatment.

This multicenter, open-label, non-inferiority, randomized clinical trial enrolled patients with LARC within 6-12 cm from the anal verge and with negative MRI-predicted MRF. Participants were randomized to the intervention group (primary surgery, in which the patients with positive pathological circumferential margins (CRM) were subjected to CRT while negative CRM undergone adjuvant chemotherapy according to pathologic staging) or the control group (preoperative CRT, in which all patients were followed by surgery and adjuvant chemotherapy). The primary endpoint was 3-year disease-free survival (DFS).

A total of 275 patients were randomly assigned to intervention (n=140) and control group (n=135), in which 33.57% and 28.15% patients were at clinical T4 stage, 85.92% and 80.45 % patients were at 'bad or ugly' risk in the intervention and control group, respectively. There were two (1.52%) and one (0.77%) patient with positive circumferential margins in the intervention and control groups, respectively (P >0.05). The non-adherence rate for intervention and control group was 3.6% and 23.7%. After a median follow-up of 34.6 (IQR: 18.2-45.7) months, 43 patients had positive events (28 patients and 15 patients in the intervention and control groups, respectively). There were six (4.4%) patients with local recurrence in the intervention group and none in the control group, which led to the stopping of the trial. The 3-year DFS rate was 81.82% (95%CI: 78.18%-85.46%) in the intervention group and 85.37% (95%CI: 81.75%-88.99%) in the control group, with a difference of -3.55% (95%CI: -3.71%- -3.39%) (HR=1.76, 95%CI: 0.94-3.30). In the per protocol dataset, the difference between 3-year DFS rate was -5.44% (95%CI: -5.63%- -5.25%) (HR=2.02, 95%CI: 1.01-4.06).

Based on the outcomes of this trial, in patients with LARC and MRI-negative MRF, primary surgery could negatively influence their DFS rates. Therefore, primary surgery was an inferior strategy, compared to preoperative CRT followed by surgery, and cannot be recommended for LARC patients in the clinical practice.