Factors influencing locoregional recurrence rates in locally advanced rectal cancer after total neoadjuvant treatment versus chemoradiotherapy in the RAPIDO trial

BACKGROUND: The RAPIDO trial compared total neoadjuvant treatment (TNT) with preoperative chemoradiotherapy (CRT), both followed by total mesorectal excision, in patients with locally advanced rectal cancer (LARC). A higher locoregional recurrence (LRR) rate was observed after TNT. This study investigates factors contributing to the difference in LRR observed. METHOD: Patients with high-risk LARC received TNT (5 × 5 Gy followed by 6 × CAPOX or 9 × FOLFOX4) or CRT (25-28 × 1.8-2 Gy with concurrent capecitabine). Patients with a local R0 or R1 resection were included in this study. Sphincter-preserving surgery encompassed (low) anterior resection and Hartmann's procedure. The influence of baseline, surgical and pathological factors on LRR was evaluated. RESULTS: Of 920 randomized patients, 849 (430 versus 419 in the TNT and CRT arms) were eligible. The cumulative incidence of LRR at 8 years was 10.8% after TNT and 5.8% after CRT (HR 1.91). Following sphincter preserving surgery, 12.1% (TNT) and 4.8% (CRT) developed LRR (HR 2.60), compared to 8.5% versus 7.5%, respectively, after abdominoperineal resection. Distal resection margin rates (DRM) of 10 mm or less after sphincter-preserving surgery were similar in both arms (TNT 17.5% versus CRT 22.1%). However, a higher cumulative incidence of LRR was observed with a DRM of 10 mm or less after TNT (25.4% versus 1.8%; HR 15.51). Other factors were similar between treatment arms with respect to LRR. CONCLUSION: The difference in LRR between TNT and CRT mainly occurred in patients treated with sphincter-preserving surgery. Baseline information on the original tumour bed should be considered when determining the surgical approach after total neoadjuvant treatment.