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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 x 5 Gy followed by 6 x CAPOX or 9 x FOLFOX4) or CRT (25-28 x 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. 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.