To analyze risk and patterns of locoregional failure (LRF) in patients of the RAPIDO trial at five years.

Multimodality treatment improves local control in rectal cancer. Total neoadjuvant treatment (TNT) aims to improve systemic control while local control is maintained. At three years, LRF rate was comparable between TNT and chemoradiotherapy in the RAPIDO trial.

920 patients were randomized between an experimental (EXP, short-course radiotherapy, chemotherapy, and surgery) and a standard-care group (STD, chemoradiotherapy, surgery, and optional post-operative chemotherapy). LRF, including early LRF (eLRF) (no resection except for organ preservation/R2 resection) and locoregional recurrence (LRR) after an R0/R1 resection, were analyzed.

Totally, 460 EXP and 446 STD patients were eligible. At 5.6 years (median follow-up), LRF was detected in 54/460 (12%) and 36/446 (8%) patients in the EXP and STD groups, respectively (P=0.07), in which EXP patients were more often treated with 3D-CRT (P=0.029). In the EXP group, LRR was detected more often (44/431 (10%) vs. 26/428 (6%); P=0.027), with more often a breached mesorectum (9/44 (21%) vs. 1/26 (4); P=0.048). The EXP treatment, enlarged lateral lymph nodes, positive circumferential resection margin, tumor deposits, and node positivity at pathology were significant predictors for developing LRR. Location of the LRRs was similar between groups. Overall survival after LRF was comparable (HR 0.76 (95%CI 0.46-1.26); P=0.29).

The EXP treatment was associated with an increased risk of LRR whereas the reduction in disease-related treatment failure and distant metastases remained after 5 years. Further refinement of the TNT in rectal cancer is mandated.