Neoadjuvant chemotherapy (NAC) followed by total mesorectal excision (TME) and adjuvant chemotherapy versus TME followed by adjuvant chemotherapy in very low-lying clinical (c) T3 rectal cancer (NAIR): A multicenter, randomized, open-label, phase 2/3 trial.
Authors: Tsukada Yuichiro , Kawashima Yoshiyuki , Fujita Fumihiko , Koda Keiji , Ohue Masayuki , Shinto Eiji , Murata Akihiko , Koide Yoshikazu , Nishizawa Yuji , Bando Hideaki , Suzuki Motoko , Misumi Toshihiro , Yoshino Takayuki , Saito Norio , Ito Masaaki 
Published: June 2023

3519 Background: Chemoradiotherapy and total neoadjuvant therapy are the standard treatments for locally advanced rectal cancer (LARC). Although radiotherapy (RT) is an integral part of treatment, it negatively impacts anal function after TME for cases of very low-lying LARCs. This trial examined the efficacy, safety, and influence on postoperative anal function of NAC without RT in patients (pts) with very low-lying cT3 LARCs. Methods: Pts with cT3N0-2M0 adenocarcinomas located within 5 cm from the anal verge, whose anuses were expected to be preserved, were randomly assigned (1:1) to either the NAC group (preoperative chemotherapy with six cycles of mFOLFOX6 or four cycles of CAPOX followed by TME; then, postoperative identical regimen) or the TME group (upfront TME followed by postoperative chemotherapy with 12 cycles of mFOLFOX6 or 8 cycles of CAPOX), stratified by cN stage, center, and sex. The primary endpoint was the 3-year recurrence-free survival (RFS), which was compared between groups using a stratified log-rank test at a one-sided alpha level of 20%. Results: Between February 2013 and March 2019, 130 pts were enrolled and randomly assigned to a treatment group. A total of 127 pts were evaluable (65 in the NAC group and 62 in the TME group). All but one patient with early progression completed preoperative chemotherapy in the NAC group, and all pts in both groups underwent TME. After a median follow-up of 37.4 months (IQR 36.5-40.5), the 3-year RFS was 75.5% (95% CI 62.5-84.5) in the NAC group vs. 70.9% (95%CI 57.2-80.9) in the TME group (hazard ratio 0.67, 95% CI 0.34-1.32; P = 0.098), and the primary endpoint was met. There were no differences in the occurrence of grade 3 or higher postoperative complications (20% in the NAC group vs. 21% in the TME group [P = 1.000]), chemo-associated grade 3 or higher adverse events (28% in the NAC group vs. 23% in the TME group [P = 0.551]), or any grade of peripheral sensory neuropathy lasting for 3 years (22.7% in the NAC group vs. 38.5% in the TME group in pts treated with mFOLFOX6 [P = 0.3163], 7.1% in the NAC group vs. 33.3% in the TME group in pts treated with CAPOX [P = 0.1038]), between the groups. No treatment-related deaths occurred in either of the groups. At 3 years after randomization, 61 pts in the NAC group (93.8%) and 52 pts in the TME group (83.9%) could defecate via their anuses (P = 0.092). The median Wexner incontinence score was 11.0 in the NAC group and 10.0 in the TME group (P = 0.3405). Conclusions: For pts with very low-lying cT3 LARC, NAC followed by TME and adjuvant chemotherapy achieved significantly better RFS and anus-preserving rates compared to upfront TME followed by adjuvant chemotherapy, without deteriorating postoperative complications or postoperative anal function. Clinical trial information: UMIN000009510 .