Total neoadjuvant therapy followed by total mesorectal excision and selective lateral lymph node dissection for locoregionally advanced low rectal cancer: A phase III randomized controlled trial (JCOG2207).

Abstract

TPS312 Background: For locally advanced low rectal cancer (RC), total neoadjuvant therapy (TNT) followed by total mesorectal excision (TME) confers a survival advantage compared with neoadjuvant chemoradiotherapy (nCRT) in the West, even though the local control rate was similar between TNT and nCRT. The Japan Clinical Oncology Group (JCOG) Colorectal Cancer Study Group has been developing therapies for RC based on recurrence risk according to presence/absence of clinical lateral lymph node metastasis (cLLNM). Our previous study in Japan showed that the standard of care (SOC) for RC is TME with lateral lymph node dissection (LLND) plus adjuvant chemotherapy (CTx). However, the prognosis for cStage III low RC remains poor regardless of cLLNM status. Therefore, new treatment strategies are needed for this population. In cLLNM-positive cStage III low RC patients, previous research suggests that adding nCRT to LLND would reduce local recurrence and improve survival. TNT and LLND may further improve outcomes. In cLLNM-negative cStage III low RC, several reports have suggested that nCRT as an alternative addition to LLND has comparable efficacy in terms of local control. Thus, in these populations, if TNT can replace LLND, adverse events due to LLND can be avoided while improving prognosis. We hypothesize that TNT + TME + selective LLND would be the most promising strategy for cLLNM-positive and -negative cStage III low RC. Methods: Eligibility criteria include low rectal adenocarcinoma or adenosquamous carcinoma, cT2-cT4 tumor depth, clinically positive lymph node metastasis, no distant metastasis, no history of pelvic irradiation or rectal surgery, age 18-75 years, and sufficient organ function. Eligible patients are randomized (1:1) with adjustment factors of institution, sex, and cLLNM status. The experimental treatment arm receives TNT, short-course radiotherapy (25 Gy/5 fractions to whole pelvis), and consolidation chemotherapy consisting of 6 courses of CAPOX (oxaliplatin 130 mg/m2 on day 1 and capecitabine 2000 mg/m2/day on days 1-14). After completing TNT, TME + selective LLND are performed for cLLNM-positive cases or TME alone for cLLNM-negative cases. The SOC arm receives TME + LLND followed by adjuvant chemotherapy with 8 cycles of CAPOX (same as above). The primary endpoint is overall survival (OS) in the intention-to-treat population. To detect an increase in 5-year OS from 76% to 84%, corresponding to a target hazard ratio of 0.64, 408 patients (108 events) would achieve 75% power at a one-sided α of 0.05, an expected accrual period of 4 years, and a follow-up period of 5 years. The total sample size was set at 420 patients to account for patients lost to follow-up. Accrual in JCOG2207 began in October 2023. Clinical trial information: s031230415 .