A prospective multicenter phase II trial of total neoadjuvant therapy for locally advanced rectal cancer in JAPAN: ENSEMBLE-1 study.

Abstract

123 Background: The short- and long-term prognosis of total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) is elucidated in the world. We evaluated the feasibility and safety of TNT for patients with LARC in Japan. Methods: This prospective, multicenter, open-label, single-arm phase II trial was conducted at five institutions. The key eligibility criteria were age ≥20 years, LARC within 12 cm from the anal verge, and cT3-4N0M0 or TanyN+M0 at the time of diagnosis that enabled curative resection. Preoperative short-course radiation therapy (SCRT) 5 Gy × 5 days (total 25 Gy) + CAPOX (6 courses) followed by total mesorectum excision (TME) was the treatment protocol. Non-operative management (NOM) was allowed if clinical complete response (cCR) was obtained in the preoperative evaluation. The primary endpoint was the pathological complete response (pCR) rate. With a pCR rate threshold of 5%, an expected value of 28%, a one-sided significance level of 5%, and a power of at least 80%, the sample size required by the exact binomial distribution method would be ≥19 patients. Considering a few dropouts, ineligible cases, and patients in which resection was not performed, the target sample size was set to 27 patients. Results: Thirty patients (male, n=26; female, n=4; median age, 62.5 [44-74] years; cT [T2, n=1; T3, n=25; T4, n=4]; cN [N0, n=13; N1, n=13; N2, n=4]) were enrolled. The final analysis included 30 patients in total. The completion rates were 100% for SCRT and 83% for CAPOX. TME and NOM were performed in 20 and seven patients, respectively. pCR was observed in six patients (30% [95% CI 14.0%–50.8%]). The primary endpoint was met. pCR+cCR was observed in 13 (43.3%) patients at TME or restaging. There were no treatment-related deaths. Grade ≥3 (CTCAE ver. 5.0) adverse events (≥20%), including diarrhea (23.3%) and neutropenia (23.3%). The median follow-up period was 21.8 (10.9-29.6) months. Recurrences in three patients (10.0%) were observed. In NOM, regrowth (28.6%) in two patients occurred, of which one patient was performed TME and one patient is on chemotherapy. Conclusions: ENSEMBLE-1 demonstrated satisfactory pCR and cCR, and well-tolerated safety of TNT for patients with LARC in JAPAN. Further long-term prognosis observation is required. A phase III trial, ENSEMBLE (NCT05646511/jRCTs031220342) is currently ongoing in JAPAN. Clinical trial information: jRCT s051200113 .