No operation after short-course radiotherapy followed by consolidation chemotherapy in locally advanced rectal cancer (NOAHS-ARC): A prospective, phase II trial.

142 Background: Total neoadjuvant therapy (TNT) improves tumor response in locally advanced rectal cancer (LARC). Watch-and-wait (WW) has been validated mainly after chemoradiation (CRT)-based TNT, but the role of short-course radiotherapy (SCRT) within TNT for organ preservation has not been prospectively tested. With its shorter schedule, SCRT may be particularly valuable in resource-limited settings such as Latin America. This study evaluated the efficacy of SCRT with consolidation chemotherapy in achieving complete response (CR) and enabling organ preservation. Methods: This was a single-arm, open-label, multicenter, public-health–based, phase II trial in Santiago, Chile. Eligible patients were ≥18 years with stage II–III (cT2N+, cT3–4a any N) palpable rectal adenocarcinoma <7 cm from the anal verge. Treatment was SCRT (25 Gy) followed by nine cycles of mFOLFOX6. Tumor response was assessed 4 weeks post-TNT using the MSKCC Regression Schema. Patients with clinical complete response (cCR) entered WW; otherwise total mesorectal excision (TME) was indicated. The primary endpoint was CR, defined as pathologic complete response (pCR) after TME and sustained cCR (>1 year) with WW, compared with a historical 12% pCR after CRT and TME. Based on an expected CR rate of 30% (effect size 18%), 48 patients were required (α=0.05, β=80%, one-sided). An interim analysis after 24 evaluable patients allowed early termination (i.e. CR > 35.7% or ≥9 responders). Secondary endpoints were toxicity, disease-free survival (DFS), and overall survival (OS). Results: At interim analysis, 10 of 24 patients (42%) achieved CR, meeting stopping criteria. By then, 39 patients had been already enrolled, thus the full intention-to-treat cohort was followed. Median follow-up was 37 months (range 19.8–40). Median age was 65 years (IQR 32–82), 64% were male, 68% cT3, and 82% node positive. All completed SCRT; toxicity was limited to grade 1–2 and chemotherapy compliance was high (89%). The CR rate was 38% in the intention-to-treat and 47% per protocol. DFS and OS are summarized in Table 1. Conclusions: SCRT-based TNT with consolidation mFOLFOX6 achieved high CR rates and survival, supporting its role as an organ-preserving strategy in LARC. As the first public-health, multicenter WW trial in Latin America, these findings provides evidence to guide TNT-based LARC management in resource-limited settings where SCRT may be particularly useful. Clinical trial information: NCT04864067 . Study main outcomes. Endpoint Intention-to-Treat (n=39) Protocol (n=32) Primary Endpoint, n(%) Complete Response (pCR + WW>1 year) 15 (38%) 15 (47%) Secondary Endpoint DFS, 24-month (95% CI) 69.9% (95% CI 55.7–87.7) 74.8% (95% CI 60.1–93.1) OS, 24-month (95% CI) 88.6% (95% CI 78.7–99.8) 93.1% (95% CI 84.3–100) WW: Watch and Wait; DFS: Disease-Free Survival; OS: Overall Survival; CI: Confidence Interval.