Journal Article

Total neoadjuvant therapy followed by non-operative management or surgery in stage II–III rectal cancer (NO-CUT): a multicentre, single-arm, phase 2 trial

Pilati, Pierluigi, Gervaso, Lorenzo, Borin, Simona, Sartore-Bianchi, Andrea, Lonardi, Sara, Medico, Enzo, Origi, Matteo, Mammano, Enzo, Mutignani, Massimiliano, Spolverato, Gaya, Gerardi, Marianna Alessandra, Mauri, Gianluca, Palazzi, Mauro Filippo, Bardelli, Alberto, Bonazzina, Erica, Bracco, Francesco, Mosconi, Stefania, Burti, Cesare, Bottiglieri, Luca, Poiasina, Elia, Isella, Claudio, Ferrari, Giovanni Carlo, Torri, Valter, Ghezzi, Silvia, Forti, Edoardo, Cristofori, Chiara, Lazzari, Luca, Ramondo, Gaetano, Bencardino, Katia, Bonoldi, Emanuela, De Roberto, Giuseppe, Mariano, Sara, Romario, Uberto Fumagalli, Sibio, Daniela, Bonaffini, Pietro Andrea, Aquilano, Maria Costanza, Zampino, Maria Giulia, Fazio, Nicola, Galuppo, Sara, Ciardiello, Davide, Filippone, Francesco Romeo, Siena, Salvatore, Marsoni, Silvia, Vanzulli, Angelo, Bergamo, Francesca, Tosi, Federica, Carnevali, Pietro, Patelli, Giorgio, Bergamaschi, Luca, Asmundo, Luigi, Funicelli, Luigi, Negrini, Giorgia, Cantarella, Daniela, Amatu, Alessio

2025

Overview

Rectal surgery after total neoadjuvant therapy is a standard of care for proficient mismatch repair or microsatellite stable (pMMR/MSS) stage II–III rectal cancer. In patients who have clinical complete response, non-operative management (avoidance or delay of surgery and intensive surveillance) offers a patient-centred opportunity. However, its effect on metastatic recurrence remains uncertain. This study aimed to determine whether non-operative management compromises distant relapse-free survival in patients with clinical complete response after total neoadjuvant therapy. NO-CUT was an investigator-driven, multicentre, single-arm, phase 2 trial across four participating cancer centres in Italy in patients aged 18 years and older with Eastern Cooperative Oncology Group performance status of 0–1, with stage II–III adenocarcinoma of the lower-to-middle rectum, and with treatment-naive disease. Patients received four cycles of capecitabine (1000 mg/m2 orally twice a day on days 1–14 every 3 weeks) and oxaliplatin (130 mg/m2 intravenously on day 1 every 3 weeks), followed by capecitabine (825 mg/m2 orally twice a day) concurrently with radiotherapy (50–54 Gy in 25 fractions during 5 weeks). Patients who had a clinical complete response according to modified Memorial Sloan Kettering Cancer Center criteria underwent non-operative management and patients without clinical complete response received surgery. The primary endpoint was 30-month distant relapse-free survival after non-operative management in the intention-to-treat population. This trial was registered on EudraCT (2017-003671-60) and is now complete. Between June 6, 2018, and Aug 22, 2023, 180 patients with stage II-III adenocarcinoma of the lower-to-middle rectum were enrolled and started treatment. 179 patients with pMMR/MSS rectal cancer were included in the intention-to-treat population, 165 (92%) of which completed total neoadjuvant therapy and 47 (26%) had a clinical complete response and entered non-operative management. After a median follow-up of 35 months (IQR 21–50), 30-month distant relapse-free survival was 95% (95% CI 88–100) in the non-operative management group and 74% (95% CI 68–82) in the overall population. Diarrhoea (eight [4%] of 180) and neutropenia (seven [4%] of 180) were the most common grade 3–4 adverse events, consistent with expected toxicity of this regimen. No treatment-related deaths occurred. In exploratory analyses, circulating tumor DNA positivity after TNT showed both predictive and prognostic value. In pMMR/MSS stage II–III rectal cancer, total neoadjuvant therapy followed by non-operative management allows organ preservation in some patients without compromising distant relapse-free survival, supporting non-operative management as a treatment option in clinical practice. Fondazione AIRC ETS, Fondazione Oncologia Niguarda ETS, Grande Ospedale Metropolitano Niguarda, Ministero Salute, and AIRC 5xMille 2018.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Adenocarcinoma / Adenocarcinoma - mortality / Adenocarcinoma - pathology / Adenocarcinoma - therapy / Adult / Aged / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Biopsy / Cancer therapies / Capecitabine - administration & dosage / Chemotherapy / Clinical medicine / Colorectal cancer / Diarrhea / Endoscopy / Female / Health surveillance / Hematology, Oncology, and Palliative Medicine / Humans / Immunotherapy / Male / Management / Medical imaging / Metastases / Middle Aged / Mismatch repair / Multidisciplinary teams / Neoadjuvant Therapy - adverse effects / Neoadjuvant Therapy - mortality / Neoplasm Recurrence, Local - pathology / Neoplasm Staging / Neutropenia / Oxaliplatin / Oxaliplatin - administration & dosage / Patients / Radiation therapy / Rectal Neoplasms - mortality / Rectal Neoplasms - pathology / Rectal Neoplasms - therapy / Rectum / Response rates / Surgery / Survival / Toxicity / Tumors / Ultrasonic imaging