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

Abstract

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: 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.

Fundings: Fondazione AIRC ETS, Fondazione Oncologia Niguarda ETS, Grande Ospedale Metropolitano Niguarda, Ministero Salute, and AIRC 5xMille 2018.