In an Italian phase II trial (NO-CUT) reported in The Lancet Oncology, Amatu et al found that total neoadjuvant therapy followed by nonoperative management in cases of complete response resulted in promising outcomes in patients with proficient mismatch repair or microsatellite stable (pMMR/MSS) stage II or III rectal cancer.
As stated by the investigators, “This study aimed to determine whether nonoperative management compromises distant relapse–free survival in patients with clinical complete response after total neoadjuvant therapy.”
Study Details
In the multicenter trial, 179 eligible patients enrolled between June 2018 and August 2023 received total neoadjuvant therapy with four cycles of capecitabine at 1,000 mg/m² twice a day on days 1 to 14 every 3 weeks and oxaliplatin at 130 mg/m² on day 1 every 3 weeks, followed by capecitabine at 825 mg/m² twice a day concurrent with radiotherapy at 50 to 54 Gy in 25 fractions over 5 weeks. Patients with clinical complete response underwent nonoperative management and patients without clinical complete response underwent surgery. The primary outcome measure was 30-month distant relapse–free survival after nonoperative management in the intention-to-treat population.
Key Findings
Among the 179 patients, 165 (92%) completed total neoadjuvant therapy; 47 (26%) had clinical complete response and underwent nonoperative management.
Median follow-up was 35 months (interquartile range = 21–50 months). Distant relapse–free survival at 30 months was 95% (95% confidence interval [CI] = 88%–100%) among the 47 patients in the nonoperative management group, 74% (95% CI = 66%–84%) among 107 patients in the surgery group (excluding those who had surgery after discontinuation), and 74% (95% CI = 68%–82%) among 179 patients in the overall population. The 2-year rectal surgery–free survival after nonoperative management was 83% (95% CI = 73%–95%).
In exploratory analysis, circulating tumor DNA positivity after total neoadjuvant therapy was associated with significantly poorer distant relapse–free survival (P = .0032).
Among all patients, grade 3 or 4 adverse events occurred in 31%, most commonly diarrhea, lymphopenia, neutropenia, and bowel obstruction (4% each). Serious adverse events occurred in 17% of patients, most commonly bowel obstruction (4%). Adverse events led to discontinuation of treatment in 7%. No treatment-related deaths were reported.
The investigators concluded: “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.”
Salvatore Siena, MD, of Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Fondazione AIRC ETS, Fondazione Oncologia Niguarda ETS, and others. For full disclosures of all study authors, visit thelancet.com.
