The NO-CUT trial, presented at the European Society for Medical Oncology (ESMO) Congress 2024, indicates that non-operative management (NOM) following total neoadjuvant therapy (TNT) does not worsen distant relapse-free survival (DRFS) in patients with mismatch repair proficient (pMMR) locally advanced rectal cancer. This multicenter, single-arm phase II trial suggests a potential shift in the standard of care, offering organ preservation for select patients.
Key Findings from the NO-CUT Trial
The study enrolled 180 patients with mid/low cT3 to cT4 and/or cN1 to cN2, cM0, pMMR/MSS rectal adenocarcinoma. Patients received four cycles of capecitabine plus oxaliplatin, followed by long-course chemoradiotherapy. After TNT, patients were assigned to either rectal surgery or surveillance based on clinical complete response (cCR) parameters.
A cCR was noted in 26% of patients, enabling them to proceed with NOM. Among those with an incomplete response, 90% underwent surgery. The DRFS rate was 96.9% (95% CI, 91.0%-100.0%) in the NOM group and 76.7% (95% CI, 69.8%-84.2%) in all patients.
Organ preservation was achieved in 85% (n = 39/46) of patients who underwent NOM. Local regrowth occurred in 4% to 18% of patients, all of whom underwent rescue surgery, with 42% (n = 3/7) having sphincter-sparing treatment.
ctDNA as a Predictive Biomarker
Circulating tumor DNA (ctDNA) analysis after TNT showed a significant association with tumor response. In ctDNA-negative patients, a cCR was observed in 92%, while an incomplete response occurred in 69%. Conversely, in ctDNA-positive patients, the cCR rate was 8%, and the incomplete response rate was 31%.
The 2-year DRFS rate for ctDNA-negative patients was 89.4% (95% CI, 81.6%-97.9%) compared to 64.0% (95% CI, 44.3%-92.5%) for ctDNA-positive patients. The 3-year DRFS rates were 85.8% (95% CI, 76.0%-96.9%) vs 64.0% (95% CI, 44.3%-92.5%), respectively (HR, 3.23; 95% CI, 1.08-9.63; P = .035).
In patients who underwent surgery, ctDNA positivity was associated with a significant increase in the risk of progression (HR, 6.99; 95% CI, 2.19-22.39; P = .001).
Expert Commentary
Alessio Amatu, MD, a surgeon and oncologist at Niguarda Cancer Center, stated, "An optimal selection of candidates to NOM may take advantage of translational biomarkers. Future trials for the cure of pMMR/microsatellite stable [MSS] locally advanced rectal cancer will aim at increasing cCR rates by refined patient selection through multi-omics studies and improved total neoadjuvant treatment strategies."
David Sebag-Montefiore, MD, Professor of Clinical Oncology at the University of Leeds, commented on the increasing interest in organ-preservation strategies, noting that the NO-CUT trial's results are reassuring and confirm oncologic safety. He emphasized the importance of ongoing research to determine the best sequence of TNT, optimal use of immunotherapy, and mechanisms of treatment response and resistance.
Implications for Clinical Practice
The NO-CUT trial suggests that NOM is a viable option for a subset of patients with locally advanced rectal cancer who achieve a clinical complete response after TNT. The use of ctDNA as a biomarker may further refine patient selection for NOM, potentially avoiding unnecessary surgery and improving quality of life.
