Organ Preservation Strategy Shows Promise in Rectal Cancer

Organ preservation may be a viable option for select patients with locally advanced rectal cancer, according to the first results of the NO-CUT trial.

The study investigated the efficacy of total neoadjuvant treatment followed by nonoperative management in patients with proficient mismatch repair (pMMR) locally advanced rectal cancer.

Alessio Amatu, MD, of the Niguarda Cancer Center in Milan, Italy, presented the findings at the European Society for Medical Oncology Congress 2024.

Study Rationale and Design

According to Amatu, radical surgery has long been the gold standard treatment for nonmetastatic rectal cancer. However, there has been growing interest in organ preservation strategies, particularly for patients who show complete clinical response after neoadjuvant therapy.

The NO-CUT trial aimed to assess whether nonoperative management negatively affects the risk for distant relapse and to identify predictive biomarkers of treatment outcomes.

The trial enrolled 180 patients with cT3-4N0/cTxN1-2 lower/middle pMMR locally advanced rectal cancer across four high-volume centers in Italy. Patients received total neoadjuvant treatment consisting of four cycles of capecitabine plus oxaliplatin chemotherapy followed by long-course chemoradiotherapy. After a 12-week treatment-free interval, patients underwent restaging. Patients with complete clinical response after total neoadjuvant treatment were assigned to the nonoperative management cohort with intensive follow-up, whereas patients with incomplete response underwent surgery followed by standard follow-up.

Effect of Total Neoadjuvant Treatment on Distant Relapse Risk

During his talk, Amatu said 26 patients achieved a complete clinical response and proceeded with nonoperative management, and 90% of patients with incomplete response underwent surgery.

The primary endpoint of 30-month distant relapse-free survival (DRFS) in the nonoperative management cohort was met, with a DRFS rate of 96.9% (95% CI, 91%-100%). During his talk, Amatu emphasized that this DRFS rate surpassed the prespecified threshold of 87% and was notably higher than the 74% DRFS observed in the surgery cohort.

David Sebag-Montefiore, MD, who was not involved in the NO-CUT trial, served as a discussant on the findings at the meeting.

“I congratulate the NO-CUT trial investigators on conducting this 180-patient trial in medium, moderate, locally advanced rectal cancer in proficient mismatch repair disease. The impressively high DRFS is very reassuring and confirmed oncological safety,” said Sebag-Montefiore, a professor of clinical oncology and health research at the University of Leeds, Leeds, United Kingdom.

Biomarkers Predicted Clinical Response and Survival

Circulating tumor DNA (ctDNA) positivity after surgery was significantly associated with worse progression-free survival.

The organ preservation rate in the nonoperative management cohort was 85% (39 of 46 patients). Local regrowth occurred in 15% of patients in the nonoperative management group, all between 4 and 18 months after treatment. All patients with local regrowth underwent successful rescue surgery and 42% were able to undergo sphincter-sparing procedures.

The NO-CUT trial includes a comprehensive translational program to identify biomarkers predictive of clinical response and survival. ctDNA analysis using the Guardant Reveal assay showed promising results, according to Amatu.

The percentage of patients without detectable ctDNA in their plasma (ctDNA-negative) was 92% in those with complete clinical response and 49% in those with incomplete response, and this difference was statistically significant (P = .008).

“The patients who were ctDNA-positive had an increased probability of distant relapse, with a three times greater risk,” Amatu said.

Analysis of DRFS in the overall population according to ctDNA status showed a hazard ratio (HR) of 3.23 (95% CI, 1.08-9.63; P = .035). Furthermore, ctDNA positivity after surgery was significantly associated with worse progression-free survival among patients in the incomplete response cohort (HR, 6.99; 95% CI, 2.19-22.39; P = .001).

In addition, RNA sequencing of pretreatment tumor biopsies revealed that a high leukocyte score was significantly associated with complete clinical response. In contrast, the CRIS-E phenotype (a Paneth cell-like subtype) correlated with reduced DRFS probability.

Commenting on the findings of these biomarker analyses, Sebag-Montefiore said, “I congratulate the investigators for their translational research, which is critically important for our scientific understanding. Particularly interesting is the hypothesis-generating findings on the leukocyte score and the CRIS-E score, helping to predict which patients would benefit from the total neoadjuvant treatment approach with capecitabine and oxaliplatin.”

Clinical Implications and Future Work

According to Sebag-Montefiore, the NO-CUT trial results contribute to a growing body of evidence supporting organ preservation strategies for rectal cancer.

“I do think we are on the verge of a new era for organ preservation. A lot of the groundwork has been done, and we now have a platform to build upon to optimize systemic and radiotherapy-based treatments to change the treatment paradigm,” he added.

Although these results are promising, both Amatu and Sebag-Montefiore emphasized the need for further studies to optimize patient selection, improve complete clinical response rates, and validate the findings of the NO-CUT trial in larger randomized trials.

Sebag-Montefiore noted uncertainties surrounding the effects of total neoadjuvant treatment on the quality of life and functional outcomes, the best radiotherapy and chemotherapy sequence, and the best chemoradiotherapy regimen.

“We also have ongoing questions about who we select and how, and most importantly, how we increase the complete clinical response rate,” he added.

Sebag-Montefiore concluded: “We’ve got evidence of oncological safety and promising early phase studies that are showing complete clinical response rates of 30%-60% and sometimes higher. To accelerate progress, we need new treatments that have a strong scientific rationale. We need randomized trials to confirm their clinical utility and their benefit to patients.”

Amatu reported financial relationships with Italfarmaco and Amgen (advisory board member). Sebag-Montefiore reported financial relationships with Cancer Research UK, Yorkshire Cancer Research, and Adlai Nortye (research funding).