Highlight
– Total neoadjuvant therapy (CAPOX + chemoradiation) produced a clinical complete response (cCR) rate of 26% and enabled non‑operative management (watch‑and‑wait) in stage II–III pMMR/MSS rectal cancer.
– Among patients managed non‑operatively after cCR, 30‑month distant relapse‑free survival (dRFS) was 95% (95% CI 88–100), indicating no apparent compromise in distant disease control.
– Treatment toxicities were consistent with expectations for CAPOX and chemoradiation; exploratory circulating tumor DNA (ctDNA) analysis showed prognostic and predictive potential.
Background
Rectal cancer management has evolved toward multidisciplinary, personalized strategies that balance oncologic control and quality of life. For most patients with stage II–III rectal adenocarcinoma, standard care has traditionally included neoadjuvant (chemo)radiation followed by total mesorectal excision (TME). However, TME can be associated with enduring bowel, urinary, and sexual dysfunction and, in low rectal tumors, a permanent stoma.
The concept of non‑operative management (NOM) or “watch‑and‑wait” after a clinical complete response (cCR) to neoadjuvant therapy aims to preserve the rectum and its function. Pioneering single‑centre series and prospective cohorts have suggested NOM is feasible in selected patients, but concerns persist about accurate identification of true complete responders, risk of local regrowth, salvage surgery success rates, and—critically—whether avoiding immediate resection might increase the risk of distant metastatic relapse.
Total neoadjuvant therapy (TNT)—delivering systemic chemotherapy before surgery, typically in combination with chemoradiation—has been adopted to improve systemic control, increase the rates of tumor regression, and potentially increase the pool of patients eligible for NOM. The NO‑CUT trial interrogates whether selecting cCR patients after CAPOX‑based TNT for NOM compromises distant control in patients with proficient mismatch repair/microsatellite‑stable (pMMR/MSS) stage II–III rectal cancer.
Study design
NO‑CUT was an investigator‑initiated, multicentre, single‑arm phase 2 trial conducted at four cancer centres in Italy. Key elements:
– Population: Adults (≥18 years) with treatment‑naive, stage II–III adenocarcinoma of the lower‑to‑middle rectum, ECOG 0–1, and pMMR/MSS tumour biology.
– Intervention: Induction chemotherapy with four cycles of CAPOX (capecitabine 1000 mg/m2 orally twice daily days 1–14 and oxaliplatin 130 mg/m2 IV day 1, every 3 weeks), followed by concomitant capecitabine (825 mg/m2 orally twice daily) with long‑course radiotherapy (50–54 Gy in 25 fractions over 5 weeks).
– Response assessment: Clinical complete response adjudicated using modified Memorial Sloan Kettering Cancer Center criteria. Patients with cCR entered NOM (intensive surveillance); patients without cCR proceeded to standard surgery (TME).
– Primary endpoint: 30‑month distant relapse‑free survival (dRFS) following NOM in the intention‑to‑treat (ITT) population.
– Ancillary analyses: Safety, organ preservation rate, and exploratory circulating tumour DNA (ctDNA) analyses as a biomarker for risk stratification.
The trial was registered on EudraCT (2017‑003671‑60).
Key findings
Population and compliance
Between June 6, 2018, and Aug 22, 2023, 180 patients were enrolled and began treatment; 179 patients with pMMR/MSS disease comprised the ITT group. Of these, 165 (92%) completed the prescribed TNT regimen.
Organ preservation and response
– 47 patients (26% of the ITT population) achieved cCR and entered NOM.
– Thus, NOM enabled organ preservation in approximately one quarter of treated patients — a clinically meaningful subset for whom surgery (and its potential morbidity) was deferred or avoided.
Oncologic outcomes
– With a median follow‑up of 35 months (IQR 21–50), the 30‑month dRFS in the NOM group was 95% (95% CI 88–100).
– By comparison, the 30‑month dRFS in the overall ITT population was 74% (95% CI 68–82). The higher dRFS in the NOM cohort likely reflects selection of responders with favorable biology and deep local response after TNT.
– The trial’s primary endpoint—30‑month dRFS after NOM—was met; these results suggest that in selected cCR patients managed non‑operatively after CAPOX‑based TNT, distant control is excellent at medium‑term follow‑up.
Safety
– Grade 3–4 toxicities were consistent with expectations for CAPOX and chemoradiation: diarrhoea in eight patients (4% of 180) and neutropenia in seven patients (4%). No treatment‑related deaths were reported.
Biomarker findings (exploratory)
– ctDNA positivity after TNT demonstrated both prognostic and predictive value in exploratory analyses. Although details (absolute risks, hazard ratios) were not provided in the summary, the observation aligns with emerging literature implicating post‑treatment ctDNA as a marker of residual systemic disease and recurrence risk.
Interpretation and clinical implications
NO‑CUT provides prospective, multicentre phase 2 evidence supporting the safety of selecting cCR patients for NOM after CAPOX‑based TNT in pMMR/MSS stage II–III rectal cancer, at least in terms of medium‑term distant relapse control. Key practical implications:
– Organ preservation is achievable without apparent sacrifice of distant disease control: a 26% organ preservation rate and a 95% 30‑month dRFS among NOM patients are encouraging for patients and clinicians prioritising function and quality of life.
– The high dRFS in NOM patients argues against the concern that avoiding immediate surgery would necessarily increase metastatic risk in properly selected responders to TNT.
– Integration of ctDNA as a risk stratification tool is promising: undetectable ctDNA after TNT may identify patients at very low risk of systemic relapse and therefore strong candidates for NOM, whereas persistent ctDNA could flag patients for intensified surveillance or adjuvant strategies.
Strengths
– Prospective, multicentre design across four cancer centres increases generalisability beyond single‑centre experience.
– Use of contemporary TNT (CAPOX induction + long‑course chemoradiation) mirrors current practice in many centres and addresses systemic disease early.
– Pre‑specified primary endpoint focused on distant relapse addresses the critical safety question for NOM: does organ preservation worsen systemic outcomes?
– Safety profile was acceptable and consistent with known toxicity of the regimen.
Limitations and caveats
– Single‑arm phase 2 design: Without a randomized control group, it is not possible to definitively attribute observed dRFS rates to the NOM pathway versus intrinsic patient/ tumor biology. The NOM cohort is inherently selected for excellent response.
– Sample size and event counts in the NOM group are modest (47 patients); the 95% CI for dRFS (88–100) is wide and longer follow‑up will be needed to confirm durability.
– Local regrowth rates, salvage surgery success, functional outcomes, and quality‑of‑life data are not presented in the summary; these are central to assessing the net benefit of NOM.
– Trial results apply to pMMR/MSS tumours; dMMR/MSI‑high disease, increasingly treated with upfront immunotherapy in some contexts, may not be comparable.
– cCR assessment used modified MSKCC criteria—successful implementation of NOM outside trial settings requires standardized, reproducible assessment protocols (high‑quality MRI, endoscopy, digital rectal examination) and rigorous surveillance pathways.
How NO‑CUT fits into current evidence and practice
NO‑CUT complements other prospective efforts that have explored TNT and watch‑and‑wait strategies, adding important multicentre phase 2 data that address the oncologic safety question of distant relapse. For clinicians, the study bolsters the argument that TNT can downstage tumours and permit NOM in a subset of patients without compromising medium‑term distant control—provided rigorous response assessment and follow‑up are available.
The exploratory ctDNA findings echo a growing body of evidence supporting ctDNA as a biomarker to guide adjuvant decisions and surveillance in colorectal cancer. Prospective validation of ctDNA‑directed NOM strategies would be a logical next step.
Practical recommendations for clinicians
– Consider a TNT‑first approach for appropriate stage II–III pMMR/MSS rectal cancer patients when the clinical objective includes increasing the chance of organ preservation.
– If NOM is contemplated after cCR, ensure that response assessment follows standardized protocols (multiparametric MRI, endoscopy with documentation, thorough clinical examination) and that the patient is willing and able to adhere to an intensive surveillance program.
– Integrate biomarkers (e.g., ctDNA) into multidisciplinary decision‑making where available and interpret them in the context of imaging and clinical findings.
– Discuss the uncertainties explicitly with patients: although medium‑term systemic control appears preserved, long‑term outcomes, local regrowth risks, functional outcomes, and the possibility of requiring salvage surgery remain important considerations.
Research implications and future directions
– Randomized trials comparing immediate surgery versus NOM after TNT in cCR patients would provide the highest level of evidence but are challenging to perform. Pragmatic randomized or well‑matched cohort studies with patient‑reported outcomes and long follow‑up remain a priority.
– Prospective validation of ctDNA to guide NOM selection and surveillance intensity is a high‑priority translational question.
– Detailed reporting on local regrowth rates, salvage surgery rates and outcomes, long‑term bowel and sexual function, and quality‑of‑life measures will be essential to fully weigh the benefits and harms of NOM.
Conclusion
The NO‑CUT trial demonstrates that CAPOX‑based TNT followed by NOM for patients with clinical complete response can achieve organ preservation in a meaningful minority of patients with pMMR/MSS stage II–III rectal cancer without compromising 30‑month distant relapse‑free survival. While encouraging, these results should be implemented with caution: robust response assessment, intensive surveillance, multidisciplinary care, and shared decision‑making are prerequisites. Larger studies and longer follow‑up—incorporating functional outcomes and validated biomarkers such as ctDNA—are needed to refine patient selection and to confirm long‑term oncologic safety.
Funding and trial registration
NO‑CUT was funded by Fondazione AIRC ETS, Fondazione Oncologia Niguarda ETS, Grande Ospedale Metropolitano Niguarda, Ministero Salute, and AIRC 5xMille 2018. The trial is registered on EudraCT (2017‑003671‑60).
Reference
Amatu A, Patelli G, Zampino MG, et al. 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. Lancet Oncol. 2025 Dec;26(12):1612‑1625. doi:10.1016/S1470‑2045(25)00542‑X. PMID: 41308677.