Locally advanced rectal cancer: what patients and practitioners should know about non-operative management

Summary

For decades, the standard of care for locally advanced rectal cancer (LARC) has consisted of rectal surgery combined with chemoradiotherapy, saving many lives but often impairing long-term quality of life. Recently, emerging evidence shows that, for up to 40% of patients, surgery may no longer be needed. Non-operative management (NOM), also known as watch-and-wait, allows patients whose tumours completely regress after treatment (whether immunotherapy or total neoadjuvant therapy) to be safely monitored without mandatory surgery; avoiding time and cost of major surgery and preserving both the rectum and quality of life. NOM is part of a broader trend in oncology: from a one-size-fits-all strategy to treatment de-escalation for those who do not need maximal intervention. In mismatch repair proficient/microsatellite stable (pMMR/MSS) LARC, this de-escalation has been paradoxically achieved by initial intensification using total neoadjuvant therapy to later omit surgery. This Viewpoint aims to outline for a broad medical audience, including non-specialist physicians and individuals in care, how recent advances are reshaping rectal cancer treatment. By discussing NOM as an opportunity to move beyond a purely surgical paradigm, we hope to increase awareness of NOM options to inform evidence-based decision-making, reduce treatment-related morbidity, and promote patient-centred models of care and shared decision-making.

Search strategy and selection criteria.

References for this Viewpoint were identified through searches of PubMed with the search terms “rectal cancer” or “locally advanced rectal cancer”, and “organ preservation” or “watch-and-wait” or “nonoperative management” or “non-operative management” or “NOM” or “W&W, from 2000 until December 2025. Articles were also identified through searches of the authors’ own files. Only papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope of this Viewpoint.

Introduction

Locally advanced rectal cancer (LARC) is a non-metastatic but invasive, high-risk tumour.^1,2 It represents one third of rectal cancers and is curable for most individuals.^1,2 For decades, combining radiotherapy, chemotherapy, and rectal surgery has been the unquestioned standard.³ This approach achieves a very low risk of tumour recurrence and high survival, yet the price of cure can impact profoundly on quality of life via ongoing problems, especially for tumours located near the anal sphincter in the middle/lower rectum.^4,5 These problems include perioperative complications, permanent colostomy, impaired bowel function, and loss or impairment of sexual function.

Recently, treatment choices have evolved beyond a single pathway. Therapeutic strategies now encompass sole immunotherapy for a small and exquisitely immune-responsive subset of LARC (referred to as mismatch repair deficient/microsatellite instable–dMMR/MSI LARC–occurring in one in 10–20 patients), and total neoadjuvant therapy (TNT) for the remaining majority of patients with mismatch repair proficient/microsatellite stable (pMMR/MSS) LARC responding to chemotherapy and radiotherapy. Both approaches deliver treatment upfront to maximise tumour regression and improve oncological outcomes.1, 2, 3

Building on these advances, a new paradigm has emerged: non-operative management (NOM). NOM allows patients whose tumours completely regress after such treatments (whether immunotherapy or TNT) to be safely monitored without mandatory surgery, avoiding the time and cost of major surgery and preserving both the rectum and quality of life^4,5 (Fig. 1).

Fig. 1.

Diagnostic and therapeutic summary diagram toward non-operative management in rectal cancer. CRT, chemoradiotherapy; dMMR/MSI, mismatch repair deficient/microsatellite instable; MMR, mismatch repair; pMMR/MSS, mismatch repair proficient/microsatellite stable.

Modern strategies to boost tumour response

These advances stem from two key research developments. The first is the recognition that not all LARC are the same: they differ in their ability to repair DNA damage depending on individual mismatch repair (MMR) status.^6,7 dMMR/MSI tumours, lacking this DNA proofreading system, accumulate DNA mutations that make them highly visible to the immune system and remarkably sensitive to immunotherapy. For these patients, immunotherapy alone leads to complete tumour disappearance in virtually all patients. In a landmark study, all 49 patients with dMMR/MSI LARC treated with dostarlimab immunotherapy achieved clinical complete response (cCR).⁷ For this reason, determining if a LARC is dMMR/MSI has become of paramount importance and mandatory for all new diagnoses.^1,2

The second development is the optimisation of conventional therapy for most patients with pMMR/MSS LARC. Traditionally, these patients received (chemo-)radiation before surgery, often followed by additional systemic chemotherapy as adjuvant treatment.³ TNT integrates all these components upfront, either as induction chemotherapy followed by chemoradiation or as consolidation chemotherapy after it. Several trials proved that this treatment reorganisation improves systemic disease control and increases the proportion of patients who achieve cCR (1 in 3–4 patients), supporting NOM strategy in selected patients.⁸ Compared with standard neoadjuvant chemoradiotherapy, TNT offers several potential advantages. By delivering systemic chemotherapy upfront, TNT not only improves treatment compliance but also allows earlier eradication of micrometastatic disease, which translates into better disease control across several studies. However, the heterogeneity of the available regimens (in terms of number of cycles, chemotherapy agents and combinations, radiotherapy schedules and boosting, and induction vs consolidation fashions) underscores the residual need for direct comparisons in survival-focused trials to optimise TNT scheduling.9, 10, 11, 12, 13, 14, 15, 16

When the tumour disappears

The emerging NOM paradigm, recently consolidated by robust studies, offers a hopeful alternative to rectal surgery. In case of cCR, some centres have begun to defer surgery and follow patients closely through intensive surveillance programmes. This NOM strategy, also referred to as watch-and-wait, turns traditional thinking on its head. Rather than removing what may already be gone, clinicians monitor carefully and intervene only if the tumour returns: a shift that spares for many patients the need of rectal resection and the potential lifelong physical/psychological consequences that follow.^4,5

The pioneering contributions of Angelita Habr-Gama in the early 2000s were pivotal in driving this paradigm shift, showing that after cCR obtained with chemo-radiation, durable tumour-free periods could be maintained without immediate surgery, and that salvage interventions after local regrowth were effective.¹⁷ For years, NOM remained controversial.^18,19 It is only recently, however, that NOM has entered guidelines as a clinical option; thanks to the publication of convincing evidence for its safety and benefit.^1,2

The OPRA clinical trial first compared two TNT strategies (induction vs consolidation chemotherapy) in 324 patients with LARC. The results showed that 74% of all patients with MSS LARC achieved cCR or near-complete response (nCR) and were offered watch-and-wait, and 50% of all patients could preserve their rectum. Nearly all cases of local regrowth were detected early and successfully treated with delayed surgery.²⁰ The proportion of patients achieving cCR was similar in the subsequent CAO/ARO/AIO-16 trial.¹²

While local regrowth post-NOM can usually be salvaged without affecting outcome, the cogent concern remained the risk of developing distant metastases, which ultimately determine survival. Therefore, the NO-CUT trial went further by focussing on patients with pMMR/MSS LARC and investigating whether and how NOM influences the risk of distant relapse post-TNT.¹⁰ Among 179 participants, about one quarter achieved cCR and entered a structured NOM programme. Two and a half years later, >95% of those managed without surgery remained free of distant relapse, and 85% eventually kept their rectum intact (with 15% experiencing local regrowth and delayed surgery).¹⁰ These findings demonstrate that, under the supervision of a dedicated multidisciplinary rectal cancer team, NOM can offer the perspective of both cure and organ preservation.

In parallel, immunotherapy has already shown how far NOM can go. As discussed, immunotherapy for dMMR/MSI LARC not only yields impressive cCR rates but also avoids surgery, with most responses durable on follow-up.⁷ Rare recurrences have been described with longer follow-up and in real-world cohorts, so structured surveillance remains essential.^7,21

Who can safely avoid surgery?

NOM is not suitable for everyone. First, NOM can be safely offered to patients who achieve cCR, confirmed through digital rectal examination (DRE), endoscopy, magnetic resonance imaging (MRI), and computed tomography (CT) scan.^1,2 Some physicians may also prescribe a restaging biopsy and ultrasounds during endoscopy. Evaluation must be carried out by an experienced multidisciplinary LARC team, generally within 8–12 weeks after completing chemoradiotherapy or immunotherapy (these timeframes remain a matter of debate).^1,2 At this restaging time, some patients might show nCR (almost but not entirely tumour-free) for which no shared definition exists. As nCR could further regress to cCR with additional waiting (e.g., 4–8 weeks) further reassessment is advisable before a decision is made toward NOM or surgery.²² Tumour response, indeed, appears to be time-dependent, and delayed regression may occur, underscoring the importance of continued monitoring before deciding on surgery.^1,2 Definitions and cCR criteria remain an active area of research, as does the identification of biomarkers that predict durable remission.

NOM also demands rigorous follow-up. Patients who cannot commit to follow-up testing should not be offered NOM. Current guidelines suggest local reassessment every three months through clinical and DRE, CEA blood marker, and endoscopy. Endoscopic photos with photo archiving are recommended. Pelvic MRI is recommended every 3 months, and CT scans every 6–12 months. This schedule is especially important during the first two years, when risk of local regrowth is highest, and can later be extended to six-month intervals.¹ If local regrowth is detected, timely surgery can restore local control without harming long-term outcomes.^1,2,10,12,20 However, this level of vigilance can be demanding for patients and health systems and should only be implemented in centres capable of rapid evaluation and salvage surgery. Also, this places a heavy emphasis on diligent follow-up: patients choosing NOM must be fully committed to adherence to the strict follow-up schedule. Clinicians play a vital role in ensuring timely access to these examinations and addressing any concerns regarding NOM in patients who do not adhere to the protocol. Watch-and-wait is not a passive approach; it requires an experienced multidisciplinary team and strict protocols for monitoring. In essence, patient selection and centre selection are both critical: not all patients will find NOM acceptable, given the psychological and logistical demands of intensive surveillance, and not every hospital is equipped to carry it out safely. This intensive surveillance, logistically challenging and anxiety-provoking, is an important part of the counselling before choosing NOM.

Quality of life and patient choice

The heart of the NOM strategy is patient-centred care. Rectal surgery, even when technically successful, can profoundly affect daily life. Up to 70% of patients experience chronic bowel dysfunction, known as low anterior resection syndrome (LARS), with major symptoms in up to 40% of cases. LARS is characterised by symptoms such as frequent bowel movements, urgency, or incontinence. Sexual and urinary side effects are also common (20–40%), due to pelvic nerve damage and could be associated with anastomotic leak or strictures and issues with perineal wound healing. If an abdominoperineal resection is required (which occurs when the tumour is too close to the anal sphincter), patients face the psychological burden of a potential permanent stoma (15–20%). Besides, most patients will experience a temporary stoma (70–80%) when surgical removal of the rectum does not allow safe reconnection of the bowel.^4,5 Moreover, because all these sequelae are greatest in low rectal cancers, NOM has its greatest benefit for patients with tumours located within 8–10 cm from the anal verge.

Avoiding rectal surgery spares many of these complications. Many studies, including a matched controlled analysis, consistently show that patients who succeed with NOM report better bowel function, less fatigue, and higher overall quality of life.²³ Yet the approach is not anxiety-free: living under close surveillance can itself be stressful. Candid sharing of decision-making between patients and physicians, guided by a multidisciplinary team, is therefore essential.^4,5

Conclusions and looking ahead

The success of NOM is part of a broader trend in oncology: from a one-size-fits-all strategy to treatment de-escalation for those who do not need maximal intervention; placing the long-term well-being of a person cured from rectal cancer at the forefront. In pMMR/MSS LARC, this de-escalation has been paradoxically achieved by initial intensification using TNT to later omit surgery.1, 2, 3 Ongoing trials are investigating how to optimise this balance. Also, by better learning who truly benefits from surgery, and who does not, we can offer more humane, tailored care. Research is moving in this direction, including assessment of tumour DNA fragments in blood by liquid biopsy.^7,10

Meanwhile, NOM is no longer an investigational approach. Instead, it stands as an accepted standard of care for selected patients with LARC, supported by clinical trials and international guidelines.^1,2,10,12,20 In these patients, NOM is now not only feasible, but often the wiser, kinder choice.

Contributors

F.T., G.P., and S.S. conceived and wrote the manuscript. In addition, S.S. provided oversight and senior revisions. A.A. provided expert revision of the manuscript focussing on management of locally advanced rectal cancers. P.C., F.B., A.A, K.B., E.F.B., G.M., D.P., F.V., A.S.B., and S.S. contributed to clinical insights and perspectives, and to critical revision of the manuscript.

Declaration of interests

F.T. is an advisory board member for Daiichi-Sankyo, AstraZeneca. A.A. is an advisory board member for Amgen and Italfarmaco. S.S. is an advisory board member for Agenus, AstraZeneca, Bayer, Bristol Meyer Squibb, CheckmAb, Daiichi-Sankyo, Glaxo, SmithKline, MSD, Merck, Novartis, Pierre Fabre, Novartis, Pfizer, Seagen, and T-One Therapeutics. A.S.B is an advisory board member for Amgen, Bayer, Servier, Pierre Fabre, and Takeda. K.B. is an advisory board member for Amgen. All other authors declare no competing interests.