Non-Operative Management (NOM) in Rectal Cancer: Current Evidence and Future Directions

Definition

Rectal cancer has become a significant health concern in current years, but there are very effective current neo-adjuvant treatment modalities which can result in the complete disappearance of the disease without surgery, which is often associated with severe post-surgical sequelae. Therefore, a significant effort has been made to identify the subset of patients who can avoid surgery and to investigate the long-term oncologic and functional results associated with the Non-Operative Management of such a disease.

1. Introduction

Rectal cancer remains a major global health concern, with new cases increasing annually [1]. The standard treatment for locally advanced disease has traditionally included neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME). Although oncologically effective, surgery is associated with considerable morbidities, including bowel, urinary, and sexual dysfunction [2,3].

The concept of Non-Operative Management (NOM), also known as the “Watch-and-Wait” (WW) strategy, has emerged as an alternative for patients achieving a clinical complete response (cCR) after neoadjuvant therapy [4,5]. Early data from the International Watch & Wait Database (IWWD) demonstrated promising long-term oncologic outcomes [6,7]. More recent evidence, including updated National Comprehensive Cancer Network (NCCN) and European Society For Medical Oncology (ESMO) guidelines, supports NOM in carefully selected patients, provided rigorous surveillance protocols are followed [8,9].

Advances in Total Neoadjuvant Therapy (TNT) have increased cCR rates, expanding the pool of patients eligible for organ preservation [10,11]. Novel immunotherapy approaches, particularly in mismatch repair-deficient (dMMR) rectal cancers, have demonstrated unprecedented response rates, raising the possibility of NOM as a curative option without radiation or surgery [12,13].

Given these developments, we present a narrative review focusing on NOM protocols, oncologic and functional outcomes, patient selection, and long-term feasibility.

2. Epidemiology and Burden of Disease

Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. In the United States, CRC is the third leading cause of cancer death among both men and women and ranks second when considering both sexes combined [1,14]. Over half of CRC cases are linked to modifiable risk factors, including tobacco use, poor diet, alcohol intake, physical inactivity, and obesity. Morbidity and mortality can be significantly reduced through timely screening and surveillance programs targeting individuals aged 50–75 [1,14].

Among colorectal malignancies, rectal cancer represents approximately one-third of cases, with rising incidence observed in both younger and older populations [1,14].

3. Rationale for Non-Operative Management

The appeal of NOM primarily stems from the morbidity associated with TME. Postoperative complications, such as low anterior resection syndrome (LARS), bowel dysfunction, urinary frequency, sexual dysfunction, and the potential need for temporary or permanent stoma, significantly affect quality of life [2,3,15].

Two primary organ-preserving approaches have been developed, namely local excision (LE) and NOM, both avoiding TME by relying on the sterilizing effect of neoadjuvant therapy on potential lymph node metastases [4,5]. NOM virtually eliminates surgical morbidity but requires careful patient selection, as approximately 25% of WW patients may experience local regrowth, necessitating salvage surgery [6,7].

Pathologic complete response (pCR) is achieved in up to 40% of patients following CRT or TNT and serves as a pivotal prognostic criterion [11]. The possibility of deferring surgery is further enhanced by TNT protocols, which improve rates of cCR and disease-free survival (DFS) [10,11].

4. Pretreatment Patient Selection

Predictors of poor response include larger tumor size, advanced T/N stage, circumferential tumor extent > 60%, elevated baseline carcinoembryonic antigen (CEA) (>2.5 ng/mL), and tumor location > 5 cm from the anal verge [16,17]. Pathologic features such as mucinous histology, poor differentiation, and ulceration also correlate with reduced response [16,17].

Radiotherapy delivery is crucial: conventionally fractionated doses < 35 Gy yield lower response rates, whereas modern CRT protocols with doses > 45 Gy and concomitant boosts significantly increase tumor regression and pCR rates [18,19]. Tumor response is also time-dependent, and longer intervals between CRT and response assessment can enhance downstaging without increasing toxicity [18,19].

5. The Use of the Current Protocols of TNT Allowed a Further Increase in cCR and DFS

Recent advances in TNT protocols have resulted in increased cCR rates and DFS [10,11]. In stage I disease, up to 50% of patients may achieve pCR with CRT alone, whereas in stage II–III disease, pCR rates range from 18% with CRT alone to 36–38% with induction or consolidation chemotherapy [10].

Patient evaluation for NOM requires multimodal assessment, including the following:

• Digital rectal examination (DRE);
• High-resolution magnetic resonance imaging (MRI);
• Endoscopy with targeted biopsies;
• Selective use of positron emission tomography (PET) imaging.

Candidates typically include patients with low-risk LARC (T2-T3, N0-N1) demonstrating cCR by these criteria [4,5,18]. Rigorous post-treatment surveillance is essential to detect minimal residual disease.

6. “Non-Operative Management” After Neoadjuvant Therapy: Oncologic Outcomes

The concept of NOM was first described by Habr-Gama in 2004 [20]. Among 265 patients treated with CRT, 71 (27%) achieved cCR and entered structured surveillance. Local tumor regrowth occurred in two patients, managed successfully with local interventions, and no significant differences in overall survival (OS) or DFS were noted compared to patients achieving pCR after TME [20].

IWWD data report:

• A 5-year OS >85%;
• Local regrowth ~25%, with most successfully salvaged;
• DFS comparable to surgical cohorts with adherence to surveillance [6,7].

Meta-analyses confirm that NOM provides oncologic outcomes comparable to TME, with slightly higher local recurrence risk but no impact on OS or DFS [21,22]. European multicenter data support similar results, emphasizing strict adherence to surveillance protocols [23,24].

In dMMR tumors, programmed death receptor-1 (PD-1) blockade has achieved complete, durable responses, offering potential for NOM without radiation or surgery [12,13].

7. Management of NOM Failure and Salvage Surgery

Approximately 20–30% of patients may experience local regrowth within two years [6,7]. Salvage TME achieves R0 resection in most cases but can be technically challenging [25]. Patient counseling is essential to discuss the risks of recurrence and the need for salvage interventions.

8. Imaging Modalities and Minimal Residual Disease Detection

MRI, endoscopy, and DRE remain the cornerstone of response assessment, but sensitivity and specificity are imperfect (MRI: 80–85% sensitivity) [18,26]. PET may complement evaluation, and multimodal integration is recommended [26]. Future directions include circulating tumor DNA (ctDNA) and molecular biomarkers to enhance diagnostic precision [27].

9. NOM in Younger Patients

The rising incidence of early-onset rectal cancer raises new considerations for NOM. Younger patients often prioritize fertility, sexual function, and long-term quality of life (QoL), making organ preservation strategies appealing. However, the potential for late recurrences, higher prevalence of hereditary syndromes such as Lynch, and longer life expectancy necessitate cautious selection and rigorous surveillance. Tailored strategies, including intensified neoadjuvant approaches (e.g., total neoadjuvant therapy, TNT) and integration of genetic counseling, are recommended in this subgroup [22,23].

10. Surgical Options and Evolving Techniques

Despite growing interest in NOM, surgery remains the standard of care for patients without cCR or where surveillance is unfeasible. Advances in minimally invasive techniques—laparoscopic, robotic, and transanal TME (TaTME)—have expanded sphincter-preserving options and improved perioperative outcomes in selected patients. For distal tumors, intersphincteric resection and restorative procedures may reduce the need for permanent stoma. These surgical innovations contextualize NOM as one option within a broader spectrum of organ-preserving strategies, rather than as a replacement for surgery [23].

11. Functional and Quality of Life Considerations

An essential component of NOM evaluation is the impact on quality of life (QoL) and functional outcomes. Several studies have demonstrated that avoiding radical surgery can significantly reduce the risk of bowel dysfunction, urinary frequency, and sexual dysfunction. Patient-reported outcome measures (PROMs) are critical tools for capturing these benefits. Validated instruments such as the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-CR29 questionnaires are commonly used to evaluate bowel and urinary function, while the ICIQ (International Consultation on Incontinence Questionnaire) specifically addresses urinary disorders. Psychological well-being can be assessed through tools such as the Hospital Anxiety and Depression Scale (HADS) and EQ-5D. Data from recent NOM cohorts suggest that patients report higher global health scores, lower rates of low anterior resection syndrome, and improved continence compared to those undergoing TME, highlighting the functional advantages of non-operative strategies.

Emerging evidence suggests that individuals managed through a NOM exhibit superior preservation of bowel function, with a significantly lower incidence of fecal urgency and incontinence compared to those undergoing TME. This functional advantage is particularly relevant in maintaining a higher degree of continence and minimizing postoperative morbidity, ultimately contributing to an improved quality of life.

No studies can be found, comparing patient reported outcomes (PROMs) in comparable populations of patients which underwent surgery and NOM of rectal cancer. A single study on 26 patients treated with NOM reports very encouraging results: major, minor, and no LARS occurred in 3 (20%), 6 (40%), and 6 (40%) patients, respectively.

Psychosocial well-being constitutes another fundamental aspect of patient-centered care. Patients undergoing NOM frequently report lower levels of anxiety related to surgical morbidity, permanent stoma formation, and associated lifestyle alterations. However, the necessity for intensive surveillance and the inherent uncertainty regarding potential tumor regrowth may contribute to psychological distress. This underscores the critical need for comprehensive patient counseling, psychosocial support, and shared decision-making strategies to optimize adherence and mitigate anxiety associated with long-term

Importantly, functional outcomes and quality of life are increasingly recognized as key endpoints. PROM-based studies have shown superior bowel, urinary, and sexual function among NOM patients compared to those undergoing TME [7]. Although we did not collect comprehensive PROM data, this remains a critical area for future prospective research.

Recent advances in immunotherapy have further expanded the NOM landscape. In dMMR rectal cancers, PD-1 blockade has achieved clinical and radiologic complete response in nearly all treated patients [4]. The integration of molecular biomarkers, including microsatellite instability (MSI)/mismatch repair (MMR) status, into treatment algorithms will be crucial for personalized NOM strategies.

Despite encouraging results, challenges remain. Reliable radiologic and endoscopic response assessment continues to be debated [6]. Adherence to intensive surveillance protocols is resource-demanding and may not be feasible in all healthcare systems [9].

While small-scale studies suggest functional advantages of NOM, including improved continence and global health status, large-scale prospective trials incorporating standardized PROMs remain limited. Future research should prioritize robust PROM-based comparisons to better quantify the quality-of-life benefits of NOM at the population level.

12. Challenges and Limitations

Despite its promising clinical benefits, the implementation of NOM is not without significant challenges and limitations. Key concerns include the following:

• The potential presence of occult residual neoplastic disease, which may remain undetected despite advanced imaging modalities.
• Variability in the accuracy and reproducibility of radiologic and endoscopic assessments, leading to discrepancies in treatment decisions.
• The psychological burden associated with stringent surveillance protocols, which may heighten patient distress and impact compliance.
• The lack of universally accepted standardized criteria to guide patient selection, treatment response evaluation, and longitudinal follow-up.

One of the foremost challenges in NOM lies in the heterogeneity of response assessment methodologies. There remains substantial interinstitutional variability in defining and monitoring a cCR, leading to inconsistencies in eligibility criteria and treatment outcomes. Additionally, the reliance on advanced imaging techniques such as MRI and endoscopic evaluation is inherently constrained by interobserver variability and the potential for false-negative interpretations. Such diagnostic limitations may inadvertently result in suboptimal clinical decision-making, either by delaying necessary intervention in cases of undetected residual malignancy or by prompting unnecessary treatment escalation.

Another critical limitation pertains to patient adherence to rigorous surveillance regimens. The requirement for frequent clinical evaluations, periodic imaging, and repeated endoscopic assessments may impose a substantial logistical and psychological burden on patients, raising concerns regarding long-term compliance. To enhance the feasibility and success of NOM, a multidisciplinary approach emphasizing patient education, structured follow-up pathways, and individualized support mechanisms is imperative in ensuring sustained engagement with surveillance protocols.

Overall, these findings suggest that NOM may represent a feasible alternative to TME in a highly selected subset of patients with LARC who achieve a cCR following neoadjuvant therapy. Nevertheless, the interpretation of data supporting NOM must be approached with caution, given that many studies in this domain are derived from retrospective institutional case series with heterogeneous patient populations, relatively limited follow-up durations, and significant variability in patient selection criteria, treatment protocols, surveillance methodologies, and response assessment definitions.

An additional limitation is the heterogeneity of data derived from registries and meta-analyses, as participating centers often differ in neoadjuvant treatment protocols, criteria used to define clinical complete response, and follow-up schedules. Therefore, pooled estimates such as the reported local recurrence rate of approximately 25% should be interpreted with caution.

Strengths of our study include a standardized surveillance protocol, multidisciplinary assessment of cCR, and detailed recording of oncologic outcomes. Limitations include the retrospective design, modest sample size, and limited availability of patient-reported outcomes. Longer follow-up will be required to confirm durability of response and late outcomes. Future prospective studies incorporating PROMs and biomarker-driven selection are warranted [6,7,21,28].

13. Future Directions

The landscape of NOM in rectal cancer is rapidly evolving. Advances in Total Neoadjuvant Therapy (TNT) have been shown to increase the rates of clinical complete response and improve disease-free survival, reinforcing its role as a cornerstone of contemporary treatment [29,30]. In parallel, immunotherapy has emerged as a paradigm-shifting strategy for patients with mismatch repair-deficient rectal cancer, with recent trials reporting unprecedented complete response rates following checkpoint inhibitor therapy. Moreover, preclinical models such as patient-derived xenografts (PDX) are enhancing our understanding of the biological mechanisms underlying treatment response and resistance, offering the potential to refine patient selection [31]. Looking ahead, personalized medicine strategies integrating clinical, radiologic, molecular, and functional data—supported by artificial intelligence—are expected to play a pivotal role in optimizing patient-tailored NOM approaches.

From a medical informatics perspective, the adoption of standardized minimum data sets and common data models is essential to ensure interoperability and comparability across centers. The use of international standards can safeguard data integrity and enhance the validity of large-scale analyses, representing a key prerequisite for the successful integration of Watch-and-Wait strategies at the health system level.

Future research is focusing on improving response assessment through advanced imaging, endoscopic molecular probes, and circulating tumor DNA (ctDNA) as a biomarker of residual disease. Immunotherapy has shown unprecedented efficacy in mismatch repair-deficient (dMMR) rectal cancer, with PD-1 blockade inducing 100% cCR in small cohorts [1,6,7,10,27,28]; ongoing trials will clarify its potential to expand NOM candidacy. Artificial intelligence tools for imaging interpretation and personalized predictive models may also enhance patient selection and surveillance safety [32].

14. Conclusions

NOM represents a paradigm shift in rectal cancer treatment, offering a feasible alternative for select patients achieving a cCR. While current evidence supports its use in well-selected cases, ongoing research and standardized surveillance strategies are critical to ensuring optimal outcomes.

NOM is a promising organ-preserving strategy in rectal cancer, offering oncologic safety and functional benefits for carefully selected patients. Future directions include the integration of molecular biomarkers, prospective incorporation of PROMs, and the application of artificial intelligence tools for response prediction and surveillance optimization. Collaboration through multicenter registries such as the IWWD will be essential to refine protocols and expand the evidence base.

Careful patient selection is paramount to the success of NOM for rectal cancer. By integrating multiple diagnostic tools, adhering to stringent evaluation criteria, and considering tumor response to neoadjuvant therapy, clinicians can optimize treatment outcomes while ensuring patient safety. Additionally, given the limitations of current imaging techniques, diligent post-treatment surveillance remains essential to detect and manage any potential recurrence at the earliest stage.

Strict surveillance protocols, including frequent clinical and radiologic assessments, are necessary to detect local regrowth, which occurs in approximately 20–30% of cases.

With the lack of definitive data, and with the great relevance of PROMs in this disease, it is of great importance to ensure a shared decision-making pathway and strict surveillance within clinical trials.

Finally, most regrowth is detected within the first two years of follow-up, underscoring the need for regular evaluations, typically scheduled every 3–4 months during the first two years, followed by semi-annual assessments up to five years post-treatment.