Near-complete clinical response after neoadjuvant therapy in rectal cancer: Decision-making between organ preservation and surgery

Abstract

Near-complete clinical response (nCR) after neoadjuvant therapy in rectal cancer represents a clinically relevant but heterogeneous intermediate state between clinical complete response and incomplete clinical response. With the growing adoption of total neoadjuvant therapy, nCR is increasingly encountered; however, its optimal management remains controversial, particularly regarding its definition, timing of assessment, and the balance between organ preservation and oncologic safety. This mini-review synthesizes current evidence regarding the definition of nCR, the associated diagnostic challenges, and multimodal assessment techniques, including endoscopy, magnetic resonance imaging, and clinical examination. Particular emphasis is placed on second restaging, which enables dynamic evaluation of tumor regression and may facilitate conversion to clinical complete response in selected patients. Emerging evidence suggests that nCR comprises two biologically distinct subgroups - favorable and unfavorable - with oncologic risk determined by response trajectory rather than by observation duration alone. Management strategies include continued observation, immediate resection, and, in selected cases, local excision. We propose a practical management algorithm integrating patient preference, response patterns, and restaging findings to guide individualized decision-making. A critical gap remains, as no direct comparisons exist between immediate and delayed resection following persistent nCR. Future studies addressing this question are essential to optimize treatment selection in this challenging population.

Key Words: Rectal neoplasms; Near-complete clinical response; Neoadjuvant therapy; Watch and wait; Organ preservation; Tumor regression; Restaging; Decision-making

Core Tip: Near-complete clinical response after neoadjuvant therapy for rectal cancer is a biologically heterogeneous entity comprising distinct favorable and unfavorable subgroups. Optimal management requires individualized assessment of response trajectory rather than observation duration alone to guide organ-preservation decisions.

INTRODUCTION

Over the past decades, the management of locally advanced rectal cancer has evolved substantially, progressing from adjuvant radiotherapy to neoadjuvant chemoradiotherapy (CRT) and, more recently, to total neoadjuvant therapy (TNT)[1]. In parallel, nonoperative management has emerged as a treatment option for patients achieving a clinical complete response (cCR), supported by evidence demonstrating favorable oncologic outcomes with a watch-and-wait (W&W) strategy[2].

Neoadjuvant CRT followed by total mesorectal excision (TME) became the standard of care for locally advanced rectal cancer after randomized evidence - most notably the German CAO/ARO/AIO-94 experience - demonstrated superior local control and lower toxicity with a preoperative approach rather than a postoperative one[3]. Although this strategy achieved excellent locoregional control, distant metastasis (DM) remained the predominant pattern of failure, affecting roughly one-quarter to one-third of patients, and adherence to postoperative adjuvant chemotherapy was frequently poor[3]. These limitations provided the rationale for TNT, in which all chemotherapy and radiotherapy regimens are delivered before surgery with the aim of improving systemic control, treatment compliance, and tumor regression.

Randomized trials have consistently shown that TNT increases complete-response rates and improves oncologic outcomes. In the RAPIDO trial, short-course radiotherapy followed by consolidation chemotherapy reduced 3-year disease-related treatment failure better than conventional CRT (23.7% vs 30.4%)[4]. The PRODIGE-23 trial, adding induction FOLFIRINOX before CRT, improved 3-year disease-free survival (DFS) from 69% to 76%[5]. The STELLAR trial reported non-inferior 3-year DFS (64.5% vs 62.3%) and superior 3-year overall survival (86.5% vs 75.1%) for short-course TNT comparisons to long-course CRT[6]. Beyond survival, TNT approximately doubles the likelihood of a complete response and thereby expands the population eligible for organ preservation; in the OPRA trial, TNT enabled durable organ preservation in about half of the patients managed by the W&W strategy[7].

Clinical response to neoadjuvant treatment, however, exists along a continuum. Between cCR and incomplete clinical response (iCR), an intermediate group - referred to as near-cCR (nCR) - has been increasingly recognized. This state is characterized by minimal residual abnormalities on clinical, endoscopic, or radiologic assessment that do not meet the strict criteria for cCR but reflect substantial tumor regression[8,9].

The optimal management of nCR remains uncertain. Key challenges include variability in its definition, limitations of current assessment modalities, and the lack of clear thresholds for selecting between continued observation and immediate surgery[10]. These uncertainties are particularly relevant in the TNT era, wherein higher response rates and delayed reassessment strategies have increased the frequency of nCR[11]. This mini-review aims to synthesize current evidence regarding the definition, assessment, and management of nCR, with a focus on practical decision-making and individualized treatment strategies.

DEFINITIONS AND DIAGNOSTIC CHALLENGES OF NCR

Assessment of tumor response after neoadjuvant therapy in rectal cancer has traditionally focused on identifying cCR, defined by the absence of detectable tumor across clinical examination, endoscopy, and imaging[7]. In contrast, iCR reflects clear residual disease, such as a persistent mass, deep ulceration, or progressive features suggestive of treatment resistance[9].

Between these two extremes lies nCR, an intermediate state characterized by substantial tumor regression accompanied by minor residual abnormalities. These may include superficial ulceration, subtle mucosal irregularity, or minimal nodularity on endoscopy, as well as equivocal findings on magnetic resonance imaging (MRI)[9]. However, the definition of nCR remains inconsistent across studies, with variability in diagnostic criteria, timing of assessment, and interpretation of post-treatment changes[10].

The diagnosis of nCR is inherently challenging for several reasons. First, assessment is partly subjective, particularly in the interpretation of subtle endoscopic findings, leading to considerable interobserver variability even among experienced clinicians[12,13]. Second, discordance between assessment modalities is common; endoscopic, radiologic, and clinical assessments may not align, and MRI has limited specificity in distinguishing fibrosis or treatment-related changes from residual viable tumor[14]. Third, tumor regression is a dynamic process, and the timing of evaluation significantly influences classification. Early assessment may underestimate treatment response, whereas delayed assessment risks postponing definitive treatment in patients with persistent disease[15,16]. Together, these factors underscore the diagnostic uncertainty inherent in nCR and highlight why rigid definitions alone are insufficient to guide management.

In a contemporary series applying standardized response categories, nCR accounted for approximately 15% of patients assessed after neoadjuvant therapy (189 of 1230) and roughly one-third of clinical responders[17]. Because up to 90% of nCR reportedly convert to cCR when observation is extended by a further 6-12 weeks[11], a practice of immediate radical surgery for all nCR cases would overtreat a substantial proportion who could otherwise retain the rectum; indeed, roughly half of patients with nCR ultimately achieve organ preservation[17].

ASSESSMENT TOOLS IN NCR

Accurate evaluation of tumor response after neoadjuvant therapy is essential in patients with suspected nCR. As no single modality can reliably differentiate residual viable tumor from post-treatment fibrosis or inflammation[13], assessment requires a multimodal approach integrating endoscopy, MRI, and clinical examination.

Endoscopic assessment

Endoscopy enables direct visualization of the treated tumor site and remains a key component of response evaluation[13]. Patients with nCR typically demonstrate subtle residual changes, such as superficial ulceration, mild mucosal irregularity, or small nodularity[9]. These findings are often indeterminate and require cautious interpretation, as they may represent either residual tumor or ongoing tissue remodeling. Among these features, nodularity may still be compatible with further tumor regression, whereas persistent ulceration is more frequently associated with residual disease, as shown in Table 1[18]. Nevertheless, interpretation remains subjective, and careful longitudinal assessment is often required.

Table 1 Key findings suggestive of favorable or unfavorable near-complete clinical response and their management implications.

Finding	Interpretation (risk of residual tumor)	Suggested clinical implication
Endoscopic nCR1
Small nodularity	Variable risk; may still evolve to cCR (favorable nCR pattern)	Supports repeat reassessment at 6-12-week intervals, with close surveillance limited to the first 6 months
Irregular mucosa	Intermediate risk; may represent either ongoing tumor regression or residual disease (unfavorable nCR pattern)	Consider early surgical intervention or intensified evaluation
Superficial ulceration	Increased likelihood of residual tumor (unfavorable nCR pattern)	Consider early surgical intervention or intensified evaluation
MRI nCR2
Absence of EMVI	Favorable biologic response pattern (favorable nCR pattern)	Supports repeat reassessment at 6-12-week intervals, with close surveillance limited to the first 6 months
Low rectal tumor location	Associated with an increased probability of complete response (favorable nCR pattern)	Supports repeat reassessment at 6-12-week intervals, with close surveillance limited to the first 6 months

¹Endoscopic features associated with favorable or unfavorable near-complete clinical response, adapted from Williams et al[18].

²Magnetic resonance imaging-based predictors of complete response, including tumor location and extramural vascular invasion status, adapted from Yilmaz et al[22].

nCR: Near-complete clinical response; cCR: Clinical complete response; MRI: Magnetic resonance imaging; EMVI: Extramural venous invasion.

MRI assessment

MRI complements endoscopy by enabling evaluation of the bowel wall and mesorectal structures[19]. In nCR, MRI often demonstrates marked tumor regression with low-signal fibrotic changes. However, distinguishing fibrosis from residual tumor remains a major limitation[20], as treatment-related changes may mimic viable disease[21]. Additional features may aid interpretation (Table 1). The absence of extramural vascular invasion[22] and significant tumor downsizing are generally associated with a favorable response, whereas persistent intermediate signal intensity or suspicious lymph nodes raise concern for residual malignancy[23]. Tumor location may also influence response patterns, with distal tumors more likely to achieve complete regression in some series[22].

Clinical examination and biopsy

Digital rectal examination provides important complementary information, particularly for distal tumors. A soft, pliable scar favors treatment response, whereas firm or irregular thickening suggests residual disease. Routine biopsy is not recommended for response assessment. Tumor regression is often heterogeneous[24], with residual tumor cells located in deeper layers such as the muscularis propria, beyond the reach of standard mucosal sampling[25]. As a result, biopsy may yield false-negative results and should not be used in isolation to guide management decisions in nCR[26].

TIMING OF RESPONSE ASSESSMENT AND THE ROLE OF SECOND RESTAGING

First restaging

The timing of response assessment following neoadjuvant therapy is a key determinant in the interpretation of nCR. Traditionally, evaluation has been performed approximately 6-8 weeks after completion of CRT[27]. However, increasing evidence suggests that tumor regression may continue beyond this interval, particularly in the context of TNT[11]. Delaying assessment to 8-12 weeks or longer has been associated with higher rates of pathological complete response[28-30], reflecting the dynamic nature of tumor regression. This potential benefit, however, must be balanced against the risk of delaying definitive treatment in patients with persistent disease[11]. While longer intervals may enhance tumor downstaging, they have not consistently translated into improved survival outcomes[31] and may increase surgical difficulty. Notably, the GRECCAR-6 trial demonstrated no improvement in pathological complete response with extended waiting intervals (11 weeks vs 7 weeks), but reported poorer quality of mesorectal excision[32]. These findings support a cautious, time-limited approach to delayed assessment.

Second restaging

Second restaging has emerged as a key strategy in patients with nCR at initial evaluation. In this approach, patients undergo repeat assessment after an additional interval, typically 6-12 weeks[11], to allow further tumor regression and potential conversion to cCR. Evidence suggests that a substantial proportion of patients initially classified as having nCR may achieve cCR on delayed reassessment, supporting the concept of ongoing tumor response beyond the first evaluation[11].

The relevance of this strategy is particularly evident in the TNT era, in which consolidation chemotherapy during the waiting interval may enhance treatment response[6,15,33,34]. However, prolonged observation is not without associated risks. Failure to achieve cCR within approximately 6 months after completion of neoadjuvant therapy is associated with a lower likelihood of organ preservation and may reflect biologically resistant disease[17]. In addition, local regrowth (LR) during extended observation has been linked to an increased risk of DM in some series[35,36]. Accordingly, second restaging should be viewed as an active, time-limited reassessment strategy rather than passive surveillance. Clinical decisions should be guided by the trajectory of tumor response over time, and prolonged delays beyond a reasonable interval should be avoided.

The type of neoadjuvant regimen also influences response patterns and the frequency of nCR. TNT schedules that include consolidation chemotherapy appear to achieve higher organ preservation than induction-based schedules; in the OPRA trial, TME-free survival was greater with consolidation than with induction chemotherapy (54% vs 39%)[7]. Short-course radiotherapy followed by chemotherapy[6,33] and long-course CRT with induction or consolidation chemotherapy all increase complete-response rates relative to CRT alone but differ in the kinetics of tumor regression. However, no study has directly compared the effect of specific radiotherapy or chemotherapy regimens on the incidence or behavior of nCR, which remains an important knowledge gap.

MANAGEMENT STRATEGIES FOR NCR

Management of nCR following neoadjuvant therapy remains challenging, as this group represents a heterogeneous spectrum ranging from ongoing tumor regression to persistent disease. Treatment decisions must balance the potential benefits of organ preservation against the risk of undertreating residual malignancy. Current management strategies include continued observation with interval reassessment, immediate oncologic resection, and, in selected cases, local excision (LE). A structured approach integrating response patterns, imaging findings, and patient preference is essential to guide individualized decision-making (Figure 1).

Figure 1 Proposed management algorithm for near-complete clinical response after neoadjuvant therapy in rectal cancer. Proposed management algorithm for patients with near-complete clinical response (nCR) after neoadjuvant therapy. Initial assessment is recommended at 8-12 weeks. Management is guided by patient preference and by clinical, endoscopic, and magnetic resonance imaging features distinguishing favorable from unfavorable nCR. Selected patients may undergo interval reassessment (6-12 weeks) to allow conversion to complete clinical response and subsequent watch-and-wait approach. Persistent nCR, local regrowth, or unfavorable features warrant oncologic resection (e.g., total mesorectal excision). Local excision may be considered in selected cases. ¹Endoscopic features adapted from Williams et al[18]. ²Magnetic resonance imaging-based predictors adapted from Yilmaz et al[22]. ³High-risk features include lymphovascular invasion, perineural invasion, extramural venous invasion, positive resection margin, tumor budding, and poor differentiation[42]. nCR: Near-complete clinical response; cCMT: Consolidation chemotherapy; EMVI: Extramural venous invasion; TME: Total mesorectal excision; cCR: Complete clinical response; LN: Lymph node.

Continued observation with second restaging

In selected patients, nCR may be managed with continued observation to allow further tumor regression and potential conversion to cCR. This approach differs from conventional W&W, as it represents a time-limited reassessment phase rather than definitive nonoperative management. Patients with favorable features - such as small nodularity without ulceration on endoscopy[18], absence of extramural vascular invasion, and low rectal tumor location[22] - may be appropriate candidates for this strategy. In contrast, persistent ulceration, irregular mucosal patterns, or suspicious radiologic findings should raise concern for residual disease. Reassessment is typically performed after an additional 6-12 weeks[11] or shorter intervals (e.g., 4-8 weeks) depending on clinical context[17].

If subsequent evaluation demonstrates conversion to cCR, patients may transition to standard W&W surveillance protocols. However, persistence of nCR without interval improvement, or the emergence of unfavorable features, should prompt consideration of surgical resection. In general, failure to achieve cCR within approximately 6 months after completion of neoadjuvant therapy suggests a lower likelihood of further regression and supports timely operative management[37].

Immediate oncologic resection

Surgical resection remains the standard of care for patients with suspected residual disease[38]. In the setting of nCR, early surgery may be favored when findings suggest treatment resistance or when reliable surveillance is not feasible[11,17]. This approach minimizes the risk of delayed intervention but may result in overtreatment in patients who might otherwise achieve cCR. Emerging evidence suggests that the risk of LR and DM may be particularly relevant in patients with nCR undergoing prolonged observation (Table 2). In one study, patients with nCR who subsequently converted to cCR at second restaging and were managed with W&W demonstrated a higher risk of DM following LR compared with those who remained classified as nCR and proceeded to surgical resection (48% vs 17%; odds ratio: 4.59)[17]. Furthermore, LR occurred more frequently in patients achieving cCR after delayed reassessment compared with those achieving cCR at initial restaging (35% vs 27%). Similarly, among patients with initial cCR managed with W&W, the risk of DM was higher than in those who underwent immediate surgery (27% vs 7%; odds ratio: 4.81).

Table 2 Quantitative outcomes reported in studies of near-complete clinical response after neoadjuvant therapy in rectal cancer.

Ref.	nCR rate	cCR rate	nCR → cCR conversion	Local regrowth (nCR vs cCR)	Distant metastasis	Organ preservation (nCR vs cCR)
Rosen et al[17], 2025	15% (189/1230)	32% (395/1230)	-	40% vs 24%1	48% vs 17%2 (OR: 4.59)	53% vs 73%
Hupkens et al[11], 2018	40% (68/170)	60% (102/170)	90% (44/49)	27% vs 16%3	-	Sustained W&W4
Verheij et al[7], 2024	-	-	-	94% < 2 years5	-	Approximately 50% (overall)

¹Three-year local-regrowth rate.

²Distant metastasis after local regrowth: Near-complete clinical response converting to clinical complete response on watch-and-wait vs persistent near-complete clinical response resected.

³Two-year local-regrowth rate (converted near-complete clinical response vs clinical complete response).

⁴Forty-four of 49 converted patients managed nonoperatively, with outcomes comparable to primary clinical complete response.

⁵Proportion of all local regrowth occurring within 2 years in the OPRA watch-and-wait cohort (99% within 3 years).

In the comparison columns, values are shown as near-complete clinical response vs clinical complete response. nCR: Near-complete clinical response; cCR: Clinical complete response; W&W: Watch-and-wait; OR: Odds ratio.

However, complementary evidence suggests that delayed resection itself may not be the primary driver of metastatic risk. In a multicenter cohort of patients with an excellent partial response (nCR), the interval between completion of neoadjuvant therapy and definitive surgery was not associated with an increased risk of DM, even among patients who underwent prolonged observation or developed LR[39]. Instead, the development of DM appeared to be more closely associated with tumor-related factors, such as LR and adverse pathological features, rather than the duration of the waiting interval.

In this context, other studies have demonstrated that patients who achieve cCR after second restaging may still be suitable candidates for a W&W strategy. In one cohort, 44 of 49 patients (90%) with nCR achieved cCR after second restaging and were managed nonoperatively. In this group, oncologic outcomes were comparable to those of patients who achieved cCR at initial assessment, with similar overall survival and non-regrowth DFS, although LR-free survival appeared numerically lower (72.9% vs 84.1%, P = 0.237)[11]. These findings suggest that delayed conversion to cCR does not preclude organ-preserving management but may represent a subgroup with distinct tumor behavior and a potentially higher risk of regrowth-related adverse outcomes. Collectively, these findings support the concept that nCR is not a uniform entity but rather comprises at least two biologically distinct subgroups: Favorable and unfavorable.

LE

LE may be considered an organ-preserving option in carefully selected patients with minimal residual abnormalities suggestive of superficial disease. This approach allows histopathologic assessment while potentially avoiding radical surgery. Prospective data support the feasibility of this approach in highly selected populations. In the ACOSOG Z6041 trial[40], patients with clinically staged T2N0 distal rectal cancer treated with neoadjuvant CRT followed by LE achieved a 3-year DFS of 88.2% (95% confidence interval: 81.3-95.8). Similarly, the randomized GRECCAR 2 trial evaluated patients with a good clinical response (residual scar ≤ 2 cm) following CRT and demonstrated comparable 3-year oncologic outcomes between LE and TME, including DFS (78.3% vs 76.1%) and overall survival (91.9% vs 91.5%), with similar rates of local and distant recurrence[41]. However, approximately 35% of patients undergoing LE required completion TME owing to unfavorable pathological findings. Importantly, this two-stage approach was associated with substantially higher morbidity, with major complication rates reaching 46% compared with 22% for primary TME and 12% for LE alone, as well as increased rates of definitive stoma formation (25%) and functional impairment.

The applicability of LE in nCR remains limited by patient selection and the inability to address mesorectal lymph nodes. As such, this strategy should be reserved for highly selected cases within a multidisciplinary framework[38], with appropriate counseling regarding the potential need for additional surgery. Management decisions should be guided by the trajectory of response rather than a single assessment time point[10,24]. Integration of clinical, endoscopic, and radiologic findings over time is essential to distinguish ongoing tumor regression from persistent disease and to optimize treatment selection.

CONCLUSION

nCR after neoadjuvant therapy is a clinically relevant but heterogeneous condition lying between cCR and iCR. Its management should be guided by the trajectory of tumor response over time rather than by the duration of observation alone. In practice, nCR comprises two biologically distinct subgroups: A favorable nCR that continues to regress and often converts to a sustained cCR, allowing organ preservation; and an unfavorable nCR that reflects treatment-resistant disease with a higher risk of LR and DM, for which timely surgery is appropriate. An important evidence gap remains, as no study to date has directly compared immediate TME with delayed salvage surgery for persistent nCR. Until such data are available, individualized decision-making integrating response dynamics, restaging findings, and patient preference remains essential for balancing organ preservation against oncologic safety.