Is salvage treatment necessary after incomplete resection of rectal neuroendocrine tumors: A systematic review and meta-analysis.

INTRODUCTION
Rectal neuroendocrine tumors (NETs) are well-differentiated neoplasms that most commonly arise from enteroendocrine L cells of the distal gut, which produce peptide YY and glucagon-like peptides. In contrast, small-intestinal NETs typically derive from enterochromaffin cells that secrete serotonin[1-3]. Although rectal NETs account for a small proportion of colorectal neoplasms, their incidence has been steadily increasing, largely because of the widespread use of screening colonoscopy and advances in endoscopic imaging techniques[4,5]. A population-based study using surveillance, epidemiology, and end result data demonstrated that rectal NETs, along with small intestinal NETs, have the highest incidence among gastrointestinal NETs over the past four decades. This trend is particularly pronounced in Asian countries[6].
Small rectal NETs measuring less than 10 mm in diameter are generally considered suitable candidates for curative endoscopic resection. Techniques, such as conventional endoscopic mucosal resection (cEMR), modified EMR (mEMR) (including cap-assisted or band ligation-assisted EMR techniques), and endoscopic submucosal dissection (ESD) are widely utilized[7-10]. Rectal NETs measuring up to 20 mm in diameter may also be amenable to endoscopic resection, provided that high-risk features, such as lymphovascular invasion, positive margins, or involvement of the muscularis propria are not present[11,12]. However, incomplete resection, defined as a positive or indeterminate resection margin or the presence of lymphovascular invasion, raises concerns regarding residual tumor or recurrence[13,14].
Currently, there is no consensus for the optimal management of incompletely resected rectal NETs. While some guidelines support close surveillance for carefully selected low-risk lesions, others endorse salvage treatments, including repeat endoscopic resection, transanal endoscopic microsurgery, or radical surgery[1,3,15,16]. Given the variability in clinical practice and the lack of robust data, the benefit of salvage therapy remains uncertain.
A clearer understanding of the recurrence risk, residual lesion rate, and treatment outcomes after incomplete resection is essential to inform evidence-based recommendations. This systematic review aimed to synthesize existing data on the natural course of incompletely resected rectal NETs and evaluate the oncological impact of salvage treatments.

MATERIALS AND METHODS

Protocol registration
This systematic review and meta-analysis followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines[17]. This study was prospectively registered in PROSPERO (registration No. CRD420251054723).

Search strategy and study selection
A comprehensive literature search was performed across three major databases: MEDLINE, EMBASE, and the Cochrane Library. The final search was completed on May 21, 2025. Detailed search strategies for each database are provided in Supplementary material.
Eligible studies investigated outcomes in patients with incompletely resected rectal NETs, defined as tumors with positive or indeterminate resection margins or the presence of lymphovascular invasion in the resected specimen. An indeterminate margin was typically described as one that could not be reliably evaluated due to cautery artifact, tissue fragmentation, or tangential sectioning, making it difficult to determine tumor involvement. Studies were included if they reported residual tumors or recurrence and evaluated salvage treatment, observation, or both. A residual tumor was defined as histologically or macroscopically confirmed tumor tissue identified during additional treatment (e.g., salvage resection) following an initial incomplete resection. Recurrence was defined as the reappearance of the tumor after a period of no detectable disease during follow-up, as confirmed by colonoscopy or cross-sectional imaging, such as computed tomography. The exclusion criteria were as follows: Case reports or small case series (n < 5); Review articles, editorials, or letters; Studies involving tumors > 2 cm in size; Studies evaluating primary surgical treatment as initial management, and studies lacking outcome data on residual tumors or recurrent disease.
Two reviewers (Kim JH and Lee JW) independently screened the titles and abstracts of the identified records, followed by full-text reviews of potentially eligible articles. Discrepancies were resolved by discussion and consensus.

Data extraction and outcomes
Data were extracted from each study in a standardized format. For each included study, we collected information regarding the first author, publication year, country of origin, and study design. Patient-related data including the number of participants, sex distribution, and age were also recorded. Tumor-related characteristics, such as the size and completeness of resection, were documented, along with the duration of follow-up and the type of management strategy applied, whether salvage treatment or observation.
The primary outcomes were the residual tumor rate following salvage treatment and the recurrence rate in patients who underwent salvage treatment compared with those managed with observation.

Statistical analysis
We conducted a meta-analysis to estimate the pooled prevalence of residual tumors after salvage treatment in patients with incomplete resection. This single-arm proportion meta-analysis was performed using the metaprop function of the meta-package in R (version 4.2.2). The Freeman-Tukey double-arcsine transformation was applied to stabilize variance and minimize bias in pooled estimates, particularly when proportions were close to 0% or 100%. Study-level 95% confidence intervals (CIs) were calculated using the Clopper-Pearson exact method and pooled estimates were obtained using a random-effects model with Hartung-Knapp adjustment. Forest plots were used to display the individual study proportions and event counts.
To evaluate the recurrence outcomes, we first conducted a pooled crude analysis comparing the recurrence rates between patients who received salvage treatment and those managed with observation. The total number of recurrence events and total number of patients were aggregated across the studies for each group. Group differences were assessed using either the χ2 test or Fisher’s exact test, as appropriate. A bar plot was generated to visualize the group-level proportions and absolute event counts.
For comparative analysis, we performed a meta-analysis limited to studies that reported recurrence outcomes in both treatment arms. Two-by-two contingency tables were constructed for each study and odds ratios (ORs) with 95%CIs were calculated. Pooled ORs were estimated using a random-effects model based on the DerSimonian-Laird method, with Hartung-Knapp adjustment to account for uncertainty. Studies with zero events in both arms were excluded, and a continuity correction of 0.5 was applied when one arm reported zero events. Between-study heterogeneity was evaluated using Cochran’s Q statistic, I2, and τ2. A forest plot was generated to illustrate both the individual and pooled effect estimates.
All statistical analyses were performed using the R software (version 4.2.2). Meta-analyses were conducted using the meta package and all visualizations were produced using ggplot2.

Risk of bias assessment
The risk of bias in nonrandomized studies was assessed using the risk of bias in nonrandomized studies of interventions (ROBINS-I) tool. This tool evaluates the bias across seven domains: Confounding factors, selection of participants, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of reported results. Each domain was rated as having low, moderate, or serious risk of bias. Two reviewers independently assessed each study and any discrepancies were resolved through discussion and consensus.

Certainty of evidence assessment
The certainty of evidence for the main outcomes, residual tumor rate, and recurrence risk was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach[18]. This approach evaluates five domains: Risk of bias, inconsistency, indirectness, imprecision, and publication bias. Based on these assessments, the certainty of the evidence was rated as high, moderate, low, or very low.

RESULTS

Study selection and baseline characteristics
A total of 1353 records were identified through database searches (MEDLINE: 381; EMBASE: 967; Cochrane Library: 5), from which 409 duplicates were removed. After screening 944 titles and abstracts, 105 full-text articles were assessed for eligibility, and 34 studies met the inclusion criteria. The study selection process is illustrated in the PRISMA flow diagram (Figure 1).
All included studies were observational in design, and the majority were retrospective, single-center studies. Most studies were conducted in Asia, primarily in Korea (n = 19), China (n = 6), and Japan (n = 6) with one study each from the United States, France, and Italy. A total of 6761 patients with rectal NETs were included in 34 studies. Among these, 2279 cases of incomplete endoscopic resection, defined as positive or indeterminate resection margins or the presence of lymphovascular invasion, have been reported. However, because some studies enrolled only patients with incomplete resection, this figure does not represent the true prevalence of incomplete resection in all rectal NET cases.
Patient characteristics such as age, sex distribution, tumor size, and follow-up duration varied across studies. Most cohorts consisted of patients who were considered appropriate for endoscopic treatment. The follow-up duration varied substantially, reflecting heterogeneity in clinical settings and institutional protocols. Salvage treatments include a range of endoscopic techniques such as cEMR and mEMR, ESD, and in select cases, surgical interventions. The detailed study characteristics are summarized in Tables 1, 2 and 3[13,14,19-50].

Residual tumors following salvage treatment for incompletely resected rectal NETs
First, the risk of incomplete resection was assessed using the initial resection method. Among the 17 studies included in this analysis, the pooled incomplete resection rates varied substantially according to technique (Figure 2). Cold snare polypectomy (CSP) exhibited the highest rate at 73.1% (95%CI: 38.3%-95.6%), followed by cEMR at 29.8% (95%CI: 24.3%-34.5%) and mEMR at 28.4% (95%CI: 25.9%-35.8%). In contrast, ESD showed the lowest incomplete resection rate at 14.7% (95%CI: 12.9%-16.4%).
Next, we evaluated the frequency of residual lesions identified on salvage pathology in patients with an incomplete initial resection. In 19 studies, residual tumor status was reported based on pathological findings from salvage procedures. A single-arm meta-analysis using a random-effects model estimated the pooled residual lesion rate to be 25.0% (95%CI: 12.0%-40.0%). The inter-study heterogeneity was substantial (I2 = 95.1%). These findings suggest that a considerable proportion of patients harbor residual disease as confirmed on salvage pathology (Figure 3).

Crude recurrence rates: Salvage treatment vs observation
Crude recurrence rates were calculated based on the data from 31 studies that reported recurrence outcomes. Among the 732 patients who received salvage treatment, 7 (0.96 %) experienced recurrence. In contrast, 34 recurrences occurred in 1148 patients (2.96%) who were managed with observation. This difference was statistically significant (P = 0.003), favoring the salvage group. These results are presented in Figure 4, which illustrates group-level recurrence proportions and absolute event counts.

Comparative meta-analysis of recurrence risk: Salvage treatment vs observation
To further evaluate the effect of salvage treatment on recurrence, a meta-analysis was conducted using nine studies that reported recurrence outcomes in both the salvage and observation groups. The pooled OR for recurrence in the salvage group compared to the observation group was 0.89 (95%CI: 0.40-2.02). Although the point estimate numerically favored salvage treatment, the difference was not statistically significant. Between-study heterogeneity was negligible (I2 = 0%, τ2 = 0, P = 0.83). These findings (Figure 5) suggest that while salvage treatment may be associated with a lower recurrence rate, current comparative evidence is insufficient to confirm its superiority over observation.

Risk of bias across studies
All the included studies were observational and exhibited varying levels of methodological rigor. According to the ROBINS-I assessment, most studies were judged to have a moderate to serious overall risk of bias, primarily because of insufficient adjustment for confounders and incomplete outcome data. A detailed breakdown of the risk assessments across domains is shown in Supplementary Figure 1.

Certainty of evidence based on GRADE
The certainty of the evidence for recurrence outcomes was rated low, primarily because of the serious risks of bias and imprecision. Although the point estimate (OR = 0.84) numerically favored salvage treatment over observation, the wide CI (95%CI: 0.42-1.68) and limited number of comparative studies contributed to serious imprecision. The certainty of evidence was rated as very low for the residual lesion rate after salvage treatment, reflecting both a serious risk of bias and high heterogeneity across studies. These assessments are summarized in the GRADE summary of findings table (Table 4).

DISCUSSION
This systematic review and meta-analysis evaluated whether salvage treatment offers a clinical advantage over observation after incomplete endoscopic resection of rectal NETs. Two principal outcomes were analyzed: (1) The prevalence of residual tumors after salvage intervention; and (2) The risk of recurrence based on the management strategy.
A pooled analysis of 19 studies showed that residual tumors were detected in approximately 25% of the patients who underwent salvage treatment[13,14,19,20,27,29,33,35-46]. This notable prevalence underscores the limitations of initial endoscopic resection, particularly in the presence of positive or indeterminate margins, or lymphovascular invasion. Accordingly, salvage interventions may serve not only as therapeutic strategies but also as diagnostic procedures for identifying and managing residual diseases.
Importantly, the likelihood of incomplete resection appeared to depend significantly on the initial resection technique. A pooled analysis of 17 studies showed that CSP had the highest incomplete resection rate (73.1%), followed by cEMR (29.8%), mEMR (28.4%), and ESD showing the lowest rate (14.7%)[19,20,24,27,28,30,33,34,37,40-42,46-50]. These findings highlight the importance of selecting the appropriate technique for treating suspected rectal NETs. Given the high incomplete resection rate, CSP may be suboptimal in this setting and should be avoided when margin assessment is critical. Where sufficient expertise is available, ESD should be considered the primary resection technique, as it offers the highest likelihood of achieving complete (R0) resection and reducing the need for subsequent salvage procedures.
For recurrence outcomes, crude pooled data from 31 studies showed a statistically significant benefit associated with salvage treatment; recurrence occurred in 0.96% of patients in the salvage group vs 2.96% in the observation group (P = 0.003)[13,14,19-35,37-39,41-43,45-50]. However, a meta-analysis limited to nine studies that included both treatment groups found no statistically significant difference in recurrence risk (OR = 0.89; 95%CI: 0.40-2.02). This discrepancy likely reflects confounding by indication and selection bias, as higher-risk patients those with positive margins, larger tumors, or lymphovascular invasion were more likely to undergo salvage treatment in the included observational studies. Therefore, the crude analysis should be interpreted with caution, as it may overestimate the effect of salvage treatment. In contrast, the comparative meta-analysis, despite its wider CIs, provides a more valid estimate of the treatment effect because it accounts for between-study variance and excludes double-zero studies.
These findings suggest the potential benefit of salvage treatment in reducing recurrence; however, the evidence remains inconclusive. Notably, the recurrence rates were low in both groups, reaffirming the favorable prognosis of small rectal NETs when appropriately managed. Routine salvage treatment may therefore offer limited additional benefits in terms of recurrence prevention and should be considered in the context of individual patient risk and procedural burden.
This study has several limitations. First, all the included studies were observational, mostly retrospective, single-center case series, introducing the potential for selection bias, reporting bias, and unmeasured confounding factors. Second, the quality of evidence was generally limited, with most studies judged to have a moderate to serious risk of bias based on the ROBINS-I assessment. Third, substantial heterogeneity was observed in the residual lesion meta-analysis (I2 = 95.1%), likely due to the variability in tumor characteristics, endoscopic techniques, definitions of incomplete resection, and follow-up protocols. Although potential sources of heterogeneity were carefully reviewed, quantitative subgroup analyses (e.g., by tumor size, lymphovascular invasion, or salvage type) were not feasible due to incomplete reporting across studies. Fourth, the exclusion of studies with zero events in both treatment arms may have reduced the precision of recurrence estimates. Finally, the low frequency of recurrence events limited the statistical power and precluded meaningful subgroup analyses to explore prognostic factors such as tumor grade, margin distance, and lymphovascular invasion.

CONCLUSION
Given the relatively high rate of residual tumors and low overall recurrence rate, salvage treatment after incomplete resection of rectal NETs may be justified as both a diagnostic and therapeutic intervention. However, based on current comparative evidence, its efficacy in reducing recurrence remains uncertain. Therefore, clinical decisions should be individualized, taking into consideration the tumor characteristics, resection margin status, and patient preferences. As the certainty of evidence is low, these conclusions should be interpreted with caution. To better inform treatment strategies and clinical guidelines, high-quality prospective multicenter studies with standardized definitions and consistent outcome reporting are urgently required.