Rectal cancer approach strategies after neoadjuvant treatment - a systematic review and network meta-analysis

Cong Meng, MM, Wenlong Shu, MM, Liting Sun, MM, Si Wu, MM, Pengyu Wei, MM, Jiale Gao, MD, Jinyao Shi, MD, Yang Li, MD, Zhengyang Yang, { \mathsf { M D } } ^ { \star } , Hongwei Yao, MD\*, Zhongtao Zhang, MD\*

Background and aims: An increasing number of patients with rectal cancer who respond wel to neoadjuvant chemoradiotherapy (nCRT) are being considered for organ preservation programs. However, due to the lack of high-level evidence, the survival outcomes of the organ preservation programs are stil full of controversy and uncertainty.

Methods: To assess the effects of total mesorectal excision (TME) surgery, watch-and-wait (W&W), and local excision (LE) on Iong-term outcomes after nCRT, we searched PubMed, Embase, and Web of Science for articles published between 1 January 2010, and 31 December 2023.

Results: We found 7029 pieces of literature, of which 26 studies met the inclusion criteria, and recruited 2778 participants in the network meta-analysis. Risk of bias assessment showed that most included studies had a low risk of bias. Low-certainty evidence suggests that the TME group was significantly superior to all other interventions for the 2-year local regrowth rate. (W&W group [OR, 0.20; 9 5 % Cl, 0.12-0.35], LE group compared with TME group [3.00; 1.60-5.80]). There was no significant difference in the 2-year local regrowth rate between W&W and LE group (OR, 0.60; 9 5 % CI, 0.32-1.20). There was high to moderate certainty evidence that at 3 years, the W&W group had a significant advantage in overal survival compared with the TME group (OR, 0.37; 9 5 % Cl, 0.09-0.95). After 5 years, no significant difference in overall survival was found between the 3 treatment modalities.

Conclusions: We concluded that TME achieved the most significant reduction in 2-year ocal regrowth rates. However, the W& strategy and LE demonstrated noninferiority to TME in long-term survival outcomes.

Keywords: local excision, network meta-analysis, total mesorectal excision surgery, watch-and-wait

Introduction

Rectal cancer (RC) is a common malignant tumor with high morbidity and mortalityll. With the continuous development of clinical treatment methods for middle and low RC, the current standard therapies are total mesorectal excision (TME) and organ preservation programs, which mainly comprise the watch-andwait (W&W) strategy and local excision \mathsf { \bar { \Pi } } _ { { ( L E ) } } [ 2 , 3 ] Traditional surgical treatment based on TME has excellent disadvantages, including the risk of multiple complications during surgery, the risk of perioperative death, and the possibility of sexual and urinary dysfunction[4,5]. For patients with sphincter preservation, intestinal dysfunction or low anterior resection syndrome can significantly affect the quality of life, and patients undergoing abdominoperineal resection (APR) will necessitate a permanent colostomy[6].

Approximately 2 0 % of patients with RC experience complete tumor regression after nCRT, and this phenomenon is known as clinical complete response ( { c C R } ) ^ { [ 7 , 8 ] } . In 2004, Habr-Gama et al first reported the results of a retrospective cohort study comparing \mathbf { \boldsymbol { w } } \mathbf { \& } \mathbf { \boldsymbol { w } } and TME in patients who achieved cCR after nCRT. They found excellent outcomes with \mathbf { \boldsymbol { \mathbb { W } } } \mathbf { \& } \mathbf { \boldsymbol { \mathbb { W } } } including a 1 0 0 % 5-year overall survival (OS) rate and a 9 2 % 5-year disease-free survival (DFS) rate[9]. Compared to TME, the \mathbf { \boldsymbol { w } } \mathbf { \& } \mathbf { \boldsymbol { w } } strategy can achieve similar OS and better preserve organ function. In addition, a meta-analysis involving 867 patients showed that TME and W&W differed only in DFS during a median follow-up period of 12-68 months, with no significant difference in { O S ^ { [ 1 0 ] } } .

Due to its less invasive nature, LE reduces the risk of surgical complications compared with TME[11,12]. Studies have shown that for patients with early-stage RC, LE such as transanal endoscopic microsurgery and transanal minimally invasive surgery, are alternatives to TME surgery[13,141. A multicenter phase 3 clinical trial (GRECCAR 2) compared LE with TME and showed no difference in oncological outcomes between LE and TME at 3 years of follow-up[15].

Although multiple colorectal cancer guidelines recommend TME after nCRT as the standard treatment for locally advanced rectal cancer (LARC)16,171, emerging strategies f neoadjuvant therapy, such as total neoadjuvant therapy (TNT), which can significantly improve the cCR rate!18,19], suggest that treatment options such as W&W and LE after nCRT are promising in the future. However, these data results come from different study designs and populations and have not been uniformly verified. Therefore, this study used a network meta-analysis considering direct and indirect evidence between studies to explore the survival outcomes of TME, W&W strategy, and LE in patients with RC. Our findings provide high-quality clinical evidence for the treatment of RC.

Methods

This work has been reported in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)[20] and AMSTAR (Assessing the methodological quality of systematic reviews) Guidelines!21]. The study protocol was established and registered in the Prospective Register of Systematic Reviews (PROSPERO ID: CRD42024503329).

Study selection

A systematic literature search was conducted in PubMed, Web of Science, and Embase (from 2010 to 31 December 2023), restricted to English. The detailed search strategy is shown in Supplementary Digital Content, Table S1 (http://links.lww.com/ JS9/D908, http://links.lww.com/JS9/D906). Two authors independently screened the titles and abstracts of all potential studies retrieved to determine which met inclusion and exclusion criteria. If there was no consensus on included studies, the third author was consulted to resolve any disagreements.

Selection Criteria

The inclusion criteria were as follows: RCTs or observational studies that (1) patients with RC undergoing nCRT for any indication, regardless of whether they ultimately achieve complete clinical response; (2) compared at least two of the three treatments (W&W, TME, and LE) in RC; (3) contained relevant, complete, and analyzed data; (4) with a median follow-up longer than 2 years. For studies that analyzed the same patients from a center, if they reported different outcomes, they were enrolled; however, if they reported the same outcomes, the study with the larger sample size was enrolled in the final analysis. For survival outcomes of studies with overlapping patients, studies with longer follow-up periods were used preferentially for analysis. The exclusion criteria are described in Supporting Methods.

Outcomes

The primary outcomes were 2-year local regrowth (LR) rates, defined as clinical, endoscopic, or radiological evidence of intraluminal tumor. Without individual patient data, we could not differentiate between mesorectal and extramesorectal regrowth. Therefore, we excluded lymph node recurrence in the definition of LR. Secondary outcomes were survival outcomes, including 2-, 3-, and 5 -year DFS and OS. Details of other secondary outcomes and their definitions are provided in Supporting Methods.

Data Extraction

A novel standardized spreadsheet was piloted in five studies and adjusted after discussion among all authors. Each eligible study underwent duplicate data extraction by two authors working independently, including independently screening the titles and abstracts of included studies, extracting data, and assessing the methodological quality of included studies. Disagreements were resolved through discussion with a third author. Data on study population characteristics, treatments, and outcomes were extracted according to Newcastle-Ottawa Scale (NOS) guidelines!22l, using the longest follow-up data for analysis. Twenty-seven baseline characteristics were extracted and are presented in Supplementary Digital Content, Table S2-3 (http://links.lww.com/JS9/D906).

Risk of Bias

The quality of the RCTs was assessed as recommended by the Guidelines of the Cochrane Collaboration[23], based on the following four risk of bias (ROB) criteria: allocation concealment, intention-to-treat, attrition, and selection reporting bias. A total ROB score was calculated for each study, ranging from 2 to 10. Scores above six are classified as overall low ROB, and scores of 6 or below are classified as overall high ROB. The methodological quality of observational cohort studies was assessed using NOS guidelines!22l. Studies with a score of 7 or above were considered to have a low risk of bias, 4-6 as moderate risk, and below 4 as a high risk of bias. Two trained authors independently assessed the certainty of the evidence using the Grading of Recommendations, Assessments, Developments, and Evaluation (GRADE) framework[24,25), rating the evidence as high, moderate, or low certainty (Supplementary Digital Content, Tables S4-9 (http:/links.lww.com/JS9/D906).

Statistical Analysis

Given the inherent heterogeneity between studies, we initially directly compared W&W, TME, and LE based on a meta-analysis model, using ORs as the effect indicator. When two or more studies are available, a random-effects Bayesian network metaanalysis was conducted to estimate the effect of comparing any two treatment modalities in RC, with effect sizes described in 9 5 % CI.26-28] All comparisons were performed using the nodesplitting method to assess potential inconsistencies between direct and indirect results, and the inverse method to derive indirect results from direct and network results and assess whether they were significantly different ( P ~ < ~ 0 . 0 5 ) ^ { [ 2 9 , 3 0 ] } Surface under the cumulative ranking curve (SUCRA) was used to examine ranking probabilities to reflect the ranking of treatments[31]. The rank probabilities would be sorted in plots. The statistical heterogeneity of our model was assessed with { I } ^ { [ 2 ] } statistic and heterogeneous variance random effects distribution[32,33]. Cochran Q tests were conducted for overall heterogeneity and inconsistencyl34,35]. We produced funnel plots to examine the presence of bias due to small study effects, which allowed us to examine symmetry visually. Network meta-analysis was performed using the R version 4.1.2 package "gemtc"

(version 3.6.2, Foundation for Statistical Computing, Vienna, Austria)361. Also, we used the "networkplot" command of Stata version 16.0 (StataCorp) to draw network plots[37].

Results

We identified 7029 potential studies from the database search, of which 26 studies involving 2778 participants met the inclusion criteria and were included[13,1s,38-61]. All studies were published between 2010 and 2023. Figure 1 shows a flowchart for this network meta-analysis.

Characteristics of included studies

The 26 included studies consist of 12 retrospective nonrandomized controlled trials, 13 prospective nonrandomized controlled trials, and 1 randomized controlled trial (Table 1). Among the 26 studies, 15 compared W&W with TME, four compared \mathbf { \boldsymbol { \mathbb { W } } } \mathbf { \& } \mathbf { \boldsymbol { \mathbb { W } } } with LE, and three compared TME with LE. For the remaining four studies, the three treatment therapies of w&W, TME, and LE were included simultaneously. The number of patients involved in each study ranged from 14 to 362. The median/mean age of included patients ranged from 50 to 74 years, and the median/mean distance from anal verge ranged from 2.0 to 7 . 0 ~ {cm } Nine studies ( 3 4 . 6 % ) were conducted in Asia and eight ( 3 0 . 8 % ) were conducted in Europe. Eighteen studies ( 6 9 . 2 % ) included predominantly male participants, and five studies ( 1 9 . 2 % ) included approximately equal proportions of male and female participants.

2-year local regrowth rate

Twenty-four studies reporting 2-year LR rates were included in the meta-analysis, involving 2490 participants[13,15,38,40-43,45-61]

The number of patients in the TME group was 1403 ( 5 6 . 3 % ) , in the W&W group was 732 ( 2 9 . 4 % ) , and in the LE group was 355 ( 1 4 . 3 % ) (Fig. 2a). Meta-analysis direct comparisons showed that W&W (OR, 8.81; 9 5 % CI, 5.23-14.85) was associated with a higher 2-year LR rate compared with TME (Fig. 3a; Supplementary Digital Content, Table S10, http:/links.lww. com/JS9/D906), while there was no significant difference in the 2-year LR rate between W&W and LE (OR, 1.05; 9 5 % CI, 0.62-1.77) (Fig. 3b; Supplementary Digital Content, Table S10, http://links.lww.com/JS9/D906). There was a significant difference in the 2-year LR rate between TME and LE (OR, 0.57; 9 5 % CI, 0.34-0.96) (Fig. 3c; Supplementary Digital Content, Table S10, http://links.lww.com/JS9/D906). As reported, 108 ( 8 1 . 2 % ) patients received salvage surgery in { w } \& { w } group while 19 ( 5 5 . 9 % ) patients received salvage surgery in LE group (Table 1).

For network meta-analysis, there are significant differences between \mathbf { \mathbb { W } } \mathbf { \& } \mathbf { \mathbb { W } } and LE compared with TME (OR, 0.20; 9 5 % CI, 0.12-0.35; OR, 3.00; 9 5 % CI, 1.60-5.80). The SUCRA values of W&W, TME, and LE were O.03, 1.00, and 0.47 respectively (Fig. 4a; Supplementary Digital Content, Figure

Figure 1. Flow diagram of included studies.

S1, http://links.lww.com/JS9/D905), indicating that TME has the highest chance of reducing the 2-year LR rate of RC among these three treatment therapies.

Overall survival

For the OS results, a total of 13 studies with 1664 participants reported outcomes at 3 years[13,39,40,44,45,48-s1,53,5s,s8,60] and nine studies reported outcomes for 1045 patients at 5 years[15,38,40,46,49-52,57] (Fig. 2b-c). At 3 years, W&W had a significant advantage in OS compared with TME (OR, 0.37; 9 5 % CI, 0.09-0.95), and the same trend was found in direct comparison (OR, 2.45; 9 5 % CI, 1.21-4.97). W&W has a 91 % probability (SUCRA \mathbf { \Phi } = \mathbf { \Phi } 0 . 9 1 ) of being the best treatment for 3-year OS (Fig. 4b-c; Supplementary Digital Content, Figures S2-5, http://links.lww.com/JS9/D905). At 5 years, no significant difference in OS was found between the three treatment therapies.

Disease-free survival

For the DFS outcome, a total of 10 studies with 1664 participants reported outcomes at 2 years138,404,4,49,501, 13 studies reported outcomes for 1045 patients at 3 years[38-40,44,45,48-s0,55,58-61] and 7 studies reported outcomes for 756 patients at 5 years15,38,40,464,0,7Fi 2d-f).At2 and3 yrs, nsigficant differences were found in DFS among the three treatment therapies (Table 2). At 5 years, TME had a significant disadvantage in DFS compared with W&W (OR, 4.30; 9 5 % CI, 1.40-15.00), and the same trend was found in direct comparison (W&W vs. TME: OR, 0.23; 9 5 % CI, 0.10-0.56). TME has an 8 4 % probability (SUCRA = 0 . 8 4 of being the best treatment for 5-year DFS (Fig. 4d-f; Figure S6-11. http:/links.lww.com/JS9/D905).

Sensitivity analysis

This study conducted a sensitivity analysis of studies with a sample size of 30 or more patients in each group. Eleven studies were ultimately included for the 2-year LR rate. Similar to the results from the analysis of all Twenty-four studies, there was no significant difference in the 2-year LR rate among the three treatment therapies in both direct comparison analysis and network meta-analysis (Table 3; Supplementary Digital Content, Figure S12, http://links.lww.com/JS9/D905).

The results of network direct comparison and indirect comparison of sensitivity analysis of OS showed that there was no significant difference in OS among W&W, TME, and LE groups (Supplementary Digital Content, Figures S13-14, http://links. 1ww.com/JS9/D905). The results of the sensitivity analysis for DFS are summarized in Supplementary Digital Content, Figures S15-16 (http://links.lww.com/JS9/D905). A total of five studies were included, showing that TME performed less favorably than { w } \& { w } in 5-year DFS (OR, 2.90; 9 5 % CI, 1.30-5.80), consistent with the previous analysis results.

Subgroup analysis

Subgroup analyses were performed for the Asian population study, studies on nCRT without oxaliplatin, and studies on assessment time ^ { < 8 } weeks after nCRT are described (Table 3; Supplementary Digital Content, Figures S17-51, http://links. lww.com/JS9/D905, and Table S11. http://links.lww.com/JS9/ D906). In the subgroup of Asian population studies, except for

Figre t - - l - - d -- is e er of std h ris, d h r. , wait l l xn xi.

TME showing a worse effect on 2-year DFS compared with previous results (OR, O.11; 9 5 % CI, 0.03-0.27), other results were consistent with the earlier analysis. In the non-Oxaliplatin subgroup analysis, whether through direct comparison or network meta-analysis, the previous findings in this subgroup analysis remained largely unchanged. However, TME did not demonstrate the earlier observed advantage over W&W in 3-year OS (OR, 0.52; 9 5 % CI, 0.18-1.40). The results of direct comparison and network comparison of studies on assessment time ^ { < 8 } weeks after neoadjuvant chemoradiotherapy showed that the OS and DFS of the three treatment therapies were almost equivalent.

Quality assessment and reporting bias

All RCTs and observational studies were of moderate or high quality (Table 1). In addition, we performed a GRADE evidence rating for the 2-/3-/5-year survival results of the network analysis (Fig. 5a-c; Supplementary Digital Content, Tables S4-9. http:/links.lww.com/JS9/D906). Visual analysis of the resulting network funnel plot revealed no apparent asymmetries between studies, indicating the absence of significant publication bias. According to funnel plots, the scatter points in the funnel plot are not entirely symmetrical, suggesting possible publication bias in the 2-year LR analysis (Fig. 6a). The publication bias for OS and DFS is deemed acceptable (Fig. 6b-f).

Figure 4. Ranking probabity and surace under the cuulative rnking cure (SR of trtegies for rimay otomes i the ntwork meta-aysis. ) 2-year ocal rrowth; ) 3-er overall suival ()5-er overall suival ()2-er dise-r surival 3-er diase-fre surial) ( \uparrow ) 5-year disease-free survival. Each line represents a treatment strategy. The x -axis indicates the ranking of strategies, with '1' representing the best. The y axis represents the probability of each ranking. W&W, watch and wait; TME, total mesorectal excision; LE, local excision.

Discussion

This study compared the effects of TME, W&W, and LE on the long-term survival outcomes of RC patients after nCRT through network meta-analysis, including 2-LR, 2/3/5-DFS, and 3/5-OS, and used SUCRA to rank the treatment therapies in the network. This study presents a novel finding based on direct and indirect evidence from 26 studies. It indicates that TME ranks highest in reducing the 2-year LR rate, significantly surpassing \mathbb { W } \& \mathbb { W } and LE. However, in terms of 3-year OS, both W&W and LE are ranked higher than TME, with \mathbf { \mathbb { W } } \mathbf { \& } \mathbf { \mathbb { W } } ranking the highest. In longer-term survival follow-up, there was no significant difference between the three treatment therapies-TME, W&W, and LE. Nevertheless, the W&W strategy achieved the highest

SUCRA score, suggesting it may be optimal for achieving positive long-term survival outcomes. Our study also found similar results in sensitivity analysis and subgroup analysis. Previous high-level studies have shown that organ preservation programs such as \mathbf { \mathbb { W } } \mathbf { \& } \mathbf { \mathbb { W } } and LE are oncologically safe, with better DFS and Os, long-term functional outcomes, and low colostomy rates[62-64]

TME is still the first-choice standard treatment after nCRT for \mathsf { R C } ^ { [ 6 5 ] } . However, after nCRT, about 1 0 { - } 2 0 % of patients observed the complete disappearance of all tumor cells in the TME resection specimen, defined as pathological complete response \mathsf { ( p C R ) } ^ { [ 6 6 ] } . At the same time, the serious complications after TME surgery are likely to lead to long-term functional impairment and poor oncological prognosis, especially for patients who also need permanent stomal4,sl. This has led to questions in the medical community about whether these patients need TME. In recent years, the \mathbf { \boldsymbol { w } } \mathbf { \& } \mathbf { \boldsymbol { w } } strategy for RC patients who achieve cCR or near-cCR after nCRT is gaining momentum. However, some studies have reported that about 2 5 % of patients who choose the W&W strategy will experience { L R } ^ { [ 7 ] } . This is consistent with our results. TME is the best treatment therapy in 2-year LR rate, followed by LE, and W&W strategy ranks last. We also found almost consistent results in sensitivity analysis and subgroup analysis of different populations, different preoperative nCRT, and different evaluation time. In addition, our study interestingly found that there was no significant difference in 5-year OS among the three treatments of TME, W&W, and LE. However, we consider that when evaluating the effects of different treatment strategies, the patient selection criteria and their potential impact on the results should be considered, which may affect the superiority of their results. This is consistent with the results of Habr-Gama et a l ^ { \left[ 9 \right] } . We believe that the main reason why the W&W strategy is superior to TME in 3-year OS and 5-year DFS is that it reduces the impact of TME postoperative complications to a certain extent. For the results analyzed in 5-year OS, we consider there are several reasons. First, although the LR rate after choosing the W&W strategy is very high, some studies have shown that salvage surgery is very effective, and the rate of unsalvageable local disease is only less than 1 % ^ { [ 1 0 ] } . Second, distant metastasis (DM) is the leading cause of death in patients with LARC. RC with complete response or near-complete response after nCRT usually has lower tumor biological activity like the expression of P53, EGFR, Ki-67, P21, and Bax/bcl- 2 ^ { [ 6 7 ] } In addition, choosing W&W strategy patients may result in a lower incidence of complications, better nutritional status, and lower medical expenses due to preserving the rectum and avoiding surgery, which may also lead to longer overall survival. Finally, patients with TME might also acquire better long-term prognosis affected from multiple perspectives due to psychosocial health related to stoma16,691. Therefore, the long-term survival outcomes of patients who chose the W&W strategy were not seriously affected, which is consistent with the results of some studies.

Over the past few years, organ preservation programs such as W&W and LE have been widely studied. For instance, Maas et al conducted a meta-analysis on the incidence of DM between cCR and pCR patients[67]. They reported that the incidence of LR in cCR patients was significantly higher than in pCR patients ( 3 0 . 7 % vs. 2 . 8 % . However, the proportion of DM was similar 1 1 . 5 % vs. 1 1 . 2 % ), with 3 0 . 7 % of cCR patients opting for the W&W strategy. The OnCoRe study(44), an observational study initiated by British researchers, utilized propensity score matching to align the baseline T stage, age, and performance status of patients. The results showed that patients who followed the \mathbf { \mathbb { W } } \mathbf { \& } \mathbf { \mathbb { W } } strategy had a higher 3-year OS than RC patients who underwent TME surgery 9 6 % vs. 8 7 % 3 P = 0 . 0 2 4 _ { . } . These findings are consistent with our network meta-analysis results.

(Continues)

Recent studies have also indicated that patients with early RC who chose LE after nCRT had an LR rate comparable to that achieved after { T M E } ^ { [ 1 5 , 5 3 ] } . The organ preservation program appears to have ushered in a new era in the treatment of RC. In this network meta-analysis, the salvage surgery rate was 8 1 . 2 % in \mathbf { \mathbb { W } } \mathbf { \& } \mathbf { \mathbb { W } } group while 5 5 . 9 % in LE group, which is consistent with current clinical practice. Salvage surgery should be the first choice for most resectable LR patients. Although there were statistical differences in 2-year local regrowth among different groups, no difference was found in long-term survival outcomes. These results confirmed that \mathbf { \mathbb { W } } \mathbf { \& } \mathbf { \mathbb { W } } and LE strategy did have sense.

Our study synthesized the evidence on the results of LR, DFS, and OS from 26 studies over the past 10 years and compared various treatment therapies directly and indirectly. Since the introduction of the organ preservation programs, a large amount of new data involving W&W and LE have become availablel73-751, but to our knowledge, this is the first network meta-analysis that summarizes the long-term outcomes of different treatment therapies after nCRT of RC. Network meta-analysis has several statistical advantages over traditional meta-analysis, such as combining direct and indirect comparisons and comparing treatment effects between multiple studies!76]. In addition, most previous meta-analyses only involved the choice of nCRT regimens!77,781, and there is a lack of high-quality research on the subsequent treatment therapies after nCRT. Since nCRT has no effect on OS and DFS in patients with \mathbf { R C } ^ { [ 7 9 ] } , the choice of TME, W&W, and LE urgently needed to be supported by high-level evidence. Importantly, our network meta-analysis added inconsistency testing, sensitivity analysis, and subgroup analysis, and a GRADE rating was used to grade the meta-analysis results, which increased the reliability of the results of this study.

Figure 5. ue ab f dfet ttmns e a a tk m-ais )-r su 3- url s ) 5- a indicates the certaint of evidence according to the Grading of Rcommendations Assessment, Dvelopment, and Ealuatio. The odds atio ( 9 5 % { ~ C l ~ } for c-d the h, r t h w wit l mesorectal excision; LE, local excision.

This network meta-analysis has a few methodological strengths but has also several limitations. First, there were few RCTs included in this study, mainly because of the enormous challenges in studying data involving W&W strategy, including heterogeneity of reporting populations, diversity of TNT strategies, different radiation doses in radiotherapy, and different response assessment intervals. Therefore, we included many observational studies in the hope of making up for the lack of RCTs, and at the same time performed subgroup analysis to minimize the impact of confounding factors in the study itself on the reliability of the results. Due to limited research, the study populations for 3-year and 5-year OS used in this study were mostly nonoverlapping, so there was a certain bias. Such bias might explain that 3-year OS is higher in W&W compared to TME, while 5-year OS is comparable to both groups. The included studies also did not divide patients whether they achieve complete clinical response, which may bias the longterm results. Furthermore, there are issues of heterogeneity between the studies, including the different chemoradiotherapy regimes used and the definitions used to determine suitability for W& W/LE approach. However, the primary outcome of this study is the impact of different strategies on long-term prognosis after neoadjuvant therapy, which mainly depends on the efficacy evaluation after nCRT or TNT with relatively unified standards to evaluate complete response, near-complete response, or incomplete response. Thus, this network metaanalysis concludes that regardless of the chosen neoadjuvant therapy strategy, once cCR is achieved, \mathbf { \mathbb { W } } \mathbf { \& } \mathbf { \mathbb { W } } is noninferior to TME in terms of long-term outcomes. In addition, several parameters that might affect response to treatment were not included in this study, including perineural, vascular invasion, EMVI, MSI status, mucinous or signet ring tumors, type of chemotherapy regimen, lateral lymph nodes, and personal characteristics. This is because most of the studies included in this network meta-analysis did not report these factors. Thus, the exact indications based on tumor and patient characteristics should be defined in the future for adopting a tailor-made approach.

Considering the significant advantages in preserving organs, avoiding postoperative complications and avoiding stoma, according to this network meta-analysis, all patients who achieve cCR after neoadjuvant therapy could benefit from W&W strategies.

Ethical approval

Review and approval by an ethics committee was not needed for this study because the study was restricted to publicly available data.

Consent

Not applicable.

Sources of funding

This work was supported by grants from the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0520302), Beijing Hospitals Authority Clinical Medicine Development of special funding support (ZLRK202302), National Key Technologies R&D Program (No. 2015BAI13B09), National Key Technologies R&D Program of China (No. 2017YFC0110904), Clinical Center for Colorectal Cancer, Capital Medical University (No. 1192070313), National Natural Science Foundation of China (No. 82202884), Training Fund for Open Projects at Clinical Institutes and Departments of Capital Medical University (No. CCMU2022ZKYXY008).

Author contributions

All authors made substantial contributions to this article. Z.Z., H.Y., and Z.Y. conceived and designed the study. C.M., W.S., L.S., S.W., P.W., J.G., J.S., and Y.L. retrieved and reviewed literatures. C.M. participated in data organization and statistical analysis. C.M. and W.S. wrote the manuscript. Z.Z., H.Y., and Z.Y. reviewed and edited the manuscript. All authors read and approved the manuscript.

Conflicts of interest disclosure

The authors declare that they have no conflict of interest.

Research registration unique identifying number (UIN)

The study protocol was established and registered in the Prospective Register of Systematic Reviews (PROSPERO ID: CRD42024503329).

Guarantor

Hongwei Yao.

Provenance and peer review

Not invited.

Data availability statement

The raw data could be available for scientific purpose by sending requests to the corresponding author.

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