Technical Feasibility and Oncological Safety of Low and High Ligation of the Inferior Mesenteric Artery in Colorectal Cancer Surgery for Asian Populations: a Systematic Review and Meta-analysis

Background: The level of ligation of the inferior mesenteric artery (IMA) is controversial. There is still no consensus on whether to preserve the left colon artery (LCA). The aim of this updated meta-analysis was to compare the technical feasibility and oncological safety of low ligation (LL) and high ligation (HL) of IMA in the treatment of colorectal cancer for Asian populations. Methods: A systematic search was conducted in the PubMed, Embase, Web of Science and China Biomedical Literature Database (CBM) for relevant studies that compared HL and LL for sigmoid or rectal cancer were published between January 2010 and August 2020 from Asian countries. The outcomes of interest include anastomotic leak, operation time, blood loss, early complications, the postoperative rst anal exhaust time, lymph node yield outcomes and involvement state, 5-year overall survival (OS), 5-year disease-free survival (DFS), and overall recurrence. Results: Twenty-one studies including 8 randomized controlled trials (RCTs) and 13 retrospective cohort studies (non-RCTs) with a total of 5947 patients (2519 patients in LL group and 3428 patients in HL group) were involved in this meta-analysis. LL group showed a lower incidence of anastomotic leakage (WMD=0.59; 95%CI=0.46~0.76; P<0.05) and earlier postoperative rst anal exhaust time (WMD=-4.55; 95%CI=-8.87~-0.24; P<0.05). In term of operation time, blood loss, early complications, the rst postoperative anal exhaust time, lymph node yield outcomes and involvement state, 5-year OS, 5-year DFS, and overall recurrence, there were no signicant differences between LL and HL group. Conclusions: Compared with HL, LL signicantly reduced the incidence of anastomotic leakage and accelerated the postoperative recovery time of bowel function in Asian populations. What's more, LL can obtain equivalent lymph node yield and long-term survival benet as compared to HL. > 0.05; Fig. with certain heterogeneity (I²=52.9%), and so the random effects model was adopted. The meta-analysis of 6 trials reporting this data indicated that there was a signicant difference between the two groups (WMD=-4.55; 95%CI=-8.87~-0.24; P < 0.05; Fig. 6) with high heterogeneity (I²=89.6%), and so the random effects model was adopted. The heterogeneity may be caused by different units of measurement. Pooled analysis showed shorter recovery time of bowel function in LL group than that of HL group.


Introduction
In 2018, there were 18.1 million new cancer cases and 9.6 million deaths worldwide, of which Asia accounted for 48.4 percent and 57.3 percent, respectively. In terms of the incidence of new cancers in 2018, colorectal cancer ranked third, accounting for 10.2 percent of all new cases, and cancer mortality ranked second, accounting for 9.2 percent of all deaths [1]. The basic principle of the treatment of colorectal cancer is based on surgical operation, including tumor resection, dissection of regional lymph nodes, extensive mesenteric resection, ligation of inferior mesenteric veins and arteries and other vessels [2]. Currently, the level of ligation of the inferior mesenteric artery (IMA) is still controversial. The controversy is whether to preserve the left colon artery (LCA) [3][4][5]. The preservation of the left colonic artery is known as low ligation (LL), which refers to the ligation below the origin of the left colonic artery. The non-preservation of the left colonic artery is known as high ligation (HL), which refers to the ligation at the origin of the inferior mesenteric artery from the abdominal aorta.
Some studies have recommended high ligation, suggesting that this technique can more thoroughly remove lymph nodes and improve lymph nodes harvest rates, thus contributing to more accurate tumor staging and better disease prognosis [6,7]. Secondly, high ligation may achieve su cient colonic length for a tension-free anastomosis [8]. Some other scholars believe that after the lower ligation, LCA and its branches can be preserved, which can provide more adequate blood perfusion to the anastomotic stoma, thus reducing the risk of anastomotic leakage, and this technique has little risk of injury to the autonomic nerve [9][10][11]. However, in terms of surgical di culty and operative time, lower ligation and lymph nodes dissection at the root of IMA may require more surgical steps [12]. Although several randomized controlled trials and retrospective cohort studies have been published in recent years to examine the oncological outcomes and safety of HL and LL, it is worth noting that the conclusions of these studies remain controversial. Si et al. and Fan et al. reported that low ligation signi cantly reduced the risk of anastomotic leakage, whereas pooled data from the studies of Hajibandeh et al. and Yang et al. showed that there was no signi cant difference in the incidence of anastomotic leakage with the two approaches [1,5,13,14] High-quality meta-analysis is increasingly recognized as one of the key tools for obtaining evidence. Therefore, it is necessary to do an updated systematic review and meta-analysis, including recently published studies, to compare the e cacy and safety of HL and LL.

Search strategy
This systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines [15]. The comprehensive publications were identi ed by searching medical electronic databases PubMed, Embase, Web of Science and China Biomedical Literature Database (CBM), which published from January 2010 to August 2020. The following MeSH terms and non-MeSH terms were used: "rectal" or "rectum" or "sigmoid" or "sigmoid" or "colon" or "colorectal" and "cancer" or "carcinoma" or "tumor" or "malignancy" or "neoplasm" and "left colic artery" or "inferior mesenteric artery" or "superior rectal artery" or "high lie" or "high ligation" or "low tie" or "low ligation". The last search was performed on September 23. The references of the relevant articles and previous meta-analysis studies were identi ed as additional articles. Title and abstracts of each identi ed article were screened, and the full text of the screened articles was assessed for eligibility. Three authors researched and reviewed independently and thoroughly through the above-mentioned search strategy.

Inclusion criteria
The inclusion criteria for our study were as follows: 1. Patients de nitely diagnosed with sigmoid or rectal cancer by enhanced computed tomography, colonoscopy, and pathological biopsy.
3. Clinical studies having compared high ligation with low ligation of the IMA for sigmoid or rectal cancer surgery, regardless of the cause of colorectal cancer, surgical procedure (open or laparoscopic) and surgical urgency (limited or emergency).

Exclusion criteria
The exclusion criteria for this study were as follows: 1. case report, letter, reply, comment, conference proceeding, and review article; 2. single arm study; 3. insu cient information concerning the outcomes of interest; 4. full-text not available; 5. published by non-Asian countries.

Data extraction
Clinical data was extracted independently and evaluated critically by two authors. The relevant data included rst author, publication year, country, study design, patient recruitment period, tumor location, surgical procedure, sample, BMI, TNM stage, and outcomes of interest. Anastomotic leak, lymph node yield outcomes and involvement state were regarded as primary outcome measures. In addition, operation time, blood loss, early complications, the postoperative rst anal exhaust time, 5-year overall survival (OS), 5-year disease-free survival (DFS), and overall recurrence were considered as secondary outcome measures. Any discrepancies between the two reviewers were resolved by discussion to reach agreement, if an agreement between the two reviewers could not be reached, a third person was involved.

Quality assessment
All studies were independently assessed by two investigators for quality and validity. We used the Newcastle-Ottawa Quality Assessment Scale (NOS) for non-RCT [16]. NOS contains 3 categories including selection, comparability, and outcome, which were scaled by eight elements; highquality elements are awarded by adding a star, no more than one stars could be added into the elements of selection and outcome, and no more than two stars could be added into the elements of comparability; then, studies were compared according to the number of stars, total score was 9 stars, 0-5 stars was considered as low-quality and 6-9 stars was considered as high quality. The Jadad scale (JCS) was used to assess the bias risk and quality of the RCTs [17]. This scoring system is based on three speci c items: randomization, blinding, and withdrawals and dropouts. The total score ranges from 0 to 5; a score of ≤ 2 indicates poor-quality evidence and a score of ≥ 3 indicates high-quality evidence. The results of this assessment are shown respectively in Table 1 and Table 2. Disagreements in the quality assessment were resolved by consensus.  Randomization: randomization was described with appropriate method -2 score, randomization was described without appropriate method -1 score, no randomization -0 score. Blinding: blinding was performed on all doctors and patients -2 score, blinding was partially performed on doctors and patients -1 score, no blinding-0 score. Withdraw and dropout: the reason of withdraw and dropout was described-1 score, the reason of withdraw and dropout was not described -0 score. Quality: high-quality trials should score ≥ 3, moderate-quality trials should score ≥ 2 Statistical analysis STATA 12.0 for window was performed for this study. Dichotomous data was calculated by relative risks (RR) with 95% con dence intervals and continuous variables were calculated by Weighted mean differences (WMD) with 95% (CI). Meanwhile, χ² test was used to assess heterogeneity, with an I² of 25-50%, 50-75% or > 75% that were considered with low, moderate or high heterogeneity [18]. Studies with low heterogeneity adopted xed-effect model, while those with high heterogeneity adopted random-effect model and subgroup analysis based on the type of study design (RCTs or non-RCTs). Funnel plots and Egger's linear regression test were used to assess the publication bias. P < 0.05 was considered to indicate statistical signi cance.

Description of study selection
The study selection process is summarized in the owchart (Fig. 1).A total of 459 studies were obtained according to the initial search strategy.
After removing duplicates, 362 studies remained. After reviewing the titles and abstracts, 299 irrelevant studies were excluded, and 63 studies were further evaluated. Among them, 16 studies were review articles, comments, letters, case reports, and 7 studies underwent resection only with low ligation or high ligation. There were 40 full-text articles assessed for eligibility. Among them, 8 studies failed to provide su cient data and 11 studies published by non-Asian countries. Finally, 21 studies including 8 RCTs and 13 non-RCTs published between 2010 and 2020 were included in this systematic review and meta-analysis [4,7,9,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. A total of 5947 patients (2519 patients in LL group and 3428 patients in HL group) were involved in the study. Among the 21 studies, 10 studies originated from China, 7 studies originated from Japan, 4 studies originated from UK. Detailed information for basic characteristics of included studies is shown in Table 1 and the tumor stage is shown in Table 3. The results of interest are shown in Tables 4 and 5.    The pooled anastomotic leakage rate was 5.5% (132/2411) in the low ligation group and 9.5% (316/3321) in the high ligation group. The metaanalysis of 20 trials reporting this data indicated that there was a signi cant difference between the two groups (RR = 0.59; 95%CI = 0.46 ~ 0.76; P < 0.05; Fig. 2) with low heterogeneity (I²=16.6%). Subgroup analysis based on published years indicated a similar result in both subgroups. The pooled data showed LL-treated patients had a lower incidence of anastomotic leakage compared to HL-treated patients.

Operation time
The meta-analysis of 13 trials reporting this data indicated that there was a signi cant difference between the two groups (WMD = 7.71; 95%CI = 0.96 ~ 14.46; P < 0.05; Fig. 3) with signi cant heterogeneity (I²=89.6%), and so the random effects model was adopted. However, the subgroup analysis based on clinical study type indicated no statistically signi cant difference in the non-RCT group (WMD = 7.03; 95%CI=-2.70 ~ 16.75; P > 0.05) and the RCT group (WMD = 8.93; 95%CI=-0.14 ~ 18.01; P > 0.05). Therefore, it cannot be concluded that the operation time of high ligation is longer than that of low ligation. More high-quality research will need to be included in the discussion.

Blood loss
The meta-analysis of 9 trials reporting this data indicated that there was no signi cant difference between the two groups (WMD = 2.20; 95%CI=-1.40 ~ 5.80; P > 0.05; Fig. 4) with certain heterogeneity (I²=64.3%), and so the random effects model was adopted.

Early complication
The meta-analysis of 9 trials reporting this data indicated that there was no signi cant difference between the two groups (RR = 0.96; 95%CI = 0.75 1.23; P > 0.05; Fig. 5) with certain heterogeneity (I²=52.9%), and so the random effects model was adopted.

The postoperative rst anal exhaust time
The meta-analysis of 6 trials reporting this data indicated that there was a signi cant difference between the two groups (WMD=-4.55; 95%CI=-8.87~-0.24; P < 0.05; Fig. 6) with high heterogeneity (I²=89.6%), and so the random effects model was adopted. The heterogeneity may be caused by different units of measurement. Pooled analysis showed shorter recovery time of bowel function in LL group than that of HL group.
Lymph node involvement around the root of the IMA The pooled rate of lymph node involvement around the root of the IMA was 5.9% (36/608) in the low ligation group and 6.1% (38/662) in the high ligation group. The meta-analysis of 5 trials reporting this data indicated that there was no signi cant difference between the two groups (RR = 1.06; 95%CI = 0.68 ~ 1.66; P > 0.05; Fig. 10) without heterogeneity (I²=0%).
Long-term prognosis
5-year disease-free survival model and subgroup analysis was adopted. Pooled analysis showed no statistically signi cant difference between the high ligation group and the low ligation group (RR = 0.90; 95%CI = 0.68 ~ 1.19; P > 0.05; Fig. 12).

Overall recurrence
Nine studies compared the recurrence rates. There was no signi cant heterogeneity among the studies (I²=0.6%). Pooled analysis showed no statistically signi cant difference between the high ligation group and the low ligation group (RR = 1.02; 95%CI = 0.83 ~ 1.25; P > 0.05; Fig. 13).

Sensitivity analysis
We performed a sensitivity analysis by investigating the in uence of a single study on the overall pooled estimates. This was achieved by eliminating one study at a time and repeating the analyses, which producing the similar outcomes. The heterogeneity may be caused by different surgical pro ciency, individual anatomical differences and outcomes measured by different methods.

Assessment of publication Bias
We only analyzed publication bias for outcomes included in 8 or more studies. After viewing the funnel plots and Egger's tests, it was concluded that there was no obvious publication bias among the studies. A funnel plot of the studies used in the meta-analysis reporting on 5-year OS after colorectal resection with low ligation and high ligation was shown in Fig. 14. None of the studies lay outside the limits of the 95% con dence interval.

Discussion
Recently, a technique involving LL and lymph nodes dissection around the root of the IMA to achieve D3 lymph nodes dissection has been widely used clinically, especially in Asian countries [37]. To compare the e cacy and safety of LL and HL, A total of 5947 patients (2519 patients in LL group and 3428 patients in HL group) were involved in this meta-analysis. The rst objective of this meta-analysis was to understand whether the two ligation methods of IMA had a certain impact on the incidence of anastomotic leakage. It has been reported that the incidence of anastomotic leakage is 2.2%~12% [38]. There are many risk factors for anastomotic leakage, however, blood perfusion and anastomotic tension are of primary concern to surgeons because good blood supply and tension-free anastomosis are critical in radical resection of colorectal cancer [8,39,40]. The colon below the root of IMA is perfused by IMA and the limbic artery from the middle colon artery(MCA) [8,41]. Some studies have shown that in patients receiving HL treatment, since the LCA and its ascending branches are ligated, the perfusion of the distal colon is completely dependent on the limbic artery from the MCA, leading to a signi cant impact on the perfusion of the distal colon [22]. Dworkin et al. used Doppler owmeter to make measurements and found that HL signi cantly reduced blood perfusion in the distal colon [42,43]. This undoubtedly increases the incidence of anastomotic leakage in HL patients. However, other studies suggest that HL can provide enough colon length for tension-free anastomosis, and the limbic artery can provide su cient blood supply to the remaining colon [44,45].
In some previously published meta-analyses, Fan et al. reported that low ligation signi cantly reduced the risk of anastomotic leakage, whereas Yang et al. reported that there was no signi cant difference in the incidence of anastomotic leakage with the two approaches [5,14]. The meta-analysis of 20 trials reporting this data indicated that there was a signi cant difference between the two groups(p < 0.05). The results showed LL-treated patients had a lower incidence of anastomotic leakage compared to HL-treated patients. This nding is consistent with a meta-analysis recently published by Si et al [1]. From an anatomical point of view, the left branch of the MCA and the ascending branch of the LCA form anastomotic branches near the splenic exion through the Riolan arch. However, this region is usually relatively thin and is absent in 5% of the cases [29]. Furthermore, postoperative systemic blood perfusion decline, elderly patients or patients with metabolic diseases and especially the increasing number of patients with vascular lesions, may become risk factors for anastomotic blood supply de ciency. Thus, low ligation is of great advantage in improving anastomotic blood supply and reducing anastomotic leakage.
Our meta-analysis con rmed that there were no signi cant differences between LL group and HL group in terms of operation time, blood loss, and early complications. This is consistent with the previously published meta-analysis [13,46]. However, we found that regarding postoperative rst anal exhaust time, LL group was earlier than HL group, which was rarely reported in previous studies. It may be because LL retains the LCA and provides better blood perfusion at the anastomosis, thus promoting the recovery time of bowel function.
Lymph node yield and involvement state, especially around the root of IMA, is a key prognostic factor for colorectal cancer [47,48]. Some studies suggest that high ligation can more thoroughly remove lymph nodes and improve lymph nodes harvest rate, thus contributing to more accurate tumor stage and better disease prognosis [6,7]. This may be because in those studies, LL group did not undergo IMA root lymph node dissection.
Moreover, with the development of laparoscopic-assisted radical resection of colorectal cancer, the techniques of low ligation and IMA root lymph node dissection to achieve D3 lymph node dissection are increasingly mature. This meta-analysis shows that, the pooled rate of total lymph node involvement was 39.8% (257/645) in the low ligation group and 38.8% (244/629) in the high ligation group, and the pooled rate of lymph node involvement around the root of the IMA was 5.9% (36/608) in the low ligation group and 6.1% (38/662) in the high ligation group. We observed that there was no statistical difference between LL group and the HL group either in terms of the harvested number of lymph nodes or the involvement state of lymph node(p > 0.05). And, the metastasis rate of the IMA root lymph nodes is stable and low. This indicated that the number of lymph nodes dissected by low ligation was similar to that by high ligation, and the oncological safety was comparable. It is not surprising, therefore, that we observed similarities in 5-year OS and 5-year DFS between the two groups(p > 0.05). Because of the differences in physical tness and dietary culture between Eastern and Western people, we only included Asian patients to assess the long-term prognosis of tumors [37]. Our meta-analysis con rmed that HL did not signi cantly improve the long-term prognosis of tumors in patients with radical resection of colorectal cancer compared with LL, which was consistent with previous studies [6,12,49] published a meta-analysis that compared stage II and III patients in greater depth and found no difference in survival between the two IMA ligation techniques [1]. Therefore, based on the available evidence, LL of IMA is recommended in colorectal cancer surgery for Asian populations regardless of tumor stage.
Some limitations exist that should not be neglected for this meta-analysis. First, many studies related with the theme are non-randomized retrospective trials. Therefore, we have analyzed both the RCTs and non-RCTs to avoid lack of samples. Second, the data including postoperative defecation, urinary and sexual function are obviously insu cient in the literatures, so the functional results are not analyzed. Third, Individual differences in patient anatomy and the skill of surgeon, as well as differences in measurement methods, led to a high degree of heterogeneity in some of the results, which may affect the quality of evidence to some extent. Finally, the meta-analysis was limited to literature in English and the studies from China accounting for a larger proportion, which is a potential source of bias.

Conclusion
In conclusion, this meta-analysis showed that compared with high ligation, low ligation reduced the incidence of anastomotic leakage and accelerated the postoperative recovery time of intestinal function for Asian populations. There were no signi cant differences between the two groups in terms of operation time, blood loss, early complications, number of harvested lymph nodes, and lymph node involvement status, 5-year OS, 5-year DFS and overall recurrence. It shows that LL can obtain equivalent lymph node yield and long-term survival bene t as compared to HL.
More high-powered, well-designed RCTs, with extensive follow-up, will be need in the future to con rm and update the results of this analysis. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
This study was supported by grants from the Project of Xiamen Scienti c and Technological Plan (No. 3502Z20194005, 3502Z20184020).