Long-term clinical outcomes after high and low ligations with lymph node dissection around the root of the inferior mesenteric artery in patients with rectal cancer

Article information

Ann Coloproctol. 2024;40(1):62-73

Publication date (electronic) : 2024 February 26

doi : https://doi.org/10.3393/ac.2023.00094.0013

Min Wan Lee¹, Sung Sil Park¹, Kiho You¹, Dong Eun Lee², Dong Woon Lee¹, Sung Chan Park¹, Kyung Su Han¹, Dae Kyung Sohn¹, Chang Won Hong¹, Bun Kim¹, Byung Chang Kim¹, Hee Jin Chang¹, Dae Yong Kim¹, Jae Hwan Oh^,1

¹Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea

²Biostatistics Collaboration Team, Research Institute and Hospital, National Cancer Center, Goyang, Korea

Correspondence to: Jae Hwan Oh, MD, PhD Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Email: jayoh@ncc.re.kr

Received 2023 January 30; Revised 2023 April 25; Accepted 2023 April 30.

Abstract

Graphical abstract

INTRODUCTION

In 2020, the World Health Organization (WHO) announced the incidence of colorectal cancer as the 3rd highest after breast and lung cancers, and the mortality rate of colorectal cancer was second after that of lung cancer [1].

According to the guidelines published by the National Comprehensive Cancer Network (NCCN) in 2022, the standard treatment for rectal cancer is to remove the primary tumor by securing an appropriate circumferential resection margin and distal resection margin (DRM), followed by total mesorectal excision (TME) [2]. In addition, inferior mesenteric artery (IMA) ligation is a necessary process during TME, and it can be divided into high ligation (HL) and low ligation (LL) depending on the location of the ligated artery. However, the NCCN guidelines do not cover the location of IMA ligation, and the debate on the location of IMA ligation has been ongoing since Moynihan [3] and Miles [4] introduced HL and LL in 1908, respectively.

HL is an IMA ligation method. Lymph node (LN) dissection from the periphery is performed by ligating the root of the IMA branching from the aorta. Laparoscopic surgery is the most widely used surgical method for treating rectal cancer. In this laparoscopic view, many surgeons prefer HL because the root of the IMA is easily accessible, and it is relatively easier than LL because only the root of the IMA branching from the aorta must be identified and ligated. Furthermore, by performing lymphadenectomy around the origin of the IMA during the ligation process, D3 lymphadenectomy, defined by the Japanese Society for Cancer of Colon and Rectum (JSCCR), is possible in HL [5]. In addition, it is possible to secure a longer mesenteric length in HL than in LL when performing anastomosis in the pelvic cavity [6, 7]. However, a significant reduction in blood flow to the anastomosis site is observed in HL compared with LL, and the length of the proximal colonic denervation is longer in HL [8, 9]. In addition, there is a high possibility of damage to the superior hypogastric plexus passing through the left and right sides of the origin of the IMA when performing HL [10]. LL can be more complicated than HL because the IMA, left colonic artery, and superior rectal artery must be identified before ligation. In addition, LN dissection is usually performed around the superior rectal artery in LL, unlike HL; however, it has recently been possible to dissect the LN from the origin of the IMA [11].

Furthermore, several debates have arisen owing to the anatomical differences between the 2 methods, which are still ongoing. First, it is thought that HL can improve oncological outcomes compared with LL because LN dissection is performed at the IMA origin, and more LNs can be harvested. Slanetz and Grimson [12] and Singh et al. [13] reported that HL was more oncologically beneficial in patients with advanced colorectal cancer. However, Yasuda et al. [14], AlSuhaimi et al. [15], and Park et al. [16] reported no significant difference in oncological outcomes between the 2 methods. Regarding the occurrence of postoperative complications, several studies have reported that ischemic colitis, necrosis, and anastomotic leak frequently occur in HL due to reduced blood flow to the anastomosis [8, 17–19]; however, other studies have reported that no difference exists in the occurrence of complications between the 2 methods, while others have indicated that HL could be a safer and more appropriate option [16, 20–22]. Regarding postoperative functional outcomes, the possibility of damage to defecatory and urogenital functions may be higher in HL than in LL because of the high possibility of proximal colonic denervation and superior hypogastric plexus damage in HL. However, some studies have reported no differences in functional outcomes between the 2 methods [23, 24]. Therefore, this study aimed to evaluate the long-term clinical outcomes based on the ligation level of IMA.

METHODS

Study design and patients

This retrospective study was conducted on patients aged ≥18 years who underwent laparoscopic low anterior resection for rectal adenocarcinoma between January 2013 and December 2019. Patients who underwent resection of other major organs, such as hepatectomy or palliative surgery at stage IV, and those who underwent lateral pelvic and para-aortic LN dissections were excluded from this study. A total of 545 patients were included: 244 patients underwent HL, and 301 patients underwent LL (Fig. 1). Their medical records were retrospectively reviewed for clinicopathological data, survival rates, complications, and functional outcomes, according to the ligation method.

Fig. 1.

Flowchart from January 2013 to December 2019. HL, high ligation; LL, low ligation.

RESULTS

Clinicopathologic characteristics

There were 244 and 301 patients in the HL and LL groups, respectively. There were no significant differences in sex, age, body mass index, comorbidities, preoperative chemoradiotherapy, tumor level, pathologic stage, intraoperative bleeding, operation time, and diverting ileostomy between the 2 groups. However, the tumor size was larger in the HL group than in the LL group (P=0.006). The number of harvested LNs was higher in the HL group than in the LL group (P=0.002). However, when LNs harvest adequacy was compared based on the evaluation criteria of 12, there was no difference between the 2 groups (P=0.260). The length of the proximal resection margin (PRM) was longer in the HL group (P<0.001), whereas the length of DRM was longer in the LL group (P<0.001). Splenic flexure mobilization was performed more frequently in the HL group (P=0.004) (Table 1).

Table 1.

Clinicopathological characteristics (n=545)

OS and RFS

The average follow-up period for survival was 56 months. There was no significant difference in the 5-year OS rate (88.3% vs. 91.4%, P=0.197) and RFS rate (84.3% vs. 81.8, P=0.844) between the 2 groups (Fig. 2). Multivariate analysis of factors affecting OS and RFS revealed that male sex (hazard ratio [HR], 2.154; 95% confidence interval [CI], 1.085–4.275; P=0.028), T3–4 stage (HR, 2.326; 95% CI, 1.217–4.446; P=0.011), nodal metastasis (HR, 1.945; 95% CI, 1.128–3.353; P=0.017), and comorbidity (HR, 1.948; 95% CI, 1.118–3.395; P=0.019) were associated with OS, whereas T3–4 stage (HR, 2.323; 95% CI, 1.322–4.083; P=0.003), nodal metastasis (HR, 4.891; 95% CI, 2.825–8.469; P<0.001), operation time (HR, 1.313; 95% CI, 1.063–1.621; P=0.011), and adjuvant treatment (HR, 0.396; 95% CI, 0.228–0.686; P=0.001) were associated with RFS. However, Cox regression analysis revealed that the ligation level (HL vs. LL) was not a significant risk factor for OS or RFS (Table 2).

Fig. 2.

Overall and relapse-free survivals of high ligation (HL) and low ligation (LL) groups. (A) Five-year overall survival (HL group [88.3%] vs. LL group [91.4%], P=0.197). (B) Relapse-free survival (HL group [84.3%] vs. LL group [81.8%], P=0.844). IMA, inferior mesenteric artery.

Table 2.

Univariable and multivariable Cox proportional hazard model for overall survival and relapse-free survival in patients (n=545)

Postoperative complication

Postoperative complication occurred in 104 (19.1%) of the 545 patients, of which 47 (45.2%) were in the HL group and 57 (54.8%) were in the LL group; however, there was no significant difference between the 2 groups. The most common complication was ileus (HL group [4.9%] vs. LL group [6.6%]), followed by anastomotic leakage (HL group [4.5%] vs. LL group [4.3%]) and urinary retention (HL group [3.7%] vs. LL group [3.0%]). There were no significant differences in ileus, anastomotic leakage, or urinary retention between the 2 groups. Ischemic colitis occurred in 3 patients in the HL group and 1 in the LL group; however, there was no significant difference between the 2 groups. Postoperative bleeding occurred in 1 patient (intra-abdominal bleeding) in the HL group and 5 (anastomotic site bleeding in 3 and intraabdominal bleeding in 2) in the LL group; however, there was no significant difference between the 2 groups (Table 3).

Table 3.

Postoperative complications (n=545)

Recurrence pattern of patients

Recurrence occurred in 83 of the 545 patients (15.2%), of which 35 (14.3%) were in the HL group, and 48 (15.9%) were in the LL group. Local recurrence occurred in 11 of the 545 patients (2.6%; HL group, 3 patients [1.2%]; LL group, 11 patients [3.6%]), and systemic recurrence occurred in 69 patients (12.7%; HL group, 33 patients [12.5%]; LL group, 36 patients [11.9%]). The most frequent site of local recurrence was the lateral side (HL group, 2 patients [0.8%]; LL group, 6 patients [2.0%]), and the most frequent site of systemic recurrence was the lungs (HL group, 24 patients [9.8%]; LL group, 24 patients [8.0%]). There were no significant differences in the recurrence patterns between the 2 groups (Table 4).

Table 4.

Recurrence patterns of patients (n=545)

Functional outcomes

Functional outcomes were analyzed for patients who responded to the preoperative questionnaire; 331 of the 545 patients responded to the FISI and IPSS questionnaires preoperatively, and 73 responded to the IIEF-5 questionnaire preoperatively. The number of patients who responded at all 4 time points approximately 36 months postoperatively was 233, 269, and 10 for the FISI, IPSS, and IIEF-5 questionnaires, respectively. There were no differences in the pattern of change in scores over time for FISI score, IPSS, and IIEF-5 score between the 2 groups; however, when comparing the changes in scores preoperatively and 12 months postoperatively between the 2 groups, there was only a significant difference in the FISI score (0 [range, –31 to 45] vs. 0 [range, –16 to 45], P=0.023) (Table 5). We analyzed changes in defecatory and urogenital functions at each point (Fig. 3).

Table 5.

Comparison of differences in the functional outcomes (n=545)

Fig. 3.

Changes in the functional outcomes of high ligation (HL) and low ligation (LL) groups. (A) Fecal Incontinence Severity Index (FISI) scores in time flow. (B) International Prostate Symptom Score (IPSS) in time flow. (C) International Index of Erectile Function (IIEF-5) scores in time flow.

DISCUSSION

This study suggested no significant differences in oncological outcomes, including OS and RFS, between the HL and LL groups. In addition, there were no differences in postoperative complications, such as anastomotic leakage and recurrence patterns, between the 2 groups. Regarding functional outcomes, it was possible to confirm the pattern of change postoperatively; however, no significant difference was observed between the 2 groups. Notably, the LL group showed a more significant recovery of defecatory function than the HL group approximately 12 months postoperatively.

Furthermore, several studies have reported more harvested LNs in the HL group [22, 24]. The present study also showed significantly more harvested LNs in the HL group than in the LL group; however, no significant difference in the number of harvested LNs (≥12) was observed between the 2 groups. Considering the variables affecting survival revealed by univariate analysis, it was confirmed that ≥12 harvested LNs did not affect survival. Therefore, although there may be differences in the number of harvested LNs, depending on the IMA ligation level, this does not seem to affect the oncological outcome. The length of the PRM was longer in the HL group, and splenic flexure mobilization was performed more frequently in the HL group. This is because HL is more capable of complete mobilization of the proximal colonic limb than LL; therefore, it can be interpreted that sufficient PRM was secured by additionally performing splenic flexure mobilization while selectively performing HL in patients with short proximal colonic limbs. Conversely, the shorter DRM length in the HL group could be attributed to selection bias, in which surgeons tend to opt for HL in patients with large sized tumors or lower tumor locations.

Furthermore, several studies have compared the oncological outcomes of the 2 ligation methods for rectal cancer. Slanetz and Grimson [12] and Singh et al. [13] reported that HL had tumor stage-specific benefits over LL. According to a study by Slanetz and Grimson [12] in 1997, the 5-year survival rate was higher in the HL group according to Duke’s classification B and C of rectal cancer patients (Duke’s B: HL [83.9%] vs. LL [73.9%], P<0.01; Duke’s C: HL [52.9%] vs. LL [42.5%], P<0.05), and Singh et al. [13] reported in 2017 that HL had more significant benefits than LL in terms of OS in the IMA positive LNs group (HR, 0.77; 95% CI, 0.66–0.89). However, several recent studies have reported no difference in survival rate according to the ligation level when performing LL with LN dissection around the IMA root [15, 16, 24, 26–28]. As a theoretical concept, HL had a better oncological outcome than LL while dissecting the mesentery from the root of the IMA; however, LL, which preserved the left colic artery while dissecting the LN around the root of the IMA, did not have a worse oncological outcome than HL, which is consistent with the present study.

Anastomotic leakage is one of the most important complications after rectal cancer surgery. The incidence of anastomotic leakage after rectal cancer surgery is 6.0% to 17.0% [29]. According to the studies by Hinoi et al. [30] and Chen et al. [31], IMA ligation level can act as a risk factor for the occurrence of anastomotic leakage, and this may be associated with the reduction in blood flow supplied to the anastomotic site according to the preservation of the left colic artery. According to Seike et al. [8], who studied the change in blood flow according to the IMA ligation level using laser Doppler, the HL and LL groups demonstrated a decrease in blood flow of 38.5%±1.8% and 16.4%±1.8%, respectively. In particular, older male patients showed >50% reduction in blood flow. This result supports the role of blood supply in the anastomotic leakage rate. A randomized controlled trial was conducted in 2018 by Fujii et al. [20] to investigate the difference in the rate of anastomotic leakage according to IMA ligation. However, there was no significant difference in the anastomotic leakage rate according to the IMA ligation level. These results are consistent with those of several other recent retrospective studies. Consistent with previous studies, the present study found no difference in anastomotic leakage according to the IMA ligation level.

Furthermore, several randomized clinical trials have been conducted regarding functional outcomes. In 2015, Matsuda et al. [32] conducted a randomized clinical trial comparing defecatory function according to the IMA ligation level and reported no significant differences in the self-assessment of defecation, the Fecal Incontinence Quality of Life (FIQL) scale, and Wexner incontinence score. However, FIQL and Wexner scores improved at 1 year than at 3 months in the LL group. A recent retrospective study by Fiori et al. [33] reported that defecatory function was more preserved in the LL group than in the HL group and also showed that the FISI score improved significantly at 1 year compared with 3 months in the LL group than in the HL group. As shown in Fig. 3A, both groups showed deterioration in defecatory function as the FISI score increased until 3 months postoperatively; however, after 3 months, the FISI score gradually decreased, and the groups showed improvement in defecatory function. At 1 year postoperatively, the FISI score was lower in the LL group than in the HL group, with a statistically significant difference between the 2 groups (P<0.023). This indicates that the recovery of defecatory function was better in the LL group than in the HL group 1 year postoperatively. Furthermore, several studies have been conducted to determine whether LL is better for defecatory function than HL; however, it seems necessary to pay attention to the study conducted by Koda et al. [9] in 2005, in which the longer the proximal colonic limb was denervated in the HL group, the more often spastic waves occurred. These spastic waves were associated with defecatory dysfunction (urgency, multiple evacuations, and major soiling). This result supports that defecatory function recovery was better in the LL group than in the HL group. Regarding urinary and sexual functions, a randomized controlled trial by Mari et al. [34] reported that urinary and sexual functions were better preserved in the LL group. However, in the present study, there was no significant difference in urinary and sexual functions between the 2 IMA ligation levels. According to a report by Heald and Ryall [35] and Havenga et al. [36], damage to the inferior hypogastric plexus and nerve must be minimized to preserve urinary and sexual functions, which is important in performing an accurate TME. There may be a correlation with damage to the superior hypogastric plexus passing around the IMA root when LNs are dissected around the IMA root; however, Nano et al. [37] demonstrated the safety of ligation around the IMA root by showing the running position of the autonomic nerve passing around the IMA root using a cadaveric study. Therefore, preserving urinary and sexual functions seems important in performing an accurate TME rather than the IMA ligation level.

This study had some limitations. First, it was a retrospective study conducted at a single institution, which may have caused an inherent potential for bias. A selection bias caused differences in tumor size, length of PRM, DRM, and splenic flexure mobilization between the 2 groups; therefore, we used multivariate analysis to evaluate the factors affecting oncological outcomes. However, these variables did not affect oncological outcomes. Additionally, it should be noted that data for classifying complications using the Clavien-Dindo classification or evaluating defecatory function with the low anterior syndrome score were not obtainable and therefore could not be included in this study. Second, the only method used for evaluating urinary function in female patients in this study was via the IPSS questionnaire. While the International Consultation on Incontinence Questionnaire (ICIQ) is generally considered a more appropriate tool for assessing urinary function in female patients, in this study, both male and female patients were evaluated using the IPSS. Third, a small sample size was used for analyzing functional outcomes. In particular, only 73 of the 545 patients participated in the evaluation of sexual function, and only 10 responded to the questionnaire at 36 months. Therefore, the data were insufficient to detect differences in sexual function between the 2 groups. However, postoperative changes in defecatory and urogenital functions were observed over time, and significant changes in defecatory function were observed in the LL group.

In conclusion, our study suggested that LL with LN dissection around the root of the IMA might not affect the oncologic outcomes compared to HL; however, it probably possesses minimal benefits for functional outcomes such as defecatory function. Therefore, well-designed randomized controlled trials are warranted to provide definite evidence for the benefits of LL.

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