Abstract
Background/Aim: This study aimed to evaluate the clinical impact of the level of inferior mesenteric artery (IMA) ligation in patients with advanced low rectal cancer. Patients and Methods: All enrolled patients (n=350) underwent curative resection of rectal cancer with D3 lymph node dissection, with either IMA (high-tie) or superior rectal artery (SRA) (low-tie) ligation. Results: There were 27 and 65 patients in the high-tie and low-tie groups, respectively. There was no significant difference in the postoperative complication rate. Postoperative anastomotic leakage developed in five patients in the low-tie group and none in the high-tie group. The overall recurrence rates were 37.0% (n=10) and 40.0% (n=26) in the high-tie and low-tie groups, respectively, with no significant difference between the two groups (p=0.748). Local recurrences and lymph node metastases developed in five and no patients in the high-tie group and in 13 and one patient in the low-tie group, respectively. In the multivariate analysis, pathological T4 and pathological N2 and N3 were independent poor prognostic factors for overall survival (OS), whereas left colic artery (LCA) preservation was not significant. Conclusion: No significant difference in oncological outcomes was observed in advanced low rectal cancer surgery with respect to the level of the IMA ligation. Thus, the less complicated high-tie procedure should be adopted as a standard procedure.
In Japan, the morbidity of colorectal cancer (CRC) has increased sharply in the last 20 years, and the resulting mortality is the second highest, after lung cancer patients. Patients with rectal cancer have a slightly worse prognosis than those with CRC (1), and the importance of multimodal therapy, such as total neoadjuvant therapy (TNT), has been shown (2). Moreover, many surgeons believe that surgical treatment plays a pivotal role in improving the prognosis of patients with CRC.
In 1908, W.E. Miles reported an abdominoperineal resection procedure for rectal cancer (3), which incorporated the removal of lymphatic tissue. His study indicated complete eradication of the zone of ‘upward spread of cancer’ from the rectum, thereby diminishing the chance of disease recurrence. Around the same time, Moynihan proposed that when performing curative resection for rectal cancer (4), the inferior mesenteric artery (IMA), including the apical group of lymph nodes within the resection, should be resected at its origin. These were the pioneering studies that reported that lymph node dissection is a key factor in rectal cancer surgery and this principle is regarded as one of the most indispensable procedures.
Lymph node metastasis is a major prognostic factor for survival after surgery for rectal cancer. Guidelines by the Japanese Society for Cancer of the Colon and Rectum for the treatment of CRC recommend that proximal lymph node dissection should be performed, including the region around the root of the IMA, for advanced rectal cancer (clinical T2 or more) (1). Several studies have reported that positive lymph node metastasis at the root of the IMA in rectal cancer is relatively low (5-7), approximately 1%. However, Huh et al. found that the frequency of lymph node metastasis at the root of the IMA in sigmoid colon cancer and rectal cancer was 7.8% (8), which is not considered negligible as compared to the rate of lymph node metastasis.
Proximal spread along the superior rectal artery (SRA) is considered the principal route of lymphatic metastasis in rectal cancer, and the need to perform sufficient proximal lymph node dissection according to each clinical finding has been shown in several previous reports (6, 9, 10). Proximal lymph node dissection for rectal cancer is achieved with either IMA or SRA ligation (high-tie or low-tie), and the favorable outcomes of each technique have long been debated (11-14). Although various reports have evaluated the effects of the level of arterial ligation in rectal cancer on blood flow of anastomosis, autonomic nerve injury, reduction of the risk of anastomotic leakage, securing the bowel length, oncological outcomes, etc., it remains controversial whether the high-tie or low-tie procedure is more beneficial.
Especially in low rectal cancer surgery, all surgeons are anxious about the tension and blood flow supply at the anastomotic site, which is thought to be involved in anastomotic failure, as much as they are concerned about curability. Reducing postoperative complications and preserving anorectal function is important, but the most important task for any surgeon is to determine whether the surgical procedure can be safely completed without compromising the long-term outcomes. In the present study, we retrospectively evaluated the clinical impact of the level of the IMA ligation in patients with advanced low rectal cancer.
Patients and Methods
Patients and design. From January 2006 to April 2015, 350 consecutive patients with rectal cancer underwent surgical resection, and 191 patients were diagnosed with low rectal cancer, at the Department of Gastroenterological Surgery of the National Kyushu Cancer Center. Low rectal cancer was defined when the lower border of the tumor was located distal to the peritoneal reflection by colonoscopy and computed tomography. The exclusion criteria were as follows: (i) pathological Tis/T1 and node negative (n=51), (ii) synchronous distant metastasis (n=21), (iii) active or recent treatment for malignancy in another organ (n=19), (iv) histological types other than adenocarcinoma (n=2), and (v) lost perioperative data (n=6). A total of 92 advanced low rectal cancer patients were eligible for this retrospective study. After surgery, patients were followed up every 3 months for the first 3 years and every 6 months thereafter, according to the surveillance of Japanese guidelines (1). Informed consent was obtained from each patient before the operation, and their medical records were retrospectively reviewed. All procedures performed in this study involving human participants were in accordance with the ethical standards of the National Kyushu Cancer Center Institutional Review Board and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Surgery and assessment parameters. All patients enrolled in this study underwent curative resection of rectal cancer with D3 lymph node dissection, and IMA ligation (high-tie) and SRA ligation (low-tie) were selected according to each surgeon’s plan. In case of high-tie patients, the IMA was divided at its origin from the abdominal aorta (Figure 1A). In case of low-tie patients, the IMA was divided immediately after branching to the left colic artery (LCA), and lymph node dissection around the root of the IMA was performed (Figure 1B). To elucidate the clinical impact of IMA level in advanced low rectal cancer, we performed retrospective analyses evaluating patient demographics, clinicopathological data, operative information, short-term outcomes, and long-term outcomes. We focused on the following information: age, sex, body mass index (BMI), preoperative serum carcinoembryonic antigen (CEA) levels, preoperative serum albumin levels, surgical approach, type of resection, duration of surgery, estimated blood loss, pathological findings, postoperative complications defined as Clavien-Dindo classification (15), recurrence-free survival (RFS) rate, and overall survival (OS) rate. Furthermore, a postoperative complication was defined as an occurrence within 30 postoperative days. Anastomotic leakage was confirmed in the case of any feculent discharge from the drain at any time after surgery, any collection of purulent material in the pelvis by CT scan.
The inferior mesenteric artery (IMA) was divided at its origin from the abdominal aorta with D3 lymph node dissection (high-tie, A). The IMA was divided immediately after branching to the left colic artery (LCA) with D3 lymph node dissection (low-tie, B). Ao: Abdominal aorta; SRA: superior rectal artery; SA: sigmoid artery.
Statistical analysis. All statistical analyses were performed using IBM SPSS Statistics version 28 (Chicago, IL, USA). Patient demographics, clinicopathological data, and operative information were evaluated using the chi-square test and Fisher’s exact test, as appropriate. Cumulative survival rates were calculated using the Kaplan–Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model to assess associations between the level of IMA ligation and RFS/OS rate. All variables that were significantly associated in the univariate analysis were included in the multivariate analysis. All tests were two-sided, and statistical significance was set at p<0.05.
Results
A flow chart of all patients enrolled in the analyses is shown in Figure 2. The 92 patients undergoing curative resection were enrolled. There were 27 patients in the high-tie group and 65 patients in the low-tie group. Patient demographics, clinicopathological data, and operative information for both groups are shown in Table I. Serum albumin levels were significantly lower in the high-tie group (p=0.020), and there were also significant differences in the surgical approach and type of resection between the groups (p=0.014). Nine patients underwent neoadjuvant therapy. Seven patients received chemoradiotherapy and two patients received chemotherapy only. No patients received TNT. Patients who received chemoradiation were treated with 45 Gy in 25 fractions, and S-1 was administered. Patients who received chemotherapy alone received the FOLFOX regimen for 2-4 months.
Flow chart of patient selection. LCA: Left colic artery.
Patient demographics, clinicopathological data, and operative information.
Pathological findings showed that the number of lymph nodes harvested was significantly higher and the number of patients with lymphatic invasion was significantly lower in the high-tie group. However, there was no significant difference in the final pathological stage between the two groups. The number of patients with pathological stage III low rectal cancer was 21 (77.8%) in the high-tie group and 50 (76.9%) in the low-tie group.
Postoperative complications and recurrence. There was no significant difference in the postoperative complication rate, and postoperative anastomotic leakage developed in five patients in the low-tie group and none in the high-tie group (p=0.138). However, anastomosis was performed in five patients in the high-tie group and 46 patients in the low-tie group, and diverting ileostomy was performed in five patients (100%) and 37 patients (80.4%), respectively. However, there were no significant differences in surgical site infection (22.2% vs. 21.5%, p=0.942), bowel obstruction (7.4% vs. 3.1%, p=0.354), or urinary dysfunction (11.1% vs. 18.5%, p=0.385) between the two groups.
The overall recurrence rate was 37.0% (n=10) in the high-tie group and 40.0% (n=26) in the low-tie group, with no significant difference between the two groups (p=0.748). Local recurrences and lymph node metastases developed in five and no patients in the high-tie group and in 13 and one patient in the low-tie group, respectively. There was no significant difference in the follow-up period between the two groups (Table II).
Postoperative complications.
Prognostic factors for low rectal cancer. Univariate and multivariate analyses of prognostic factors for RFS and OS in patients with low rectal cancer are shown in Table III and Table IV, respectively. Univariate analyses showed that pathological N2, N3 (p<0.001) was the only significant association with poorer RFS after curative surgery, and open surgery (p=0.025), estimated blood loss ≥200 (p=0.029), pathological T4 (p=0.003), pathological N2, N3 (p=0.009), and presence of lymphatic invasion (p=0.009) were significantly associated with poorer OS after curative surgery.
Risk factors associated with recurrence-free survival.
Risk factors associated with overall survival.
In the multivariate Cox proportional hazards analysis, only two factors, pathological T4 and pathological N2 and N3, were independent poor prognostic factors for OS, whereas LCA preservation, CEA≥5, operative procedure, postoperative complication grading, lymphatic invasion, and venous invasion were not significant.
Long-term outcomes according to the level of IMA ligation. On Kaplan–Meier analysis, the 5-year RFS rates for the high-tie and low-tie groups were 50.7% and 56.3%, respectively, with no statistically significant difference between the two groups (p=0.985) (Figure 3A). In contrast, the 5-year OS rates for the high-tie and low-tie groups were 78.2% and 68.0%, respectively. Although there was no statistically significant difference with respect to the level of IMA ligation (p=0.249), the high-tie group had prolonged OS by approximately 10% (Figure 3B). Moreover, when restricted to node-positive patients only, the high-tie group had an approximately 13% improved 5-year OS rate compared to the low-tie group (76.9% vs. 63.8%, p=0.265), although no significant difference was observed.
Kaplan–Meier survival analysis comparing high-tie (solid line) and low-tie (dashed line) in respect to recurrence-free survival (A) and overall survival (B).
Discussion
In rectal cancer surgery, every surgeon is sufficiently concerned about perioperative complications such as anastomotic blood supply, anastomotic tension, preservation of the autonomic nervous system, as well as oncological outcomes. Notably, the clinical impact with respect to the level of IMA ligation has been previously considered, but there seems to be a lack of a clinical consensus. Although several studies have focused on the level of ligation of the IMA in rectal cancer surgery, the details of the clinical outcomes of IMA ligation level limited to advanced low rectal cancer have not been described in the literature to date. Therefore, we focused on the clinical and oncological impact of IMA ligation in advanced low rectal cancer.
Hinoi et al. (16) retrospectively evaluated the clinical significance of LCA preservation in middle and low rectal cancer surgery at the Japan Society of Laparoscopic Colorectal Surgery. Although this study was a retrospective study, a multicenter study across Japan showed that preservation of the LCA in laparoscopic anterior resection for middle and low rectal cancers was associated with a lower anastomotic leakage rate. There was no significant difference in survival rates between the two groups with radical resection. In contrast, a Japanese single-center randomized control trial showed that LCA preservation in rectal cancer surgery was not associated with anastomotic leakage, and there was no significant difference in long-term outcomes (17). Therefore, they concluded that it is better to treat high-tie as a standard procedure than technically complex low-tie with dissection around the root of the IMA.
We believe that the IMA ligation (high-tie) is technically easier to perform than the SRA ligation (low-tie) using the avascular windows superior and inferior to the IMA and inferior mesenteric vein. The low-tie with D3 lymph node dissection is a complicated procedure, whether open or laparoscopic, because lymph nodes at the root of the IMA must be dissected en-bloc.
Another consideration in regards to high versus low tie is genitourinary dysfunction. In the HIGHLOW trial, in which genitourinary dysfunction due to the level of IMA ligation was evaluated as the primary outcome, it was shown that the low-tie group had better genitourinary function preservation (13). Mari et al. suggested that arterial ligation far from the hypogastric plexus could help preserve pelvic autonomic functions, resulting in a better quality of life of patients. Other studies also showed that low-tie may provide improved blood supply to the proximal end of the anastomosis and reduce the risk of autonomic nerve injury (18, 19). In our study, genitourinary dysfunction was not significantly observed in the high-tie group. We believe that visualization of the nervous system, including the lumbar splanchnic nerve, leads to the preservation of genitourinary function.
In a recent meta-analysis (20), no difference was found between the high-tie and low-tie of the IMA in rectal cancer surgery in terms of lymph node yield and postoperative morbidity and mortality outcomes. These analyses indicate that long-term survival outcomes are under investigation and depend on future randomized trials. To the best of our knowledge, there are no reports of improved oncologic prognosis with low-tie as compared to high-tie in rectal cancer surgery.
The data collected in this study show a statistically significant difference between serum albumin and surgical approach, which likely influenced the level of IMA ligation. This decision is left to the discretion of each surgeon. Importantly, there was no statistically significant difference in postoperative complications between LCA ligation levels in advanced low rectal cancer surgery. However, the number of patients requiring anastomosis in the high-tie and low-tie groups was five (18.5%) and 46 (70.8%), respectively, and diverting ileostomy was performed in 100% and 80.4% of the patients, respectively. Thus, it can be considered that sufficient comparative results of the anastomotic leakage rate have not been analyzed. However, major complications other than suture failure were not significantly different between the two groups. In particular, urinary dysfunction occurred in 5% and 7% of patients in the high-tie and low-tie groups, respectively, and the surgical procedure of lymph node dissection around the root of the IMA did not adversely affect autonomic nervous system preservation. In contrast, the local recurrence rates were 18.5% and 20.0% for the high-tie and low-tie groups, respectively, with no significant difference. Regarding long-term outcomes, our findings underscore the fact that the level of IMA ligation is not a predictor for recurrence and survival, and no significant difference was observed between the two groups in both 5-year RFS and OS rates.
In 2000, the National Cancer Institute sponsored a panel of experts to systematically review the current literature and to draft guidelines that provide uniform definitions, principles, and practices. They showed that although the level of evidence is weak, the recommended level of proximal vascular ligation for rectal cancer is at the origin of the SMA. This recommendation is based on the same data used to indicate primary feeding vessel ligation for colon cancer (21). In addition, several previous studies have recommended low-tie in terms of blood flow to the anastomotic site and autonomic nerve injury (14, 22). In Japan, exploratory analyses using data from JCOG0404 (23) investigated the clinical impact with respect to the level of ligation of the IMA. Akagi et al. showed that oncological outcomes were better in D3 dissection with LCA preservation than in D3 dissection without LCA preservation, although this study targeted patients with stage II-III sigmoid and rectosigmoid colon cancer (24). Nevertheless, a previous study has advocated the principal concept that the tumor-bearing specimen should be harvested as an enveloped package to minimize the risk of tumor cell spillage and local recurrence (25). Culligan et al. indicated that inadequate resection of the mesocolon is associated with adverse outcomes in colon cancer (26). In CRC surgery, it is considered desirable to perform lymph node dissection according to the staging while maintaining the integrity of the mesenteric lymphatic package (27, 28). Therefore, a low-tie with lymph node dissection around the root of the IMA for advanced low rectal cancer may be associated with the risk of tumor cell spillage and local recurrence. Although our study did not reveal a significant difference, we believe that the ligation of the root of the IMA may improve long-term oncological outcomes in curative resection of stage II-III rectal cancer.
This study has several limitations. First, this study was a retrospective evaluation with a small number of patients analyzed at a single center. Therefore, the preference for surgical techniques may have affected the oncological outcomes. Second, there is a possibility of selection bias due to differences in the patients who underwent preoperative and postoperative treatments. However, these perioperative treatments were not identified as prognostic factors in the multivariate analyses. Finally, although lymph node dissection of the root of the IMA was performed in every patient, the surgeon decided whether to preserve the LCA or not. Each surgeon may decide whether or not to preserve the LCA by preoperative diagnosis.
In conclusion, the present study showed no significant difference in oncological outcomes in advanced low rectal cancer surgery with the respect to the level of IMA ligation. We believe that the high-tie procedure should be adopted as a standard procedure in advanced low rectal cancer rather than the low-tie procedure, which is a technically complicated procedure. Especially for patients strongly suspected of having regional lymph node metastasis, we believe that the high-tie procedure may provide better long-term oncological outcomes. The necessity for a randomized trial is mandatory to assess oncological outcomes with respect to the level of IMA ligation in low anterior resection and intersphincteric resection for advanced low rectal cancer.
Acknowledgements
The Authors would like to thank Editage (www.editage.com) for English language editing.
Footnotes
Authors’ Contributions
D.Y. and M.S. contributed to the conception and design of the study, data collection, data analysis, and manuscript writing. K.N., T.O., T.H., S.K., T.M., M.Y., and M.M. provided critical revisions that were important for the intellectual content. H.K., Y.T., and T.Y. approved the final version of the manuscript.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
- Received April 17, 2023.
- Revision received May 6, 2023.
- Accepted May 8, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
