Does the level of inferior mesenteric artery ligation affect short-term and long-term outcomes of patients with sigmoid colon cancer or rectal cancer-a single-center retrospective study?

DOI: https://doi.org/10.21203/rs.3.rs-1692435/v1

Abstract

Background: For patients with sigmoid colon cancer or rectal cancer, a definite consensus in terms of the optimal level ligating the inferior mesenteric artery (IMA) has not been reached. We performed this retrospective study to determine whether the ligation level significantly affected short-term and long-term outcomes of patients with sigmoid colon cancer or rectal cancer after curative laparoscopic surgery.

Methods: Medical records of patients with sigmoid colon cancer or rectal cancer who had undergone curative laparoscopic surgery (High tie or low tie of IMA) at The Department of Gastrointestinal Surgery, Guangdong Provincial Hospital of Traditional Chinese Medicine were reviewed. Then hie tie group (HTG) was compared with low tie group (LTG) in terms of short-term and long-term outcomes.

Results: Between January 2008 and December 2014, a total of 590 patients with sigmoid colon cancer or rectal cancer underwent curative laparoscopic surgery at our center. No significance between two groups regarding baseline characteristics. Patients in the HTG had a significantly higher risk of anastomotic fistula than LTG (21/283 VS 11/307, P=0.040). However, two groups were not significantly different from each other regarding operative time (P=0.075), blood transfusion (P=1.000), estimated blood loss (P=0.239), 30-day mortality (P=1.000), ICU stay (P=0.674), postoperative hospital stay(days) (P=0.636), bowel obstruction (P=0.659), ileus (P=0.637), urinary dysfunction (P=1.000), surgical site infection (SSI) (P=0.121), number of retrieved lymph nodes (P=0.501) and number of metastatic lymph nodes (P=0.131). Subsequently, it was revealed that level of IMA ligation did not significantly influence overall survival (P=0.474) and relapse-free survival (P=0.722). Additionally, it was revealed that ligation level did not significantly affect overall survival (OS) (P=0.460) and relapse-free survival (RFS) (P=0.979) of patients with stage I cancer, which was observed among patients with stage II or stage III cancer. Ultimately, ligation level was not an independent predictive factor for either OS or RFS.

Conclusions: HT resulted in a significantly higher incidence of anastomotic fistula. Level of IMA ligation did not significantly affect long-term outcomes of patients with sigmoid colon cancer or rectal cancer after curative laparoscopic surgery. 

Background

Colorectal cancer (CRC) is the third most common cancer and causes the second most cancer-related deaths[1, 2]. Of all the colorectal cancers, rectal cancer and sigmoid colon cancer are the most common[3]. Curative surgery remains cornerstone of treating rectal cancer and sigmoid colon cancer. In 1908, Miles for the first time introduced the concept of en bloc removal of cancerous tissues and drainage lymph node systems[4]. Miles suggested that inferior mesenteric artery (IMA) should be dissected to the distal part of the branch of the left colic artery, which was referred to as a low tie (LT) procedure for ligating IMA[4]. In the same year, another surgeon, Moynihan advocated that IMA should be dissected until its origin from the abdominal aorta had been exposed as well as dissection of apical lymph nodes[5]. This technique described by Moynihan was described as a high tie (HT) procedure for ligating IMA[5].

HT ligation of IMA has been advocated for curative resection and precise pathological staging[68]. Recently, LT has been recommended considering the fact that some studies report that HT and LT are not significantly different from each other in terms of long-term survival[911]. Additionally, in some other studies, LT has been proposed due to the decreased blood flow to the proximal colon after HT[1215]. Similarly, the American Society of Colon and Rectal Surgeons has proposed LT in the textbook of Colon and Rectal Surgery considering the decreased blood supply in the proximal colon observed after HT. Moreover, in the textbook of Colon and Rectal Surgery, it was recommended that HT should be performed among patients who were suspected to have involved lymph nodes around IMA or situations where extra vascular dissection was needed to obtain additional proximal colon to avoid excessive tension of anastomosis[16]. According to Japanese guidelines on colorectal cancer, for patients with T2 or more advanced disease, lymph node dissection around IMA should be performed[17]. However, not any studies reporting the most appropriate level at which IMA should be ligated have been published. And several reviews have reported that LT and HT are not significantly different from each other in terms of short-term and long-term outcomes and in these studies, large-scaled randomized controlled trials are suggested[1820]. Therefore, the clinical problem whether preserving blood supply to proximal colon by low tie technique would decrease incidence of anastomotic fistula remains to be solved. Furthermore, effects of level of IMA,s being ligated on other short-term results and overall survival and recurrence-free survival should also be evaluated. Thus, we performed the present study to evaluate whether level of IMA ligation would significantly affect short-term and long-term outcomes of patients with rectal cancer or sigmoid colon cancer.

Methods

Patients

Medical records of patients with rectal cancer or sigmoid cancer who had undergone curative laparoscopic surgery between January 2008 and December 2014 at The Department of Gastrointestinal Surgery, Guangdong Provincial Hospital of Traditional Chinese Medicine were retrospectively reviewed. The following clinicopathological variables were retrieved from their medical records: demographic variables, surgery-related variables, pathological variables, postoperative complications,  adjuvant chemotherapy, and follow-up variables. 

Inclusion criteria were as follows: 20 years or older, pathologically confirmed adenocarcinoma of rectum or sigmoid colon, no distant metastasis, elective procedure, no history of abdominal surgery, and providing written informed consent. Clinical TNM staging was identified by combining results of colonoscopy, enhanced CT (thoracic, abdominal and pelvic) and/or magnetic resonance imaging (MRI). 

Exclusion criteria included the following: synchronous or metachronous malignant tumors of other organs, multiple colorectal cancer in other segments of large bowel, acute intestinal obstruction or perforation caused by rectal cancer or sigmoid cancer, pregnant patients and patients lost during early follow-up. General conditions of all the patients were evaluated preoperatively by an experienced anesthesiologist from our center. Abdominoperineal resection, rectal intersphincteric resection and Hartmann,s operation were excluded from this study. This study was approved by The Ethical Committee of Guangdong Provincial Hospital of Traditional Chinese Medicine. All the patients had given his or her written informed consent. Declaration of Helsinki was adhered to during the whole process of this study[21].

Procedure

Surgeries were accomplished byadvanced general surgeons specialized in colorectal cancer surgery. All the surgeons accomplishing these surgeries had at least 10 years of clinical experience in tertiary hospitals. All the surgeries were performed according to Chinese guidelines on colorectal cancer[22, 23]. 

Previously, for patients with a giant tumor (6 cm or larger), conventional open surgery was preferred. However, in our study, all the patients underwent laparoscopic surgeries. All the laparoscopic surgeries were accomplished in a medial-to-lateral way. Firstly, we dissected lymph nodes around IMA and performed a retroperitoneal dissection. In the HT group, the IMA was divided and ligated at its origin from the abdominal aorta while for patients in the LT group, IMA was divided at the level of LCA branching and a simultaneous lymph node dissection around IMA was performed. Secondly, the left colon was mobilized. Thirdly, we cut the distal rectum using a linear stapler after irrigating the rectum. Fourthly, the removed specimen was taken out via a small incision after the proximal colon was cut approximately 10 cm from the cancer. The proximal margin was at least 10 cm while a distal margin of 3 cm was needed for cancer of the upper rectum and 2 cm for cancer of the lower rectum. The upper part of rectum was divided from the lower part of rectum by the peritoneal reflexion. Blood flow to the proximal colon stump in both arms was evaluated by performing a hemorrhage test of the marginal artery. Presence of palmic hemorrhage was indicative of sufficient blood supply. Resection of the proximal colon was not performed until confirmation of sufficient bleeding. Anvil of circular stapler was installed and fixed to the stump of the proximal colon. After the pneumoperitoneum was re-established, a pelvic sidewall lymphadenectomy was performed among patients with clinical T3 or deeper cancers with involvement of drainage lymph nodes identified by preoperative imaging examination. Finally, a double stapling technique was adopted to perform reconstruction. All the anastomotic reconstructions were accomplished in a straight fashion. After accomplishing reconstructions, we performed air leak tests to detect imperfections. Proximal colon of the anastomosis is closed using forceps after the circular stapler was fired. A small quantity of saline was put into the pelvic cavity and appearance of a bubble around the anastomosis was tested by pumping in air from the anus. If a bubble was detected, the anastomosis would be reinforced by the suture. 

  Surgeons in charge would decide whether a diverting stoma should be constructed among patients with a narrow male pelvic, positive result of air leak test, and an anastomotic level lower than 5cm from the anal verge. If a diverting stoma was not constructed, an intraluminal drainage tube would be inserted to decrease pressure within the anastomosis. 

Adjuvant therapy

All patients with stage III cancer and II cancer with some high risk factors (such as microvascular invasion and nerve invasion) were recommended by surgeons in charge to receive postoperative adjuvant chemotherapy and patients who had given written informed consent subsequently underwent adjuvant chemotherapy. For stage III cancer, the regimen including oral fluoropyrimidine and oxaliplatin was preferred while oral fluoropyrimidine was recommended for stage II cancer. Neither preoperative nor postoperative radiotherapy was not routinely applied.

Follow-up 

Unless otherwise contraindicated, all the patients were instructed to attend a recommended follow-up. The follow-up plan was made according to the Chinese guideline on CRC[21, 22]. For stage I CRC, the follow-up took place every six months for 5 years. While for stage II and III CRC, the follow-up took place every three months for the first three years then every six months for two more years. Five years after surgery, for stage II and III CRC, follow-up took place every one year for five years. The following aspects were included in follow-up regimens: physical examination, carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA-199), liver ultrasonography examination (stage I and II), contrast-enhanced CT (every one year, for colon cancer) or MRI (for rectal cancer, every one year), and colonoscopy (every one year for three years). Recurrence was confirmed by combining medical history, physical examination, CT or MRI examination, and histopathological examination was the ultimate diagnostic criterion whenever possible. Positron emission tomography-computed tomography (PET-CT) would be performed if recurrence was suspected but not confirmed by other examinations. 

Assessment parameters

Preoperative parameters included the following ones:sex, age, body mass index (BMI), previous surgery history (mainly abdominal surgery) and concomitant disease (such as hypertension and diabetes mellitus). Operation-related parameters included the following aspects: date of operation, operation time, estimated blood loss (EBL), level of IMA ligation and blood transfusion. And parameters assessing cancer characteristics: histological component, differentiation, depth of invasion (T stage), lymph node metastasis (N stage) and pTNM stage. The following parameters assessing postoperative outcomes were retrieved: early and late complications, degree of complications, ICU stay, and length of hospital stay after surgery. Complications occurring within 30 days after surgery were defined as early complications while those occurred after 30 days were defined as late complications. Anastomotic fistula was detected by CT examination after finding of purulent discharge through the drainage tube or the presence of peritonitis. Complications were graded according to the Clavien–Dindo classification[24]. Overall survival (OS) was defined as the duration between curative surgery and death while the time length between curative surgery and cancer recurrence was defined as relapse-free survival (RFS). Both OS and RFS were calculated by performing the Kaplan-Meier analysis and corresponding differences betwen LT and HT group were compared using log-rank test. pTNM stages of all the patients were reassessed according to the eighth edition of International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) TNM staging system for colorectal cancer. And for patients with CRC included in this study, at least 12 lymph nodes should be obtained. 

Statistical analysis

Continuous variables were demonstrated as medians while categorical variables were presented as frequencies and percentages. Differences in proportions were evaluated by Chi-square test while significance of differences for continuous variables were assessed by Independent-Samples t test. Kaplan-Meier method was adopted to calculate OS and RFS and corresponding differences betwen LT and HT group were compared using log-rank test. Cox regression analysis (both univariate and multivariate) was performed to identify independent predictive factors for OS and RFS. P values less than 0.05 were recorded as statistically significant. Statistical Product and Service Solutions 22.0 (SPSS22.0, SPSS Inc, Chicago, IL) was used to performed statistical analyses involved in this study. 

Results

Patients and baseline characteristics

Between January 2008 and December 2014, a total of 283 patients with sigmoid or rectal cancer were assigned into the HT group while the LT group included 307 patients. Representative images showing LT and HT were demonstrated in Fig. 1. LT group was compared with the HT group regarding baseline characteristics, results of which revealed that two groups were not significantly different in terms of these baseline characteristics (Table 1). For approximately 40% of the patients in this study, two or more linear stapler cartridges were used to transect the rectum.  

Table 1

Comparisons between LT and HT regarding baseline characteristics

Characteristics

Ligation level

χ2/t

P

 

Low(N = 307)

High (N = 283)

Value

Value

Age

58.47 ± 12.82

57.53 ± 12.36

0.908

0.364

≤ 65y

209

201

0.603

0.437

༞65y

98

82

   

Gender

   

2.976

0.085

Male

175

181

   

Female

132

102

   

Tumor size

   

0.595

0.441

≤ 5cm

218

209

   

༞5cm

89

74

   

Gross morphology

   

0.632

0.729

Mass-forming

97

95

   

Ulcerative

174

160

   

Infiltrative

36

28

   

Differentiation

   

2.430

0.297

Well

18

20

   

Moderate

257

223

   

Poor

32

40

   

Histological component

   

0.825

0.662

Adenocarcinoma

295

268

   

Mucinous carcinoma

11

13

   

Signet-ring cell carcinoma

1

2

   

Vascular invasion

   

0.992

0.319

No

295

267

   

Yes

12

16

   

Nerve invasion

   

0.184

0.668

No

301

276

   

Yes

6

7

   

Depth of invasion

   

6.306

0.098

T1

12

7

   

T2

72

46

   

T3

141

149

   

T4

82

81

   

Lymph node metastasis

   

2.450

0.294

N0

189

159

   

N1

71

81

   

N2

47

43

   

pTNM

   

5.285

0.071

69

43

   

120

116

   

118

124

   

CEA level(µg/L)

   

0.653

0.419

≤ 5

205

180

   

༞5

102

103

   

Chemotherapy

   

2.059

0.151

No

170

140

   

Yes

137

143

   


Short-terms outcomes

Anastomotic fistula

The incidence of anastomotic fistula was 7.42 (21/283) for patients in the HT group while that of the LT group was 3.58% (11/307). The HT group had a significantly higher incidence of anastomotic fistula than the LT group (P = 0.04, Table 2). Among patients in LTG experiencing anastomotic fistula, 7 ones had grade 2 anastomotic fistula, 3 ones grade with 3b anastomotic fistula and 1 one with grade 5 anastomotic fistula (Table 3). Among patients in HTG experiencing anastomotic fistula, 15 ones had grade 2 anastomotic fistula, 5 ones grade with 4 anastomotic fistula and 1 one with grade 5 anastomotic fistula (Table 3) .  

Table 2

Comparisons between LT and HT in terms of short-term outcomes

Characteristics

Low tie(N = 307)

High tie(N = 283)

χ2/t

P

Operation time

214.46 ± 83.90

216.90 ± 78.71

-0.365

0.715

Blood transfusion

3

2

0.000

1.000

Estimated blood loss

159.65 ± 29.65

157.11 ± 22.58

1.179

0.239

30-day mortality

1

0

0.000

1.000

ICU stay

3

1

0.177

0.674

Postoperative hospital stay(days)

11.06 ± 1.84

11.29 ± 1.72

−0.475

0.636

Bowel obstruction

5

6

0.194

0.659

Ileus

3

5

0.223

0.637

Anastomotic fistula

11

21

4.227

0.040

Urinary dysfunction

2

2

0.000

1.000

Surgical site infection

7

13

2.407

0.121

Number of retrieved lymph nodes

20.40 ± 8.32

20.89 ± 9.11

-0.673

0.501

Number of metastatic lymph nodes

1.55 ± 3.29

2.09 ± 5.08

-1.513

0.131

Table 3

Anastomotic fistula

Grade of leakage

Low tie(N = 307)

High tie(N = 283)

Grade 2

7

15

Grade 3a

0

0

Grade 3b

3

0

Grade 4

0

5

Grade 5

1

1

Total

11

21


Other complications and operation-related parameters

Apart from comparing two groups regarding incidence of anastomotic fistula, we also assessed the impacts of ligation level on incidence of other complications, results of which revealed that HT group was not significantly different from the LT group in terms of bowel obstruction (P = 0.659), surgical site infection (P = 0.121), ileus (P = 0.637), and urinary dysfunction (P = 1.000) (Table 2).

Additionally, operation-related parameters of two groups were compared, results of which demonstrated that the HT group was not significantly from the LT group in terms of operation time (216.90 ± 78.71 VS 214.46 ± 83.90, P = 0.715), estimated blood loss (159.65 ± 29.65 VS 157.11 ± 22.58, P = 0.239), blood transfusion (P = 1.000), 30-day mortality (P = 1.000), ICU stay ( P = 0.674), and hospital stays after operation ( 11.06 ± 1.84 VS 11.29 ± 1.72, P = 0.636) (Table 2).

Long-term outcomes

Survival rate

Five-year survival rates of the HT group and the LT group were 74.0% and 76.5%, respectively. And two groups were not significantly different regarding five-year survival rate (P = 0.509). Five-year relapse-free rates of the HT group and the LT group were 70.0% and 70.3%, respectively. And two groups were not significantly different regarding five-year relapse-free rate (P = 0.917). Then we performed Kaplan-Meier analysis to further evaluate the impacts of ligation level on long-term outcomes of patients with rectal or sigmoid cancer, revealing that OS of patients in the HT group was not significantly different from that in the LT group (P = 0.474) and RFS (P = 0.722) of patients in the HT group was not significantly different from that in the LT group (Fig. 2). Similarly, for patients with stage I cancers, ligation level did not significantly affect either OS (P = 0.460) or RFS (P = 0.979) (Fig. 3), which was also demonstrated among patients with stage II (Fig. 3) or stage III cancers (Fig. 3).

Independent predictive factors for OS and RFS identified by Cox regression analysis

In order to further evaluate the impacts of ligation level on OS and RFS of patients with rectal or sigmoid cancer who had undergone curative surgery, we then accomplished both univariate and multivariate Cox regression. Initially, univariate Cox regression was performed to identify variables significantly associated with OS, demonstrating that age (P = 0.007, HR = 1.527, 95%CI: 1.125–2.074), differentiation (P < 0.001, HR = 0.291, 95%CI: 0.211-0.400), histological component (P < 0.001, HR = 2.291, 95%CI: 1.483–3.539), T stage (P < 0.001, HR = 1.581, 95%CI: 1.285–1.946), N stage (P < 0.001, HR = 2.059, 95%CI: 1.718–2.469), pTNM (P < 0.001, HR = 2.126, 95%CI: 1.681–2.688), vascular invasion (P < 0.001, HR = 4.157, 95%CI: 2.603–6.638), nerve invasion (P = 0.002, HR = 3.063, 95%CI: 1.506–6.233) and CEA (P = 0.008, HR = 1.505, 95%CI: 1.112–2.035) were significantly associated with OS (Table 4). Subsequently, those variables significantly associated with OS proven by univariate Cox regression analysis were included in multivariate Cox regression analysis to determine independent predictive factors for OS, revealing that age (P < 0.001, HR = 2.011, 95%CI: 1.464–2.763), differentiation (P < 0.001, HR = 0.436, 95%CI: 0.288–0.662), N stage (P = 0.007, HR = 1.577, 95%CI: 1.133–2.196), TNM stage (P = 0.038, HR = 1.609, 95%CI: 1.344–2.079) and vascular invasion (P = 0.029, HR = 1.832, 95%CI: 1.063–3.159) were independent predictive factors for OS (Table 4).

 
Table 4

Cox proportional-hazard regression for O

Characteristics

Univariate analysis

Multivariate analysis

P

Value

HR

95% CI for Exp(B)

P

Value

HR

95% CI for Exp(B)

Lower

Upper

Lower

Upper






Gender

0.659

1.071

0.791

1.449

       

Age

0.007

1.527

1.125

2.074

0.000

2.011

1.464

2.763

Tumor size

0.265

0.819

0.577

1.163

       

Gross morphology

0.813

1.029

0.811

1.307

       

Differentiation

0.000

0.291

0.211

0.400

0.000

0.436

0.288

0.662

Histological component

0.000

2.291

1.483

3.539

       

T

0.000

1.581

1.285

1.946

       

N

0.000

2.059

1.718

2.469

0.007

1.577

1.133

2.196

pTNM

0.000

2.126

1.681

2.688

0.038

1.609

1.344

2.079

Vascular invasion

0.000

4.157

2.603

6.638

0.029

1.832

1.063

3.159

Nerve invasion

0.002

3.063

1.506

6.233

       

CEA

0.008

1.505

1.112

2.035

       

Ligation level

0.475

1.115

0.827

1.503

       

In a similar way, we then accomplished both univariate and multivariate Cox regression. Initially, univariate Cox regression was performed to identify variables significantly associated with RFS, demonstrating that differentiation (P < 0.001, HR = 0.317, 95%CI: 0.232–0.433), histological component (P = 0.008, HR = 1.849, 95%CI: 1.178–2.901), T stage (P < 0.001, HR = 1.680, 95%CI: 1.371–2.060), N stage (P < 0.001, HR = 2.343, 95%CI: 1.965–2.793), pTNM (P < 0.001, HR = 2.690, 95%CI: 2.102–3.443), vascular invasion (P < 0.001, HR = 4.328, 95%CI: 2.764–6.779), nerve invasion (P < 0.001, HR = 4.146, 95%CI: 2.251–7.636) and CEA (P = 0.034, HR = 1.378, 95%CI:1.025–1.852) were significantly associated with RFS (Table 5). Subsequently, those variables significantly associated with RFS proven by univariate Cox regression analysis were included in multivariate Cox regression analysis to determine independent predictive factors for RFS, revealing that differentiation (P = 0.002, HR = 0.548, 95%CI: 0.374–0.802), N stage (P = 0.003, HR = 1.598, 95%CI: 1.168–2.186), TNM stage (P = 0.028, HR = 1.897, 95%CI: 1.248–2.257) and nerve invasion (P = 0.047, HR = 1.946, 95%CI: 1.010–3.751) were independent predictive factors for RFS (Table 5).

Table 5

Cox proportional-hazard regression for RFS

Characteristics

Univariate analysis

Multivariate analysis

P

Value

HR

95% CI for Exp(B)

P

Value

HR

95% CI for Exp(B)

Lower

Upper

Lower

Upper






Gender

0.891

1.021

0.759

1.373

       

Age

0.174

1.237

0.910

1.680

       

Tumor size

0.109

0.753

0.532

1.066

       

Gross morphology

0.810

1.029

0.815

1.299

       

Differentiation

0.000

0.317

0.232

0.433

0.002

0.548

0.374

0.802

Histological component

0.008

1.849

1.178

2.901

       

T

0.000

1.680

1.371

2.060

       

N

0.000

2.343

1.965

2.793

0.003

1.598

1.168

2.186

pTNM

0.000

2.690

2.102

3.443

0.028

1.897

1.248

2.257

Vascular invasion

0.000

4.328

2.764

6.779

       

Nerve invasion

0.000

4.146

2.251

7.636

0.047

1.946

1.010

3.751

CEA

0.034

1.378

1.025

1.852

       

Ligation level

0.722

1.054

0.788

1.410

       

Discussion

The optimal level for ligating IMA in surgery for rectal cancer or sigmoid cancer has been a controversial topic for more than 100 years and remains to be solved[812]. The controversies lie in whether long-term outcomes and short-term outcomes would be affected by ligation level. In studies recommending HT ligation, a curative therapy and accurate staging could be achieved and both long-term outcomes and short-term outcomes are excellent. However, in studies supporting LT ligation, excellent blood flow to the proximal colon was the most important characteristics of LT ligation and equivalent long-term survival is also achieved. Both HT and LT proponents have reached an opposing conclusion to the other side. Therefore, this study was performed to give an answer to this controversial topic.

Firstly, we compared LT with HT in terms of anastomotic fistula. Before this study, a series of studies had reported that a significantly higher incidence of anastomotic fistula was expected among patients undergoing HT, which was consistent with results of our study. Despite the fact that incidence of anastomotic fistula is not solely affected by the blood flow from the inferior mesenteric artery, blood flow to anastomosis, however, is the most important one factor. In theory, blood flow to anastomosis is significantly better preserved after LT than that after HT. As a matter of fact, it was reported by several previous studies that in comparison with LT, HT resulted in lower blood flow to the proximal colon[12, 14, 15]. Therefore, it is no surprise to us that incidence of anastomotic fistula after LT was significantly lower than that after HT. Whereas, other studies insisted that HT would not increase the risk of anastomotic fistula[2527]. Some studies have adopted several tests to make sure that blood flow to proximal colon is adequate. In the study by Fujii S et al, the authors performed a hemorrhage test to decide a proximal portion of colonic stump before anastomosis[28]. However, their method was not a quantitative one and they argued that quantitative methods should be developed to more accurately assess blood flow to the proximal colon. Some other studies reported that intraoperative fluorescence angiography using indocyanine green (ICG) was efficient in evaluating blood flow to the proximal colon[2932]. More quantitative methods should be designed helping surgeons assess perfusion of the proximal colon during surgery for rectal or sigmoid cancer.

However, decreased blood flow to the anastomosis was not the only factor leading to anastomotic fistula. Other factors such as male gender and distance between the anastomosis and the anal verge were also factors for anastomotic fistula[28]. Thus, it is undisputed that technical factors are involved in the occurrence of anastomotic fistula but not all. Additionally, low perfusion to the distal rectum and high tension around the anastomosis were also factors contributing to anastomotic fistula. Therefore, we could conclude that anastomotic fistula was the result of multiple factors. It is not difficult for us to understand why in some studies, ligation level does not significantly affect the incidence of anastomotic fistula. Apart from assessing the impacts of ligation level on incidence of anastomotic fistula, we subsequently evaluated the effects of ligation level on incidence of other complications and revealed that ligation level did not significantly affect occurrence of other complications. According to a study by Fujii S et al, it was demonstrated that patients who had undergone HT ligation had a significantly higher incidence of bowel obstruction than those after LT ligation[28]. Fujii S et al speculated that wider dissected range of retroperitoneal surface in HT was the possible reason [28]. Consistent with some other studies, we advocated LT since it was indeed demonstrated that LT resulted in significantly less anastomotic fistula. Some marginal arteries between superior mesenteric artery (SMA) and IMA has been proposed. These marginal arteries included Riolan arch, Drummond artery, and Moskowitz artery [3335]. These marginal arteries have been thought as the basis of avoiding anastomotic fistula after HT. However, it has been a cotroversy whether these marginal arteries exist [3335]. Therefore, it is necessary for us to design methods assessing distribution of collateral artery between IMA and SMA since knowing the distribution of these collateral arteries could help us choose the reasonable ligation level. A few methods assessing distribution of collateral artery between IMA and SMA have been reported. Some other studies reported that intraoperative fluorescence angiography using indocyanine green (ICG) was efficient in evaluating blood flow to the proximal colon [2932]. CT angiography-based small vessel imaging has also been investigated in surgery for rectal or sigmoid cancer[33, 36]. Therefore, in our opinion, preoperative CT angiography or intraoperative fluorescence angiography using indocyanine green should be performed to evaluate the distribution of collateral artery between SMA and IMA to identify patients without adequate collateral artery between SMA and IMA who may have a higher incidence of anastomotic fistula. And these patients with high risk of anastomotic fistula should undergo LT rather than HT, which, however, should be further investigated by more in-depth studies.

In addition to short-term outcomes, we also evaluated the effects of ligation level on long-term survival. Results of this study demonstrated that neither OS nor RFS was significantly affected by ligation level. Additionally, it was also revealed that ligation level did not significantly affect long-term outcomes of patients with cancer of different stages. Results of this study were consistent with many other studies. Boström P et al reported that level of tie did not influence any patient-oriented oncological outcome[37]. Luo Y et al reported that LT and HT were not significantly different from each other in terms of 3- and 5-year overall and disease-free survival[38]. According to AlSuhaimi MA et al, low IMA ligation with dissection of LNs around the IMA origin showed no differences in anastomotic leakage rate compared with high IMA ligation, without affecting oncologic outcomes[39]. Thus, LT plus lymphadenectomy around IMA could offer comparable OS and RFS to HT. Like in these studies, we also compared the number of dissected lymph nodes of the two groups and demonstrated that two groups were not significantly from each other. Thus, considering all these findings, we may draw the conclusion that HT and LT is not significantly different from each other in terms of long-term outcomes and short-term outcomes except anastomotic fistula. However, patients with sigmoid colon cancer or rectal cancer had better undergo LT rather than HT, especially those with high risk of anastomotic fistula identified by preoperative CT angiography or intraoperative fluorescence angiography using indocyanine green .

However, our studies also have some shortcomings. Firstly, this study was a retrospective one in nature and prospective studies were needed to assess the imapcts of ligation level on short-term outcomes and long-term outcomes. Secondly, this study included not so many patients as in other studies, warranting studies including more patients. Thirdly, we excluded patients receiving neoadjuvant chemotherapy or radiotherapy from this study. Therefore, findings of this study could not be directly applied among patients who had undergone neoadjuvant chemotherapy or radiotherapy. As a matter of fact, patients receiving chemotherapy or radiotherapy before surgery were at risk of postoperative complications and LT rather than HT should be performed to minimize the risk of complications especially anastomotic fistula. And studies comparing LT and HT among patients receiving neoadjuvant chemotherapy or radiotherapy should be performed. Fourthly, patients in this study had different background from those in studies performed in other countries. Studies including patients from western countries should be performed. Fifthly, we did not perform CT angiography or intraoperative fluorescence angiography as suggested by other studies. However, despite these drawbacks, our study still could provide some useful suggestions for clinical practice since the optimal level ligating IMA is still a controversial topic in the area of general surgery.

In conclusion, for patients with sigmoid or rectal cancer undergoing an anterior resection, LT could efficiently prevent anastomotic fistula. LT was not significantly different from HT in terms of long-term outcomes. Despite the technical complexity of LT, we should perform LT as a routine operation for patients with rectal or sigmoid cancer especially for those with high risk of anastomotic fistula identified by preoperative CT angiography or intraoperative fluorescence angiography using indocyanine green. However, findings of this study should be assessed by more in-depth studies.

Abbreviations

IMA:inferior mesenteric artery;HTG:hie tie group;LTG:low tie group;SSI: surgical site infection; OS: overall survival; RFS: relapse-free survival; CRC: colorectal cancer; MRI: magnetic resonance imaging; LCA: left colic artery; CEA: carcinoembryonic antigen; CA-199: cancer antigen 19-9; PET-CT: positron emission tomography-computed tomography; BMI: body mass index; EBL: estimated blood loss; UICC/AJCC: International Union Against Cancer/American Joint Committee on Cancer; SPSS 22.0: Statistical Product and Service Solutions 22.0; HR: hazard ratio; CI: confidential interval; ICG: indocyanine green

Declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee, Traditional Chinese Medicine Hospital of Guangdong Province and all the patients included in this study had given his or her informed consent in the written form. 

Consent for publication

Not applicable. 

Availability of data and materials

The datasets generated and/or analysed during the current study are not publicly available due to the fact that some patients in this study did not agree to make their information publicly available but are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported by Science and Technology Innovation Foundation of Shenzhen (No.JCYJ20180228164603659) and (No.JCYJ20180507182437217) Clinical research and cultivation project of Shenzhen People's Hospital (No.SYLCYJ202003). 

Authors' contributions

Yawei Wang, Tailai An, Liaonan Zou and Jiling Jiang designed this study. Jiling Jiang and Tailai An supervised this study. Yawei Wang, Liaonan Zou, Tianchong Wu and Linsen Liu collected the data. Lingna Deng, Linsen Liu and Tailai An re-assessed TNM stage of each patient. Tailai An, Yawei Wang and Yan Wang accomplished the statistical analyses in this study. Yawei Wang, Liaonan Zou and Yan Wang prepared the manuscript. Jiling Jiang and Tailai An revised the manuscript. All the authors read and approved the final version of this study.

Acknowledgements

The authors would thank Lyujia Cheng from Jinan University (Guangzhou) for his help with this study.

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