Risk and early predictive factors of anastomotic leakage in laparoscopic low anterior resection for rectal cancer

A total of 154 patients consecutively underwent elective laparoscopic low anterior resection (LAR) with a DST anastomosis at the Department of Surgical Oncology, Gifu University Graduate School of Medicine, between February 2008 and November 2017. Among those patients, 53 were excluded for tumor histopathology other than adenocarcinoma (n = 6); conversion to open surgery (n = 2); lateral lymph node dissection (n = 2); simultaneous resection of other organs (n = 13); and construction of protective diverting stoma (DS) (n = 30) (Fig. 1). Ultimately, a total of 101 patients with primary rectal cancers were included in this study. We included only symptomatic AL requiring therapeutic interventions or an operation in the present study. Therefore, DS cases were excluded. No patients had preoperative chemotherapy or chemoradiotherapy. In our department, primary resection is routinely performed before chemotherapy, even for the cases with distant metastases. In addition, preoperative chemotherapy or chemoradiotherapy is selected for difficult cases such as bulky tumors or extramural invasion. Preoperative treatment should be performed in those cases after construction of the colostomy for safer treatment.

The location of the tumor and distance from the anal verge was determined by computed tomography (CT), colonoscopy (CS), and either CT colonography (CTC) or barium enema (BE) preoperatively and confirmed during surgery. The maximum tumor diameter, clinical tumor depth, and lymph node metastasis were also determined by CT, CS, and CTC or BE preoperatively and confirmed through postoperative histopathological examination findings. Clinically positive lymph node metastasis was defined as nodes with a short-axis diameter of at least 8 mm by CT. In the present study, postoperative fever was defined as a body temperature ≥ 38 °C and postoperative tachycardia as a heart rate ≥100 bpm.

Patient-, tumor-, and surgery-related variables were included in the analysis. The patient-related variables were age, sex, body mass index (BMI), American Society of Anesthesiologists physical status classification (ASA), diabetes mellitus, serum albumin (Alb), and prognostic nutritional index (PNI). The tumor-related variables were tumor location, maximum tumor diameter, distance from the anal verge, circumferential tumor, preoperative stent placement, and clinical and pathological Union for International Cancer Control-TNM classification (8th edition) [10]. The intraoperative surgery-related variables were operation time, blood loss, lymph node dissection level (D2 or D3), left colic artery (LCA) preservation, mobilization of the splenic flexure, number of linear staples used for rectal transection, size of the circular staple, placement of the transanal drain, and surgeon qualifications. The postoperative surgery-related variables were white blood cell (WBC) count, C-reactive protein (CRP) levels, fever, tachycardia, watery stools after surgery, and first defecation day after surgery. To resolve clinical questions, they were classified into pre-, intra-, and postoperative factors.

All procedures were conducted at our department by an experienced laparoscopic colorectal surgeon qualified by the Endoscopic Surgical Skill Qualification System of the JSES. “Qualified surgeon,” one of the surgery-related factors, indicates a case in which a qualified surgeon completed the operation as the main operator. In all other cases, a qualified surgeon supervised as the first assistant.

According to the recommended clinical pathway, all patients received standard bowel preparation by the administration of magnesium citrate and sennoside 2 days before surgery (only mechanical prophylaxis, no antibiotic prophylaxis). In cases where a stent was placed, bowel preparation was slowly performed for 2–3 weeks after placement. Thereafter, a total colonoscopy was performed to confirm that there were no other lesions and that sufficient preparation was done before the surgery was approved and carried out.

We routinely performed high ligation of the inferior mesenteric artery, although preservation of the LCA was considered depending on blood vessel condition. The splenic flexure was mobilized either totally or partially, depending on the bowel length. After mobilization of the descending colon, tumor-specific mesorectal dissection was performed by sharp mesorectal dissection with a nerve-preserving technique. After clamping the distal side of the tumor to wash out the rectum, the rectum was transected using a linear staple (Echelon 60 or Powered Echelon 60, Gold cartridge, Ethicon Endo-Surgery, Cincinnati, OH, USA). After the surgical specimen was removed through the small incision, the anvil head of a circular staple was positioned in the proximal colon. The circular staple (CDH, 25 mm or 29 mm, Ethicon) was inserted through the rectum, and DST anastomosis was completed intracorporeally. Airtightness was routinely tested by transanal instillation of air. If the leak test was positive, an intracorporeal reinforcement suture with 3–0 vicryl was placed at the weak point. The placement of a pelvic drain was routinely performed, and placement of the transanal drain (pleated drain-soft type, 10 mm, Sumitomo Bakelite Company Limited, Shinagawa, Tokyo, Japan) was performed depending on the location of the tumor and the height of the anastomosis from the anal verge. The transanal drain was removed 4–5 days after surgery.

AL was investigated in the presence of clinical leakage signs such as the discharge of pus or feces from the pelvic drain and evidence of peritonitis, including abdominal pain, tenderness, fever, tachycardia, or severe inflammation in blood tests. If leakage was suspected, CT was performed to check for AL. Diagnosis required positive findings on CT, such as an abscess and fluid collection or air bubbles surrounding the anastomosis site. Asymptomatic anastomosis leakage was not considered as contrast enemas were not routinely performed in our department.

Continuous variables were expressed as median values, while categorical and ordinal variables were expressed as frequencies (percentages). For comparisons of variables between the non-AL and AL groups, Fisher’s exact test was used for categorical variables, and Wilcoxon rank sum tests were used for continuous and ordinal variables. To test the independence of risk and early predictive factors for AL, significant variables in univariate analyses were included in a final model of logistic regression. All statistical analyses were performed using JMP software (SAS Institute Inc., Cary, NC, USA).

In total, 101 consecutive patients underwent laparoscopic LAR with DST anastomosis, 53 (52.5%) were male and 48 (47.5%) were female. The median age was 64 years (range, 18–83 years) and their median BMI was 22 kg/m² (range, 15.4–29.7 kg/m²). Twenty-five patients (24.7%) had rectosigmoid (RS) cancer, 63 (62.4%) had upper rectal (Ra) cancer, and the remaining 13 (12.9%) had lower rectal (Rb) cancer.

Among the patients, symptomatic AL occurred in 13 patients (12.9%), of whom 10 were male and 3 were female. Their median BMI was 22.7 kg/m² (range, 17.9–26.4 kg/m²). The AL rate was 12.0% (3/25) in patients with RS cancer, 7.9% (5/63) in Ra cancer, and 38.5% (5/13) in Rb cancer. AL requiring re-operation (stoma construction) occurred in 5 cases (38.5%), while there were 8 cases (61.5%) of AL that did not require re-operation and were treated by irrigation and drainage through the pelvic drain. Antibiotics were administered in all AL cases until the inflammatory response was reduced or there were no signs of inflammation. The median time at which AL was confirmed was POD 4 (range, 1–10 days), and the median time until hospital discharge was 43 days post-surgery (range, 24–242 days). There were no deaths related to AL in this study.

Patient-related factors are summarized in Table 1. No significant differences were found, which was consistent even when converting continuous and ordinal variables into categorical variables [age (≥ 75 years/< 75 years), BMI (≥ 25 kg/m²/< 25 kg/m²), ASA (≥ 2/< 2), Alb (≥ 3.5 g/dl/< 3.5 g/dl), and PNI (≥ 45/< 45)]. In this study, we set a BMI cutoff value of ≥ 25 kg/m² based on the definition of obesity in the Japanese Society for the Study of Obesity (JASSO) instead of 30 kg/m² as per the International Federation of Surgery for Obesity and Metabolic disorder (IFSO).

Clinical and pathological tumor-related factors are summarized in Table 2. AL was significantly associated with tumor location (p = 0.031) and distance from the anal verge (p = 0.040). There were significant differences in tumor location (Rb, p = 0.0046) and distance from the anal verge (< 6 cm, p = 0.0090) after converting continuous and ordinal variables into categorical variables [tumor location (Rb/not Rb), tumor diameter (≥ 40 mm/< 40 mm), distance from the anal verge (≥ 6 cm/< 6 cm), cT (≥ 3/< 3), cN (positive/negative), cStage (≥ III/< III), pT (≥ 3/< 3), pN (positive/negative), and fStage (≥ III/< III)].

Surgery-related factors are summarized in Table 3. AL was significantly associated with the number of linear staples (p = 0.046), tachycardia-POD1 (p = 0.023), CRP-POD3 (p = 0.036), fever-POD3 (p < 0.0001), and first defecation day after surgery (p = 0.022). There were significant differences in intraoperative blood loss (≥ 50 ml, p = 0.012), CRP-POD 3 (≥ 15 mg/dl, p = 0.046), and first defecation day (< POD3, p = 0.0059) after converting continuous and ordinal variables into categorical variables [operation time (≥ 240 min/< 240 min), intraoperative blood loss (≥ 50 ml/< 50 ml), WBC-POD1 (≥ 10,000/μl/< 10,000/μl), CRP-POD1 (≥ 5 mg/dl/< 5 mg/dl), WBC-POD3 (≥ 10,000/μl/< 10,000/μl), CRP-POD3 (≥ 15 mg/dl/< 15 mg/dl), and first defecation day (≥ POD3/< POD3)].

To resolve clinical questions, we classified patient-, tumor-, and surgery-related categorical factors, which were significantly different in univariate analysis, into pre-, intra-, and postoperative factors (Fig. 2).

Among the pre- and intraoperative factors, AL was significantly associated with the following four factors in univariate analysis: tumor location (Rb), distance from the anal verge (< 6 cm), intraoperative blood loss (≥ 50 ml), and the number of linear staple (≥ 2). In multivariate analysis, distance from the anal verge (< 6 cm) was excluded to avoid confounding with tumor location (Rb); only intraoperative blood loss (≥ 50 ml) maintained a significant correlation with AL (Table 4; odds ratio (OR) 4.59; 95% confidence interval (CI) 1.04–19.52; p = 0.045).

Among the postoperative factors, AL was significantly associated with the following four factors in univariate analysis: tachycardia-POD1 (≥ 100 bpm), CRP-POD3 (≥ 15 mg/dl), fever-POD3 (≥ 38 °C), and first defecation day after surgery (< POD3). In multivariate analysis, fever-POD3 (≥ 38 °C) and first defecation day after surgery (< POD3) remained significantly correlated with AL (Table 5; OR 30.97; 95% CI 4.68–311.22; p = 0.0003 and OR 5.82; CI 1.34–31.30; p = 0.019, respectively).