International Journal of Colorectal Disease

, Volume 25, Issue 7, pp 843–849

Delayed anastomotic leakage following sphincter-preserving surgery for rectal cancer

Authors

  • Ui Sup Shin
    • Department of Colonic and Rectal Surgery, Asan Medical CenterUniversity of Ulsan College of Medicine
  • Chan Wook Kim
    • Department of Colonic and Rectal Surgery, Asan Medical CenterUniversity of Ulsan College of Medicine
  • Chang Sik Yu
    • Department of Colonic and Rectal Surgery, Asan Medical CenterUniversity of Ulsan College of Medicine
    • Department of Colonic and Rectal Surgery, Asan Medical CenterUniversity of Ulsan College of Medicine
Original Article

DOI: 10.1007/s00384-010-0938-1

Cite this article as:
Shin, U.S., Kim, C.W., Yu, C.S. et al. Int J Colorectal Dis (2010) 25: 843. doi:10.1007/s00384-010-0938-1

Abstract

Purpose

The aim of the present study was to investigate the characteristics of patients who developed delayed anastomotic leakage (DAL) following sphincter-preserving surgery for rectal cancer. We evaluated the following factors: (1) the incidence of DAL, (2) the clinical features of patients who developed DAL, (3) the risk factors for DAL, and (4) treatment outcomes.

Methods

We reviewed the case histories of 1,838 rectal cancer patients who had undergone curative resection with sphincter preservation and without protective stoma formation between January 2000 and December 2006. DAL was defined as the development of a pelvic abscess or fistula around the anastomosis more than 3 weeks post-surgery in patients without tumor recurrence who had resumed a normal diet and defecation.

Results

In 1.3% (24/1,838) of the patients, DAL developed on median postoperative day 99 (range 22–2,069). Pelvic abscess (50%) and anastomotic–vaginal fistula (41.7%) were the most common causes of DAL. Independent risk factors for the development of DAL were: (1) female gender (hazard ratio 3.03; 95% CI 1.06–8.8), (2) low-level anastomosis (≤4 cm from the anal verge) (hazard ratio 5.76; 95% CI 1.37–22.39), and (3) preoperative chemoradiation therapy (hazard ratio 4.56; 95% CI 1.4–14.92). Stoma formation was performed in all of the 24 patients. The 3-year stoma-retention rate in patients with DAL was significantly higher than in patients with early anastomotic leakage (72.2% vs 17.5%, P < 0.001).

Conclusions

DAL following sphincter-preserving surgery for rectal cancer occurred relatively frequently in our sample and was associated with female gender, a low level of anastomosis, and preoperative radiotherapy. DAL patients required long-term or permanent stomas.

Keywords

Rectal cancerDelayed anastomotic leakagePreoperative chemoradiation therapyPelvic abscessRecto-vaginal fistula

Introduction

Advances in stapling techniques and preoperative chemoradiation therapy as well as an increased tendency for the use of shorter distal resection margins are factors that have increased the rate of sphincter preservation in low-level anastomosis rectal surgery [1, 2]. Although this has encouraged a wider use of this surgical approach, this has in turn increased the likelihood of anastomotic leakage. The reported incidence of anastomotic leakage varies according to the diagnostic criteria used, and rates range between 4% and 19% [35]. The major predisposing factors for anastomotic leakage following rectal cancer surgery are male gender and low-level anastomosis [68]. Other factors include total mesorectal excision (TME) and preoperative chemoradiation therapy [8, 9].

Various pathologies may develop around the anastomosis in the months or years following sphincter-preserving surgery for rectal cancer, even in the absence of malignant recurrence. These include intrapelvic abscesses, recto-vaginal fistulas, and recto-vesical fistulas. Delayed anastomotic leakage (DAL) is embarrassing for the patient and can result in the loss of sphincter function due to the inevitable need for the formation of a stoma. The development of such pathologies may also reflect poorly on the competence of the surgeon. Most studies of anastomotic leakage have limited their investigation time to a period of 30 days post-surgery. To the best of our knowledge, no previous study has evaluated delayed anastomotic leakage.

The aim of the present study was to investigate the characteristics of patients who developed DAL following sphincter-preserving surgery for rectal cancer. We evaluated the incidence of DAL, the clinical features of patients who developed DAL, and risk factors for the development of DAL following sphincter-preserving surgery for rectal cancer. We compared these factors with those associated with early anastomotic leakage (EAL). We also describe the clinical course, sequelae, and management of DAL.

Patients and methods

A total of 2,204 patients underwent sphincter-preserving surgery for rectal cancer at the Asan Medical Center between January 2000 and December 2006. We excluded 237 patients who had undergone palliative surgery, 10 patients who had had local recurrence, and 119 patients who had undergone the formation of a protective stoma. It was necessary to exclude the latter group since a protective stoma may mask the symptoms of anastomotic leakage. The remaining 1,838 patients were included in the present study.

A diagnosis of DAL was assigned in patients who met all four of the following criteria: (1) anastomotic leakage had been detected more than 3 weeks post-surgery; (2) a normal diet and defecatory function had been resumed within 1 week of surgery; (3) the anastomotic leakage had developed without the occurrence of any signs or symptoms of peritonitis such as leukocytosis (≥10,000/µl), pyrexia, abdominal tenderness, or ileus within 3 weeks of surgery; and (4) no local recurrence had developed during the period of follow-up. At 3 weeks post-surgery, most patients have recovered sufficiently to tolerate adjuvant therapy. The causes of leakage in our sample were pelvic abscess and various types of fistula (anastomotic–vaginal, anastomotic–vesical, and anastomotic–enteric). Diagnosis was confirmed in all patients by performance of a computed tomography scan and a water-soluble contrast study of the colon.

EAL was defined as the development of clinical signs of leakage, such as purulent discharge from the drainage catheter with peritonitis and pyrexia (>38°C), within 3 weeks of surgery.

We randomly selected a control group of 159 age-matched patients from among 1,759 patients who did not develop anastomotic leakage.

Radiotherapy

The patient was placed in a prone position. Pre- and postoperative radiotherapy was administered using a linear accelerator (Varian, Clinac 1800; Varian Medical Systems, Palo Alto, CA, USA). Radiotherapy was administered to the pelvis through three or four fields with an energy level of 6 or 15 MV 5 days per week at a daily dose of 1.8–2 Gy. The total dose was 45–50.4 Gy. Concomitant 5-flurouracil or capecitabine-based chemotherapy was administered over a period of 5–6 weeks.

Surgery

Surgery was performed by one of four qualified colorectal surgeons (>5 years experience, >50 rectal cancer operations per year). Tumor-specific mesorectal excision, including TME, was the standard surgical approach for curative rectal cancer surgery and the precise procedure used was selected according to tumor location. Briefly, following exploratory laparotomy, lymph node sampling was performed during inferior mesenteric artery (IMA) dissection to allow frozen section evaluation of inferior mesenteric lymph node (IML) status prior to IMA ligation and excision. Low-level IMA ligation was the standard procedure used. IML+ patients underwent limited lymph node dissection involving the paraaortic and aortocaval lymph nodes from the level of the IMA to the bifurcation of the aorta. Mobilization of the rectum with preservation of the autonomic nerves was achieved using sharp dissection, and was performed under direct vision in order to ensure that the visceral pelvic fascia surrounding the mesorectum remained intact. The majority of patients with mid- and distal rectal cancer underwent TME. For all tumors of the upper rectum and some tumors of the middle rectum, transection of the rectum and mesorectum was performed at least 5 cm below the lower border of the tumor using sharp perimesorectal dissection. Straight-pattern colorectal or coloanal anastomosis was performed using circular staplers. A closed suction drain was inserted to provide postoperative pelvic drainage.

Statistics

The chi-squared test or the Fisher’s exact test was used to analyze the association between clinicopathological variables and anastomotic leakage as appropriate. Variables with P-values of less than 0.5 were selected for multivariate analysis. The Kaplan–Meier method was used to calculate the 3-year stoma-retention rate, and between-group comparisons were then performed using the log-rank test. All statistical tests were two-sided, and P < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS® version 13.0 (SPSS Inc, Chicago, IL, USA).

The present study was approved by the Institutional Review Board for Human Research of the University of Ulsan.

Results

Clinical characteristics and risk factors for the development of delayed anastomotic leakage

Of the 1,838 patients who underwent sphincter-preserving surgery for rectal cancer without a protective stoma, 55 (3.0%) developed EAL and 24 (1.3%) developed DAL.

The median postoperative day for the development of EAL was day 10 (range, 2–15). The median postoperative day for the development of DAL was day 99 (range 22–2,069). The most frequent cause of DAL was an intrapelvic abscess (12 cases, 50%) and the second most frequent cause was an anastomotic–vaginal fistula (10 cases, 41.7%). The remaining two cases were caused by an anastomotic–vesical fistula and an anastomotic–ileal fistula, respectively.

We examined the correlation between DAL and radiation therapy. In patients with no history of radiation therapy, DAL developed on mean postoperative day 38 (SD, 17.4). In patients with a history of preoperative radiation therapy, DAL developed on mean postoperative day 203 (SD 217). In patients with a history of postoperative radiation therapy, DAL developed on mean postoperative day 563 (SD 734) (P = 0.03) (Table 1).
Table 1

Delayed anastomotic leakage, detection time, and type of leakage according to mode of adjuvant therapy

 

Preoperative RT

Postoperative RT

None/chemotherapy only

P-value

Number

12

7

5

 

Detection (postoperative day)

 Mean ± SD (range)

203 ± 217.1 (22–630)

563 ± 734.6 (99–2,069)

38 ± 17.4 (24–66)

0.09

Type of leakage

 Pelvic abscess

6 (50%)

4 (57.1%)

2 (40%)

0.35

 Anastomotic–ileal fistula

 

1 (14.3%)

  

 Anastomotic–vesical fistula

 

1 (14.3%)

  

 Anastomotic–vaginal fistula

6 (50%)

1 (14.3%)

3 (60%)

 

RT radiation therapy

We examined the correlations between specific clinical characteristics and the development of EAL or DAL, and compared these clinical characteristics with those of the control group. EAL was associated with male gender, advanced stage disease (AJCC stage III, IV), and a histological finding of poorly differentiated or mucinous adenocarcinoma (P < 0.05). DAL was associated with a lower tumor location, a low-level anastomosis (≤4 cm), and a history of preoperative chemoradiation therapy (P < 0.05) (Table 2).
Table 2

Clinicopathological characteristics of each group

 

DAL

EAL

Control

P-value

Number

24

55

159

DAL:control

EAL:control

Age ≥60 years

11 (45.8%)

30 (54.5%)

82 (51.6%)

0.6, 0.7

Male

9 (37.5%)

43 (78.2%)

92 (57.9%)

0.06, 0.007

Body mass index ≥25 kg/m2

9 (37.5%)

16 (29.1%)

72 (45.3%)

0.47, 0.04

Comorbidity

8 (33.3%)

23 (41.8%)

51 (32.1%)

0.9, 0.19

Location of tumor

 Upper rectum

7 (4.2%)

1 (12.7%)

35 (22.0%)

 

 Mid rectum

33 (58.3%)

14 (60.0%)

98 (61.6%)

 

 Lower rectum

15 (37.5%)

9 (27.3%)

26 (16.4%)

0.02, 0.07

Size of tumor (≥4 cm)

15 (68.2%)

42 (79.2%)

104 (68.9%)

0.95, 0.16

Level of anastomosis (≤4 cm)

21 (87.5%)

28 (50.9%)

67 (42.1%)

<0.001, 0.26

Preoperative radiation therapy

12 (50%)

8 (14.5%)

16 (10%)

<0.001, 0.36

Postoperative radiation therapy

7 (29.2%)

 

37 (23.3%)

0.25

Dose of RT (cGy)

 Preoperative

5,000 ± 0

 

4,829 ± 592

0.49

 Pre- and postoperative

5,005 ± 14

 

4,699 ± 932

0.21

Stage III/IV

16 (66.7%)

32 (58.2%)

65 (40.9%)

0.03, 0.03

PD/MUC

1 (5.0%)

6 (11.1%)

5 (3.1%)

0.9, 0.03

T3/4

22 (91.7%)

43 (78.2%)

102 (64.2%)

0.009, 0.07

Lympho-vascular invasion

5 (20.8%)

10 (18.2%)

32 (20.8%)

1, 0.7

DAL delayed anastomotic leakage, EAL early anastomotic leakage, Control control group, RT radiation therapy, PD poorly differentiated, MUC mucinous adenocarcinoma

Multivariate analysis showed that male gender was the only independent risk factor for EAL (P < 0.001). The independent risk factors for DAL were female gender, a history of preoperative chemoradiation therapy, and an anastomosis that was located less than 4 cm above the anal verge (Table 3).
Table 3

Risk factors for early and delayed anastomotic leakage according to multivariate analysis

 

DAL

EAL

HR

95% CI

P-value

HR

95% CI

P-value

Age ≥60 years

1.02

0.36–2.94

0.96

1.2

0.58–2.46

0.62

Sex (male)

0.33

0.11–0.94

0.04

3.93

1.65–9.37

<0.001

Preoperative radiotherapy

4.56

1.4–14.92

0.01

1.07

0.31–3.62

0.92

Depth of invasion (T3/4)

3.58

0.72–17.9

0.12

1.73

0.69–4.38

0.24

Stage III/IV

1.43

0.48–4.27

0.52

1.28

0.60–2.73

0.53

Level of anastomosis (≤4 cm)

5.76

1.37–22.39

0.02

1.18

0.53–2.59

0.69

Lower rectum

1

0.3–3.31

1

2.19

0.86–5.59

0.1

Comorbidity

   

1.38

0.65–2.93

0.4

Tumor size ≥4 cm

   

1.88

0.74–4.73

0.18

HR hazard ratio, CI confidence interval

Clinical course and treatment outcome of DAL and EAL

Stoma formation was performed in 78 of the 79 cases of EAL and DAL in order to provide fecal diversion. The remaining case had EAL and was treated by primary repair (via the anus) and pelvic drainage; no signs of sepsis were observed during a 30-month period of follow-up.

Of the 54 EAL cases who underwent diversion, two had end-type stomas and 52 had loop-type stomas. In one of the end-type stoma cases, ischemic change at the proximal colon developed, which necessitated total colectomy with an end ileostomy. In the other end-type stoma case, a Hartmann’s procedure was performed since the defect in the anastomosis was so large that natural healing was considered unlikely. Of the cases with loop-type stomas, 51 (94.4%) underwent loop ileostomy.

Of the 24 cases of DAL, two underwent formation of an end-type stoma. One case required abdominoperineal resection 2 months after the initial operation as a result of the development of severe inflammation and the formation of an abscess. The other case required a transverse end colostomy 19 months after the initial operation as a result of the development of a large anastomotic defect and severe radiation proctitis. In cases with loop-type stomas, transverse colostomies were performed more commonly in the DAL group than in the EAL group (41.7% vs 1.8%) (Fig. 1).
https://static-content.springer.com/image/art%3A10.1007%2Fs00384-010-0938-1/MediaObjects/384_2010_938_Fig1_HTML.gif
Fig. 1

Schematic algorithm for the management of anastomotic leakage

The median period of postoperative follow-up was 31 (1–85) months for EAL and 35 (4–76) months for DAL. Of the 78 stomas, 47 were closed after healing of the anastomotic defect had been confirmed by performance of a water-soluble contrast colon study. Thirteen EAL stomas and 18 DAL stomas were retained during the follow-up period. In eight retained EAL stoma cases and 17 retained DAL stoma cases, persistent anastomotic leakage into perirectal cavities, or a vaginal or vesical fistula, was confirmed by performance of a gastrograffin colon study or a computerized tomography scan. One retained DAL stoma was non-reducible since the patient had undergone perineal resection. The reasons for stoma retention in the other five EAL cases were: (1) unsuitability for general anesthesia due to advanced age (two cases), (2) anastomotic stricture (one case), and (3) continued administration of chemotherapy for distant metastases identified during follow-up (two cases). Kaplan–Meier analysis showed that the overall 3-year stoma-retention rate was 34.6%, and that this rate was much higher for DAL than for EAL (72.2% vs 17.5%, P < 0.001) (Fig. 2).
https://static-content.springer.com/image/art%3A10.1007%2Fs00384-010-0938-1/MediaObjects/384_2010_938_Fig2_HTML.gif
Fig. 2

Kaplan–Meier curves showing stoma-retention rates according to type of leakage

We compared the 3-year stoma-retention rates of four groups who were classified according to the type of leakage and their history of radiation therapy. The 3-year stoma-retention rate for the DAL without radiotherapy (D−RT) group was approximately 30%, which was similar to that of the EAL group. However, the rate for the DAL with radiotherapy (D+RT) group was 81.9%, which was significantly higher than for the EAL and D−RT groups (P < 0.001) (Fig. 3).
https://static-content.springer.com/image/art%3A10.1007%2Fs00384-010-0938-1/MediaObjects/384_2010_938_Fig3_HTML.gif
Fig. 3

Kaplan–Meier curves showing stoma-retention rates according to radiotherapy regimen

Discussion

Clinically manifest anastomotic leakage is one of the most serious complications of rectal cancer surgery and is reported to be associated with a poor prognosis in patients with rectal cancer [10]. Although the incidence of anastomotic leakage varies according to the definition used, recent well-controlled studies have reported an incidence of 4–19% [35]. In the present study, the overall incidence of anastomotic leakage was 4.3%, whereas the incidence of EAL was 3.0%; these levels are thus at the lower end of the range reported by other groups. However, previous studies have generally limited their investigation time to a period of 30 days post-surgery. The findings of the present study demonstrate that DAL cannot be considered a rare sequela of post-rectal surgery. The incidence of DAL in our sample was 1.3%, i.e., approximately half that of EAL. Surgeons should therefore provide long-term follow-up and remain alert to the possible development of DAL.

As well as impairing long-term functional outcomes by triggering the development of fibrotic change around the anastomosis [11, 12], anastomotic leakage is thought to increase the risk of local and systemic recurrence, although this effect has recently been questioned [10, 13, 14]. Well-established risk factors for anastomotic leakage are male gender and the distance between the anastomosis and the anal verge [4, 6, 8, 9]. Other possible factors include a history of TME, preoperative radiotherapy, intraoperative complications, blood loss, and smoking [4, 9, 15]. Although a protective stoma has little influence on the rate of anastomotic leakage following rectal resection, it has been shown to reduce the need for subsequent surgery [1618].

The present study investigated risk factors for the development of anastomotic leakage, in particular the development of DAL. The only independent risk factor identified for EAL in our sample was male gender. This may reflect the fact that the female pelvis is considerably broader than the male pelvis and contains less muscle and mesorectal fat tissue, thus rendering surgery much easier. The independent risk factors identified for DAL were female gender, a low-level anastomosis (≤4 cm above the anal verge), and a history of preoperative chemoradiation therapy. Thus, the risk factors for DAL did not reflect the higher degree of surgical difficulty encountered in male patients. Furthermore, in view of the timepoint of the period during which DAL develops, delayed leakage cannot be considered a consequence of surgical difficulty (i.e., technical factors), but may result instead from other predisposing factors or disease processes.

The main focus of the present study was anastomotic leakage that developed 3 weeks or more after the performance of sphincter-preserving surgery for rectal cancer. When collecting information on DAL patients, we defined DAL according to the timepoint at which it actually developed rather than the timepoint at which it was first detected. This was our rationale for including selection criteria 3 and excluding patients in whom anastomotic leakage had been detected more than 3 weeks post-surgery but who had developed signs or symptoms suggestive of pelvic inflammation within 3 weeks of surgery. Such cases may in fact have developed EAL. Insufficient pelvic drainage may explain the development of late-detected anastomotic leaks. However, non-infected residual pelvic fluid is likely to have been reabsorbed within 3 weeks of surgery and is thus unlikely to have caused an anastomotic leak. If residual pelvic fluid had induced anastomotic insufficiency, it may well have become infected in which case signs and symptoms of pelvic inflammation would have presented within 3 weeks of surgery. Furthermore, residual pelvic fluid was rarely detected during pre-discharge computerized topography scanning.

The most common cause of DAL in the 15 female cases in our sample was an anastomotic–vaginal fistula (10 cases, 66.7%). Although the pathophysiological mechanism underlying the development of such fistulas is unclear, the direct incorporation of the posterior vaginal wall into the anastomosis between the proximal colon and rectum has been proposed as a possible cause [19, 20]. However, our observations suggest this is unlikely to have been the cause in the cases in our sample. In the present study, fistulas of this type were not detected until median postoperative day 37, with the latest case being detected 630 days post-surgery (data not shown). Furthermore, none of the pathology specimens (including the doughnut EEA rings) contained vaginal tissue. We therefore propose that leakage at the colorectal anastomosis with subsequent tracking to the vaginal wall is a more plausible explanation. Some reports have suggested that subclinical anastomotic leakage may result in the formation of a perianastomotic collection that dissects along the path of least resistance, i.e., a defect in the vaginal wall, and thus becomes clinically detectable DAL. It has also been suggested that the vaginal wall may often be damaged during pelvic surgery, particularly in elderly patients who have a thin atrophic vaginal wall secondary to a relative lack of estrogen [21]. Although the treatment of an anastomotic–vaginal fistula includes primary repair or mucosal advancement flap surgery with or without fecal diversion, the results of such treatment are unsatisfactory in patients receiving radiotherapy. Recent reports have suggested that a good surgical outcome can be achieved through the use of obturator fasciocutaneous thigh flaps or gluteal fold flaps [22, 23].

In the present study, we found that a history of preoperative chemoradiation therapy was a risk factor for DAL. Although not identified as a risk factor of EAL in the present study, this is one of the most frequently discussed risk factors for anastomotic leakage. Preoperative chemoradiation therapy may impair the healing of the anastomosis tissue, and the distal region of the anastomosis is often included in preoperative radiation fields. Animal studies have shown that preoperative pelvic fractionated irradiation with 5-fluorouracil delayed anastomotic healing and weakened the tensile strength of the anastomosis, and that these problems can be partially compensated for by preoperative colon irrigation with short chain fatty acids [24, 25]. Chronic radiation also has an effect on the intestine and may induce widespread collagen deposition and fibrosis as well as occlusive vasculitis in small arterioles. These effects develop over a period of several months or years and result in the development of bowel strictures, ulceration, and fistulas. We hypothesize that the pathophysiology of DAL is initiated by poor and delayed healing of the anastomosis in the irradiated rectum which induces subclinical leakage, precipitated by factors that increase intraluminal pressure such as fecal impaction and enemas. This subclinical leakage results in an accumulation of microabscesses around the anastomosis which may lead to the development of pelvic abscesses or fistulas.

In the present study, we found that following the formation of a stoma for fecal diversion, the stoma-retention rate was higher in D+RT cases than in EAL cases, but that the rates in D−RT and EAL cases were similar. These findings indicate that radiation therapy is the most important factor in the development and treatment of DAL. Our findings also indicate that the history of radiation therapy should be taken into account when selecting stoma type in patients who are expected to require long-term or permanent stoma retention.

Conclusions

The maintenance of sphincter function is a major determinant of the quality of treatment for rectal cancer. We found that the development of delayed anastomotic leakage was a relatively common occurrence, and was associated with female gender, a low level of anastomosis, and a history of preoperative radiotherapy. We also found that DAL cases required long-term or permanent stoma retention.

Acknowledgments

This study was supported by a grant from the Korean Health 21 R&D project of the Ministry of Health & Welfare, Republic of Korea (A062254).

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© Springer-Verlag 2010