Research Article

The Effects of NT and Adjuvant Treatments on Anastomotic Leakage in Rectal Cancer


  • Nigara Asratova
  • İbrahim Ethem Cakcak
  • İrfan Coşkun

Received Date: 05.01.2021 Accepted Date: 14.04.2021 Turk J Colorectal Dis 2021;31(3):182-190


Anastomosis leakage (AL) is a major complication following colorectal surgery. The present study aims to investigate the effects of adjuvant (AT) and neoadjuvant (NT) treatments on AL in surgical patients with rectal cancer.


The study followed 319 patients (age >18 years) who were diagnosed with rectal cancer and underwent surgery with AT or NT treatment between January 1, 2010 and December 31, 2018. We evaluated demographic data, tumor stage, metastasis status, organ and lymph node involvement, surgery type, use of AT and NT, the presence of AL, mortality status, and serum carcinoembryonic antigen levels.


A total of 179 (56.1%) patients were male, 140 (43.9%) were female (mean age =58.6±13.2 years). In terms of additional treatment, 48.6% (n=155) received AT and 51.4% (n=164) received NT. Data revealed that 13.1% (n=42) of the patients received only radiotherapy (RT), 10.6% (n=34) received only chemotherapy (CT), and 76.2% (n=243) received both RT and CT (CRT). Additionally, 23.5% (n=75) of the patients had AL. In terms of AL frequency, we found no difference between the patients receiving AT or NT (p=0.758). Additionally, RT and CT had no effect on the development of AL (p=0.827 and p=0.1, respectively). Finally, mortality was not higher in patients with AL.


In terms of AL development, we found no differences between patients receiving NT or AT and those using RT or CT alone or together. We recommend that these rectal cancer treatments should be continued because of their better local control, overall survival rate, and sphincter function preservation rates.

Keywords: Rectum cancer, radiotherapy, chemotherapy, anastomotic leakage


Colorectal cancer (CRC) is one of the most common and life-threatening cancers worldwide. Since the treatment for stage II and stage III CRC now involves a multidisciplinary structure of combined therapy rather than surgery alone, combined chemotherapy (CT) has become the preferred adjuvant (AT) therapy for stage III colon cancer.1 Similarly, combined radiotherapy (RT) is also recommended for rectal cancer. Previous studies have shown reductions of local recurrence and improvement in survivability in locally advanced rectal cancer using combined AT RT and CT2, while others report decreased recurrence rates using total mesorectal excision (TME).3,4  Neoadjuvant (NT) chemoradiotherapy (CRT) has become the preferred treatment method in all stage II and III rectal cancers because of better outcomes compared with AT CRT, better patient tolerance, and downstaging in many cases, thus preventing permanent ostomy.5

Anastomotic leakage (AL) is defined as a defect of the intestinal wall in the anastomosis region (including the sutures and staple lines of the neorectal reservoirs), leading to transition between the intra- and extraluminal compartments.6 It is a crucial and potentially life-threatening postoperative complication following colorectal surgery, causing around one-third of deaths after surgery.7 Although AL mortality can be prevented if managed well 8, patients with AL who undergo treatment and survive have increased perioperative morbidity and lower survival in the long term.9,10,11

Based on numerous studies focusing on the predisposing factors for AL, the leak is thought to be caused by a large spectrum of both preventable and unavoidable factors.12 Even with perioperative management (Enhanced Recovery After Surgery) and the improvement and optimization of surgical techniques (minimally invasive surgery), AL frequency has remained high (8%-20%) over time.12,13,14,15 Among many local and general factors causing AL16 is the patient’s exposure to CT and/or RT. While some studies showed that NT RT or CRT did not increase AL development.17,18,19,20,21,22 A study with a five-year follow-up period comparing the use of AT and NT CRT detected AL in 11% of the NT  CRT arm and 12% of the AT CRT arm, with no differences found between the two groups.5 Thus, the present study aims to investigate the effects of NT and AT therapies on AL in patients with rectal cancer who underwent surgery.

Materials and Methods

Patient Selection

We conducted retrospective file scans of patients with rectal cancer who underwent surgery between January 1, 2010 and December 31, 2018, in Trakya University General Surgery Department. The study included patients who were older than 18 years, were diagnosed with rectal cancer, underwent surgery in our clinic, and were given AT or NT by the radiation oncology and medical oncology clinics. We obtained patient data from the central and oncology clinic archives. Patients were grouped according to AT or NT status. We recorded demographic data, tumor stage, metastasis status, organ and lymph node involvement, surgery type, use of AT and NT, the presence of AL, mortality, and serum carcinoembryonic antigen (CEA) levels from patient files. The patients had 2-8 years of follow-up.

Chemotherapy and Radiotherapy Protocols

Surgery was performed according to TME principles. While RT and CT were generally applied together as AT or NT, RT or CT was administered alone in some patients. A total of 50.4 Gy (single dose of 1.8 Gy) RT was applied to the tumor and pelvic lymph nodes for five weeks as per protocol.23 For CT, 5-fluorouracil (5-FU) was administered in a 120-hour continuous infusion at a dose of 1,000 mg/m2/day in the first and fifth weeks of RT. Four cycles of 5-FU were additionally administered as bolus injection at a dose of 500 mg/m2/day in 5 consecutive days for 4 weeks. Unlike in NT, an additional 5.4 Gy of RT was administered to the tumor bed for 3 days in AT. Surgical treatment was performed 4-6 weeks after completing the concurrent use of NT CT and RT, while the remaining four cycles of 5-FU were started 3-4 weeks after surgery. Alternatively, surgical treatment was performed first and AT started 1-2 weeks after surgery.

Approach to Anastomotic Leaks

We used the following AL grading system recommended by Rahbari et al.6: grade A does not require a therapeutic intervention, grade B requires active intervention without laparotomy, and grade C requires laparotomy. Based on literature, CT scan was performed for diagnosis when a leak was suspected, followed by contrast enema and endoscopy, then reoperation.24 where the anastomosis was usually removed, and a permanent stoma was created. If possible, anastomosis was fixed in grade A and B leaks, with or without drainage and/or antibiotic treatments.25,26

Statistical Analysis

We used the Statistical Package for the Social Sciences (SPSS) package program version 22 for data analysis. We investigated the normality of the distribution of the data using the Kolmogorov-Smirnov and Shapiro-Wilk tests. Mean ± standard deviation or median (minimum-maximum) was used for continuous variables, and frequency and percentage (%) were used for categorical variables. We used the Mann-Whitney U test to compare categorical variables that were not normally distributed as well as continuous variables obtained in laboratory measurements. We used Pearson’s chi-square test for comparisons between categorical variables. We used the McNemar test for comparisons between dependent categorical variables. The level of statistical significance was accepted as p≤0.05.


The average age of the patients was 58.6±13.2 (range: 27-85) years. In total 179 (56.1%) patients were male. The mean body weight of the patients was 74.52±13.7 kg.

We found that 48.6% (n=155) of the patients received AT while 51.4% (n=164) received NT. Furthermore, 13.2% (n=42) received only RT, 10.7% (n=34) received only CT, and 76.2% (n=243) received both. In terms of NT use (n=164), 18 (11.0%) received only RT, 21 (12.8%) received only CT, and 125 (76.2%) received both. In terms of AT use (n=155), 25 (16.1%) received only RT, 12 (7.7%) receivd only CT, and 118 (76.1%) received both (Table 1).

We found that 16.3% (n=52) of the patients underwent anterior resection, 73.0% (n=233) had low anterior resection, and 10.7% (n=34) received a very low anterior resection.

We investigated perineural invasion in 83.1% (n=265) of the patients and detected it in 16.6% (n=44). We also investigated lymphatic invasion in 84.9% (n=271) and found it in 16.6% (n=44). Meanwhile, we detected AL in 23.5% (n=75) of the patients. Unfortunately, 90 (28.2%) patients died.

The average age of the deceased patients was 58.68±0.87 years, while the average age of survivors was 58.4±1.39 years. We found no significant differences between the ages of survivors and those who died (p=0.871). Likewise, we found no statistically significant difference in terms of body weight between the survivors and those who died (p=0.822). A total of 50 (55.6%) male patients and 40 (44.4%) female patients died. Still, we found no significant differences between the sexes of the survivors and those who died (p=0.900).

Among the survivors and deceased patients, there were no differences in terms of TNM stage, surgery type, preoperative and postoperative CEA levels, anastomosis leaks, RT and/or CT use, and perineural and lymphatic invasions (Table 2).

Similarly, there were no differences in terms TNM stage, surgery type, preoperative and postoperative CEA levels, anastomosis leak, mortality, and perineural and lymphatic invasions among patients receiving AT or NT (Table 3).

When the average age and body weight of the patients were compared in terms of the presence of AL, we found no significant difference between the ages of those with and without AL (p=0.227). However, the average body weight of patients with AL was lower than that of patients without AL (p=0.042). Similarly, when sex distribution of the patients was compared, we found no significant difference between those with and without AL.

Table 4 shows the predictive factors to AL development. In univariate analysis, the relationship between gender, age, weight, surgery type, laparoscopic surgery, tumor size, lymph node involvement, NT or AT use, perineural involvement, lymphatic invasion, RT or CT use, and AL were examined. We found a relationship (p=0.021) between N2 lymph node involvement and AL. Also, we observed that RT, CT, or CRT did not have statistically significant effects on AL development.

Finally, we found no significant differences between postoperative and preoperative serum CEA levels in patients receiving AT and NT, in patients who survived and died, and in patients with and without AL (p>0.001) (Table 5).


Based on our findings, we found no difference in terms of AL development between patients receiving NT and AT. We also found no difference between the uses of CRT and either RT or CT alone as NT or AT in terms of AL development. However, in patients with AL, we observed more frequent N2 lymph node involvement and lower body weight. Development of AL did not affect mortality in patients.

Presently, colorectal cancer accounts for approximately 10% of cancer-related mortality in Western countries.27 New treatments for primary and metastatic colorectal cancer include laparoscopic surgery, radiotherapy, and NT, and palliative CT. Every method used in cancer treatments has its own side effects and complications, and these are additive in combined therapy. The appearance of AL at the suture line of the bowel folds after tumor removal is one of the most feared surgical complications. The AL incidence is 1%-19% and complications cause 6%­-22% of postoperative mortality28,29,30,31,32 or about one-third of deaths after colorectal surgery.7 Gessler  et al.33 reported that the AL rate was 10% in patients operated on for colorectal cancer and 18.8% in rectal resections. Additionally, other studies have observed that mortality is higher in AL after rectal resection with rates reaching up to 22%-50%.7,34,35 Therefore, the risk factors causing AL should be well defined in order to treat it effectively once it develops.

Previous studies have associated AL with male sex, advanced age, lower anastomosis, malignant disease, high American Society of Anesthesiologists (ASA) score, long surgical time, emergency surgery, preoperative RT, perioperative blood loss, and transfusion.30,36,37,38,39,40,41,42,43 One study showed that male sex and rectal cancer were independent risk factors for both early and late AL. For early AL, younger age, increased body mass index (BMI), laparoscopic surgery, emergency surgery, and lack of guided ileostomy were deemed risk factors, while the Charlson Comorbidity Index, high ASA scores, additional resection due to tumor growth, and preoperative RT were deemed risk factors for late AL. Several studies have discovered higher AL frequency in males than in females, probably due to differences in pelvic anatomy29,44,45, while others found no difference between the sexes in terms of AL.46,47,48 Many of the surgical-related risk factors for early AL reflect surgical difficulty. One study showed that laparoscopic surgery was an independent risk factor for early AL.22 whereas others found no difference in terms of AL between laparoscopic surgery and open surgery.49,50 In two separate studies, AL frequencies in patients with low anterior resection were 10%8 and 11%.51 Those studies that included patients who underwent anterior resection, low anterior resection, or very low anterior resection found no difference between these types of surgeries in terms of AL development. However, AL was detected in 23.5% of our patients, which was slightly higher than the rates in the literature. Mortality rate in AL patients was 28.2%, suggesting that AL development did not increase mortality. In addition, our univariate analysis showed that sex, age, tumor size, perineural involvement, and lymphatic invasion did not have significant effects on AL development. Although stage 3-4 rectal cancer and poorly differentiated or mucinous adenocarcinoma were shown as independent risk factors for early AL in one study21, this was not the case in another study.22 In fact, we observed a relationship between N2 lymph node involvement (stage 3C and 4 rectal cancer) and AL, similar to the study by Shin et al.21

The effects of NT RT or CRT on AL development are controversial. A prospective study showed that short-term NT RT does not increase AL risks.17 In while another prospective study showed that NT CRT therapy was a risk factor for AL in patients undergoing laparoscopic surgery with change in the direction of stoma. However, the same study could not demonstrate NT CRT therapy as a risk factor for AL in all patients undergoing low anterior resection due to cancer.18 Similarly, other studies showed that preoperative RT or CRT are a risk factor for late AL.19,20,21,22 However, in a study comparing AT and NT CRT, no difference was found between the two groups in terms of AL development5 Likewise, our study found no difference in AL between patients who received CRT and patients who received CT or RT as NT. We also found no difference in AL between patients who received CT and RT as CRT and AT.

Although serum CEA increased in 17%-47% of patients with colorectal cancer52,53, its sensitivity is not high enough to be used as a screening test. Nevertheless, serum CEA levels may have a prognostic value for rectal cancer as prognosis worsens in patients with the same stage of the disease but with CEA values higher than 5 ng/mL.54 In our study, the CEA cut-off value was accepted as 10 ng/mL since our biochemistry laboratory used different reference values. Our data on high mortality rate in patients with higher CEA levels are consistent with the literature. The absence of relationships between preoperative and postoperative CEA levels, as well as postoperative CEA levels and survival, confirms that serum CEA levels cannot be used as a screening test because of the lack sensitivity.

Study Limitations

Our study has some limitations due to its single-centered and retrospective nature. We also excluded patients undergoing abdominopelvic resection and those undergoing emergency surgery from the study. Additionally, early and late AL discrimination was not performed in patients with AL. Furthermore, we had no data regarding interventions performed on patients who developed AL. On the other hand, our study’s strength lies in its high number of patients (n=319), reflecting 10-year clinical data with 2-8 years of follow-up.


In conclusion, we found no difference in terms of AL development between patients receiving NT and patients receiving AT. The use of RT, CT, or CRT as NT or AT did not increase the risk of AL. Additionally, mortality did not increase in patients with AL. We recommend the continued use of these treatments for rectal cancer because of better local control, overall survival, and sphincter function protection rates.


Ethics Committee Approval: Trakya University Faculty of Medicine Scientific Research Ethics Committee (no: 18/13, date: 06.11.2019)

Peer-review: Internally peer reviewed.

Authorship Contributions

Surgical and Medical Practices: N.A., İ.E.C, İ.C., Concept: N.A., İ.E.C, Design: N.A., İ.E.C, Data Collection or Processing: N.A., İ.E.C, Analysis or Interpretation: N.A., İ.E.C, Literature Search: N.A., İ.E.C, Writing: N.A., İ.E.C

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.


We would like to acknowledge for their outstanding scientific proofreading and editing services that was provided for this manuscript.

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