Low Anterior Rectal Resection; The Impact of Anastomotic Fistula on Incidence and Severity of Low Anterior Resection Syndrome

Highlights

✓

Despite its higher frequency, anastomotic leakage does not appear to substantially increase the risk of LARS.

✓

Conversely, the main factors influencing the occurrence of LARS included neoadjuvant chemotherapy and biological sex.

Abstract

Objectives. Low anterior resection is a common surgical procedure for rectal cancer, but it is associated with a distressing complication known as Low Anterior Resection Syndrome (LARS). The incidence of LARS varies, with severe symptoms persisting in some patients even years after surgery. This study aimed to investigate the association between anastomotic leak and LARS severity in rectal cancer patients. Methods. A retrospective analysis was conducted on 100 rectal cancer patients who underwent LAR between 2017 and 2021. Patients were categorized based on LARS questionnaire responses into groups with anastomotic leakage and LARS, LARS alone, or no LARS. Various factors, including demographics, comorbidities, tumor characteristics, and surgical details, were analyzed for their association with LARS. Results. In our study, anastomotic leakage was observed in 23 patients, and 17 of them subsequently developed LARS. Male gender, age over 70, and neoadjuvant therapy were identified as risk factors for LARS. Additionally, LARS was more prevalent in patients with medium and low rectal cancers and those with a protective ostomy. Conclusion. Our findings suggest that male sex and neoadjuvant chemoradiotherapy are associated with the development of LARS in rectal cancer patients undergoing low anterior resection. The timing of stoma closure and the extent of neorectal reservoir may also impact LARS severity.

Introduction

The most commonly cited medium-term adverse consequence of low anterior resection (LAR) in recent times is bowel function disorder, termed "low anterior resection syndrome"(LARS). Manifestations of LARS are fecal incontinence, abnormal stool frequency, urgency, voiding, and sexual dysfunction [1,2].

LARS exerts a direct and discernible influence on the individual’s quality of life (QoL), with its profound implications extending to encompass the overall well-being, which is significantly shaped by both the syndrome itself and the associated disease and therapeutic interventions [3].

The incidence of LARS varies between studies, but is commonly reported in more than half of rectal resection patients. According to a cohort study in Denmark on 961 rectal resection patients, LARS occurred in 64% of rectal resection patients; of these, with 41% experiencing severe symptoms [4]. LARS symptoms typically improved or resolved within 6 months to 1 year postoperatively [1,5]. However, there are reports that about 50% of patients complain of symptoms even at 15 years after surgery [6,7]. Therefore, LARS can significantly impact patients’ quality of life over an extended period.

Treatment for LARS varies depending upon symptom severity. "Minor LARS" can be treated conservatively, while surgery is reserved for patients with more severe symptoms or "major LARS" [8].

Risk factors affecting the incidence and severity of LARS include preoperative radiotherapy, anastomosis near the anal verge, anastomosis without a protective ileostomy and anastomotic leakage (AL) [2]. AL is a complication encountered in approximately 20% of patients undergoing end-to-end anastomosis after rectal resection and is a strong risk factor for permanent stoma [9,10]. However, in cases where patients reject a permanent ostomy, the operator maintains continuity of the intestinal tract, except in unavoidable cases such as sepsis due to AL. In the long term, all of these factors can worsen the quality of life of patients [11]. Numerous studies have explored the relationship between anastomotic leakage and low anterior resection with a focus on prevention [10,12]. However, limited research was invested into the relation between AL and the development of LARS. Currently there is a lack of clinical evidence demonstrating that inflammatory reactions, such as fibrotic scarring or chronic sinus formation induced by AL can lead to damage in the remaining rectum and subsequently result in LARS. If research can establish a clear association between LARS and AL, it could provide a rationale for preventing AL as a means of averting the occurrence of LARS.

Therefore, the primary objective of this study was to analyze the relationship between AL and the severity of LARS in patients diagnosed with rectal cancer.

Materials and Methods

Study Design

We performed a retrospective analysis on patients undergoing low anterior resection for rectal cancer. The study period was from January 2017 to December 2021 and was carried out in the Ist Clinic of Surgery at the Emergency Clinical Hospital of Craiova.

Patients were meticulously selected based on specific inclusion and exclusion criteria. The inclusion criteria consisted of patients diagnosed with rectal cancer, undergoing total mesorectal excision (TME), with the tumor location ranging from 5 to 15 cm from the anal margin, or tumors located over 15 cm but with a low infraperitoneal anastomosis. The exclusion criteria consisted of patients with unresectable disease, patients with TME with tumor invaded margins or tumor ruptured during surgery, and those with colon or small bowel resection involving more than 100 cm of bowel. Cases that were lost to follow-up due to various reasons, such as patient death, patients who declined to participate in the study or who could not be reached by the study investigators, were also excluded.

Following the surgical procedure, patients were asked to complete the LARS questionnaire. Subsequently, patients were categorized into the following groups based on their responses: <AL + LARS Group>, <LARS group>, and <No LARS Group>.

Statistical Analysis

Data were analyzed using descriptive and inferential statistics. Continuous variables were expressed as mean±standard deviation (SD) or median (interquartile range, IQR). Categorical variables were expressed as number (percentage). The impact of all risk factors was calculated using Chi-squared or Fisher’s Exact Test for categorical variables. Mann-Whitney’s test was used to assess the differences between continuous variables. Univariate and multivariate binary logistic regression was performed to assess the risk factors for LARS (major or minor). All p values reported were obtained at the significance level of 5%, at two-sided. Data were analyzed using GraphPad Prism 10.0.3 (GRAPHPAD SOFTWARE, LLC, Boston, USA).

Ethics Committee

This study involving human participants adhered to the principles outlined in the Declaration of Helsinki and followed internationally recognized ethical guidelines for medical research. All participants provided informed consent before their inclusion in the study, and measures were taken to protect their confidentiality throughout the research process. Ethical approval was sought and obtained from the Ethics Committee of the University of Medicine and Pharmacy of Craiova (no. 121/30.07.2021).

Diagnosis and Staging

In all patients, diagnosis was made upon colonoscopy with biopsy, patients with obstructing tumors that could not be passed by the endoscope were submitted to careful colic intraoperative exploration and colonoscopy after an interval of 1-3 months postoperatively.

Laboratory workup consisted in complete blood count, blood chemistry and coagulation tests, and tumor markers (CEA, CA 19-9). Stadialization of the disease was made with pelvic MRI to assess local extension and chest, abdomen, and pelvic CT scan with intravenous contrast for detection of distant disease spread.

Preoperative Preparation

Every patient underwent mechanical bowel preparation with 4 liters of polyethylene glycol (PEG) administered 48 hours before the intervention. Additionally, antibiotic prophylaxis with Metronidazole 500 mg was administered three times per day, starting concurrent with the mechanical preparation. Oral food and liquids were discontinued at least 6 and 4 hours before surgery, respectively.

A single dose of second-generation cephalosporin was administered at the induction of anesthesia, and it was repeated if the intervention lasted longer than 3 hours or in case of severe intraoperative bleeding. In some patients, when there was an intraoperative spillage of bowel content, the prophylaxis was continued for 24 hours postoperatively. Intraoperatively, a standard general anesthesia with orotracheal intubation and goal-directed fluid therapy was administered by the anesthesiology team.

Thrombosis prophylaxis was provided using LMWH (low molecular weight heparins), started in the postoperative period after at least 8 hours. In high-risk patients for developing deep vein thrombosis, as estimated by the Caprini score [13], LMWH was administered more than 8 hours before surgery.

Technique

Patient was positioned in a Lloyd Davies position, with right arm tucked to the body. For the open approach, a midline laparotomy prom pubis to umbilicus extended cranially in case of splenic flexure mobilization was preferred. A high tie was employed in all cases to allow good mobilization of the descending and sigmoid, splenic flexure was mobilized in case of short sigmoid and on every occasion that the surgeon considered necessary, in order to assure a tension free anastomosis. Rectum was dissected in the mesorectal plane. Distal rectum was cut with TA type staplers and anastomosis confectioned with circular stapler 24-29 mm depending on the size of descending or sigmoid colon to accommodate the anvil.

For the laparoscopic approach the same principles were followed. Distal rectum was sectioned with one or two applications of linear endoscopic stapler and then a circular stapled anastomosed was achieved. Drains were used both in open and laparoscopic surgery.

Postoperative Follow-Up

ERAS (enhanced recovery after surgery) principles were followed. Nasogastric suction was removed at the end of surgery, patients were helped out of bed in the next morning and encouraged to walk a few meters in the evening of the 1st postoperative day. A regimen of non-opioid analgesics was employed in all cases, based on paracetamol and metamizole. Clear fluids were initiated in the afternoon of the 1st postoperative day, and semi-solid food from the 2nd postoperative day. In case of postoperative ileus, medication was instituted accordingly and a nasogastric suction was inserted medication failed. The urinary catheter was removed the 3-4th postoperative day, and reinserted in case of urinary retention. All patients had their temperature recorded, drains were verified daily for pus or feces. Anastomosis was checked by digital rectal examination on the 5th or 6th postoperative day. In case of integrity, normal leucocytes, no fever, drains were removed. In case of ileus, fever or leukocytosis, and equivocal findings on digital rectal examination, an abdominal X-ray with water soluble contrast instilled into the rectum through a Foley catheter was performed to identify any possible leak. The procedure was performed either under X-ray or pelvic computed tomography (CT) with i.v. contrast. In case of minimal defect with minimal leak the case was managed conservatively. In those leaks that occurred after the removal of the drains the leakages were managed by transanal drainage with sponge placed through the anastomotic defect.

LARS Questionnaire

For evaluation of LARS the questionnaire developed by Emmertsen and Laurberg was used [4]. Patients were followed for at least one year after surgery and completed a LARS score questionnaire. The LARS questionnaire assesses bowel function and includes the following items: flatus incontinence, liquid stool status, frequency, clustering and urgency. Each item has three options with a defined scoring system used to assess severity. Patients were divided into LARS groups according to their total score - no LARS (0-20), minor (21 - 29) and major (30 - 42).

Anastomotic Leak

AL is a defect in the intestinal wall of the anastomosis site and evidenced by clinical and imaging examination, that is classified into: grade A fistula - does not require therapeutic intervention and does not affect patient management; grade B fistula - requires active therapeutic intervention but can be managed without surgical procedure; and grade C fistula requires reoperation [14]. Clinically, AL signs were defined as fever, abdominal pain, purulent or fecal drainage, signs of peritoneal irritation and postoperative pelvic abscess. All clinically diagnosed AL were confirmed by digital rectal examination, CT scan or contrast-enhanced X-ray.

Results

The study included 100 patients with an average age of less than 70 years, of whom 63 were men and 37 were women. Most cases of LARS were minor (35 vs 21 patients); however, no case of minor LARS was documented among any of the patients diagnosed with AL (

Table 1. General characteristics of the group.

).

Forty-nine patients underwent neoadjuvant therapy represented by radiotherapy or chemo-radiotherapy. The most common comorbidity was cardiovascular disease (41%), followed by obesity (21%), diabetes (13%), lung disease (10%) and smoking (8%); none of these factors was significantly associated with LARS (

Table 2. General characteristics and possible risk factors for LARS.

).

LARS appeared to be more frequent in male patients (p=.0039), in patients aged over 70 years (p=.0227), and in patients undergoing neoadjuvant therapy (p=.0042) (Table 2).

In our study, 15 patients were diagnosed with low rectal cancer, 34 with medium rectal cancer and 51 patients with middle-high rectal cancer. LARS was found to be more frequent in medium and low rectal cancers (p=.0001), but no statistical difference was observed between low and ultralow anastomosis. No statistical difference was found between LARS and cancer staging and surgical approach. The presence of a protective ostomy was also significantly associated with the occurrence of LARS, evident in 13 out of 21 patients who developed this syndrome. Among the different ostomy types, patients with an ileostomy exhibited the highest incidence of LARS cases (p=.0001) (Table 2).

On the univariate analysis, gender and neoadjuvant therapy were found to be risk factors of overall LARS (major and minor). On the multivariate analysis, they were confirmed as independent risk factors for the development of LARS (

Table 3. Univariate and multivariate analysis for development of LARS (major and minor).

).

Of the 54 patients with protective stoma 83.33% were patients with LARS or cases with LARS and AL, and in 75.55% of cases stoma suppression was performed at about 3 months interval.

Among the cohort of 100 patients, 23 individuals experienced anastomotic leakage, with 17 of these cases (77.2%) subsequently developing LARS. However, based on the univariate analysis, none of the three degrees of AL expressed statistical significance in relation to the occurrence of LARS (Table 3).

Discussions

Our study suggests that gender and neoadjuvant chemoradiotherapy concurred to the increased incidence of LARS and symptoms of defecation disorders in rectal cancer patients who underwent LAR. While potential risk factors such as AL, anatomic site of anastomosis, and tumor location might appear as tempting predictors for LARS due to their interconnected pathophysiological mechanisms, our analysis did not provide supporting evidence for these presumptions. These results are complementary to those of previous studies that also evaluated factors affecting LARS and defecation symptoms [15,16].

The accurate assessment of LARS diagnosis hinges upon the precise formulation of questions concerning the patient’s symptoms. Studies indicate that there are a number of factors that aggravate LARS, such as AL, low tumors, preoperative chemo-radiotherapy, extensive rectal excision, and type of preparation. Through this investigation, our aim was to underscore the exacerbating role of AL in the context of LARS.

Daams et al. indicated that healing of gastrointestinal anastomosis in an experimental model occurred through the formation of a fibrotic ’plug’ at the serosal part, which formed a matrix for fibroblasts [17]. Based on this result, the occurrence of AL is considered a negative event for bowel function because of inflammatory changes and excessive fibrotic scarring that may subsequently develop in the pelvic cavity. This can alter the compliance and capacity of the neorectum, which can induce urgency, incontinence and straining [18,19].

AL-induced pelvic sepsis and failure to heal per primam can lead to granulation tissue formation and perianastomotic fibrosis, as well as anastomotic stricture and reduced neorectal reservoir function. Many surgeons advocate routine ileostomy performed in all low rectal anastomoses, although a recent meta-analysis from the UK highlights the importance of complications other than anastomotic fistulas in the ileostomy group, which should always be considered [20]. The same results are highlighted in the RALAR multicenter study of 24 Italian reference centers. Ileostomy did not affect the risk of AL; it prevents disastrous septic outcomes and the need for reintervention [21].

A fundamental question that emerges revolves around determining the optimal timeframe for stoma closure. A recent meta-analysis showed some advantages of early closure in terms of fewer cases of small bowel obstruction and complications at the ostomy site [22].

Some studies have shown that surgery 6 weeks after completion of neoadjuvant therapy leads to LARS, which is aggravated by ischemia and fibrosis caused by progressive endarteritis obliterans and late radiotherapy toxicity. Gastrointestinal tract ulceration causes symptoms such as perforation, fistulization and peritonitis and is associated with an extensive area of fibrosis [23]. Anal sphincter damage is also induced by radiotherapy, which is due to myenteric plexus lesion and smooth muscle hypertrophy [24]. Residual rectum length on magnetic resonance imaging affects the severity of LARS and it is reported that LARS severity is high when residual rectum length is less than 4 cm [25,26].

Reduction in the volume of the neorectal reservoir causes urgency or incontinence. Studies have shown that low tumors or anastomoses < 5 cm from the anal verge are risk factors for exacerbation of LARS symptoms [27,28]. Damage to the internal anal sphincter during rectal mobilization causes passive incontinence, and damage to pelvic floor innervations leads to fecal incontinence and urgency [29,30].

In Ashburn’s study from a US tertiary care institution and in the study by Hultberg et al. negative effects of an LA on LARS were shown, with predominantly disorders of accentuated bowel movement frequency, urgency and increased episodes of incontinence [31,32,33].

Our research is constrained by several limitations, including its retrospective design and a limited patient sample size. Furthermore, only a limited scope of factors has been considered. Aspects such as the histopathologic, biological or intraoperative features can play a significant role in patients’ overall prognosis and may have a certain influence in the occurrence of LARS [34,35].

Conclusions

This study indicates that male patients with neoadjuvant therapy are at risk for LARS after low anterior resection. More multicenter studies are needed to confirm the negative prognostic factors of AL and the relationship with major LARS.