Background
Colorectal cancer (CRC) is the third most common malignancy among men and women [
1], and rectal cancer accounts for up to 50% of all colorectal cancers. Neoadjuvant chemoradiotherapy followed by total mesorectal excision (TME) has become the standard care for T3-4 and node-positive tumors in rectal cancer [
2]. However, after TME surgery, a certain number of patients will experience anastomotic complications, including anastomotic leakage and stenosis. Anastomotic leakage is a feared complication after anterior resection as it increases postoperative mortality. A temporary ileostomy created at the time of surgery may reduce the potential leak [
3]. Rectal stenosis represents a challenging complication after rectal resection and can become a long-term complication among rectal cancer patients, it will seriously affect the quality of life in high-grade stenosis patients. The pathophysiology and contributing factors have only been partially understood. Postoperative anastomotic leakage and radiotherapy have been reported as predisposing factors [
4‐
6]. In most of the views, pelvic radiotherapy is the most important reason for rectal stenosis. However, patients without receiving radiotherapy also suffer stenosis. Few studies published to date have analyzed the incidence of rectal stenosis after ARR in rectal cancer patients. This study evaluated the incidence and risk factors of rectal stenosis so that effective measurements can be adopted to mitigate the event.
Patients and methods
Patients and treatment
All of the consecutive patients diagnosed with rectal adenocarcinoma and who received anterior rectal resection (ARR) at Fudan University Shanghai Cancer Center between January 2006 and December 2018 were retrospectively studied, including receiving neoadjuvant chemoradiotherapy and without receiving radiotherapy. The exclusion criteria were short-course radiotherapy (5 Gy × 5 fractions), no colonoscopy follow-up, abdominoperineal resection (APR), and palliative resection. Neoadjuvant chemoradiotherapy was indicated for patients with lesions of the lower and middle rectum as T3 or T4 and for those lymph nodes suspected of being metastatic. The intensity-modulated radiation therapy (IMRT) technique was performed with a photon beam of 6-MV energy. The planned treatment dose of radiation was 50 Gy in 25 fractions (2 Gy/fraction), 5 fractions/week. The RTOG contouring atlas was referenced for clinical tumor volume (CTV) contouring [
7]. Concurrent chemotherapy was conducted in 97% of all the patients, and concurrent chemotherapy regimens are capecitabine, oxaliplatin and irinotecan (Additional file
1: Table S1). Capecitabine was administered concurrently with radiotherapy on radiation days. Patients received capecitabine 825 mg/m
2 bid orally on radiation days for the capecitabine regimen. Approximately ten years ago, we conducted a phase 2 clinical trial that explored oxaliplatin's role with capecitabine concurrent with radiotherapy in advanced rectal cancer patients (unpublished data). For the oxaliplatin regimen, patients received oxaliplatin 50 mg/m
2 every week, concurrent with capecitabine 625 mg/m
2 bid orally on radiation days. Recently, irinotecan and capecitabine concurrently with radiotherapy showed excellent effects in our phase 1, 2 [
8,
9] and phase 3 trials [
10]. Patients received capecitabine (625 mg/m
2, bid) orally along with weekly irinotecan for 5 weeks according to the UGT1A1/28 genotype. The weekly irinotecan dose was 80 mg/m
2 in patients with the *1*1 genotype and 65 mg/m
2 in those with the *1*28 genotype. Surgery was undertaken following the principles of TME for patients. 439 patients received neoadjuvant chemoradiotherapy following ARR and 545 patients underwent ARR without preoperative or postoperative radiotherapy.
We also retrospectively studied 33 patients who received non-operative strategy after achieving clinical complete response (cCR) between 2015 and 2020.
The potential risk factors analyzed for the stenosis were gender, age, tumor distance from the anal margin (≤ 5 cm or > 5 cm), tumor staging (cT and cN status were assessed by magnetic resonance imaging (MRI)), body mass index (BMI), smoking, drinking, hypertension, diabetes, radiotherapy dose (RT dose), concurrent chemotherapy, pattern of surgery (open or laparoscopic), occurrence of anastomotic fistula, protective ileostomy, tumor regression grade (TRG) score, and RT response (pCR[pathologic complete response]/almost pCR or poor response). The work was in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) and was approved by the hospital's Medical Ethics Committee.
Evaluation of rectal stenosis
Rectal stenosis is difficult to diagnose and grade, colonoscopy is commonly used to evaluate stenosis. Patients were encouraged to engage in a regular follow-up after the operation. Colonoscopy was performed before the restoration of protective ileostomy or the first year after surgery, and every 2–3 years after that, or in case of new symptoms or suspected relapse. Anastomotic or rectal stenosis was diagnosed when a 12-mm diameter colonoscopy could not be passed through the rectum. We found that stenosis was mainly located above the anastomoses, and not at the site of anastomoses. Colonoscopy was performed on 439 patients, who underwent neoadjuvant chemoradiotherapy followed by ARR. A group of 545 patients who received ARR without radiotherapy and underwent colonoscopy examination was formed to explore whether other factors affect rectal stenosis regardless of radiotherapy. Further, 33 patients who received nonoperative management when exhibiting cCR after neo-adjuvant chemoradiotherapy was analyzed for stenosis.
Statistical analysis
Statistical analysis was conducted using SPSS software. We analyzed the categorical variables using the chi-square test and the quantitative ones with the Student's t-test (mean and standard deviation [SD]). Initially, we performed a univariate analysis for each independent variable. Then, the candidates who had a p-value ≤ 0.05 were considered for the multivariate model. P < 0.05 was considered statistically significant and marked with asterisks (*).
Discussion
Radiotherapy is an important management among multidisciplinary treatment in rectal cancer, reducing local recurrence and increasing organ preservation. Radiotherapy also plays more important roles in immunotherapy era. However, radiotherapy is always challenged by its adverse effect, such as proctitis and stenosis. In most of the views, rectal stenosis after anterior resection for rectal cancer results from pelvic radiotherapy. However, patients without receiving radiotherapy also suffer from stenosis. Adverse effects cannot be simply attributed to radiotherapy when patients receive multidisciplinary treatments. We were interested in answering the question that which factors are associated with rectal stenosis and which is the most important factor. We studied three groups of patients to explain this issue: patients receiving neoadjuvant chemoradiotherapy followed by ARR, patients receiving ARR without neoadjuvant or adjuvant radiotherapy and patients receiving non-operative management after achieving cCR. From our data, both radiotherapy and preventive ileostomy were implicated in rectal stenosis and were independent risk factors.
It has been reported that the incidence of rectal stenosis ranges from 2 to 30% [
11‐
14]. The incidence of stenosis was 26.0% in patients with preoperative radiotherapy and 7.5% in patients without radiotherapy at our center. The incidence of stenosis is in accordance with the reported range of 2–30%. The absence of a precise definition account for this wide range. It is high in the preoperative radiotherapy group at our center. There are some reasons to explain this finding. First, we recorded all the patients who had difficulty in passing a 12-mm colonoscopy, including asymptomatic patients. Second, radiotherapy contributed to stenosis; the high rate of stenosis was in the preoperative group. Preoperative radiotherapy is widely used at our center for patients with locally advanced disease. Finally, patients who received preoperative radiotherapy were more likely to have a lower tumor location and undergo preventive ileostomy; after that, the occurrence of stenosis was more frequent.
In most of the views, pelvic irradiation induces rectal stenosis [
6]. According to our univariate analysis, males, smoking and ileostomy were significant risk factors for stenosis in the preoperative chemoradiotherapy group. Multivariate analysis confirmed the significance of ileostomy, as 30.5% of patients with ileostomy experienced stenoses, whereas the incidence was only 16.1% in the non-stomy group (
P < 0.001). In non-radiotherapy patients, stoma was also the only independent factor in multivariate analysis (OR = 2.533,
P = 0.001). Preventive ileostomy was the only independent factor associated with stenosis in both preoperative radiotherapy and non-radiotherapy patients in our study. Most patients with resectable tumors would undergo surgery either after neoadjuvant radio- or chemotherapy or as the first step of the treatment. The common and dangerous complication is anastomotic leakage, particularly in tumors located not far from the anal verge. Due to the fistula's high rate, most authors recommend performing a loop ileostomy for protecting anastomoses [
3,
15]. The stomy will be closed several months later. Some patients will lose the chance of stoma closure for several reasons, such as distant metastasis and stenosis. Interestingly, the rate of stenosis was very low in patients with non-operative management, indicating that radiotherapy is not the main factor to rectal stenosis. In fact that radiation treatment is not so important in the pathogenesis of rectal stenosis, is also highlighted by the lack of increase of this complication when delivering higher radiotherapy doses, up to 60 Gy, with simultaneous integrated boost. [
16,
17]
We found that most of the stenoses occurred above the anastomosis instead of at the anastomosis. MRI images showed that the thickness of the bilateral obturator interrus increased significantly after chemoradiotherapy compared to pretreatment [
18]. Rectal stenosis may be caused by radiation-induced fibrosis of the pelvic wall soft tissue. Muscle fibrosis may restrict the movement of the rectum, and this lack of motion lead to stenosis. On the other way, pelvic nerve damage induced by surgery or radiotherapy will limit the motion of the rectum too [
19]. It was revealed that male and smoking are stenosis risk factors in our univariate analysis in preoperative patients. This agrees with the results of Kim MJ and Bannura GC, i.e., that a history of heavy smoking was significantly associated with anastomotic complications, such as leakage and stricture [
20,
21]. Smoking exerts a negative effect on tissue oxygen supply through several mechanisms. Ischemia at the anastomosis site can cause anastomotic leakage or stricture by impeding the healing process.
The identification of risk factors for anastomotic complications can help decrease their frequency. Potential risk factors associated with rectal stenosis are preoperative radiotherapy and preventive ileostomy. Preoperative radiotherapy is confirmed as a standard treatment for locally advanced rectal cancer because it reduces local recurrence compared with postoperative radiotherapy [
11,
22]. Thus, it cannot be omitted. Preventive ileostomy reduces the occurrence of leakage. Stools were not excreted through the rectum in patients with ileostomy; pelvic fibrosis can easily form because the rectum and pelvic muscles cannot move. The longer the preventive ileostomy remains, the more easily the fibrosis and stenosis will occur. In our study, the restoration of preventive stomy for more than six months will increase the occurrence of stenosis. Early closure of the protective ileostomy and anal functional training may be essential to reduce stenosis after surgery. Patients do not receive restoration during adjuvant chemotherapy result to late closure of preventive ileostomy. According to the trial of IDEA [
23], some patients with low risks need fewer chemotherapy cycles and can receive early closure of stomy. Recently, the total neoadjuvant therapy (TNT) has been showing increased pCR and outcomes [
24,
25]. In this new mode of treatment, patients do not need postoperative chemotherapy or need less. Thus, preventive ileostomy can be closed early. Some anti-fibrotic medicines have been evaluated by pre-clinical studies. Several clinical trials have shown some effects on radiation-induced fibrosis or other fibrotic diseases, such as idiopathic pulmonary fibrosis [
26‐
28]. However, these have not been widely used as a standard treatment at the clinic for radiation fibrosis. More effective and tolerable anti-fibrotic drugs should be studied for use at the clinic to reduce stenosis.
There are limitations in this study. First, this is a retrospective study, there can be a recall bias, and the symptoms associated with stenosis did not been record. A further limitation is that stenosis could not be graded according to retrospective colonoscopy reports.
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