The study protocol was approved by the Medical Ethics Committee of Peking University Cancer Hospital, and the content was in accordance with Helsinki Declaration
Data and participants
A retrospective cohort study was performed in Beijing Cancer hospital. Eligible patients received follow-up phone calling to complete the LARS score. The inclusion criteria were 1) an anterior resection performed for a diagnosis of rectal adenocarcinoma between 0 and 15 cm from the anal verge, including patients with neoadjuvant chemoradiotherapy and direct surgery; 2) The patients were followed up for more than 3 years. The five problems related to anal function were as follows: exhaust control; fecal retention of loose stools; frequency of defecation; defecation within 1 hour; urgency of defecation; the incidence of diarrhea; 3) with complete baseline MRI examination; 4) with complete clinical information, including age, gender, BMI, TNM stage, the distance between the lower edge of tumor and anal edge, operation method (laparoscopy or laparotomy), postoperative complications, temporary stoma or not. The exclusion criteria were an incomplete cancer resection, recurrence, metastatic disease, intestinal stoma or patients whose bowel continuity had been restored for <12 months, dementia; with pelvic surgery history before; long term use of drugs that may affect intestinal function and anal defecation function (such as lactulose and other drugs that may affect gastrointestinal motility and defecation condition) after anal preservation; (4) lack of complete clinical and pathological materials and follow-up data; (5) postoperative complications (such as rectovaginal fistula, anastomotic leakage, etc.) affect the quality of defecation; (6) patients with mental disorders and other patients who cannot accurately judge and describe their own conditions; (7) if there is a lack of answers in questionnaires, they shall be eliminated.
LARS score questionnaire
The Low Anterior Resection Syndrome (LARS) score was developed on the basis of patient reported symptoms. The LARS score was computed and categorized into 3 groups: no LARS (0–20 points), minor LARS (21–29 points), or major LARS (30–42 points), according to the guidelines . The time of questionnaire survey was from March 2019 to November 2019. The patients were followed up by face-to-face interview or telephone. Before filling in, the questionnaire will be explained to the patients in detail, and the patients or their families will fill in the questionnaire according to the actual situation. Some questionnaires with missing answers were excluded.
MRI scanning and measurement
All MRI examinations were performed with a 3.0-T MR unit (Discovery 750; GE Healthcare, Waukesha, Wis) by using an eight-channel phased-array body coil in the supine position. Without any bowel preparation, patients were injected intramuscularly with 20 mg of scopolamine butylbromide 30 minutes prior to imaging to reduce colonic motility. The rectal MRI protocol included axial, axial oblique, coronal, and sagittal T2-weighted images; transverse T1-weighted images; diffusion-weighted images. DWI images were obtained using single-shot echo-planar imaging with 2b-factors (0 and 1,000s/mm2), and repetition time (TR)= 2800ms, echo time (TE)=70ms, field of view (FOV)=340x340mm, matrix=256x256, thickness=4.0mm, and gap=1.0mm. Apparent diffusion coefficient (ADC) maps were generated automatically and included both b values in a monoexponential decay model. High-resolution T2WI images were obtained using fast recovery fast spin echo with TR=5694ms, TE=110ms, FOV=180x180mm, echo train length=24, matrix=288x256, thickness=3.0mm, and gap= 0.3 mm.
MRI measurements included (Figure 1): the thickness of levator ani (TLA), Anal-rectal joint (ARJ)(TARJ), internal and external anal sphincter complex thickness (TIS and TES), the distance between tumor’s lower edge and ARJ (DTA), the distance between tumor’s lower edge and anal verge (DTV: DTA + anal canal length), anal canal length, anorectal angle, interspinous diameter (ISD).
Neoadjuvant therapy, surgery and follow-up
All patients received preoperative chemoradiotherapy followed by TME. Intensity-modulated radiation therapy (IMRT) was administered using a Varian Rapidarc system (Varian Medical Systems). The IMRT regimen comprised 22 fractions of 2.3Gy (gross tumor volume, GtV) and 1.9Gy (clinical target volume, CtV). A total dose of 50.6Gy (GtV) /41.8Gy (CtV) was administered 5 times per week over a period of 30days [11,12]. The GtV was defined as the volume of the primary tumor including the mesorectum. The CtV was defined as the primary tumor, mesorectal region, presacral region, mesorectal lymph nodes, lateral lymph nodes, internal iliac lymph node chain, and pelvic wall area. Capecitabine treatment was administered concurrently with IMRT at a dose of 825mg/m2 orally twice per day. Low-anterior resection (LAR) based on the principle of TME was recommended 8-12 weeks or more after the completion of chemoradiotherapy. The decision of an LAR were discussed through a MDT discussion before surgery and finally made by intraoperative discretion by the senior surgeon. Double-stapling technique was used for all cases, and a safe distal margin of at least 2cm was achieved in most of cases. Creation of a defunctioning ileostomy and placing pelvic drainages were routinely performed. Adjuvant chemotherapy was routinely recommended to the patients. Capecitabine alone, mfolfoX6, or Capeox were prescribed at the discretion of the physician. Patients were followed at 3-month intervals for the first 2 years after treatment and then at 6-month intervals for the next 3 years. Evaluations consisted of physical examination, serum CEA, a complete blood cell count, and blood chemical analysis. Proctoscopy, abdominal ultrasonography, CT scanning of the abdomen and pelvis, chest X-ray/CT were also routinely performed every 6 to 12 months.
All analysis was conducted using SPSS (Version 22.0, SPSS Inc, Chicago). A two-tailed P value less than 0.05 indicated statistically significance. Continuous variables were described as means ± standard deviations, categorial variables were described as numbers and proportions. Independent t test and/or chi-square test were used to compare factors between two groups for detecting LARS-associated factors. Multivariate logistic regression was conducted to screen for independent factors for predicting severe LARS, odds ratios were calculated with 95% confidence interval. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance for predicting severe LARS; the area under the ROC curve (AUC) with its 95% CI was calculated. The cutoffs were determined using the maximum Youden’s method.