Patients
The study was approved by our institutional review board (KNUCH 2020-04-034). In accordance with the institution’s guidelines and regulations for retrospective study, the institutional review board waived the requirement for informed consent (institutional review board of Kyungpook National University Chilgok Hospital). We performed this study according to the Declaration of Helsinki.
We analyzed data from our hospital’s prospectively collected colorectal cancer registry for patients treated between January 2011 and March 2017. We reviewed patients with rectal cancers located within 12 cm from the anal verge during initial imaging and who underwent neoadjuvant CRT. Patients with stage IV tumors were excluded. Tumor location was assessed using digital examination, rigid sigmoidoscopy, or pelvic magnetic resonance imaging (MRI). All patients underwent physical examinations and chest, abdominal, and pelvic computed tomography (CT) and pelvic MRI. After neoadjuvant CRT, restaging was performed 6–7 weeks later via pelvic MRI and chest, abdominal, and pelvic CT.
Neoadjuvant Treatments
Neoadjuvant CRT was recommended for patients with cT tumors of any N1–2 stage or cT3–4N0 disease. Patients underwent concurrent CRT, comprising a total irradiation dose of 45–50.4 Gy, delivered at 2 Gy per day, 5 days per week for 5 weeks, and concurrent chemotherapy included a continuous infusion of 5-fluorouracil (5-FU)/leucovorin or oral capecitabine. During the study period, the most common chemotherapeutic regimens consisted of 5-FU 425 mg/m2 intravenous bolus plus leucovorin 20 mg/m2 intravenous bolus for 4 days, during weeks 1 and 5 of radiation, or oral capecitabine 825 mg/m2 twice daily, 5 days per week for 5 weeks. Surgery was scheduled 7–9 weeks after the completion of radiation.
Surgical Procedures
Patients underwent mechanical bowel preparation before surgery. A standard total mesorectal excision was performed as described previously [22,23]. We performed a high ligation of the inferior mesenteric artery, medial-to-lateral mobilization of the left colon, complete mobilization of the splenic flexure, and sharp dissection of the pelvis with a nerve-sparing technique. Selective lateral pelvic lymph node dissection was performed in patients with suspected lateral pelvic node metastases identified using initial imaging [24]. Sphincter-saving was performed in all patients, except when the levator ani muscle had been invaded by the tumor. Our policy was a DRM is >2 cm for upper and mid rectal cancers. For low rectal cancers, we attempted to achieve a distal clearance margin of ³0.5 cm for sphincter preservation. Anastomosis was performed using either double-stapled, end-to-end, or hand-sewn techniques, except for abdominoperineal resections (APRs). All procedures were performed by four experienced surgeons (G.-S.C., J.S.P., S.Y.P., and H.J.K.) who have each performed over 100 colorectal cancer surgeries per year.
Histopathology
The surgical specimens were first inspected externally to locate the tumor, and the presence of any obvious perforation was recorded intraoperatively [25]. The specimens were then transferred to the pathology department and examined by two specialist pathologists (G.S.Y. and A.N.S.) with > 10 years of experience in colorectal cancer pathology. The non-peritonealized surface of the specimen was marked with green ink to enable subsequent identification of the CRM. After this, the specimen was opened along the anterior aspect and fixed in a large volume of 10% neutral-buffered formalin overnight. Subsequently, the tumor size and distance of the tumor from the proximal and distal resection margins were measured. The DRM was defined as the distance between the lower edge of the primary rectal cancer to the resection margin of the specimen. In the case of stapled anastomoses, donut rings were not included in the measurement but were examined microscopically to determine the involvement of any viable tumor cells. If proximal or distal resection margins of £1.5 cm were detected visually, appropriate blocks were selected to cover the closest approximation to those margins and then evaluated microscopically. The CRM was defined as the closest distance from the outermost part of the viable tumor cells to the inked resected specimen. The CRM was measured using a microscope graticule or ruler, and CRM negativity was defined as a distance of >1 mm [26]. The pathologic stage of each tumor was assigned following the guidelines from the 7th edition of the American Joint Committee on Cancer staging manual for colorectal cancers [27]. Regression of the primary tumor in response to neoadjuvant CRT was assessed based on the TRG, as described by Rodel et al. [28].
Adjuvant Chemotherapy
The most common adjuvant chemotherapeutic regimens were four more cycles of fluorouracil and leucovorin (fluorouracil 400–425 mg/m2 per day plus leucovorin 20 mg/m2 per day on days 1–5, every 4 weeks) or eight more cycles of modified FOLFOX 6 (oxaliplatin 85 mg/m2 on day 1, leucovorin 400 mg total dose over 2 h on day 1, fluorouracil 400 mg/m2 bolus on day 1, followed by 2,400 mg/m2 over 46 h, every 2 weeks).
Follow-up
Patients were followed up via clinical examination; blood assays for carcinoembryonic antigen; and chest, abdominal, and pelvic CT every 3 months within the first 2 years and every 6 months thereafter. Patients routinely underwent colonoscopy in the first and fourth years after surgery. Local recurrence was defined as recurrent disease within the true pelvis with or without distant metastases and classified into central (anastomotic, anterior, presacral, and perineal) and lateral (pelvic sidewall) recurrence [11,12]. Distant recurrence was defined as recurrence beyond the locoregional area.
Statistical Analysis
Continuous variables were first tested for normality (Shapiro–Wilk Normality test). The two groups based on DRM (≥1 cm and <1 cm) were compared using two-sample Student’s t tests or Kruskal–Wallis Rank Sum tests. Categorical variables were assessed using the chi-square test or Fisher’s exact test. Logistic regression was applied to multivariable analysis to identify independent risk factors for local recurrence. Variables with a p-value of <0.2 in the univariate analysis were selected for the multivariable analysis. DFS was defined as the period from the date of initial surgery to the date of disease recurrence or death. Time to local recurrence was calculated from the date of initial surgery until local recurrence was noted; patients with no recurrence were censored at the date of the last follow-up, or at death. Patient survival was estimated using the Kaplan–Meier method, and survival curves were compared using a log-rank test. All analyses were conducted using the R project for Statistical Computing, Version 4.0.1 (R Development Core Team, Vienna, Austria; https://www.r-project.org), and p values <0.05 were considered statistically significant.