In addition to local recurrence and survival rates, circumferential margin (CRM) positivity represents another important endpoint to evaluate

the effectiveness of neoadjuvant treatment, since most local relapses originate from the surgical margin. This Istanbul R0-1 prospective randomized study was designed to compare the efficacy of four-week (4 w) versus eight-week (8 w) delay before surgery after concomitant neoadjuvant chemoradiotherapy in terms of local recurrence, circumferential margin positivity, and overall survival in cT3-4/N0+, mid- and distally localized (intraperitoneal) rectal cancers. Material and methods Patient eligibility and enrollment To be eligible Inhibitors,research,lifescience,medical for this single Inhibitors,research,lifescience,medical center prospective randomized trial, patients had to present with locally advanced (T3-4 or N0/N+) low-

(Level I or below 59 mm from the anal verge) or mid-rectum (Level II or 60-119 mm from the anal verge) rectal adenocarcinoma. Exclusion criteria included secondary malignancy, inflammatory bowel disease, uncontrolled diabetes Inhibitors,research,lifescience,medical or infection, pregnancy, and an ECOG performance status greater than 2. The study protocol was approved by Surgical Review Board of Istanbul University, Istanbul Medical Faculty. Study procedures were in accordance with Declaration of Helsinki and all patients gave informed consent prior to study entry. Primary endpoint was local recurrence and secondary endpoints were overall survival and circumferential margin positivity. Randomization and treatments Patients were randomly assigned into two groups: Group A (4 w) and Group B (8 w). All patients received neoadjuvant chemoradiotherapy prior to surgery. Patients in Group A (4 w) underwent total mesorectal excision Inhibitors,research,lifescience,medical (TME) with curative Inhibitors,research,lifescience,medical intent four weeks after neoadjuvant therapy,

whereas patients in Group B (8 w) received surgery after eight weeks. For pretreatment staging, flexible colonoscopy, endorectal ultrasonography (EUS), computerized tomography (CT) or magnetic resonance imaging (MRI) of the pelvis were used. In addition, abdominal or thoracic CT was used to rule out distant metastasis. The neoadjuvant radiotherapy regimen included 45 cGy radiation delivered to the posterior pelvis below in 25 Mdm2 signaling pathway inhibitors fractions (1.8 Gy per fraction) over 5 weeks. Neoadjuvant chemotherapy consisted of 225 mg/m2·day 5-fluorouracil infusion using catheter or implantofix over the same 5 weeks. All patients were examined every week by attending physicians during chemoradiotherapy. After total mesorectal excision, optional adjuvant chemotherapy was offered as 4 cycles of FU-FA treatment (Mayo regimen) within the six weeks after surgery. Pathological examination of the surgical specimens Resection specimens were thoroughly sectioned and at least five sections were submitted per tumor (unless the primary was so small that fewer sections can be done) for microscopic examination.