Summary Background Patients with locally advanced rectal cancer who achieve a pathological complete response to neoadjuvant chemoradiation have an improved prognosis. The need for surgery in these patients has been questioned, but the proportion of patients achieving a pathological complete response is small. We aimed to assess whether adding cycles of mFOLFOX6 between chemoradiation and surgery increased the proportion of patients achieving a pathological complete response. Methods We did a phase 2, non-randomised trial consisting of four sequential study groups of patients with stage II–III locally advanced rectal cancer at 17 institutions in the USA and Canada. All patients received chemoradiation (fluorouracil 225 mg/m2 per day by continuous infusion throughout radiotherapy, and 45.0 Gy in 25 fractions, 5 days per week for 5 weeks, followed by a minimum boost of 5.4 Gy). Patients in group 1 had total mesorectal excision 6–8 weeks after chemoradiation. Patients in groups 2–4 received two, four, or six cycles of mFOLFOX6, respectively, between chemoradiation and total mesorectal excision. Each cycle of mFOLFOX6 consisted of racemic leucovorin 200 mg/m2 or 400 mg/m2, according to the discretion of the treating investigator, oxaliplatin 85 mg/m2 in a 2-h infusion, bolus fluorouracil 400 mg/m2 on day 1, and a 46-h infusion of fluorouracil 2400 mg/m2. The primary endpoint was the proportion of patients who achieved a pathological complete response, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00335816. Findings Between March 24, 2004, and Nov 16, 2012, 292 patients were registered, 259 of whom (60 in group 1, 67 in group 2, 67 in group 3, and 65 in group 4) met criteria for analysis. 11 (18%, 95% CI 10–30) of 60 patients in group 1, 17 (25%, 16–37) of 67 in group 2, 20 (30%, 19–42) of 67 in group 3, and 25 (38%, 27–51) of 65 in group 4 achieved a pathological complete response (p=0.0036). Study group was independently associated with pathological complete response (group 4 compared with group 1 odds ratio 3.49, 95% CI 1.39–8.75; p=0.011). In group 2, two (3%) of 67 patients had grade 3 adverse events associated with the neoadjuvant administration of mFOLFOX6 and one (1%) had a grade 4 adverse event; in group 3, 12 (18%) of 67 patients had grade 3 adverse events; in group 4, 18 (28%) of 65 patients had grade 3 adverse events and five (8%) had grade 4 adverse events. The most common grade 3 or higher adverse events associated with the neoadjuvant administration of mFOLFOX6 across groups 2-4 were neutropenia (five in group 3 and six in group 4) and lymphopenia (three in group 3 and four in group 4). Across all study groups, 25 grade 3 or worse surgery-related complications occurred (ten in group 1, five in group 2, three in group 3, and seven in group 4); the most common were pelvic abscesses (seven patients) and anastomotic leaks (seven patients). Interpretation Delivery of mFOLFOX6 after chemoradiation and before total mesorectal excision has the potential to in...

Anastomotic leaks are frequently diagnosed late in the postoperative period and often after initial hospital discharge, highlighting the importance of prospective data entry and adequate follow-up. CT scan is the preferred diagnostic modality when imaging is required. More than half of leaks can be managed without fecal diversion.

PURPOSE Prospective data on the efficacy of a watch-and-wait strategy to achieve organ preservation in patients with locally advanced rectal cancer treated with total neoadjuvant therapy are limited. METHODS In this prospective, randomized phase II trial, we assessed the outcomes of 324 patients with stage II or III rectal adenocarcinoma treated with induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either total mesorectal excision (TME) or watch-and-wait on the basis of tumor response. Patients in both groups received 4 months of infusional fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous infusion fluorouracil or capecitabine during radiotherapy. The trial was designed as two stand-alone studies with disease-free survival (DFS) as the primary end point for both groups, with a comparison to a null hypothesis on the basis of historical data. The secondary end point was TME-free survival. RESULTS Median follow-up was 3 years. Three-year DFS was 76% (95% CI, 69 to 84) for the INCT-CRT group and 76% (95% CI, 69 to 83) for the CRT-CNCT group, in line with the 3-year DFS rate (75%) observed historically. Three-year TME-free survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 62) in the CRT-CNCT group. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival. Patients who underwent TME after restaging and patients who underwent TME after regrowth had similar DFS rates. CONCLUSION Organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, TME, and postoperative chemotherapy.

Summary Background Local excision is an organ-preserving treatment alternative for patients with stage I rectal cancer. However, local excision alone is associated with a high risk of local recurrence and inferior survival compared to transabdominal rectal resection. Here we investigate the oncologic and functional outcomes of neoadjuvant chemoradiotherapy and local excision for T2N0 rectal cancer. Methods This was a prospective, multi-institutional, single arm phase 2 trial for patients with clinically-staged T2N0 distal rectal cancer, treated with neoadjuvant chemoradiotherapy consisting of capecitabine (original dose 825mg/m2, twice daily, on days 1-14 and 22-35) , oxaliplatin (50mg/m2 weeks 1, 2, 4, 5), and radiation (5 days/week at 1.8 Gy/day for 5 weeks to a dose of 45 Gy, then a boost, for a total dose of 54 Gy) followed by local excision. Due to adverse events during chemoradiotherapy, the dose of capecitabine was reduced to 725 mg /m2, twice daily, 5 days/week, for 5 weeks, and the total dose of radiation to 50.4 Gy. Patients were followed at scheduled intervals and evaluated for recurrence and survival. Anorectal function (ARF) and quality of life (QOL) were assessed at baseline and one year after surgery, using validated instruments. The primary endpoint was 3-year disease-free survival for all eligible patients and for patients who completed chemotherapy and radiation, and had ypT0, ypT1, or ypT2 tumors, and negative resection margins. This trial is registered with ClinicalTrials.gov, number NCT00114231. Findings Seventy-nine eligible patients were accrued to the trial, and started nCRT. Three patients did not complete nCRT or LE per-protocol. Four additional patients completed protocol treatment, but one had a positive margin and three had ypT3 tumours. Median follow-up was 56 months. Of the 79 patients, five (6%) developed distant recurrence, and three (4%) recurred locally. All but two underwent salvage surgery. Three-year disease-free survival and overall survival for the entire group were 88% (0.88 (95% CI: 0.81, 0.96) and 95% (95% CI: 0.90, 1.00), respectively. Overall 14 (29%) of 79 patients had grade 3-4 gastrointestinal adverse events, 12 (16%) of 79 patients had grade 3-4 pain as an adverse event, 12 (16%) of 79 patients had grade 3-4 hematological adverse events, and 9 (11%) of 79 patients had grade 3 dermatologic adverse events during chemoradiation. Six (8%) of the 77 patients who had surgery had grade 3 pain, 3(4%) of 77 patients had grade 3-4 hemorrhage, 3 (4%) of 77 patients had gastrointestinal adverse events, 2 (3%) of 77 patients had infectious/febrile neutropenia, 2 (3%) of 77 patients had hematological adverse events, and one (1%) had neurological adverse events. The rectum was preserved in 72 of the 79 (91%) patients. ARF and QOL were unchanged one year after surgery compared to baseline. Interpretation Most patients with T2N0 rectal cancer treated with nCRT and LE achieved organ preservation without deterioration of their quality of life. The estimated 3-year DFS rate wa...

Transanal endoscopic microsurgery is the technique of choice for local excision of rectal neoplasms.