Background: After preoperative chemoradiation and surgery, many patients (pts) with clinical stage II-III rectal cancer are unable to tolerate adjuvant FOLFOX chemotherapy, which may compromise disease-free and overall survival (DFS/OS). This study was designed to assess treatment delivery, toxicity and impact on pathologic response of administering chemotherapy prior to chemoradiation and surgery. Methods: Pts with clinical T3-4 and/or N1-2 rectal cancer, staged by endorectal ultrasound (ERUS) and pelvic MRI, received modified (m) FOLFOX6 every two weeks x eight cycles, followed by 50.4 Gy IMRT with concurrent capecitabine 825mg/m² BID, 5 days per week, followed by surgery 4-8 weeks later. Results: There were 39 pts enrolled between August 2010 and June 2012; median age was 61 (30-79); clinical stage II n=7, stage III n=32. Distance from the anal verge: <3cm n=5; 3-5cm n=5; >5cm n=29. There were four pts presented with lumen obstruction preventing advancement of the endoscope and 31 with rectal bleeding. There were 36 pts (92%) completed eight cycles of mFOLFOX6. Grade 3 toxicities during chemotherapy included diarrhea (n=2), neutropenia (n=6), and renal dysfunction (n=1). There was one pt with a cardiovascular disease had a TIA (grade 4). There was one pt had grade 4 neutropenia. All pts had resolution of bleeding and improvement of obstructive symptoms, with no complications requiring surgical intervention. There as two pts declined radiation after completing chemotherapy, and one withdrew due to grade 3 diarrhea. At surgery, pathologic complete response (ypT0N0) (pCR) was confirmed in 13 pts (33%; 95% CI 18.24%-47.76%), residual stage I in 10 (26%), stage II in seven (18%), and stage III in eight (20%); one pt did not undergo surgery. There was two pts with microsatellite unstable tumors had no evidence of response to treatment. Conclusions: Over 90%of pts wereable to complete mFOLFOX6 when administered prior to chemoradiation and surgery. The pCR rate was higher than typically seen with chemoradiation alone. A randomized study would be required to determine if improved delivery of chemotherapy using this approach improves DFS/OS, but CONTRE represents a well-tolerated alternative to the current standard treatment sequence and could serve as a platform for clinical trials in rectal cancer. Clinical trial information: NCT01363843.