Adult patients with locally advanced rectal cancer who have completed conventional long-course chemo-radiation of 54Gy with capecitabine will be randomized 1:1 to a total neo-adjuvant therapy (TNT) protocol or to a control group. Patients in the TNT arm will receive 4 cycles of interval chemotherapy with FOLFIRINOX (5-FU, irinotecan, oxaliplatin) between the end of chemo-radiation and re-staging and those in the control group will undergo standard post-radiation care during this period. All patients will be re-staged with colonoscopy and pelvic MRI 12 weeks after the end of chemo-radiation. Those with a complete clinical response will be placed under a watch-and-wait protocol with digital rectal examinations every 2 months and pelvic MRI and sigmoidoscopy every 6 months. Those wih residual tumors will undergo resection with total mesorectal excision (TME). Patients with a "near complete response", as defined by a multidisciplinary tumor board, will be re-staged at week 16 or 18 after chemo-radiation before undergoing surgery. Adjuvant chemotherapy will be done following the local standard of care.
