Rectal Cancer Consortium

Inclusion Criteria: * Patients must have histologically proven adenocarcinoma of the rectum with no evidence of distant metastases. * The tumor must be clinically Stage II (T3-4 N0) or III (T1-4 N1-2). * Patients must have no evidence of distant metastases including liver metastases, peritoneal seeding, or inguinal lymphadenopathy. * Patients who completed or are actively enrolled in the CONTRE study and patients undergoing treatment for rectal cancer following the TNT (Total Neoadjuvant Treatment) format (see below) for whom sufficient tissue is available for the required research analyses may be enrolled in this study retroactively. * For those who have not yet received treatment for rectal adenocarcinoma, these patients must not have received prior chemotherapy or pelvic radiation for rectal cancer, or prior pelvic radiation for any other malignancy that would prevent the patient from receiving the required radiation treatments for this study. * Patients must not have an active concurrent invasive malignancy other than non-melanoma skin cancers. Patients with malignancies diagnosed within 5 years prior to randomization which have been effectively treated and are deemed to be at low risk for recurrence are eligible. * Patients must be \> 18 years of age, ECOG (performance status) 0-1. * ANC (absolute neutrophil count) \>1,500/µl, platelets \>100,000/µl, total bilirubin \<2.0 mg/dl or direct bilirubin \<1.0 mg/dl, alkaline phosphatase \<3xULN, ALT \<3xULN, creatinine \<1.5xULN. * Signed informed consent; able to comply with study and/or follow- up procedures * Peripheral neuropathy \< grade 1. * The intention of the treating physicians is to administer Total Neoadjuvant Treatment as per the suggested treatment guidelines in section 4 and section 5 or as per standard institutional policies. Exclusion Criteria: * Evidence of metastatic disease. * Rectal cancers other than adenocarcinoma, i.e., sarcoma, lymphoma, carcinoid, squamous cell carcinoma, cloacogenic carcinoma, etc. * Pregnancy or lactation at the time of proposed randomization. Eligible patients of reproductive potential (both sexes) must agree to use adequate contraception. * Synchronous invasive colon cancer. * Nonmalignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude the patient from receiving any chemotherapy treatment option or would prevent required follow-up. * Patients with active inflammatory bowel disease, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0 or other serious medical illness which might limit the ability of the patient to receive protocol therapy. * Known hypersensitivity to 5-fluorouracil or oxaliplatin * Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements. * Insufficient tumor tissue available for the required genomic analyses and patient unable or unwilling to undergo repeat examination and biopsies.