The Radiation Oncology-Biology Integration Network (ROBIN) Molecular Characterization Trial (MCT) of Standard Short Course Radiotherapy for Rectal Cancer.

Inclusion Criteria: * Histologically confirmed diagnosis of adenocarcinoma of the rectum * Age ≥ 18 years * ECOG performance status 0-1 * cT2-T3N0 or cT1-3N1 or cT4 or cN2 * Rectal cancer amenable to total mesorectal excision * No evidence of distant metastases * No prior pelvic radiation therapy * No prior chemotherapy or surgery for rectal cancer * Total neoadjuvant therapy (short course radiotherapy followed by consolidative chemotherapy) is allowed * No infections requiring systemic antibiotic treatment * Hgb \>8.0 gm/dL, PLT \> 150,000/mm3, total bilirubin ≤ 1.5x upper limit of normal, AST ≤ upper limit of normal, ALT ≤ 3x upper limit of normal * Patients must read, agree to, and sign a statement of informed consent prior to participation in this study. Patients who do not read or understand English or eligible but must have the consent form read to them in its entirety by an official translator. Informed consent for non-literate or non-English speaking patients may not be obtained by using a relative or a member of the patient's clinical team as a translator. * Female participants or reproductive potential, defined as not surgically sterilized and between menarche and 1 year post menopause, must have a negative serum pregnancy test within 4 weeks prior to initiation of study treatment. * Women with childbearing potential who are negative for pregnancy (urine or blood) and who agree to use effective contraceptive methods. A woman of childbearing potential is defined by one who is biologically capable of becoming pregnant. Reliable contraception should be used from trial screening and must be continued throughout the study. Exclusion Criteria: * Recurrent rectal cancer * Primary unresectable rectal cancer is defined as a primary rectal tumor which, on the basis of either physical exam or pelvic MRI, is deemed to be adherent or fixed to adjacent pelvic structures (en bloc resection will not be achieved with negative margins). * Patients who have received prior pelvic radiotherapy * Patients with prior allogenic stem cell or solid organ transplantation. * Patients receiving treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor-α agents) administered at \>10 mg/day prednisone or equivalent within 2 weeks prior to initiation of study treatment. * Patients with any other concurrent medical or psychiatric condition or disease which, in the investigator's judgment would make them inappropriate candidates for entry into this study * Patients receiving other anticancer or experimental therapy. No other experimental therapies (including chemotherapy, radiation, hormonal treatment, antibody therapy, immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, matrix metalloprotease inhibitors, thalidomide, anti-VEGF/Flk-1 monoclonal antibody, or other experimental drugs) of any kind are permitted while the patient is receiving study treatment. * Women who are pregnant or breastfeeding. Women of childbearing potential who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period and for up to four weeks after the study.