PROSPECT: Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients With Locally Advanced Rectal Cancer Undergoing Surgery

Registration Inclusion Criteria: 1. Age ≥ 18 years at diagnosis 2. Diagnosis of rectal adenocarcinoma 3. Radiologically measurable or clinically evaluable disease as defined in the protocol 4. ECOG Performance Status (PS): 0, 1 or 2 5. For this patient, the standard treatment recommendation in the absence of a clinical trial would be combined modality neoadjuvant chemoradiation followed by curative intent surgical resection 6. Candidate for sphincter-sparing surgical resection prior to neoadjuvant therapy according to the primary surgeon 7. Primary surgeon is credentialed or is willing to be credentialed in Total Mesorectal Excision (TME), which entails submission of photos of a single TME specimen either before enrolling the first patient or by using the surgeon's 1st accrued case. 8. Clinical Stage: T2N1, T3N0, T3N1. * N2 disease is to be estimated as four or more lymph nodes that are ≥ 10 mm. * Clinical staging should be estimated based on the combination of the following assessments: physical exam by the primary surgeon, CT or PET/CT scan of the chest/abdomen/pelvis and either a pelvic MRI or an ultrasound (ERUS). If a pelvic MRI is peformed, it is acceptable to perform CT of the chest/abdomen, ommitting CT imaging of the pelvis. 9. The following laboratory values obtained ≤ 28 days prior to registration: * Absolute neutrophil count (ANC) ≥ 1500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Hemoglobin \> 8.0 g/dL * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) * SGOT (AST) ≤ 3 x ULN * SGPT (ALT) ≤ 3 x ULN * Creatinine ≤1.5 x ULN 10. Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only 11. Patient of child-bearing potential is willing to employ adequate contraception 12. Provide informed written consent 13. Willing to return to enrolling medical site for all study assessments Registration Exclusion Criteria: 1. Clinical T4 tumors 2. Primary surgeon indicates need for abdominoperineal (APR) at baseline 3. Evidence that the tumor is adherent to or invading the mesorectal fascia on imaging studies such that the surgeon would not be able to perform an R0 resection (one with negative margins) 4. Tumor is causing symptomatic bowel obstruction (patients who have had a temporary diverting ostomy are eligible). 5. Chemotherapy within 5 years prior to registration. Hormonal therapy is allowable if the disease free interval is ≥ 5 years. 6. Any prior pelvic radiation 7. Other invasive malignancy ≤ 5 years prior to registration. Exceptions are colonic polyps, non-melanoma skin cancer, ductal carcinoma in situ, bladder carcinoma in situ, or carcinoma-in-situ of the cervix. 8. Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. * Pregnant women * Nursing women * Men or women of childbearing potential who are unwilling to employ adequate contraception 9. Co-morbid illnesses or other concurrent disease which, in the judgment of the clinician obtaining informed consent, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.