This is phase 2 trial of neoadjuvant therapy and short-course radiotherapy in resectable rectal cancer.

This trial involves 4 cycles of systemic chemotherapy followed by short-course RT with concurrent 5-FU neoadjuvant chemoradiotherapy (CRT) and subsequent consolidation with 4 cycles of systemic chemotherapy prior to surgery or, for those who achieve cCR, the option of non-operative active surveillance.Three-year disease free survival (DFS) defined as the percentage of patients alive without recurrence of disease at 3 years measured from the date of clinical complete response (cCR) or date of total mesorectal excision (TME) at surgery (whichever is earlier).

Inclusion Criteria:

• Pathologic diagnosis of adenocarcinoma of the rectum (diagnosis by tissue biopsy) within 90 days prior to registration. At least a portion of the tumor must be located below the peritoneal reflection or begin within 12 cm of the anal verge on flexible endoscopy
• Clinically staged (AJCC 8th ed.) T3-4 N0 M0 or T any N1-2 M0 based upon the following minimum diagnostic workup:
• Colonoscopy, unless patient presents with an obstructing lesion
• Within 30 days before initiating MFOLFOX6 treatment:
• History/physical examination
• Imaging to exclude distant metastases: either contrast-enhanced CT of the chest, abdomen, and pelvis; or whole-body PET-CT; or MRI
• Pelvic MRI (preferred) or transrectal ultrasound (TRUS) for T staging Note: Patients may have initiated standard mFOLFOX6 treatment before study registration provided that they met the above criteria before initiating treatment and can feasibly continue to CRT according to the timeline described in Section
• ECOG Performance Status ≤2
• Age ≥ 18 years
• Adequate bone marrow function defined as follows:
• Absolute neutrophil count (ANC) ≥ 1,200 cells/mm3
• Platelets ≥ 100,000 cells/mm3
• Hemoglobin ≥ 8.0 g/dL (Note: The use of transfusion or other intervention to achieve Hgb ≥8.0 g/dL is acceptable.)
• Adequate liver and renal function defined as follows:
• AST and alkaline phosphatase < 2.5 x upper limit of normal (ULN)
• Bilirubin ≤ 2.5 ULN
• Calculated creatinine clearance (CrCl) > 30 mL/min using Cockcroft-Gault formula as calculated by the standard Cockcroft-Gault equation using age, actual weight, creatinine, and gender
• Must be deemed a candidate for curative resection by the surgical oncologist who will be performing the operation
• Women of childbearing potential (WCBP) must have a negative serum pregnancy test performed within 7 days prior to the start of chemotherapy.
• WCBP and men must agree to use a medically accepted form of birth control during the treatment and for 3 months following completion of chemotherapy.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Prior RT that would result in unsafe overlap of RT fields with the planned study treatment, per the treating radiation oncologist
• Clinically significant cardiac disease, including major cardiac dysfunction, that in the opinion of the treating medical oncologist would preclude them from receiving systemic therapy with 5-fluorouracil, leucovorin or oxaliplatin.
• Serious (ie, ≥ grade 3) uncontrolled infection
• Pulmonary or respiratory condition that, in the opinion of the treating medical oncologist would preclude them from receiving systemic therapy with 5-fluorouracil, leucovorin or oxaliplatin.
• Major surgery within 28 days of study enrollment (other than diverting colostomy)
• History of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis) requiring significant intervention (eg, hospitalization, surgery, immunosuppressive medications) that would, in the opinion of the investigator, preclude study therapy
• Prior known allergic reaction to 5-fluorouracil, leucovorin, or oxaliplatin
• Known dipyrimidine dehydrogenase deficiency (DPD)
• Any evidence of distant metastases (M1)
• Pregnant or breast feeding
• Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk or limit the patient's adherence with study requirements