The study is designed to test the hypothesis that patients with Locally advanced rectal cancer ( LARC) treated with Total neoadjuvant therapy (TNT) and Total mesorectal excision (TME) or Non-operative management (NOM) will have an improved 3-year disease-free survival (DFS) compared to patients with similar tumors treated with Chemoradiation therapy (CRT), Total mesorectal excision (TME) and Adjuvant chemotherapy (ACT).

Inclusion Criteria:

• Histologically confirmed diagnosis of adenocarcinoma of the rectum
• Clinical Stage II (T3-4, N-) or Stage III (any T, N+) based on MRI
• Rectal tumor at baseline which would be considered to require complete TME
• No evidence of distant metastases
• No prior pelvic radiation therapy
• No prior chemotherapy or surgery for rectal cancer
• Age ≥ 18 years The minimum legal age of consent for select Canadian provinces is 19
• No active infections requiring systemic antibiotic treatment (oral antibiotics are acceptable at the discretion of the treating physician)
• ECOG Performance status 0-2
• Women with childbearing potential (WOCBP) who are negative for pregnancy test (urine or blood) and who agree to use effective contraceptive method. A woman of childbearing potential is defined of one who is biologically capable of becoming pregnant. Reliable contraception should be used from trial screening and must be continued throughout the study.
• 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 are eligible and may be consented according to institutional and federal regulations.
• ANC > 1.5 cells/mm3, HGB > 8.0 gm/dl, PLT > 150,000/mm3 total bilirubin ≤ 1.5 x ULN (except in patients with Gilbert's Syndrome who must have total bilirubin ≤ 3.0 x ULN), AST≤ 3 x ULN, ALT ≤ 3 x ULN.

Exclusion Criteria:

• Recurrent rectal cancer
• Primary unresectable rectal cancer. A tumor is considered unresectable when invading adjacent organs and an en block resection will not achieve negative margins.
• Creatinine level greater than 1.5 times the upper limit of normal.
• Patients who have received prior pelvic radiotherapy.
• Patients who are unable to undergo an MRI.
• Patients with a history of any arterial thrombotic event within the past 6 months. This includes angina (stable or unstable), MI, TIA, or CVA.
• Patients with a history of venous thrombotic episodes such as deep venous thrombosis, pulmonary embolus occurring more than 6 months prior to enrollment may be considered for protocol participation, provided they are on stable doses of anticoagulant therapy. Similarly, patients who are anticoagulated for atrial fibrillation or other conditions may participate, provided they are on stable doses of anticoagulant therapy.
• 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.
• WOCBP who are unwilling or unable to use an acceptable method of avoiding pregnancy for the entire study period.
• Women who are pregnant or breast-feeding.
• 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 with a history of a prior malignancy within the past 5 years, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.