A Phase II Clinical Trial Platform of Sensitization Utilizing Total Neoadjuvant Therapy (TNT) in Rectal Cancer

• The patient must have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

• Diagnosis of adenocarcinoma of the rectum with the major portion of the tumor intact; Note: prior to randomization, the investigator must specify and document each of the following:

‣ Distance of the lowest tumor margin from the anal verge; and

⁃ Intent for sphincter sparing or non-sphincter sparing surgical resection according to the primary surgeon; and

⁃ The majority of the untreated tumor must be \< 12 cm from the anal verge or below the peritoneal reflection as determined by the treating surgeon

• The tumor must be clinically determined to be locally advanced stage II or stage III rectal cancer, and must also meet any ONE of the following criteria:

‣ Distal location (as defined by measurement on magnetic resonance imaging \[MRI\], transrectal ultrasound \[ERUS\]/pelvic computed tomography \[CT\] \[with IV contrast\] scan or palpable on digital rectal examination \[DRE\]): cT3-4 =\< 5 cm from the anal verge, any N

⁃ Bulky: any cT4 or evidence that the tumor is adjacent to (defined as within 3 mm of) the mesorectal fascia on MRI or ERUS/pelvic CT (with IV contrast) scan

⁃ High risk for metastatic disease with 4 or more regional lymph nodes (cN2); clinical nodal or cN status for eligibility includes the total number of nodes (N2 = 4 or more) in the mesorectal and superior rectal stations measuring \>= 1.0 cm in any axis on cross sectional or endoscopic imaging; Note: nodes must measure 1.0 cm or greater to be considered positive for this eligibility requirement

⁃ Not a candidate for sphincter-sparing surgical resection prior to neoadjuvant therapy (as planned by the primary surgeon)

∙ Note: clinical stage of the primary tumor and nodes may be determined locally by rectal endoscopic ultrasound or pelvic MRI (pelvic MRI is strongly preferred); CT scan with IV contrast is acceptable provided there is evidence of T4 and/or N2 disease

• Patients must have the ability to swallow and retain oral medication

• Absolute neutrophil count (ANC) must be \>= 1200/mm\^3 (within 28 days before randomization)

• Platelet count must be \>= 100,000/mm\^3 (within 28 days before randomization)

• Hemoglobin must be \>= 10 g/dL (within 28 days before randomization)

• Total bilirubin must be =\< ULN (upper limit of normal) for the lab unless the patient has a bilirubin elevation \> ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin (within 28 days before randomization)

• Alkaline phosphatase must be =\< 3 x ULN for the lab (within 28 days before randomization)

• Aspartate aminotransferase (AST) must be =\< 3 x ULN for the lab (within 28 days before randomization);

‣ Note: if alanine aminotransferase (ALT) is performed instead of AST (per institution's standard practice), the ALT value must be =\< 3 x ULN; if both were performed, the AST must also be =\< 3 x ULN; if AST and/or ALT is \>= ULN but =\< 3 x ULN, serologic testing for hepatitis B and C must be performed and results for viral infection must be negative

• Serum creatinine =\< ULN for the lab and measured or calculated creatinine clearance \> 60 mL/min (within 28 days before randomization)

• Serum potassium, magnesium, and calcium levels within 28 days before randomization must be within normal limits (WNL) for the lab

• International normalized ratio of prothrombin time (INR) within 28 days before randomization must be =\< ULN for the lab; patients who are therapeutically treated with an agent such as warfarin may participate if they are on a stable dose and no underlying abnormality in coagulation parameters exists per medical history

• Patients with acquired immunodeficiency syndrome (AIDS-related illnesses) or known human immunodeficiency virus (HIV) disease must:

‣ Have a cluster of differentiation (CD)4 count \>= 200 cells/uL within 30 days before beginning study therapy

⁃ Be off all antiretroviral therapy (prophylaxis/treatment) more than 60 days before beginning study therapy, and

⁃ Have no evidence of opportunistic infections

• Pregnancy test (urine or serum beta-human chorionic gonadotropin \[HCG\]) done within 72 hours before randomization must be negative (for women of childbearing potential only); if urine pregnancy results are positive or cannot be confirmed as negative, a serum pregnancy test will be required