This phase I trial studies the side effects and best dose of fluorouracil when given together with radiation therapy followed by combination chemotherapy before and after surgery in treating patients with rectal cancer that has spread from where it started to nearby tissue or lymph nodes. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as fluorouracil, leucovorin calcium, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving additional combination chemotherapy after surgery may kill any remaining tumor cells. Giving radiation therapy and fluorouracil followed by combination chemotherapy before and after surgery may be a better treatment for rectal cancer.

OUTLINE: This is a dose-escalation study of fluorouracil.

CHEMORADIATION: Patients undergo intensity-modulated radiation therapy (IMRT) once daily (QD) over 5 days for a total of 5 fractions and concurrently receive fluorouracil intravenously (IV) continuously over 96 hours.

PREOPERATIVE CHEMOTHERAPY: Within 2 weeks of completing chemoradiation, patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV as a push followed by IV continuously over 46 hours on day 1. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.

SURGERY: Within 4-8 weeks of completing preoperative chemotherapy, patients undergo total mesorectal excision.

POSTOPERATIVE CHEMOTHERAPY: Within 4-8 weeks after surgery, patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in preoperative chemotherapy. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 1 year or until removal from the study or death, whichever occurs first.

Inclusion Criteria:

• Pathologically proven diagnosis of adenocarcinoma of the rectum (located below the peritoneal reflection or begins within 15 cm of the anal verge on flexible endoscopy) within 90 days of registration; diagnosis of rectal adenocarcinoma must be obtained by biopsy technique that does not completely excise the lesion (eg, fine needle aspiration, core needle biopsy)

• Clinically determined to be clinically staged (American Joint Committee on Cancer (AJCC) 7th edition [ed.]) T3-4 N0 M0 or T any N1-2 M0 based upon the following minimum diagnostic workup within 90 days prior to registration:

  • Colonoscopy
  • History/physical examination (including medication history screen for contraindications)
  • Contrast-enhanced imaging of the abdomen and pelvis either by computed tomography (CT), magnetic resonance imaging (MRI), or whole body positron emission tomography (PET)-CT (preferred)
  • Chest x-ray (or CT) of the chest to exclude distant metastases (except for those who have had whole body PET-CT per above bullet point)
  • Transrectal ultrasound (TRUS) or MRI for T staging

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1

• Absolute neutrophil count (ANC) >= 1,800 cells/mm^3

• Platelets >= 100,000 cells/mm^3

• Hemoglobin >= 8.0 g/dL (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dL is acceptable)

• Aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN)

• Alkaline phosphatase < 2.5 x ULN

• Bilirubin =< 1.5 ULN

• Calculated creatinine clearance (CrCl) > 50 mL/min using Cockcroft-Gault formula

• Must be deemed a candidate for curative resection by the surgical oncologist who will be performing the operation

• Must provide study-specific informed consent prior to study entry

• Must have a negative serum pregnancy test

Exclusion Criteria:

• Prior radiotherapy to the region of the body that would result in overlap of RT fields with the current protocol treatment

• Severe, active comorbidity, defined as follows:

  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 12 months
  • Transmural myocardial infarction within the last 6 months
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days prior to registration
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
  • Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol
  • Evidence of uncontrolled seizures, central nervous system disorders, or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of treatment protocol or follow up
  • Known, existing uncontrolled coagulopathy; subjects on therapeutic anticoagulation may be enrolled provided that they have been clinically stable on anti-coagulation for at least 2 weeks
  • Major surgery within 28 days of study enrollment (other than diverting colostomy)
  • Crohn's disease or ulcerative colitis requiring hospitalization, surgery or immunosuppressive medications

• Prior allergic reaction to 5-Fluorouracil or oxaliplatin

• Any evidence of distant metastases (M1)

• Extension of malignant disease into the anal canal

• Pregnant as determined by a positive serum pregnancy test within 14 days prior to registration on study (for females of childbearing potential)