Radiation Therapy and Fluorouracil With or Without Combination Chemotherapy Followed by Surgery in Treating Patients With Stage II or Stage III Rectal Cancer

OBJECTIVES:

I. To determine the rate of pathologic complete response to chemoradiation (no evidence of
residual tumor in the resected specimen) of Stage II and Stage III rectal cancers that are
staged preoperatively by endorectal ultrasound (ERUS) or magnetic resonance imaging (MRI),
treated according to a standardized chemoradiation and surgery protocol, and evaluated by a
systematic pathologic exam of the surgical specimen.

II. To study the effect of different chemoradiation-to-surgery intervals on the rate of
pathologic complete response, on surgical difficulty, and on postoperative complications.

III. To investigate the feasibility of using sensitive molecular assays to detect tumor cells
in the tumor bed and regional lymph nodes of rectal cancer specimens, with or without
pathologic complete response to preoperative chemoradiation.

OUTLINE:

Patients are assigned to 1 of 4 treatment groups. All patients undergo chemoradiation therapy
comprising radiation therapy once daily 5 days a week for 5 weeks and fluorouracil
intravenously (IV) continuously over 24 hours 7 days a week for 6 weeks.

GROUP I (closed to enrollment): Patients undergo standard surgical resection after completion
of chemoradiation therapy.

GROUP II (closed to enrollment): Beginning 4 weeks after completion of chemoradiation
therapy, patients receive modified FOLFOX-6 chemotherapy comprising oxaliplatin IV over 2
hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over
46 hours on days 1-2. Treatment repeats every 14 days for 2 courses. After the last week of
post-radiation chemotherapy, patients undergo standard surgical resection.

GROUP III: Beginning 4 weeks after completion of chemoradiation therapy, patients receive
modified FOLFOX-6 chemotherapy as in group II. Treatment repeats every 14 days for 4 courses.
After the last week of post-radiation chemotherapy, patients undergo standard surgical
resection.

GROUP IV: Beginning 4 weeks after completion of chemoradiation therapy, patients receive
modified FOLFOX-6 chemotherapy as in group II. Treatment repeats every 14 days for 6 courses.
After the last week of post- radiation chemotherapy, patients undergo standard surgical
resection.

In all groups, treatment continues in the absence of disease progression or unacceptable
toxicity. A

fter completion of study treatment, patients are followed up for 5 years.

Inclusion Criteria:

- Patients must have an Eastern Cooperative Oncology Group (ECOG) Status of 0 or 1, or
comparable Karnofsky performance status

- Patients must have histologically confirmed invasive adenocarcinoma of the rectum
Distal border of the tumor must be within 12 cm from the anal verge as measured on
rigid proctoscopic exam

- Patients must have Stage II (uT3-4, uN0) or Stage III (any T, uN1-2) tumors, as
confirmed by ERUS or MRI; females with anterior tumors invading the posterior vaginal
wall (uT4) and males with anterior tumors that invade the seminal vesicles or adjacent
organs (uT4) will also be eligible provided they undergo an extended resection
including the organs involved

- Patients with high grade obstruction that impedes the ERUS exam are eligible for the
study provided they can be staged by MRI

- Patients with synchronous or metachronous colorectal cancer are eligible for the study
on condition that they are treated for rectal cancer in accordance with the protocol

- Patients with the following are NOT allowed on study:

- Metastatic disease or other primaries

- Locally recurrent rectal cancer

- Previously documented history of Familial Adenomatous Polyposis

- History of Inflammatory Bowel Disease

- History of prior radiation treatments to pelvis

- History of clinically significant cardiac disease (i.e., Class 3-4 congestive
heart failure, symptomatic coronary artery disease, uncontrolled arrhythmia,
and/or myocardial infarction within the previous 6 months

- History of uncontrolled seizures or clinically significant central nervous system
disorders

- History of psychiatric conditions or diminished capacity that could compromise
the giving of informed consent, or interfere with study compliance

- History of allergy and/or hypersensitivity to 5-fluorouracil (fluorouracil),
leucovorin (leucovorin calcium), and/or oxaliplatin

- History of difficulty or inability to take or absorb oral medications

- Patients must have adequate bone marrow, hepatic and renal function within 7 days
prior to registration

- White blood cells (WBC) >= 3,000 mm^3

- Absolute neutrophil count (ANC) > 1,500 mm^3

- Hemoglobin > 9.5 mg/dl

- Platelet count >= 100,000 mm^3

- Total bilirubin =< 1.5 mg/dl

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =<
2.0 times institutional upper limit of normal (ULN)

- Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.0
times ULN

- Alkaline phosphatase =< 2.0 times ULN

- Serum creatinine =< 1.5 times ULN

- Patients with hereditary non-polyposis colorectal cancer are eligible for the study
provided they meet the rest of the eligibility criteria

- Patients who have experienced a prior malignancy should have received potentially
curative therapy for that malignancy, and should be cancer-free for at least five
years from the date of initial diagnosis (Exceptions: patients treated for basal cell
carcinoma, or carcinoma in-situ of the cervix)

- Patients of reproductive potential should agree to use an effective method of birth
control when undergoing treatments with known or possible mutagenic or teratogenic
effects; all female participants of childbearing potential must have a negative urine
or serum pregnancy test within two weeks prior to study registration

- Patients or the patient's legally acceptable representative must provide written
authorization to allow the use and disclosure of protected health information; NOTE:
this may be obtained in either the study-specific informed consent or in a separate
authorization form and must be obtained from the patient prior to study registration
or the initiation of any study-specific procedures