Neoadjuvant Chemoradiotherapy and Adjuvant Chemotherapy in Treating Patients Who Are Undergoing Surgical Resection for Locally Advanced Rectal Cancer

OBJECTIVES:

- Evaluate the pathologic complete response rate in patients with locally advanced rectal
cancer undergoing surgical resection treated with 2 different regimens of neoadjuvant
chemoradiotherapy and adjuvant chemotherapy.

- Evaluate the time to treatment failure and patterns of failure in patients treated with
these regimens.

- Evaluate the incidence of hematologic and non-hematologic grade 3-4 toxicity
(preoperatively, postoperatively, and overall) in patients treated with these regimens.

- Evaluate the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
clinical stage of tumor (T3 vs T4). Patients are randomized to 1 of 2 treatment arms.

- Arm I: Neoadjuvant chemoradiation with irinotecan: Patients receive neoadjuvant therapy
comprising radiotherapy once daily, 5 days a week, for 6 weeks and concurrent oral
capecitabine 1200 mg/m^2 daily (5 days a week) for 6 weeks and irinotecan IV over 1
hour on days 1, 8, 22, and 29.

Patients undergo surgical resection 4-8 weeks after completing radiotherapy.

Beginning 4-6 weeks after surgery, patients receive adjuvant chemotherapy comprising
oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil
IV continuously over 46 hours beginning on day 1. Treatment repeats every 14 days for a
total of 9 courses.

- Arm II: Neoadjuvant chemoradiation with oxaliplatin: Patients receive neoadjuvant
therapy comprising radiotherapy and capecitabine 1650 mg/m^2 daily as in arm I (except
for capecitabine dose) and oxaliplatin IV over 2 hours on days 1, 8, 15, 22, and 29.

Patients undergo surgical resection 4-8 weeks after completing radiotherapy.

Beginning 4-6 weeks after surgery, patients receive adjuvant chemotherapy comprising
oxaliplatin, leucovorin calcium, and fluorouracil as in Arm I adjuvant chemotherapy.
Treatment repeats every 14 days for a total of 9 courses.

Quality of life is assessed at baseline, within 1 week after completion of radiotherapy,
within 1 week after completion of adjuvant chemotherapy (12 months), and then at 24 months.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then
annually thereafter.

PROJECTED ACCRUAL: A total of 141 patients (approximately 70 per treatment arm) will be
accrued for this study within 2 years.

DISEASE CHARACTERISTICS:

- Diagnosis of adenocarcinoma of the rectum

- Clinical stage T3 or T4 disease by endorectal ultrasound or physical examination
(for T4 lesions only)

- Tumor originating at or below 12 cm from the anal verge

- No extension of disease into the anal canal

- No evidence of distant metastases

- No synchronous primary colon carcinomas except T1 lesions

- Potentially resectable en bloc disease

PATIENT CHARACTERISTICS:

Age

- 18 and over

Performance status

- Zubrod 0-2

Life expectancy

- Not specified

Hematopoietic

- Absolute neutrophil count > 1,500/mm^3

- Platelet count > 100,000/mm^3

Hepatic

- AST (aspartate aminotransferase) < 2.5 times upper limit of normal (ULN)

- Alkaline phosphatase < 2.5 times ULN

- Bilirubin ≤ 1.5 times ULN

- No known uncontrolled coagulopathy

Renal

- Creatinine clearance > 50 mL/min

Cardiovascular

- No congestive heart failure

- No symptomatic coronary artery disease

- No uncontrolled cardiac arrhythmias

- No myocardial infarction within the past year

- No other clinically significant cardiac disease

Other

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 30 days after
completion of study treatment

- No concurrent serious uncontrolled infection

- No malabsorption syndrome

- No lack of physical integrity of the upper gastrointestinal tract

- No evidence of uncontrolled seizures, central nervous system (CNS) disorders, or
psychiatric disability that, judged by the investigator, is clinically significant,
precludes giving informed consent, or interferes with compliance of oral drug intake

- No other malignancy within the past 5 years except nonmelanoma skin cancer, carcinoma
in situ of the cervix, or ductal carcinoma in situ of the breast

- No other serious uncontrolled medical condition that would preclude study
participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

- No concurrent routine prophylactic filgrastim (G-CSF)

Chemotherapy

- No prior anticancer chemotherapy

Endocrine therapy

- Not specified

Radiotherapy

- No prior radiotherapy to the pelvis

- No concurrent intensity-modulated radiotherapy

Surgery

- More than 4 weeks since prior major surgery

Other

- More than 4 weeks since prior participation in another clinical trial

- No concurrent cimetidine

- No concurrent sorivudine or brivudine