RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Chemoradiotherapy (combining chemotherapy with radiation therapy) before surgery may shrink the tumor so that it can be removed. Giving chemotherapy after surgery may kill any remaining tumor cells.

PURPOSE: Randomized phase II trial to compare the effectiveness of two different regimens of neoadjuvant chemoradiotherapy and adjuvant chemotherapy in treating patients who are undergoing surgical resection for locally advanced rectal cancer.

Condition	Treatment or Intervention	Phase
stage III rectal cancer adenocarcinoma of the rectum stage II rectal cancer	Drug: capecitabine  Drug: fluorouracil  Drug: irinotecan  Drug: leucovorin calcium  Drug: oxaliplatin  Procedure: adjuvant therapy  Procedure: chemotherapy  Procedure: conventional surgery  Procedure: neoadjuvant therapy  Procedure: radiation therapy  Procedure: surgery	Phase II

Further Study Details: 

OBJECTIVES:

• Compare 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.
• Compare the time to treatment failure and patterns of failure in patients treated with these regimens.
• Compare the incidence of hematologic and nonhematologic grade 3-4 toxicity, preoperatively, postoperatively, and overall, in patients treated with these regimens.
• Compare 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.

• Patients receive neoadjuvant therapy comprising radiotherapy once daily, 5 days a week, for 6 weeks and concurrent oral capecitabine twice daily (7 days a week) for 6 weeks and irinotecan IV over 1 hour on days 1, 8, 15, and 22. Patients undergo surgical resection 4-8 weeks after completing radiotherapy.

Beginning 4-6 weeks after surgery, patients with completely resected disease and negative surgical margins receive adjuvant chemotherapy comprising irinotecan IV over 90 minutes 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.

• Patients receive neoadjuvant therapy comprising radiotherapy and capecitabine as in arm I 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 with completely resected disease and negative surgical margins receive adjuvant chemotherapy comprising oxaliplatin IV over 2 hours on day 1 and 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 2 weeks before surgery, within 1 week after the completion of adjuvant chemotherapy, and then at 12 and 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 106 patients (53 per treatment arm) will be accrued for this study within 2 years.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of adenocarcinoma of the rectum
• Clinical stage T3 or T4 disease by endorectal ultrasound or physical examination (for T4 lesions only)
• Located up to 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 ≤ 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 1.5 times ULN
• Bilirubin ≤ 1.5 times ULN
• No known uncontrolled coagulopathy

Renal

• Creatinine clearance > 50 mL/min

Cardiovascular

• No uncontrolled cardiac arrhythmias
• No clinically significant cardiac disease
• No congestive heart failure
• No symptomatic coronary artery disease
• No myocardial infarction within the past year

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 30 days after study participation
• No concurrent serious uncontrolled infection
• No CNS disorder
• No history of uncontrolled seizures
• No malabsorption syndrome
• No lack of physical integrity of the upper gastrointestinal tract
• No psychiatric disability that would preclude study compliance or giving informed consent
• 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

Study chairs or principal investigators

Neal Jay Meropol, MD,  Study Chair,  Fox Chase Cancer Center   

Study ID Numbers:  CDR0000350136; RTOG-0247; NCT00081289
Record last reviewed:  May 2004
Last Updated:  December 6, 2004
Record first received:  April 7, 2004
ClinicalTrials.gov Identifier:  NCT00081289
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08