Oxaliplatin, Fluorouracil, and External-Beam Radiation Therapy Followed by Surgery in Treating Patients With Locally Advanced Cancer of the Rectum

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of oxaliplatin when combined with fluorouracil and external beam radiotherapy in patients with locally advanced adenocarcinoma of the rectum.

(Phase I closed to accrual effective 03/27/2003). II. Determine the pathological response rate in patients treated with this preoperative regimen and surgical resection.

III.Determine the late toxicity of this preoperative regimen in these patients. IV. Determine, in a preliminary manner, the progression-free survival, local control, and overall survival in patients treated with this regimen.

OUTLINE: This is a dose-escalation, multicenter study of oxaliplatin.

Patients receive oxaliplatin IV over 1 hour on day 1, fluorouracil IV continuously on days 1-7, and radiotherapy on days 1-5. Treatment repeats weekly for a maximum of 6 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of oxaliplatin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, additional patients are treated at that dose level in the phase II portion of the study. (Phase I closed to accrual effective 03/27/2003). Patients may undergo radical resection of rectal tumor within 4-6 weeks after completion of chemoradiotherapy.

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

PROJECTED ACCRUAL: A total of 9-24 patients will be accrued for phase I of the study (phase I closed to accrual effective 03/27/2003) and a total of 19 patients will be accrued for phase II of the study within 12-18 months.

Inclusion criteria

• Histologically proven previously untreated adenocarcinoma of the rectum thatbegins within 12 cm of the anal verge by sigmoidoscopy and/or colonoscopy

• Locally advanced disease defined as any of the following:

• Fixed or immovable tumor on physical exam
• T4 disease with invasion of adjacent structures (e.g., pelvic sidewall, sacral pelvis, bladder, or prostate) by CT scan, rectal ultrasound, or MRI
• T3 disease with invasion through the wall of the muscularis propria by transrectal ultrasound, CT scan, or MRI
• No distant metastatic disease
• Performance status - ECOG 0-2
• Granulocyte count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Bilirubin no greater than upper limit of normal (ULN)
• SGOT/SGPT no greater than 2.5 times ULN
• Creatinine no greater than 1.5 mg/dL
• Creatinine clearance at least 60 mL/min
• No active second malignancy except nonmelanomatous skin cancer or carcinoma in situ of the cervix
• Patients are not considered to have an active second malignancy if they have completed therapy and are at less than 30% risk of relapse
• No prior or concurrent evidence of neuropathy
• No history of allergy to platinum compounds or antiemetics
• Not pregnant or nursing
• Fertile patients must use effective contraception
• No prior fluorouracil or platinum-based therapy for any malignancy
• No other concurrent chemotherapy
• Hormonal therapy allowed only for non-disease related conditions (e.g., insulin for diabetes) OR intermittently as an antiemetic (e.g., dexamethasone)
• No prior pelvic irradiation
• No concurrent antiretroviral therapy (HAART) for HIV positive patients