A Phase I/II Study of Preoperative Oxaliplatin (NSC# 266046), 5-Fluorouracil, and External Beam Radiation Therapy in Locally Advanced Rectal Cancer
A Phase I/II Study of Preoperative Oxaliplatin (NSC# 266046), 5-Fluorouracil, and External Beam Radiation Therapy in Locally Advanced Rectal Cancer
Drugs used in chemotherapy use 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. Combining chemotherapy, radiation therapy, and surgery may be a more effective treatment for cancer of the rectum. Phase II trial to study the effectiveness of combining oxaliplatin, fluorouracil, and external-beam radiation therapy followed by surgery in treating patients who have 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:
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