A phase I/II study of preoperative oxaliplatin (O), 5-fluorouracil (5-FU), and external beam radiation therapy (XRT) in locally advanced rectal cancer: CALGB 89901.

3560 Background: 5FU and XRT administered preoperatively is a standard regimen for patients with T3/T4 rectal cancer. Preclinical data demonstrate radiation sensitization for O and 5FU. The aims were to determine the MTD of weekly O with 5FU and XRT and to determine the pathological response at the MTD. METHODS: Eligibility criteria included adenocarcinoma of the rectum within 12 cm of the anal verge; T3/T4 disease as demonstrated by endorectal USG or MRI; no metastatic disease; adequate bone marrow, liver, and kidney function. 5FU 200 mg/m(2) was administered over 24 hours daily. XRT was delivered at 1.8 Gy per day, 5 days/week (28 fractions total). O was administered over 1 hour on day 1 of each week. Surgical resection was recommended 4-6 weeks after chemoradiation. DLTs included grade 4 neutropenia, grade 3/4 thrombocytopenia or grade 3/4 nonhematologic toxicity requiring > 7 days interruption in therapy. A traditional phase I accrual design was followed. The MTD is the dose level below the level where 2 of 6 patients experience DLT or a maximum dose of O of 60 mg/m(2). RESULTS: 18 patients (7 women, 15 caucasian, median age 56.5) were enrolled to 4 dose levels of O (30, 40, 50, 60mg/m(2)). No DLTs were observed in the first 3 dose levels. 2 patients were replaced in dose level 2 (1 hypersensitivity reaction, 1 colonic obstruction). The third patient enrolled at dose level 4 experienced a DLT (diarrhea week 4) and a patient at this level was replaced due to disease related bowel perforation. Three additional patients were enrolled at dose level 4 without any DLTs. Two patients experienced grade 3 neutropenia. No patient experienced grade 3 thrombocytopenia or neuropathy. Grade 3 diarrhea occurred in one patient each at the 30 and 50 mg/m(2) dose levels during weeks 4 and 1, respectively, and 3 patients at 60 mg/m(2) during weeks 2, 3, and 4, respectively. An additional 19 patients have been accrued at dose level 4. CONCLUSIONS: The recommended phase II dose of weekly O when administered with 5FU and XRT is 60mg/m(2). Updated toxicity and pathological response rate for 25 patients treated at the MTD will be available in Spring 2004. [Table: see text].

Duke Scholars

Author Donna Niedzwiecki Biostatistics & Bioinformatics, Division of Biostatistics