Addition of oxaliplatin to continuous fluorouracil, L-folinic acid, and concomitant radiotherapy in rectal cancer:: The Lyon R 97-03 Phase I trial

Purpose: Oxaliplatin could increase the efficacy of fluorouracil (5-FU)/folinic acid chemoradiotherapy in rectal cancer. We tested three dose levels to identify a feasible oxaliplatin dose for combination therapy. Patients and Methods: Between February 1998 and April 2000, we included 17 rectal adenocarcinoma patients in a single-center phase I study, Patients had T4 rectal carcinoma, T1-T3 disease with colostomy refusal, or potentially operable T2/T3 M1 requiring local treatment, Pelvic radiotherapy was 45 Gy over 5 weeks, 1.8 Gy/fraction, with concomitant chemotherapy weeks 1 and 5. Chemotherapy was oxaliplatin 80, 100, or 130 mg/m(2) 2-hour infusion on day 1 followed by L-folinic acid 100 mg/m(2)/d intravenous bolus, and 5-FU 350 mg/m2/d continuous infusion on days 1 to 5 (FolfoR1). Six patients refusing surgery received additional contact radiotherapy +/- brachytherapy. Dose escalation proceeded if less than two of six patients had dose-limiting toxicity (DLT) at a given dose-level. Results: All except two patients completed treatment; patients at level 1 (prolonged grade 1 thrombocytopenia) and level 3 (prolonged cold-related dysesthesia) had no second chemotherapy course. Median follow-up is 14 months (range, 2 to 28 months). One elderly patient at dose level 1 herd DLT asthenia, severe diarrhea and vomiting, and more than 10% weight loss. There were no other DLTs and no severe rectitis or gastrointestinal toxicity. There were objective responses at all doses and no progressions. Fight patients underwent radical surgery after chemoradiotherapy. Two had complete pathologic responses. Conclusion: FolfoR1 seems feasible and effective. Dose escalation did not increase toxicity. Although the MTD was not reached in this study, we recommend oxaliplatin 130 mg/m2 for phase ii studies because it is the dose determined from studies in metastatic patients with no toxicity when given concurrently with radiation. J Clin Oncol 19:2433-2438. (C) 2001 by American Society of Clinical Oncology.