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)/fol inic acid chemoradiotherapy in rectal cancer. We tested three dose levels t o 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 h ad T4 rectal carcinoma, T1-T3 disease with colostomy refusal, or potentiall y operable T2/T3 M1 requiring local treatment, Pelvic radiotherapy was 45 G y 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 refu sing surgery received additional contact radiotherapy +/- brachytherapy. Do se 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 dys esthesia) 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 asthe nia, severe diarrhea and vomiting, and more than 10% weight loss. There wer e no other DLTs and no severe rectitis or gastrointestinal toxicity. There were objective responses at all doses and no progressions. Fight patients u nderwent radical surgery after chemoradiotherapy. Two had complete patholog ic responses. Conclusion: FolfoR1 seems feasible and effective. Dose escalation did not i ncrease toxicity. Although the MTD was not reached in this study, we recomm end oxaliplatin 130 mg/m2 for phase ii studies because it is the dose deter mined from studies in metastatic patients with no toxicity when given concu rrently with radiation. J Clin Oncol 19:2433-2438. (C) 2001 by American Soc iety of Clinical Oncology.