Annals of Oncology 13:1874-1881, 2002
© 2002 European Society for Medical Oncology
Original Paper |
Oxaliplatin plus irinotecan and leucovorin-modulated 5-fluorouracil triplet regimen every other week: a dose-finding study in patients with advanced gastrointestinal malignancies
1 Division of Medical Oncology A, 2 Division of Surgical Oncology C, 3 Service of Radiology, 4 Service of Nuclear Medicine, National Tumour Institute, Naples, Italy
Received 28 February 2002; revised 10 May 2002; accepted 28 May 2002
Background:
Oxaliplatin (OXA) and irinotecan (IRI) are active drugs in first-line as well as second-line treatment of advanced colorectal cancer patients, their toxicity profiles are not overlapping, and both drugs have shown synergism with folinic acid-modulated 5-fluorouracil (5-FU). We planned this phase I study to define the dose-limiting toxicities (DLTs), the maximum tolerated doses (MTDs), and the recommended doses (RDs) for a triplet regimen including OXA plus IRI on day 1, and 6S-folinic acid (LFA) plus 5-FU on day 2, every 2 weeks.
Patients and methods:
At least three patients had to be treated at each dose level, and the trial proceeded if no more than 33% of patients showed a DLT after the first cycle. Starting from OXA 85 mg/m2 (over 2 h) and IRI 150 mg/m2 (over 1 h), an alternated escalation was planned up to 110 mg/m2 and 200 mg/m2, respectively. Thereafter, a fixed dose of LFA, 250 mg/m2 (as 2-h infusion), plus an escalating dose of 5-FU (from 650 to 800 mg/m2 as an intravenous bolus) was added on day 2 to the previous dose level of OXA and IRI.
Results:
Forty-six patients, all but four affected by advanced colorectal primaries, entered this study. The MTDs for OXA and IRI given on the same day were 110 and 200 mg/m2: these doses caused a DLT in three of six patients. The previous dose level (110 and 175 mg/m2, respectively) on day 1 was safely followed on day 2 by LFA plus 5-FU up to 800 mg/m2. Indeed, only one of three patients treated at this last level had a DLT. This cohort was then expanded including a total of 14 patients, and on the whole series five cases of DLT occurred: WHO grade 4 neutropenia (two patients), grade 3 or 4 diarrhoea (three patients). Cumulative toxicity was analysed in 43 patients for a total of 347 cycles: grade 4 neutropenia was detected in 13 patients (30%); it was not dose-related, nor was it exacerbated by the addition of modulated 5-FU. Febrile neutropenia occurred in four patients. Grade 3 or 4 diarrhoea was suffered by nine (21%) and five (12%) patients, respectively. Two complete and nine partial responses were reported on 40 evaluable patients (six patients were disease-free at study entry), giving a response rate of 27.5% (95% confidence interval 15% to 44%); nine of 18 (50%) assessable patients of the two last cohorts treated with the triplet regimen achieved a complete response (two patients) or a partial response (seven patients).
Conclusions:
The RDs for this biweekly regimen were: OXA 110 mg/m2 plus IRI 175 mg/m2 on day 1, and LFA 250 mg/m2 plus 5-FU 800 mg/m2 on day 2. This regimen appeared active in pretreated gastrointestinal malignancies, and it is worthy of being evaluated in advanced colorectal carcinoma after failure of 5-FU-based adjuvant or palliative treatment.
Key words: biweekly regimen, colorectal carcinoma, 5-fluorouracil, irinotecan, oxaliplatin, triplet regimen
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