A dose-finding study of gemcitabine and vinorelbine in advanced previously treated malignancies

Purpose: Gemcitabine and vinorelbine are active drugs with broad spectrum of activity and manageable toxicity in clinical trials. The aims of this study were to describe the toxicity, to determine the dose-limiting toxicity, and to define the doses of gemcitabine and vinorelbine to be recommended for phase II studies in patients with advanced cancers. Patients and methods: Drugs were given as 30-min infusions on day 1 and 8 (vinorelbine before gemcitabine) every 3 weeks. Thirty-six patients (male : female ratio 25 : 11; mean age 54, PS > 60) were treated including 1 retroperitoneal sarcoma, 7 head and neck, 10 lung, 4 thyroid, 6 pancreatic, 1 bladder, 2 ovary, 2 gastric, 1 rectum, 1 unknown primary, and 1 renal cell carcinoma. Doses of gemcitabine/vinorelbine ranged from 800/20 mg/m(2) to 1500/30 mg/m(2). Results: The dose-limiting toxicity was neutropenia. A transient grade 2-3 elevation of transaminases was frequently observed at several dose-levels, although this toxicity did not appear to be dose dependant and was reversible at day 21 before the next cycle. Other toxicities were mild and easily manageable, consisting of fatigue and flu-like syndromes. Since the MTD was not reach at the higher dose-level, the recommended dose level of the gemcitabine-vinorelbine combination was 1500/30 mg/m(2). One toxic death due to hematologic toxicity was reported in a heavily pretreated patient who underwent prior chemotherapy and pelvic radiotherapy. A total of 12 patients were treated at the recommended dose level which was associated with grade 3-4 neutropenia in 3 of 12 patients and in 22.9% of cycles. Conclusions: This study estimates that the recommended dose for phase II studies of gemcitabine-vinorelbine is 1500/30 mg/m(2) at day 1 and 8 every three weeks. A careful monitoring of the hematologic toxicity is recommended in heavily pretreated patients and in patients who received pelvic radiotherapy. Partial responses observed in a patient with an advanced cisplatin-5-fluorouracil-resistant pancreatic adenocarcinoma and in a patient with mesothelioma support further evaluation of this combination in patients with tumors refractory to classical antitumor agents.