Number of included patients:
- Clin Cancer Res. 2009 Oct 6.
Dose-Ranging Study of Metronomic Oral Vinorelbine in Patients with Advanced Refractory Cancer.
Briasoulis E, Pappas P, Puozzo C, Tolis C, Fountzilas G, Dafni U, Marselos M, Pavlidis N.
Affiliations: University of Ioannina, Medical School, Medical Oncology
Division and University of Ioannina, Medical School, Department of
Pharmacology; and University Hospital of Ioannina, Ioannina, Greece;
University of Thessaloniki, Medical School, Medical Oncology Division,
Thessaloniki, Greece; Institute de Recherche Pierre Fabre, Castres,
France; and Frontier Science Foundation Hellas, Athens, Greece.
To determine the safe dose range and pharmacokinetics of metronomic
oral vinorelbine and obtain preliminary data on biomarkers and efficacy
in patients with advanced cancer. Methods: Successive cohorts of
patients received escalated doses of oral vinorelbine given thrice a
week until disease progression, unacceptable toxicity (UT), or consent
withdrawal. UT was any grade 4 toxicity, or grade 2 or 3 toxicity that
would result to longer than 2-week break during the first 2 months of
treatment. Blood samples were collected for pharmacokinetics and
quantification of angiogenesis regulatory proteins.
patients (median age, 60 years) enrolled at six dose levels from 20 to
70 mg and received treatment for median 12.25 weeks (range, 2-216+).
Unacceptable toxicity occurred in two of six patients treated at 60 mg
(leucopenia grade 4 and epistaxis grade 2) and in one at 70 mg
(leucopenia grade 2). The upper metronomic dose was 50 mg. Objective
antitumor response documented in eight cases and 32% of patients
experienced disease stability for minimum 6 months. Three responders
(renal cancer, medullary thyroid carcinoma, and Kaposi sarcoma)
received nonstop treatment for over 3 years without overt toxicity. Low
pretreatment levels of circulating interleukin-8, vascular endothelial
growth factor, and basic fibroblast growth factor were found predictors
of efficacy. Steady-state concentrations of vinorelbine and its active
metabolite ranged from 0.5 to 1.5 ng/mL.
administration of oral vinorelbine is feasible at doses up to 50 mg
thrice a week and can yield sustainable antitumor activity without
overt toxicity, probably through antiangiogenic mechanism.