Dose-Ranging Study of Metronomic Oral Vinorelbine in Patients with Advanced Refractory Cancer.

Primary tabs

field_vote: 
Average: 6 (1 vote)
Publication type: 
Number of included patients: 
References: 
Therapeutic intervention: 
Therapeutic Substance(s): 

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.
Authors'
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.
Aim:
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.
RESULTS: Sixty-two
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.
CONCLUSIONS: Metronomic
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.