Clinical outcomes of oral metronomic vinorelbine in advanced non-small cell lung cancer: correlations with pharmacokinetics and MDR1 polymorphisms.
PURPOSE
This study investigated correlations of the clinical outcomes of oral metronomic vinorelbine (VNR) with VNR pharmacokinetics and MDR1 polymorphisms.


METHODS
Eighty-two patients with metastatic non-small cell lung cancer (NSCLC) unfit for standard chemotherapy were treated with VNR at the oral doses of 20-30 mg every other day or 50 mg three times a week. They had a performance status (PS) ≤ 3, were > 70-year-old and drug-naïve or cisplatin-pretreated. MDR1 2677G > T and 3435C > T polymorphisms were analysed and blood concentrations of VNR and desacetyl-VNR (dVNR: active metabolite) assayed. Overall survival (OS), treatment duration and drug-related toxicity were the main endpoints.


RESULTS
Median OS and treatment duration were 27 weeks (range 1.3-183) and 15 weeks (range 1.3-144), respectively. OS was directly correlated with the duration of VNR treatment and number of therapy lines after VNR treatment (multiple linear regression: adjusted r2 = 0.71; p < 0.00001). Neither MDR1 genotypes nor VNR/dVNR concentrations predicted OS. VNR blood levels were positively correlated with platelet counts (r2 = 0.12; p = 0.0036). Patients who had long-term benefit (treated for ≥ 6 month without toxicity) showed lower VNR concentrations than those who had not. Twelve patients stopped therapy due to grade 3-4 toxicity. Toxicity was associated with blood concentrations of VNR ≥ 1.57 ng/mL and dVNR ≥ 3.04 ng/mL, but not with MDR1 polymorphisms.


CONCLUSIONS
Neither pharmacokinetic nor pharmacogenetic monitoring seem useful to predict OS. On the other hand, high VNR and dVNR blood levels were associated with severe toxicity.
['Gusella|Milena|M|0000-0002-6257-0282', 'Pasini|Felice|F|', 'Caruso|Donatella|D|', 'Barile|Carmen|C|', 'Modena|Yasmina|Y|', 'Fraccon|Anna Paola|AP|', 'Bertolaso|Laura|L|', 'Menon|Daniela|D|', 'Crepaldi|Giorgio|G|', 'Bononi|Antonio|A|', 'Spezzano|Roberto|R|', 'Telatin|Giorgia Anna|GA|', 'Corona|Giuseppe|G|', 'Padrini|Roberto|R|']
D018435:ATP Binding Cassette Transporter, Subfamily B D059250:Administration, Metronomic D000284:Administration, Oral D000328:Adult D000368:Aged D000369:Aged, 80 and over D000972:Antineoplastic Agents, Phytogenic D002289:Carcinoma, Non-Small-Cell Lung D004305:Dose-Response Relationship, Drug D064420:Drug-Related Side Effects and Adverse Reactions D005240:Feasibility Studies D005260:Female D005500:Follow-Up Studies D006207:Half-Life D006801:Humans D008175:Lung Neoplasms D008297:Male D008875:Middle Aged D009367:Neoplasm Staging D020641:Polymorphism, Single Nucleotide D012372:ROC Curve D012720:Severity of Illness Index D016019:Survival Analysis D016896:Treatment Outcome D000077235:Vinorelbine
Metronomics Vinorelbine Lung cancer Pharmacokinetics MDR1 polymorphisms.