Milena Gusella1, Felice Pasini2, Donatella Caruso3, Carmen Barile4, Yasmina Modena4, Anna Paola Fraccon2, Laura Bertolaso4, Daniela Menon4, Giorgio Crepaldi4, Antonio Bononi4, Roberto Spezzano3, Giorgia Anna Telatin4, Giuseppe Corona5, Roberto Padrini6. 1. AULSS5 Polesana, UOC Oncologia, Ospedale Santa Maria della Misericordia, viale Tre Martiri, 140, 45100, Rovigo, Italy. milenagusella@libero.it. 2. Servizio di Oncologia, Ospedale Pederzoli, Peschiera del Garda, Verona, Italy. 3. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy. 4. AULSS5 Polesana, UOC Oncologia, Ospedale Santa Maria della Misericordia, viale Tre Martiri, 140, 45100, Rovigo, Italy. 5. Dipartimento di Ricerca Traslazionale, IRCCS Centro di Riferimento Oncologico, Aviano, Italy. 6. Servizio di Farmacologia Clinica, Dipartimento di Medicina, Università di Padova, Padua, Italy.
Abstract
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.
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.
Authors: Vittorio Gebbia; Marco Maria Aiello; Giuseppe Banna; Giusi Blanco; Livio Blasi; Nicolò Borsellino; Dario Giuffrida; Mario Lo Mauro; Gianfranco Mancuso; Dario Piazza; Giuseppina Savio; Hector Soto Parra; Maria Rosaria Valerio; Francesco Verderame; Paolo Vigneri Journal: Ecancermedicalscience Date: 2020-09-29