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A. Tufman



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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.07 - Daily administration of oral vinorelbine: data from a phase I trial in patients with advanced Non-Small Cell Lung Cancer (NSCLC) (ID 2395)

      16:15 - 17:45  |  Author(s): A. Tufman

      • Abstract
      • Presentation
      • Slides

      Background
      Metronomic regimens, in which small, frequent doses of chemotherapy are administered, have been suggested to lower treatment-associated toxicities while maintaining, or even improving, efficacy. The high frequency of administration aims to expose tumour cells continuously to the drug, preventing recovery between cycles and possibly improving tumour control. We present the clinical and pharmacokinetic data of a phase I dose finding study in which the maximum tolerated dose (MTD) of daily oral vinorelbine was determined in pretreated patients with advanced NSCLC.

      Methods
      Patients (pts) were treated daily with oral vinorelbine (Navelbine® Oral) at fixed doses of 20 mg/d, 30 mg/d, 40 mg/d or 50 mg/d for 21 days of each four-week cycle. Blood sampling for pharmacokinetic assessment was carried out in the first cycle just before drug intake (trough concentrations) on days 1, 8, 15 and 21 and additionally at 1 h, 3 h and 24 h after drug intake on days 1 and 21.

      Results
      Daily administration of oral vinorelbine was well tolerated up to 30 mg/d without any dose limiting toxicities (DLT). At 40 mg one of three patients experienced DLT in cycle 1 and another patient in cycle 2. The MTD was reached at 50 mg/d when three out of six pts experienced DLT in cycle one. The reported DLTs included febrile and non-febrile neutropenia (6 DLTs) as well as fatigue (1 DLT). One patient had an exceptionally good clinical response with a long-lasting tumour remission. Twenty-one pts were evaluable for pharmacokinetic analysis. Blood concentrations of vinorelbine increased with escalating dose levels. Pts were continuously exposed to the drug over the 21-day treatment period as indicated by measurable trough concentrations on days 8, 15 and 21. A slight accumulation of vinorelbine was observed until day 8 based on residual concentrations (ratio c~24h ~ranged 1.96-2.03 between day 1 and either day 8, 15 or 21). The accumulation had no impact on global exposure at repeated dosing, as only minor differences in blood concentrations were detected between day 1 and day 21 (ratio d21/d1 median AUC~0h-24h~: 0.81, 0.92, 1.07, 0.56 at 20 mg/d, 30 mg/d, 40 mg/d and 50 mg/d, respectively). Data on four pts experiencing DLT were available (1 pt at 40 mg/d, 3 pts at 50 mg/d). Only one DLT correlated with an evidently high 24 h blood exposure to vinorelbine.

      Conclusion
      The recommended dose for daily administration of oral vinorelbine is 30 mg in cycle 1 followed by 40 mg in subsequent cycles in the absence of DLT. Further studies are necessary to determine the clinical impact, and possible anti-angiogenic profile of the daily administration schedule of vinorelbine.

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    P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.05-014 - Schedule-dependent Interactions between Pemetrexed and Vinorelbine in Human Lung Cancer Cells (ID 2387)

      09:30 - 16:30  |  Author(s): A. Tufman

      • Abstract

      Background
      Lung cancer is the leading cause of cancer deaths worldwide. Despite advances and progresses in surgery, chemotherapy, and radiotherapy over the last decades, the death rate from lung cancer has remained largely unchanged, which is mainly due to metastatic disease and multi drug resistance. Because of the overall poor prognosis, new treatment strategies for lung cancer patients are urgently needed. The aim of this study was to investigate the interactions between pemetrexed and vinorelbine for human adenocarcinoma via various chemotherapy schedules.

      Methods
      HCC cells and cisplatin resistant HCC cells (HCC-res) were treated with different schedules of combination of cisplatin (Cis), vinorelbine (Vin), and pemetrexed (Pem) respectively, more specific as Cis, Vin, Pem, Cis+Vin, Cis+Pem, Vin+Pem, Vin→Pem, Pem→Vin, Cis+Vin+Pem, Cis→Pem→Vin, and Cis→Vin→Pem. Cell growth inhibition was determined by cell viability analysis. Cell apoptosis was analyzed via annexin V staining and FACS analysis. And cytoplasm Ca[2+] was measured with Ca[2+] indicator dye Fura-2 AM.

      Results
      Vin and Pem caused a strong dose-dependent cytotoxic effect in both HCC and HCC-res cells. The IC50 values of Vin against HCC and HCC-res cells were 10.34 ± 1.12 nM and 9.98 ±2.12 nM, respectively. The IC50 values of Pem against these cells were 110.77 ± 17.28 nM and 118.89 ±18.77 nM respectively. The application of different therapy schedules induced a significant time dependent cell growth inhibition on HCC naïve and cisplatin resistant cells. The therapy scheme of Cis→Pem→Vin showed the strongest inhibitory effect on both HCC and HCC-res cells. The application of different therapy schedules on HCC and HCC-res cells increased the percentage of cells undergoing apoptosis, except the application of Vin alone. In both HCC and HCC-res cells, Cis→Pem→Vin was found the most effective to induce apoptosis. The application of different therapy schedules on HCC and HCC-res cells increased [Ca[2+]]~c~. Only the application of Vin alone failed to increase [Ca[2+]]~c~ in HCC cells. The most elevated [Ca[2+]]~c ~was found in the cells treated with Cis→Pem→Vin in both HCC and HCC-res cells

      Conclusion
      We demonstrated that the sequential application of Cis, Vin and Pem has a synergistic effect in cell growth inhibition, apoptosis induction, and [Ca[2+]]~c~ elevation in HCC and HCC-res cells. The Ca[2+ ]overload could lead to apoptosis, which was related to the cell growth inhibitory effect of chemotherapeutics in lung cancer cells. It might cast a light to develop chemotherapy schedules for patients, and to overcome cisplatin resistance in lung cancer.