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R.M. Huber



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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): R.M. Huber

      • 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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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-022 - Central European Initiative against Lung Cancer: Results of the Inaugural Workshop (ID 1401)

      09:30 - 16:30  |  Author(s): R.M. Huber

      • Abstract

      Background
      Lung cancer is a major health problem in Central Europe where some of the countries have the world-wide highest incidence rates of this cancer. The CENTRAL EUROPEAN INITIATIVE AGAINST LUNG CANCER aims at decreasing the burden of lung cancer in this region. The Inaugural Workshop of this Initiative was planned in order develop strategies to achieve this goal.

      Methods
      Participation at the Workshop was by invitation and more than 100 lung cancer experts from several Central European Countries and Israel did participate. The participants discussed the current status of lung cancer management and suggested strategies for improvement in the various areas of lung cancer management.

      Results
      The Workshop focused on all aspects of lung cancer. There was agreement that lung cancer is a major health problem in all Central European countries and that improvement in all aspects of lung cancer management must be attempted. Prevention strategies have steadily been improved but remain insufficient in most countries. The potential of screening was recognized but routine implementation of screening was not considered to be feasible in most Central European countries at this time. Access to modern radiological imaging such as PET-CT must be improved in many centers. A future project will assess the accuracy of radiological staging in several hospitals. Molecular diagnosis is increasingly implemented in most countries but patient selection for molecular analyses varies between countries. A major area of discussion was the implementation of standard treatments. Multidisciplinary tumor boards have been established in most centers but participants disagreed on whether all or only selected patients should be presented during tumor board meetings. Concerning stage III NSCLC, great heterogeneity with regard to both staging and treatment has been recognized. A future project plans to assess current management of patients with stage III NSCLC and to define areas for improvement. Access to systemic treatment has improved over the years but timely access to novel and expensive drugs remains challenging in several countries. Strategies to increase the scientific co-operation and education have also been discussed and should increasingly be implemented in the future.

      Conclusion
      The Workshop did outline the current status including challenges in the management of patients with lung cancer in Central Europe. Next projects will assess staging accuracy and detailed treatment of patients with locally advanced NSCLC. Future events such as the 14th Central European Lung Cancer Congress in 2014 and the 17th World Congress on Lung Cancer in 2016 in Vienna should also have a major impact on decreasing the burden of lung cancer in Central European countries.

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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): R.M. Huber

      • 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.