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| Optimized Intrapleural Cisplatin Chemotherapy with a Fibrin Carrier After Extrapleural Pneumonectomy - A Pre-Clinical Study |
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Isabelle Opitz1, Barbara V. Erne1, Seval Demirbas1, Alexander Jetter2, Burkhardt Seifert4, Rolf Stahel3, Walter Weder1; 1Division of Thoracic Surgery, University Hopsital, Zurich, Switzerland; 2Institute for Pharmacology and Toxicology, University Hospital, Zurich, Switzerland; 3Department of Oncology, University Hospital, Zurich, Switzerland; 4Institute for Biostatistics, University, Zurich, Switzerland Objective: The aim of the study was to evaluate whether platinum concentration in the subpleural tissue and in the blood are optimized by local application of cisplatin loaded to a fibrin carrier compared to cisplatin-solution in a randomized setting of a pig model. Methods: After left-sided pneumonectomy plus parietal pleurectomy the pigs were randomly assigned to receive either 90 mg/m2 cisplatin intrapleural solution (control, n=5) or to receive 5mg cisplatin combined to a fibrin sealant applied on a predefined area of the chest wall (study group, n=5). Platinum concentration in the plasma was determined at several early time points (1-24h) and at 2 and 5 days following treatment. Chest wall biopsies were assessed for platinum concentration after 2 and 4 hours and at day 2 and 5 after cisplatin application. The level of total platinum was measured by means of inductively coupled plasma sector field mass spectrometric detection with a matrix-matched calibration procedure. Results: The dose- and surface-corrected mean concentration of cisplatin in the chest wall tissue 2 h after the application was 504.1 g/L in animals treated with cisplatin-fibrin (geometric coefficients of variation, CV, 88%), compared to 249.1 g/L (CV 261%) in the control group. Five days after the application, mean concentrations in the tissue were 72.5 g/L (CV 216%) and 21.8 g/L (CV 427%) in fibrin- and solution treated animals, respectively. In plasma, the dose- and application surface-corrected exposure towards cisplatin (area under the concentration-time curve from 0 - 5 d after surgery) was clearly and significantly lower with cisplatin-fibrin than with cisplatin- solution: 68.5 g/L*h (CV 28%) versus 755.8 g/L*h (CV 110%). This is also reflected by significantly reduced serum-creatinine values in the study group in comparison to the control group (p=0.02) as well as significantly better well-being scores for the animals treated with cisplatin-fibrin at each day of the observation (all p<0.05). Conclusion: Cisplatin tissue concentration after cisplatin-fibrin treatment was at least two fold higher at 2 h and 5 d while systemic cisplatin concentrations were significantly reduced. This finding offers a clear advantage since rate and severity of systemic adverse events can be reduced while local cytotoxic concentrations are at least maintained, what will be soon evaluated in a phase-I study. Back to 2010 Annual Meeting Back to Program Outline Back to Main Program |
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