Intrapleural topical application of cisplatin with the surgical carrier Vivostat increases the local drug concentration in an immune-competent rat model with malignant pleuromesothelioma

The Journal of Thoracic and Cardiovascular Surgery. 2006 Mar;131(3):697-703.e3. Received 2 June 2005;  revised 5 August 2005;  accepted 17 August 2005.  Available online 2 March 2006. [Link]

D. Lardinois MD^a, F.J. Jung MD^a, I. Opitz MD^a, K. Rentsch MD^b, C. Latkoczy MD^c, V. Vuong PhD^d, Z. Varga MD^e, V. Rousson PhD^f, D. Günther MD^c, S. Bodis MD^d, R. Stahel MD^g and W. Weder MD^a

^aDivision of Thoracic Surgery, University Hospital, Zurich, Switzerland
^bInstitute of Clinical Chemistry, University Hospital, Zurich, Switzerland
^dDepartment of Radiation Oncology, University Hospital, Zurich, Switzerland
^eInstitute of Clinical Pathology, University Hospital, Zurich, Switzerland
^fInstitute of Biostatistics, University Hospital, Zurich, Switzerland
^gDivision of Oncology, University Hospital, Zurich, Switzerland
^cLaboratory of Inorganic Chemistry, ETH, Zurich, Switzerland

Abstract

Objective: We sought to investigate whether intrapleural topical application of cisplatin with a surgical carrier has a prolonged local tissue level in comparison with cisplatin solution while reducing systemic toxicity.

Methods: Forty immune-competent Fischer rats were inoculated with 10⁶ mesothelioma cells. Ten days later, left pneumonectomy with tumor debulking was performed. Twenty animals underwent local application of cisplatin solution (100 mg/m²), whereas the same quantity of cisplatin was topically applied as a gel with the Vivostat (Vivolution) system in 20 other animals. In each group 5 subgroups of 4 animals were defined according to the harvesting time of blood and tissue samples (2, 4, 24, and 72 hours and 1 week) after local therapy. Platinum concentrations in serum and tissue and systemic toxicity were analyzed.

Results: Platinum concentrations in tissue were significantly higher in the gel group (group 1) than in the solution group (group 2) at 1, 3, and 7 days after therapy (1510, 1224, and 1069 pg/mg for group 1 vs 598, 382, and 287 pg/mg for group 2; P = .007, P = .005, and P = .0002, respectively). Laboratory findings showed renal insufficiency in the animals of the solution group at 1 week, with values of 98 mmol/L versus 7.7 mmol/L for urea and 410 μmol/L versus 43 μmol/L for creatinine (P = .02 and P = .01, respectively), which was confirmed by means of pathologic analysis.

Conclusions: Intrapleural administration of cisplatin with the carrier Vivostat significantly provides sustained higher platinum concentrations up to 1 week in tissue in comparison with application of cisplatin solution without conferring systemic toxicity in this model.