pazopanib and Cardiovascular-Diseases

Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited by its cardiovascular side effects. Pazopanib and other vascular endothelial growth factor receptor tyrosine kinase inhibitors have been associated with the development of hypertension, QT interval prolongation, and other cardiovascular events; however, these mechanisms are largely unknown. Gaining a deeper understanding of these mechanisms is essential for the development of appropriate surveillance strategies and possible diagnostic biomarkers to allow us to monitor patients and modulate therapy prior to significant cardiac insult. This approach will be vital in keeping patients on these life-saving therapies and may be applicable to other tyrosine kinase inhibitors as well. In this review, we provide a comprehensive overview of the preclinical and clinical side effects of pazopanib with a focus on the mechanisms responsible for its toxicity to the cardiovascular system.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Renal Cell; Cardiovascular Diseases; Cardiovascular System; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Risk Assessment; Risk Factors; Sarcoma; Soft Tissue Neoplasms; Sulfonamides; Treatment Outcome

The role of pazopanib in the second-line setting of refractory metastatic transitional cell carcinoma of the urothelium has not been defined clearly. The aim of this phase I/II trial was to assess the safety, tolerability, and efficacy of combining pazopanib and vinflunine in patients with metastatic transitional cell carcinoma of the urothelium after failure of first-line platinum-containing therapy. From May 2011 to December 2011, five patients were enrolled in this trial. Pazopanib was the investigated compound; four levels were planned (200, 400, 600, and 800 mg/day). Vinflunine was dosed at 280 mg/m for the first dose and 320 mg/m every 3 weeks thereafter. After the definition of a tolerated dose for the combined therapy, a subsequent phase II study was planned. At the starting level, pazopanib 200 mg/day, dose-limiting toxicities were observed in two of five patients. One patient experienced grade 4 febrile neutropenia, which led to treatment discontinuation. A second patient showed grade 3 hepatobiliary disorder with an increase in γ-glutamyltransferase. The study was interrupted at dose level 1 for safety reasons. The initially planned phase II study was therefore not carried out. This phase I study showed that combined therapy of daily pazopanib (200 mg) and vinflunine (280/320 mg/m) every 3 weeks is poorly tolerated in patients with refractory advanced urothelial cancer.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cardiovascular Diseases; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Early Termination of Clinical Trials; Humans; Indazoles; Male; Neutropenia; Organoplatinum Compounds; Palliative Care; Prospective Studies; Pyrimidines; Salvage Therapy; Sulfonamides; Thrombocytopenia; Urologic Neoplasms; Vinblastine