Brain Metastases from Renal Cell Carcinoma in the Era of Tyrosine Kinase Inhibitors

Sorafenib or sunitinib prolongs survival in patients with renal cell carcinoma metastatic to the brain. Although the prevalence of renal cell carcinoma brain metastases is comparable in the "cytokine" and "tyrosine kinase inhibitor" eras, there is a decreased frequency of brain metastases per unit of time in the "tyrosine kinase inhibitors" era. Background: The effectiveness of tyrosine kinase inhibitors (TKI) in preventing brain metastases in patients with renal cell carcinoma is unclear. Methods: Preclinical studies were conducted to determine the steady-state brain and plasma concentrations of sorafenib and sunitinib in mice deficient in the drug efflux transporters; p-glycoprotein, and breast cancer resistance protein. A single-institution retrospective analysis of patients treated from 2008 to 2010 was conducted to assess the incidence of brain metastases before and during TKI treatment. Results: Transport of sorafenib and sunitinib across the blood-brain barrier was restricted. Retrospective analysis revealed that the median time to develop metastatic brain disease was 28 months (range, 1-108 months) while on TKI therapy and 11.5 months (range, 0-64 months) in patients who did not receive TKI therapy. The incidence of brain metastases per month in patients not treated with TKI therapy was 1.6 higher than the incidence in patients treated with TKI therapy. Conclusions: Penetration of sorafenib or sunitinib through an intact blood-brain barrier to brain tissue is limited; however, the incidence of brain metastases per unit time is decreased in patients on TKI therapy in comparison with the "cytokine" era. (C) 2013 Elsevier Inc. All rights reserved.