Journal
CLINICAL CANCER RESEARCH
Volume 15, Issue 19, Pages 6250-6257Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-09-0058
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Funding
- A Cancer and Leukemia Group B Foundation Oncology Fellow Clinical Research Award
- ASCO Young Investigator Award
- National Institute of General Medical Sciences [5T32GM007019-31]
- National Cancer Institute [K23CA124802]
- National Center for Research Resources [M01-RR000055]
- University of Chicago Cancer Research Center [P30-CA014599]
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Purpose: Hypertension is a mechanism-based toxicity of sorafenib and other cancer therapeutics that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. This prospective, single-center, cohort study characterized ambulatory blood pressure monitoring as an early pharmacodynamic biomarker of VEGF signaling pathway inhibition by sorafenib. Experimental Design: Fifty-four normotensive advanced cancer patients underwent 24-hour ambulatory blood pressure monitoring before and between days 6 and 10 of sorafenib therapy. After blood pressure changes were detected among the first cohort within 10 days, ambulatory blood pressure monitoring was done during the first 24 hours of treatment for the second cohort. Results: For the entire patient population, the blood pressure increase [mean systolic, +10.8 mm Hg; 95% confidence interval (95% CI), 8.6-13.0; range, -5.2 to +28.7 mm Hg; mean diastolic, +8.0 mm Hg; 95% Cl, 6.3-9.7; range, -4.4 to +27.1 mm Hg] was detected between days 6 and 10 (P < 0.0001 for both) and plateaued thereafter. Variability in blood pressure change did not associate with: age, body size, sex, self-reported race, baseline blood pressure, or steady-state sorafenib plasma concentrations. In the second cohort, the blood pressure elevation was detected during the first 24 hours (mean systolic, +8.2 mm Hg; 95% Cl, 5.0-11.3; mean diastolic, +6.5 mm Hg; 95% Cl, 4.7-8.3; P < 0.0001 for both). Conclusions: Ambulatory blood pressure monitoring detects the blood pressure response to VEGF signaling pathway inhibition by sorafenib during the first 24 hours of treatment. The magnitude of blood pressure elevation is highly variable and unpredictable but could be important in optimizing the therapeutic index of VEGF signaling pathway inhibitor therapy. (Clin Cancer Res 2009;15(19):6250-7)
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