Hypertension, Proteinuria, and Antagonism of Vascular Endothelial Growth Factor Signaling: Clinical Toxicity, Therapeutic Target, or Novel Biomarker?

Abstract

There are three US Food and Drug Administration-approved angiogenesis inhibitors for the treatment of cancer that specifically target vascular endothelial growth factor (VEGF) signaling. Bevacizumab (monoclonal antibody to VEGF) has been shown to confer a survival advantage when used in combination with cytotoxic chemotherapy in patients with colorectal cancer and nonsmall-cell lung cancer. 1,2 Sorafenib and sunitinib are orally bioavailable, small-molecule tyrosine kinase inhibitors that target the intracellular tyrosine kinase domain of the VEGF receptor (VEGFR) among other tyrosine kinase targets. Sorafenib has been shown to increase progression-free survival in patients with renal cell carcinoma. 3 Sunitinib has been shown to increase progressionfree survival in patients with renal cell carcinoma and GI stromal tumors. [4][5][6] A plethora of new small-molecule tyrosine kinase inhibitors are in preclinical development and early-phase clinical trials that target VEGFR with varying degrees of specificity, including AZD2171, which is the subject of a published report by Drevs et al in this issue of the Journal of Clinical Oncology. 7,8 Notable clinical and biologic observations reported in their phase I study were correlation between AZD2171 pharmacokinetics and perturbation of tumor blood flow in part A of their study (not confirmed in part B, perhaps attributable to smaller dose range investigated); increased VEGF levels and decreased VEGFR-2 for which there were no clear pharmacodynamic correlations, and only a possible hint of a dose-response effect; and demonstrable clinical activity. The appearance of hypertension as the most common dose-limiting toxicity and hypertensive crisis in three patients, we feel, is also very interesting, and it is the subject of our invited commentary. There is a possible dose-response effect but a missed opportunity to correlate hypertensive changes with either drug concentration or exposure and perhaps even clinical response (though limited in phase I setting). Hypertension with this class of anticancer compounds is an emerging toxicity that oncologists must be comfortable in managing. Furthermore, it is

Phase I Study of Cediranib in Combination with Oxaliplatin and Infusional 5-Fluorouracil in Patients with Advanced Colorectal Cancer

“…Like other agents targeting angiogenesis, hypertension was a common side effect seen in this study with 11 of 16 patients developing hypertension (23). However, it was easily managed with calcium channel antagonists.…”

A Phase I Study of Foretinib, a Multi-Targeted Inhibitor of c-Met and Vascular Endothelial Growth Factor Receptor 2

“…A unique toxicity shown in two patients was a transient (<24 hours) confusional state, with an expressive language disorder and apraxia in one. These occurred in the setting of grade 2 hypertension and proteinuria and were considered related to the inhibition of the VEGF axis (18,19). No specific dose-limiting toxicity could be ascribed solely to inhibition of the HGF-Met axis, although fatigue, nausea, diarrhea, and elevations of hepatic transaminases are frequently seen in patients treated with several tyrosine kinase inhibitors of differing target specificity (20).…”

“…These changes were generally of grade 1 or 2, and resolved with scheduled dose delay or dose reduction. Two commonly observed events, hypertension and proteinuria, are linked to inhibition of VEGF-mediated angiogenesis (18). Patient-specific management of hypertension proved to be effective without disrupting drug administration.…”

Anti-VEGF Therapy in Cancer: A Double-Edged Sword

“…This decrease in blood pressure is caused by the generation of blood capillaries, which increases the total cross-sectional surface area available for blood to low and thereby reduces blood pressure, and VEGF-induced vasodilation, which occurs when VEGF induces the production of nitric oxide and PGI 2 as part of its signal transduction pathway [63]. VEGF inhibitors therefore cause hypertension by inhibiting the production of nitric oxide and PGI 2 , leading to vasoconstriction and an increase in blood pressure [64,65]. Hypertension caused from VEGF inhibition can be managed using standard therapies, such as angiotensin-converting enzyme inhibitors, beta blockers, calcium channel blockers, diuretics, and angiotensin II receptor blockers [66].…”