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Journal of Clinical Oncology, Vol 25, No 21 (July 20), 2007: pp. 2993-2995 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.5113
Hypertension, Proteinuria, and Antagonism of Vascular Endothelial Growth Factor Signaling: Clinical Toxicity, Therapeutic Target, or Novel Biomarker?Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University (CASE), School of Medicine, Cleveland, OH
Division of Cardiology, Department of Medicine, CASE School of Medicine, Cleveland, OH
Division of Hematology/Oncology, Department of Medicine, CASE School of Medicine, Cleveland, OH
Developmental Therapeutics Program, CASE Comprehensive Cancer Center, University Hospitals CASE Medical Center, Cleveland, OH 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 non–small-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 progression-free survival in patients with renal cell carcinoma and GI stromal tumors.4-6 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 not inconceivable that changes in blood pressure could possibly serve as a therapeutic target and, hence, a putative novel clinical biomarker that needs to be further explored and defined in the clinic. Vascular adverse effects of the entire class of angiogenesis inhibitors that affect VEGF signaling include hypertension, proteinuria, thrombosis, and hemorrhage.9 A meta-analysis of randomized controlled trials with patients receiving bevacizumab indicated a relative risk of 1.4 for proteinuria with bevacizumab at low dose (2.5 to 7.5 mg/kg) and 1.6 for high dose (10 to 15 mg/kg); and a relative risk of hypertension 3.0 for low dose and 7.5 for high dose.10 In a phase III clinical trial of sorafenib in patients with renal cell carcinoma, 4% of patients receiving sorafenib developed grade 3 or 4 hypertension compared with less than 1% in patients receiving placebo.3 In a pilot study, patients receiving sorafenib 400 mg by mouth twice a day had a mean elevation of 10 mmHg systolic and 7 mmHg diastolic blood pressure once steady-state levels of sorafenib were achieved.11 In a phase III clinical trial of sunitinib in patients with GI stromal tumors, 8% of patients developed grade 3 or 4 hypertension compared with 0% of patients treated with placebo.5 In a phase I trial of KRN951, a small-molecule VEGFR tyrosine kinase inhibitor, 14 of 15 patients developed hypertension, and grade 3 proteinuria was a dose-limiting toxicity.12 In their study, Drevs et al reported grade 3 or 4 hypertension in 29 (35%) of 83 patients receiving increasing doses of AZD2171, and hypertensive crisis in three patients, but did not report any proteinuria (although the authors did not report that patients were specifically tested for proteinuria).8 The pathogeneses of VEGF signal inhibitor–induced hypertension and proteinuria are not thoroughly understood. Glomerular structure and function are thought to be maintained through proper VEGF expression via maintenance of endothelial cells and podocytes.13 VEGF dysregulation appears to be an important component of the pathogenesis of pre-eclampsia because elevated levels of soluble VEGFR-1 protein are observed in women with preeclampsia.14 In animals, artificially-induced decreases in VEGF result in a glomerulopathy associated with proteinuria, endotheliosis, and hyaline deposits similar to those seen in renal biopsies of women with preeclampsia.15 Increased hypertension may also contribute to the proteinuria observed in patients receiving inhibitors of VEGF signaling. VEGF itself may be important in maintaining proper blood pressure, as intravenous administration of VEGF caused a dose-related decrease in mean arterial blood pressure in rats thought to be mediated through nitric oxide and prostacyclin synthesis.16,17 On the basis of this evidence, it has been proposed that VEGF signal antagonism leads to inhibition of nitric synthase with a subsequent decrease in nitric oxide leading to vasoconstriction and decreased sodium ion renal excretion and to elevated blood pressure.10 Others have suggested that angiogenesis inhibitor-induced hypertension may be secondary to vascular rarefaction (a functional decrease in the number of arterioles and capillaries) leading to increased peripheral vascular resistance.18 The prevalence of hypertension with agents that target VEGF signaling has led Maitland et al to propose that elevation of blood pressure be used as a biomarker for efficacy of VEGF signal inhibition, and that dose titration of the agent until blood pressure elevation in an individual patient may lead to better antitumor efficacy and, hence, improved outcomes.11,19 Alternatively, absence of blood pressure response may herald lack of antitumor effect leading to change in therapy more expeditiously. This hypothesis-driven, novel, inexpensive, and readily testable therapeutic strategy is deserving of prospective evaluation. As patients live longer with cancer, thanks to the development of newer antineoplastic agents and better regimens, oncologists need to be aware of long-term adverse effects from chronic dosing schedules (especially those with small molecules) and conversant in the management of associated toxicities, including elevation of blood pressure.9,20 What is potentially worrisome is that, as the cancer population ages, comorbidities such as atherosclerotic cardiovascular disease will present increasing challenges to cancer physicians. This is akin to the bygone era of neurologic complications encountered in oncology practice, with only modest improvements in overall survival for many solid tumor patients. In this regard, an increase in late-stage cardiovascular complications of newer anticancer therapy is likely on the horizon. This may be further substantiated from careful perusal of the recent Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack trial (33,357 patients), which demonstrated that lowering blood pressure by a mean of 0.8 mmHg (systolic blood pressure, P = .30; and diastolic blood pressure, P < .001) during a period of 4 to 8 years led to better cardiac outcomes with a diuretic than with a calcium channel blocker or an angiotensin-converting enzyme (ACE) inhibitor, respectively.21 This is an order of magnitude (1 log) lower than the differences in blood pressure observed with current agents that inhibit VEGF signaling.11 Patients being treated for cancer may be taking angiogenesis inhibitors for many months to years. This suggests that oncologists treating patients with angiogenesis inhibitors need to be vigilant about blood pressure monitoring and control.22 Unfortunately, regulation of angiogenesis inhibitor-induced hypertension remains controversial. Both calcium channel blockers and ACE inhibitors have been used with success to control blood pressure in patients on these agents.23 It has been proposed that utilizing ACE inhibitors is more rational on the basis of the proposed mechanisms of angiogenesis-induced hypertension acting through nitric oxide, which is affected by ACE inhibitors and not calcium channel blockers.24 In patients with hypertension and either microalbuminemia or frank proteinuria secondary to diabetes, the American Diabetes Association recommends ACE inhibitors or angiotensin-receptor blockers as first-line antihypertensive agents.25 In their study, Drevs et al suggest using the Joint National Committee 7 guidelines for the treatment of elevated blood pressure as an algorithm for treating patients with angiogenesis inhibitor-induced hypertension.26 Novel adverse effects of the angiogenesis inhibitors such as hypertension and proteinuria should not to be taken lightly by oncologists more accustomed to treating adverse effects of older and more traditional cytotoxic chemotherapy regimens. Patients should be screened for proteinuria before administration of bevacizumab. Baseline blood pressures should be obtained before the administration of any agent that inhibits the VEGF signaling pathway, monitored regularly (especially at the outset of therapy) while patients are treated with these agents, and any significant rise in blood pressure should be treated with antihypertensive agents. Clearly, carefully designed prospective studies are warranted to better define optimal antihypertensive regimens with concomitant VEGF signaling inhibition and, perhaps more importantly, to determine whether targeting a therapeutic blood pressure is a reasonable strategy to identify patients who may in derive better antitumor effects with such therapy. Until then, it is reasonable to follow the Joint National Committee 7 guidelines in the absence of better information for the management of VEGF signal inhibitor–induced hypertension. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Willem J. van Heeckeren, Scot C. Remick Administrative support: Scot C. Remick Collection and assembly of data: Willem J. van Heeckeren, Scot C. Remick Data analysis and interpretation: Willem J. van Heeckeren, Matthew M. Cooney, Jose Ortiz, Scot C. Remick Manuscript writing: Willem J. van Heeckeren, Scot C. Remick Final approval of manuscript: Willem J. van Heeckeren, Matthew M. Cooney, Jose Ortiz, Scot C. Remick REFERENCES
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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