VEGF signaling pathway inhibitors and hypertension: A review for oncologists

Angiogenesis has long been recognized as an important target for anticancer therapy. During the last decade, several new targeted therapies have been developed and demonstrate clinical efficacy in a variety of cancers — for example, renal cell, lung, breast and colon cancers.

The VEGF signaling pathway has been identified as a major player in the angiogenesis process. There are currently four agents commercially available in the United States that target the VEGF signaling pathway (VSP inhibitors). These include bevacizumab (Avastin, Genentech), sorafenib (Nexavar, Bayer), sunitinib (Sutent, Pfizer), and pazopanib (Votrient, GlaxoSmithKline; see table 1).

Bevacizumab, approved in 2004, was the first antiangiogenesis agent approved for clinical use in combination with fluorouracil-based chemotherapy for the treatment of metastatic colorectal cancer. It is a humanized monoclonal antibody targeted against the VEGF-A ligand and exerts its effects primarily through prevention of VEGF-A binding to VEGF receptor (VEGFR), which in turn inhibits downstream signaling, preventing angiogenesis.

Laura Boehnke Michaud

Sorafenib, sunitinib and pazopanib are all small molecule multityrosine kinase inhibitors that inhibit all of the VEGFRs (1, 2, and 3) in addition to other targets (eg, CRAF, BRAF, KIT, FLT-3, RET, PDGFRs, and others). Each of these multitargeted agents differs slightly in the other proteins they target. However, the biologic effects of inhibiting angiogenesis are paramount to inferring clinical activity with this class of agents.

Hypertension

Although these agents target different aspects of the VSP, they all appear to be associated with hypertension as an adverse effect. The exact mechanisms by which VSP inhibitors increase blood pressure remain unknown, but some hypotheses have been suggested and it may actually be a surrogate marker of effective inhibition of the VSP.

Also of significance is the fact that the TKIs target more than just VEGF and other targets may contribute to cardiotoxicity as well. Inhibition of VEGF leads to decreases in nitric oxide production, which leads to vascular constriction and reduction in sodium ion renal excretion, which ultimately leads to increased blood pressure.

Secondarily, vascular rarefaction (a depletion of the arterioles and capillaries) may also play a role, inhibiting the growth factors required to construct new capillaries and recruit endothelial progenitor cells. Clinical analyses examining the relationship between hypertension and outcome have been reported in breast, renal cell, pancreatic, colon cancers, non-small cell lung cancer and glioblastoma.

In metastatic breast cancer patients treated with bevacizumab and paclitaxel, those patients with grade-3 or -4 hypertension had significantly longer OS compared with those patients who did not experience hypertension. In metastatic renal cell carcinoma patients, response and time to progression were improved in those patients requiring antihypertensive medication during bevacizumab therapy. Similar data has been reported with pancreatic, colon and NSCLC patients.

In contrast, one study with glioblastoma patients failed to demonstrate a correlation between hypertension and cancer outcome when bevacizumab was administered every two weeks at 10 mg/kg. It is not clear at this time how these associations will play out in other tumor types, but clearly this is an adverse event that should be monitored for and appropriately managed.

Managing hypertension

Hypertension is one of the most common toxicities patients experience with VSP inhibitors and appropriate management is important to prevent effects on morbidity and mortality that may occur (see table 2). In the general population, effectively lowering blood pressure reduces the 10-year mortality rate by 9% (number needed to treat is 11), making hypertension a public health problem that should be addressed in patients of all ages. However, in a metastatic cancer population, patients have limited life expectancy, and long-term mortality risk reduction resulting from blood pressure management does not appear to be clinically relevant for most patients receiving VSP inhibitors today.

However, acute adverse events such as reversible posterior leukoencephalopathy syndrome, renal dysfunction and other cardiotoxic events (eg, heart failure, myocardial infarction, arrhythmias) may be more prevalent in patients with uncontrolled hypertension and minimized through early identification and management of blood pressure. Also, maximizing dose and duration of VSP inhibitor therapy may prove to be beneficial in terms of improving survival, even in metastatic patients.

Lastly, ongoing clinical trials incorporating VSP inhibitors into treatment for earlier stages of cancer may prove to be effective, and long-term therapy may be required. Thus, the management of reversible toxicities such as hypertension becomes clinically relevant and important for the success of such therapies.

Recommendations

Based on these factors, the Investigational Drug Steering Committee of the NCI formed a Cardiovascular Toxicities Panel, joining members of its Angiogenesis Task Force with experts in the management of hypertension and cardiovascular toxic effects in cancer patients to generate consensus recommendations to optimize risk assessment, monitoring and safe administration of new agents. This group recently published a commentary on the topic, given the lack of data specifically addressing this issue in the literature.

The frequency at which hypertension occurs varies slightly with each agent and the disease state being studied. Most clinical trials in oncology utilize the Common Terminology Criteria for Adverse Events (CTCAE) to describe toxicities associated with drug therapy. Unfortunately, these criteria do not align with any typical hypertension classification, and little evidence is available to indicate comparable efficacy of antihypertensive approaches in this population; therefore, developing specific management recommendations is challenging.

The new CTCAE version 4 Hypertension scale has now been aligned with the U.S. National High Blood Pressure Education Program (the JNC) categories to improve communication among medical specialties. In the future, more evidence may be available to facilitate more robust recommendations. Currently, most of the recommendations from the NCI Cardiovascular Toxicities Panel refer to recommendations by the JNC as best general medical practice, but other cancer-specific factors should also be considered (see table 3 and table 4).

In the commentary mentioned above, the panel recommends:

• Formal risk assessment and screening for cardiovascular complications before VSP inhibitor therapy.
• Recognition that pre-existing hypertension will be common, and proper identification and management before initiation of VSP inhibitor therapy is important.
• Active monitoring of blood pressure during therapy with more frequent monitoring during the first cycle is key to early intervention and avoidance of more serious complications.
• The general goal for control should be less than 140 mm Hg/90 mm Hg, with consideration for a lower target in patient with multiple preexisting risk factors for adverse consequences of hypertension.
• Manage elevations in blood pressure aggressively to avoid development of complications with attention to proper agent selection, dosing and scheduling of follow-up to ensure efficacy and to control adverse events associated with the antihypertensive agents.

Details regarding which antihypertensive agents and/or combination of agents should be utilized in which patients is well beyond the scope of this article. The readers are referred to the referenced commentary for more details and table 4 for general considerations. The goal of this article is to raise awareness regarding screening, monitoring and aggressively managing hypertension associated with VSP inhibitor therapy. Recognition of the problem and proper referral to a hypertension specialist — cardiologist, nephrologist, endocrinologist, or certified hypertension specialist — when needed is paramount to minimizing the risk for more serious complications with VSP inhibitor therapy and optimizing both the quantity and the quality of life for our patients.

Laura Boehnke Michaud, PharmD, BCOP, FASHP, is Manager of Clinical Pharmacy Services at The University of Texas M.D. Anderson Cancer Center, Houston.

For more information:

• Chobanian AV. JAMA. 2003;289:2560-2572.
• Dahlberg SE. J Clin Oncol. 2010;28:949-954.
• Maitland M. J Natl Cancer Inst. 2010; doi:10.1093/jnci/djq091.
• Snider KL. Targ Oncol. 2009;4:67-76.
• Wick A. J Neurooncol. 2010;97:157-158.