Cancer patients being treated with drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway should have their blood pressure (BP) monitored regularly throughout treatment, particularly during the first cycle of therapy.
These patients might also need treatment with antihypertensive agents for the BP elevations that occur as an adverse effect of these anticancer drugs, say the authors of a new set of recommendations published in the May 5 issue of the Journal of the National Cancer Institute.
Drugs acting on the VEGF signaling pathway include bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent), and pazopanib (Votrient).
These drugs are already marketed worldwide for use in the treatment of variety of different cancers, but there are several similar drugs in the late stages of clinical development, including aflibercept, axitinib, cediranib, motesanib, and vandetanib.
The VEGF inhibitors are potentially life-saving in the treatment of cancer, the authors note, but their mechanism of action can lead to cardiovascular adverse effects, which in some cases have led to treatment cessation and even life-threatening consequences.
Hypertension has been reported as an adverse event of all of these drugs, and in some cases the BP elevation has been “dramatic,” the authors write.
Their paper details a new set of recommendations to deal with this adverse event, and they hope it will “guide safer, more expansive use of these drugs.”
“This paper should [have an] impact [on] practice today,” Michael Maitland, MD, PhD, assistant professor of medicine at the University of Chicago Medical Center, in Illinois, said in a statement.
Coauthor George Bakris, MD, director of the Hypertensive Diseases Unit at the Chicago University Medical Center, described the paper as a “seminal effort to provide some kind of general guidance . . . [on] how to successfully manage patients to make sure the outcome is ideal across the board.”
The authors of the paper made up the Cardiovascular Toxicities Panel, convened by the Angiogenesis Task Force of the Investigational Drug Steering Committee of the National Cancer Institute.
“This is a very useful and insightful paper in a rapidly growing field characterized by hypertension and other cardiovascular effects from the VEGF-targeted agents,” said Toni Choueiri, MD, from the Dana-Farber Cancer Institute at Harvard Medical School in Boston, Massachusetts.
Dr. Choueiri was not involved in drawing up the new recommendations, but he has reported on the cardiovascular adverse effects of VEGF inhibitors, as previously reported by Medscape Oncology.
“I think that blood pressure elevation is well recognized as a side effect of these drugs by most oncologists, but I do not think it is being treated aggressively,” he said. “I have also seen physicians giving up on potentially beneficial drugs because of blood pressure, despite minimal efforts to control it.”
“Oncologists should follow, as closely as possible, these recommendations,” Dr. Choueiri added.
Steps for Management
The report focuses on BP elevation because it is “the most common and the easiest to address” of all the adverse effects reported for this groups of anticancer drugs, the authors explain. Others adverse effects include hemorrhage, thrombosis, nephrotoxicity, and cardiac toxic effects.
In their recommendations for BP management in cancer patients taking VEGF inhibitors, the group suggests a formal risk assessment of cardiovascular complications before staring therapy. This should include:
* BP measurement on at least 2 separate occasions, bearing in mind the potential for “white coat hypertension.”
* Recognition that preexisting hypertension is common in cancer patients, and addressing it before initiating therapy.
* Active monitoring of BP throughout treatment, with more frequent assessments during the first cycles of therapy, when the bulk of the BP elevation is expected to occur.
* A maximum hypertension goal of 140/90 mm Hg, although this would be lower for patients with preexisting conditions, such as diabetes and/or chronic kidney disease.
The panel also suggests that if at any time the oncologist or treating physician has any difficulty reaching or maintaining this BP goal, there should be a prompt consultation with the local hypertension specialist (or cardiologist, nephrologist, or endocrinologist).
In an interview with Medscape Oncology, Dr. Maitland said that this collaboration is key because the management of drug-induced hypertension in cancer patients who are probably also on chemotherapy can be rather complicated, especially if the patient has other cardiovascular risk factors, such as kidney disease or diabetes. Oncologists who are “out of their comfort zone” should reach out to cardiovascular colleagues for help, he added.
Many cancer patients are able to tolerate modest elevations in BP, and many oncologists might not be concerned about modest elevations, with everything else that is happening in these patients, he noted. It is not the jump in BP alone that is important, it is how it relates to everything that has gone before, particularly in relation to a patient’s cardiovascular risk profile. “That is one of the main points of the paper ??? that cancer patients need to be assessed for cardiovascular risk factors before these drugs are prescribed,” he said.
The average elevation in BP seen with these drugs is about 8 to 10 mm Hg, both diastolic and systolic, Dr. Maitland said. This is a greater magnitude than can be lowered by standard antihypertensive drugs, he added. However, BP elevation is also highly variable, with some patients not showing much of an effect, and some showing a jump of more than 25 mm Hg.
The main message is to keep BP below 140/90 mm Hg, and even lower for patients with diabetes or chronic kidney disease, Dr. Maitland pointed out. Because many patients with cancer are elderly, and therefore at higher risk for hypertension, BP might be above this target even before treatment with VEGF inhibitors is started.
In the paper, the authors recognize that implementing a specific approach to BP management in cancer patients receiving VEGF inhibitor drugs “presents logistical challenges,” but they also emphasize that this process is “a natural extension of good general medical care.”
“If a patient is hypertensive, a physician should not dismiss that as irrelevant just because they have advanced cancer,” Dr. Maitland explained. “We already know that ignoring comorbidities in a cancer patient can generate as much risk for their long-term survival as the stage of cancer.”
In these patients, the easiest approach to maintaining BP within a safe range might be weekly office nursing visits or home BP monitoring, the authors note.
Any emergent hypertension that develops during VEGF inhibitor therapy can be controlled by any one of a variety of antihypertensive drugs (thiazide diuretics, beta blockers, calcium-channel antagonists, angiotensin-converting-enzyme [ACE] inhibitors, and angiotensin-receptor antagonists). Each of these classes has been used successfully to control hypertension resulting from VEGF inhibitor therapy, the authors note, and “whether any one agent is superior to another in the successful control rates remains to be determined.”
The paper summarizes points that need to be kept in mind when prescribing these agents to cancer patients; for instance, ACE inhibitors should be avoided in patients who are on chemotherapy that requires renal clearance, such as cisplatin and pemetrexed.
Finally, the panel notes that the BP elevation caused by VEGF inhibitors will dissipate when the drug is discontinued, so physicians need to anticipate discontinuing or reducing the dose of any antihypertensive drug that has been prescribed.
Mechanism of Action
There are 2 theories as to why VEGF inhibitor anticancer drugs increase hypertension, Dr. Maitland said. VEGF signaling directly regulates the enzyme functioning of nitric oxide synthetase, and these drugs have the immediate effect of reducing nitric oxide production and constriction of small blood vessels, which causes an immediate rise in BP. Indeed, Dr. Maitland reported, “we have instances where BP is elevated in the first day of taking these drugs.”
There is also work showing that in patients taking bevacizumab, there is a loss of capillaries in skin biopsies, suggesting rarefaction, which would take days and weeks. Some patients develop BP elevations more than a week after taking these drugs, he added.
It might be that both processes are underway; these theories are not competing, Dr. Maitland said. “We also think that all of these drugs are similar [in their effects on BP], but nobody really knows,” he added.
Dr. Maitland reports receiving research funding from Bayer and Genentech. Several of his coauthors report relevant financial relationships, which are detailed in the paper.
J Nat Cancer Inst. 2010;102;596-604. Abstract
Zosia Chustecka has disclosed no relevant financial relationships.