The Heart: An Unintended Victim of Some Targeted Cancer Therapies
An afternoon session on the last day of a large scientific conference is typically a recipe for poor attendance. That’s what Dr. Edward T.H. Yeh expected last March at the American College of Cardiology (ACC) annual meeting in Orlando, where he moderated a session on cancer treatment-induced heart failure.
“I was hoping to see 20 or 30 people,” said Dr. Yeh, who directs the cardiology department at the University of Texas M. D. Anderson Cancer Center, one of the few cancer centers with a dedicated cardiology unit. “But there were about 300 people. The room was filled!”
Heart failure—when the heart is unable to pump enough blood to meet the body’s needs—is among the most common “cardiotoxicities” associated with certain cancer treatments, in particular the class of chemotherapy drugs known as anthracyclines. But as the use of targeted therapies becomes more widespread, there is mounting scrutiny of their cardiac effects, which can include heart failure, fatal rhythm disturbances, blood clots, and hypertension. Late last year, for example, a phase III breast cancer trial involving the targeted therapy bevacizumab (Avastin) had to halt enrollment temporarily because of an excess number of congestive heart failure cases. (Enrollment was reopened several months later.)
The potential impact of cardiotoxicities on cancer care is so significant, an Italian research group recently wrote, that it should spur the formation “of a novel discipline, which could be termed cardio-oncology or onco-cardiology,” Dr. Adriana Albini and colleagues proposed in the January 6 Journal of the National Cancer Institute.
Discussions with both oncologists and cardiologists indicate there is no consensus on that point, but they do suggest that the concern about cardiotoxicities is very real and is beginning to be tackled in a more direct and collaborative manner.
How Much of a Concern?
Mechanisms of Cardiotoxicity
What cancer therapies do on a molecular level to cause toxic effects in the heart is becoming clearer. With trastuzumab, for instance, by inhibiting the HER2 protein, the drug “can block different growth factor signaling pathways in cells that express HER2,” Dr. Yeh explained. “And it turns out that a lot of those signaling pathways are shared by cells in the heart and cancer cells.” Cancer cells rely on those pathways to proliferate, he continued, “but the heart cells rely on them to survive.” So killing cancer cells by blocking these signaling pathways could also be damaging heart cells.
The TKIs, meanwhile, hit numerous cellular targets, including those that relate to cell metabolism, added Dr. Lenihan. “The heart muscle is very metabolically active,” he said. “Any drug that has a transient effect on metabolism in your body has a high potential to affect the heart muscle.”
Among the targeted agents, the monoclonal antibody trastuzumab (Herceptin), which is used in women with both metastatic and early-stage breast cancer, has probably received the most attention for its cardiotoxicities. But it’s far from unique. Other established agents, including those in the class known as tyrosine kinase inhibitors (TKIs), such as sorafenib (Nexavar) and sunitinib (Sutent), can also have potentially serious effects on the heart.
In patients with more advanced cancer who are candidates for treatment with agents that have been linked with cardiac side effects, the anticancer benefit tends to outweigh the potential risks, explained Dr. Dawn Hershman, who co-directs the breast cancer program at Columbia University’s Herbert Irving Comprehensive Cancer Center. “But now we’re treating more patients with earlier stage disease, with a low recurrence risk and high survival probability, so long-term effects become a much bigger deal,” she said.
In the clinical trials that established trastuzumab as an effective adjuvant therapy in women with early-stage breast cancer, the incidence of cardiac side effects was around 4 percent. But the patients in these trials, said Lisa Stegall Moss, a nurse practitioner who works in oncology outreach clinics operated by Duke University Medical Center, aren’t necessarily “representative of the patients we typically see, who are often overweight and have underlying heart disease or diabetes.”
For many cancer patients, added Dr. Daniel Lenihan, director of clinical research at the Vanderbilt University Medical Center’s Heart and Vascular Institute, heart disease and cancer go hand in hand. “The fact is, most people who get cancer, in general, are exactly the same demographic we see for cardiovascular disease,” he said. In some cases, patients being treated for cancer have undiagnosed heart disease, and their cancer treatment “might unmask that underlying tendency toward heart problems.”
There is some evidence to support that view. For example, in one recent study of 61 women with breast cancer being treated with trastuzumab, 19, or nearly one-third, of the women experienced a cardiac side effect, and 7 had to halt treatment altogether.
Unlike trastuzumab, some targeted therapies associated with cardiac side effects are almost strictly used to treat patients with advanced cancer. Sunitinib, which inhibits blood vessel formation, or angiogenesis, and is most commonly used to treat advanced kidney cancer, can significantly decrease the heart’s ability to pump effectively, leading to heart failure.
Hypertension is also a well-documented side effect of sunitinib and another anti-angiogenesis drug, sorafenib, said Dr. Percy Ivy of the Cancer Therapy Evaluation Program in NCI’s Division of Cancer Treatment and Diagnosis. “Any therapy intended to influence the vasculature is likely to have an impact on vascular pressure and blood pressure,” Dr. Ivy explained.
Consequently, cardiac effects will need to be closely watched in the trials testing these agents as adjuvant therapy in patients with earlier-stage kidney cancer, said Dr. Arthur Sagalowsky, who specializes in the treatment of urologic cancers at the UT Southwestern Medical Center. Some community oncologists already “have made the leap” of using sunitinib and sorafenib as adjuvant therapy in patients with earlier-stage disease who are at high risk for their disease returning, Dr. Sagalowsky warned, without understanding the potential cardiac implications, not to mention the lack of efficacy data.
Cardiotoxicities are definitely on the minds of both the private sector and the research community. “We’re seeing the industry starting to pay more attention to the side effect profile of their cancer drugs,” Dr .Yeh said, “because eventually they’re going to be competing against each other based on both efficacy and side effects.”
Meanwhile, the NCI-sponsored ASSURE trial, led by the Eastern Cooperative Oncology Group, is testing sorafenib and sunitinib as adjuvant therapy in patients with earlier-stage kidney cancer who are at higher risk of their cancer recurring. Built into the trial is a sub-study that will entail extensive cardiac monitoring of study participants to determine the extent of cardiac risk associated with either drug.
A New Field?
Dr. Yeh, the founding chair of the cardiology department at M. D. Anderson, isn’t convinced that a formal cardio-oncology field is needed. His department has 12 full-time cardiologists, all of who work with the oncology staff to assess and manage cardiac side effects in patients undergoing or about to receive cancer treatment. “Both communities need to appreciate the problem and talk to each other more often,” he said. “I hope that more cardiologists will be trained or versed in the [cardiotoxicity] literature, and the same [goes] for oncologists. It requires a mutual understanding of the scope of the problem.”
As the session at the ACC meeting suggests, some of that is starting to happen. A similar session may be held at the upcoming American Society of Clinical Oncology (ASCO) annual meeting. There have been limited efforts to develop general clinical guidelines on cardiotoxicities, but nothing that has borne fruit as of yet, said Dr. Lenihan. No formal clinical guidelines on cancer treatment-related cardiotoxicities are under development by the ACC, ASCO, or the National Comprehensive Cancer Network, according to representatives from those organizations.
However, a forthcoming paper from NCI researchers will lay out strategies that have proven effective for managing hypertension in patients being treated with antiangiogenic therapies, Dr. Ivy noted. The guidance was developed based on experiences in NCI-sponsored clinical trials, often done in consultation with cardiology colleagues. “We’ve been able to show that we can control blood pressure appropriately in these patients, and we can sustain it through the course of treatment,” she said.
Developing ways to identify patients at increased risk for cardiac side effects, as well as early markers of cardiac effects and best practices for managing cardiotoxicities, will be critical in moving forward, Dr. Hershman stressed. In the meantime, oncologists have to take a delicate approach toward discussing the issue with patients.
“It’s a difficult balance, because you want to inform patients of the risks, especially patients for whom the benefits [of treatment] may be borderline,” she said. “But at the same time, the treatments really work and if you’re talking about somebody at high risk, you don’t want them to be afraid to take what could be a life-saving therapy.”
Medical Societies Highlight Concerns on Androgen Deprivation Therapy
As is the case with chemotherapy and some targeted therapies, there are emerging data that indicate there may be cardiac risks associated with a prostate cancer treatment known as androgen deprivation therapy (ADT), which is increasingly being used in men with high-risk, localized prostate cancer, as well as men whose PSA level has begun to rise sharply after primary therapy or those who have overt metastatic disease.
Just last month, a panel convened by the American Heart Association, the American Cancer Society, and the American Urological Association issued a science advisory on several studies that have shown an association between ADT and an increased risk of cardiovascular events in certain patient groups, in particular, men with a prior history of a heart attack or heart failure.
The available data aren’t sufficient to make specific recommendations with regard to patient treatment with ADT, Dr. Sagalowsky explained, but “overall cardiac risk factors need to be monitored” and taken into consideration in patients who are candidates for ADT, he said.