TONYA TOWERY was in the hospital and partway through her first cycle of drug treatment for acute myeloid leukemia in late 2012 when the shortness of breath she’d been feeling for the past month began to worsen. Then, her heart rate quickened.
Towery’s doctors at the University of Michigan Health System in Ann Arbor wanted to rule out any potential heart causes. So they called in cardiologist Monika Leja, co-founder of the health system’s recently opened cardio-oncology clinic. Leja ordered a series of tests including an echocardiogram—an ultrasound that shows a heart’s structure and functioning. The tests revealed that Towery, who was on a typical leukemia regimen of daunorubicin and cytarabine, was in the early stages of heart failure. Leja suspected the culprit was daunorubicin, part of the anthracycline family of drugs that’s been linked to heart failure.
Leja immediately prescribed Coreg (carvedilol), a drug used to treat congestive heart failure. It allowed Towery to complete all three prescribed chemotherapy cycles—successfully putting the 39-year-old program analyst from Battle Creek, Mich., in remission. “Actually, [Towery’s] biggest problem right now is her heart,” Leja says. So even though Towery’s symptoms have subsided, Leja continues to closely monitor her blood pressure and heart rate, with the goal of quickly identifying any further deterioration in heart function.
The University of Michigan cardio-oncology clinic opened its doors in 2012. Physicians like Leja believe that by teaming up cardiologists with oncologists, these programs will not only better care for existing patients but also start to address many of the unanswered questions in the emerging field. Ideally, these collaborations will prevent or limit heart-related side effects attributed to radiation and some cancer drugs. These specialists also want to help adults who are already coping with a heart problem when diagnosed with cancer. (Though heart-related damage has been studied and monitored, particularly in the last decade, in children who develop leukemia or other childhood cancers, the attention to adult cancer patients is relatively new.) Above all, Leja and her colleagues hope to boost awareness among adult cancer survivors, even those in their 30s or 40s, that they shouldn’t dismiss even vague symptoms—potential red flags of heart problems—such as fatigue, changes in endurance or leg swelling.
“There are a lot of patients who are having these symptoms and they don’t come to their doctors,” Leja says. “And they don’t know that their drugs could have caused the problems.”
Heart Effects
Cardiologist Edward T.H. Yeh opened one of the first onco-cardiology centers for adults in the United States at the University of Texas M. D. Anderson Cancer Center in Houston in 2000. (These programs are referred to as both cardio-oncology and onco-cardiology programs.) The exact number of clinics that have opened since then isn’t known, but Yeh says an international workshop on onco-cardiology that M. D. Anderson held in November 2013 included 418 participants from 150 institutions in 26 countries.
The proliferation of cardio-oncology clinics reflects in part an aging population—both cancer and heart disease are more common later in life—along with an evolving understanding of drug and radiation side effects, says Ana Barac, a cardiologist who directs the cardio-oncology program that opened in 2011 at MedStar Heart Institute in Washington, D.C. Technological advances that allow cardiac imaging to capture subtle changes in heart function and identify potential problems earlier in cancer patients have also played a role in the growth of these new programs, she says.
Meanwhile, researchers continue to learn more about how targeted cancer therapies may harm the heart. “In a way, the heart effects [from these drugs] were unexpected, perhaps naively,” Barac says. Scientists have known that cancer cells and the heart share certain proteins, and some drugs, like Gleevec (imatinib), target proteins that are found in cancer cells and also are essential to heart health. This is thought to be one reason a small number of patients taking Gleevec have developed heart damage.
Another is that a targeted therapy may block proteins in addition to those it is specifically designed to target. Some scientists think this may help explain why Sutent (sunitinib) can increase the risk of cardiovascular side effects. But the cause isn’t always easy to identify. Researchers still puzzle over why Herceptin (trastuzumab), which is used to treat HER2-positive breast tumors, causes heart problems in certain patients. And similar questions now surround the leukemia drug Iclusig (ponatinib), which has been linked to serious cardiovascular problems.
Patients who get radiation to the chest region also can be at risk, with 10 to 30 percent experiencing heart disease related to their treatment during the subsequent decade. However, those numbers might be reduced with today’s more modern techniques, according to a review of heart issues published by an American Society of Clinical Oncology (ASCO) expert panel in 2007 in the Journal of Clinical Oncology. Charles Shapiro, the chair-elect of ASCO’s survivorship committee and a member of the expert panel, cautions against overstating the risks of treating adults with modern radiation therapy, particularly in light of the treatment’s cancer-fighting benefits. Childhood cancer is another story.
Since the 1980s, says Shapiro, a breast cancer specialist at the Ohio State University Comprehensive Cancer Center in Columbus, heart-sparing techniques have been developed to reduce radiation exposure for patients who require treatment to the chest, such as those with breast cancer or Hodgkin lymphoma. As for anthracyclines, “cardiac damage from [these drugs] is a small problem when you’re getting treatment or soon after treatment,” he says. “The question, and it’s unanswered, is whether these drugs set you up for cardiac problems in the subsequent decades.”
The FDA has agreed to allow sales of the drug to resume.
By Sue Rochman
When Iclusig (ponatinib) received accelerated approval from the U.S. Food and Drug Administration (FDA) in December 2012, it brought new hope to adults with two rare types of blood and bone marrow cancers: chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). But that hope turned to confusion when the FDA suspended sales of Iclusig in late October 2013 after its use was linked to serious cardiovascular problems, including fatal heart attacks and strokes. Now, the FDA has agreed to allow sales of the drug to resume—but it is approved for a narrower group of patients, and the boxed warning specifically mentions the serious risk for blood clots and heart failure.
Under the new prescribing information the FDA approved in late December, Iclusig, a tyrosine kinase inhibitor, is indicated only for adult patients with CML or Ph+ ALL who have tumors that test positive for a T315I mutation or who have already tried or are not able to use any other tyrosine kinase inhibitors approved for treating these cancers. Iclusig previously had been approved for patients who had tried only one other tyrosine kinase inhibitor—and T315I mutation status was not addressed.
Blood clots and severe narrowing of the arteries—which can lead to heart attacks and strokes—are two key concerns. “It is not clear why Iclusig may be associated with [these problems],” says Neil Shah, a hematologist at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. It is possible that Iclusig is blocking proteins that support blood vessel growth, he says, but it could also be blocking other proteins that are, in turn, affecting the cardiovascular system.
Whether patients will be leery of the drug remains to be seen. “Due to the aggressive nature of advanced phase CML and Ph+ ALL, a greater degree of treatment-related risk is generally accepted in this patient population,” says Shah.
Identifying Patients at Risk
Not every cancer patient needs to visit a cardio-oncologist, and specialists are still assessing which patients will benefit most. Although guidelines currently exist for heart screening for patients on some cancer treatments, there are not yet any guidelines—from ASCO or another professional group—regarding which patients should be referred to a cardio-oncology program.
One challenge to developing guidelines, oncologists and cardiologists say, is the large number of variables involved, including the many types of cancer treatments, as well as the mix of malignancies and differing risk profiles of the patients themselves. Most commonly, patients are referred to a program because, as in Towery’s case, she had developed symptoms of a potential heart problem.
Cancer patients and survivors should strongly consider seeing a cardio-oncologist if:
- They have significant heart disease risk factors, such as diabetes or a prior heart attack, and the proposed treatment increases heart disease risk.
- They received high doses of radiation in the chest area or high doses of anthracyclines.
- They develop a worrisome symptom, even if relatively vague, such as fatigue or shortness of breath.
Barac and Leja suggest that patients with a history of heart problems, such as a prior heart attack or diabetes, ask their oncologist if they should be referred to a formal program “to make sure that [the] heart condition doesn’t get to the point that it prevents [the patient] from getting cancer treatment,” Barac says, “and that the cancer treatment doesn’t adversely affect [the patient’s] heart.” Still, uncertainties persist for patients and doctors alike, says Shapiro. At this point, there’s no way to determine which patients might run into difficulties, even when a treatment poses a potential cardiac risk, he says. Furthermore, better diagnostic tests are needed to help pinpoint earlier changes in the heart before functioning difficulties become evident on imaging tests. To that end, MedStar Heart Institute and other cardio-oncology research programs are currently conducting studies to identify proteins in a patient’s blood that signal problems or even earlier signs of heart strain that can be picked up by an echocardiogram. A research group from Spain is trying to determine if heart medications such as ACE inhibitors and beta-blockers that are administered to non-cancer heart failure patients would be similarly beneficial for cancer patients. “The cardio-oncology field is just filled with questions,” Barac says.
The long-term heart risk for childhood and adolescent cancer patients is well-documented.
Compared with that of adults, the long-term heart risk for childhood and adolescent cancer patients is a far more documented phenomenon, says Steven Lipshultz, a pediatric cardiologist at Wayne State University School of Medicine in Detroit.
Researchers have learned that cancer treatments over time can be particularly toxic to the developing bodies of children, says Lipshultz. During the 30 years after treatment, pediatric cancer survivors were shown to be eight times as likely to die of a heart-related cause as the general population, according to the National Cancer Institute, making it important for them to be monitored through a survivorship program.
A key problem: Chemotherapies that have dramatically extended survival for some patients with common childhood cancers, such as leukemia, also have been shown to inflict collateral damage on healthy growing cells. “If [patients on anthracyclines] lose heart muscle cells, those cells never grow back,” Lipshultz says.
Screening and Monitoring
Sally Brown, diagnosed in 2010 with stage II breast cancer, learned she was at risk for heart-related side effects when she was told her treatment would include Herceptin. Because the drug has been linked to heart problems, Brown’s heart functioning was routinely evaluated. She was more than six months into her yearlong regimen when an echocardiogram showed a borderline low ejection fraction— a measurement of how well the heart pumps out blood each time it contracts—leading her doctors to stop the Herceptin. (She was able to resume taking the drug, but did not complete the full regimen.)
Brown, now 61, didn’t have any symptoms of heart problems. But she was determined to protect her heart’s health, so she boosted her already extensive exercise regimen, working out for an hour on an elliptical machine each morning and trying not to fret about her long-term heart disease risk. Yet when information about MedStar Heart Institute’s cardio-oncology program arrived in the mail in 2012, she didn’t hesitate to schedule an appointment, even though she was no longer taking Herceptin.
Because routine monitoring picked up Brown’s subtle decline in heart function, she considered herself someone who might benefit from a cardio-oncology program. However, it’s not clear yet if a patient who doesn’t develop problems during treatment but may be at risk should be monitored. “That’s something we need to learn,” says Shapiro.
Shapiro also worries about how survivors will respond to the information. It’s a confusing message to try to convey, he says: “ ‘You have a borderline low ejection fraction, but we don’t know what that means.’ That could do harm. That person’s quality of life could well be impacted.”
Brown, though, says that she appreciated the cardiac heads-up. After meeting with Barac, she completed a series of tests that ruled out other causes for her borderline low ejection fraction. Then the Potomac, Md., woman’s luck turned. Brown had been warned that full function is unlikely to return if it doesn’t reverse within a year. But in the fall of 2012, shortly after she’d had another echocardiogram, Barac came into an exam room and high-fived her: The results were normal.
Both Brown and Towery, who continue to be monitored through their respective programs, describe the suspect drugs as representing a catch-22 of cancer treatment. Brown still vividly recalls learning that her tumor was HER2-positive, making her a candidate for Herceptin. “I thought, ‘Great. There is this magic bullet. I’m going to be fine.’” She was warned about the potential heart problems, but because she was relatively fit, she had dismissed the risk.
Towery, back working full-time by April 2012, describes “the heart thing as another bump in the road.” Her University of Michigan doctors had been upfront about the heart risk, but her overriding priority was “getting rid of the leukemia.” She knew, she says, “that if I ended up developing [heart problems], then we’d deal with that when it came up.”
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