As more people survive cancer, doctors are discovering the long-term side-effects of their treatments.
When she was just a year old, Brenda Yano was diagnosed with acute leukemia. She was one of the lucky ones, cured by aggressive chemotherapy. Years later, Yano was told the cure had come with a cost: She could never have a baby. But no one cautioned her about the potential damage four years of chemotherapy would do to her heart.
Her unexpected pregnancy late last year, at 25, made a hash of the doctors’ predictions. It also sent Yano careening into progressive heart failure, putting her life at risk and complicating the birth of her daughter, Isabelle, in September.
Surviving cancer is a relatively new phenomenon. Fifteen years ago, breast cancer patients had a 50 percent chance of living five years after their diagnosis. Today, more than 90 percent survive five years or longer. Two decades ago, about 50 percent of patients with chronic myeloid leukemia survived five years; today, with better treatment, more than 95 percent of patients live at least five years.
As survival goes up, the more evident it becomes that chemotherapy, radiation and revolutionary, targeted cancer treatments—such as Herceptin for breast cancer—can wreak off-target havoc in other organs, especially the heart.
“It’s a major set of issues that weren’t a problem 30 years ago, because we didn’t have that many survivors,” says Steven Lipshultz, chief pediatrician at Children’s Hospital of Michigan.
Now medicine is starting to fight back. A growing number of academic medical centers are teaming cardiologists with cancer specialists to pioneer specialized “cardio-oncology” clinics for cancer patients. Two of the busiest specialties in medicine – cancer is the nation’s second biggest killer, heart disease the first – are beginning to collaborate in unprecedented ways to help cancer patients survive not only their disease but the life-saving treatment.
The overarching goal is to assess newly diagnosed cancer patients’ heart risks, determine which types of patients are most likely to suffer heart damage from chemotherapy and radiation and find new ways to protect the heart, all without letting up on life-saving cancer therapy.
“For the first time ever, what these treatments do to the heart really matters,” says Dr. Javid Moslehi, director of cardio-oncology at Vanderbilt University Medical Center.
The collaborative approach has won critical backing from such professional organizations as the American College of Cardiology (ACC) and the American Society of Clinical Oncology, which have begun a dialog about the issue. Clinicians who focus on the intersection of cancer and heart disease have formed their own professional association, The International Cardioncology Society, which held a global summit Oct. 15 and 16 in Nashville. A new medical journal has begun publishing research reports.
No one knows precisely how many cancer survivors develop treatment-related heart disease. Many of those who are deemed cured are lost to follow-up. The number of survivors are expected to grow dramatically as new treatments are introduced and as more patients go into long-term remission or are cured. Approximately 14.5 million survivors in the U.S. already owe their lives, at least in part, to chemotherapy or radiation.
“That’s a significant number,” Vanderbilt’s Moslehi says. “Over the next decade, it will probably double.”
Yano’s cardiologist, Dr. Eric Yang, of UCLA, says a diagnosis of heart disease can be frightening for cancer survivors, who have been through so much already. “The last thing they want to discover is that they have developed side effects to a treatment aimed to save their lives,” he says.
The first hint that survival might be possible came more than half a century ago when Dr. Sidney Farber, of Children’s Hospital of Boston, achieved the first partial remission in a 4-year-old girl with leukemia. Until Farber’s breakthrough, children often died soon after they were diagnosed. By the 1970s, due to the introduction of multi-drug, team-based therapy, childhood leukemia survival soared. It is now approximately 90 percent.
But cancer specialists’ jubilation was tinged with worry. Increasingly, survivors of pediatric cancer were trickling in with heart failure—or worse, suffering unexpected heart attacks, some in their 20’s and 30’s. Lipshultz invited long-term survivors back to see if he could figure out what was going on. Outwardly, the patients seemed fine.
“They all said they were feeling terrific,” he says. “Their parents said so, too.” But Lipshultz wasn’t satisfied. He put the survivors through series of heart tests. “We found that two-thirds of those who survived childhood cancer had abnormal hearts that were getting worse as they got older,” says Lipschulz, editor of the journal CardioOncology.
The biggest culprit is a class of cancer-fighting agents, anthracyclines, which are a mainstay of cancer treatment and which permanently damage the heart muscle. When these drugs combine with iron, they form molecules that punch holes in heart cells, damaging large swaths of tissue and setting the stage for heart failure.
Doctors now attempt to limit anthracycline damage by giving patients a drug, dexrazoxane, which locks up iron and carries it out of circulation during chemotherapy. When dexrazoxane is used, Lipshultz says, “We found that the number of dead and dying heart cells went down dramatically.”
But cardio-protective drugs are an imperfect shield—and are unevenly used. Doctors say that chemotherapy weakens the heart muscle until it resembles the heart of someone decades older. Irradiating tumors in the region around the heart has the same devastating impact.
“It ages the heart on many levels, the muscle, the coronary arteries, the valves,” says Yang, the UCLA cardiologist who cares for Yano and many other cancer survivors.
Childhood cancer patients like Yano are often unaware of their enhanced risk, because their cancer treatment occurred when they were so young. If doctors thought to tell parents, the warning is often long forgotten. Many survivors only discover their hearts’ fragility, as Yano did, when physical or psychological stresses tip them into heart failure or cause a heart attack.
“Lots of patients have a clean bill of health, no high cholesterol or blood pressure, and [then] something catastrophic happens,” says Dr. Patricia Ganz, director of cancer prevention and research at the UCLA Jonsson Comprehensive Cancer Center. Ganz arranged for Yano to visit a cardiologist through UCLA’s LiveStrong Foundation cancer survivorship program.
Often such patients are turned away, because “When a 29-year-old comes to the emergency room clutching his chest, you don’t normally think of a heart attack,” Lipshultz says.
It took a drug breakthrough to broaden cardiologists’ focus from kids to adults, says Dr. Richard Steingart, chief of cardiology at Memorial Sloan Kettering Cancer Center in New York. “Everything changed with Herceptin,” he says.
Herceptin is the brand name for trastuzumab, a targeted antibody drug that disables a protein found in certain breast and stomach cancers. Without the protein, known as HER2, cancer cells stop growing and die. Women with Herceptin-treatable cancers account for about a quarter of all breast malignancies.
Before Herceptin came along, these cancers were universally fatal, Steingart says. Today, up to 90 percent of patients survive.
But in 1 percent to 4 percent of women, Herceptin causes heart failure—and the risk is highest when Herceptin is combined with an anthracycline, such as Adriamycin.
“It’s a second hit to the heart,” says Dr. Sandra Swain, a breast-cancer specialist at MedStar Washington Medical Center.
Herceptin’s value as a breast cancer treatment launched the specialty of cardio-oncology, as doctors found themselves dealing with a new population at high risk for heart problems. Cardiologists began sparring with cancer specialists over ways to eradicate cancer while sparing the heart. Standard heart failure drugs, including ace inhibitors and beta blockers, are useful in these patients, experts say.
Both sides say they would benefit from scientific data, showing which woman are most likely to suffer heart damage, how best to monitor cancer patients for heart damage and what treatment protocols offer the best hope at the lowest risk. It may take years to generate answers in a field teeming with unknowns. Paradoxically, the research may also benefit heart patients without cancer.
For the first time, Steingart says, researchers can “actually study the heart in cardiomyopathy,” the muscle breakdown that causes heart failure, and try to figure out how to block it.
Similar questions are likely to spill into other cancers, too. Consider prostate cancer, which is treated by blocking male hormones called androgens. Androgen deprivation therapy affects blood pressure, blood sugar and cholesterol, says Vanderbilt’s Moslehi, “All of which contribute to having heart problems later on.”
The good news for patients is that cardio-oncology is taking root, but progress has been uneven. For all the activity in academic centers, the concept hasn’t caught on yet in community hospitals, where vast numbers of cancer patients are treated. And, although many cardiologists and oncologists in Western states—such as Yang and Ganz at UCLA—are attentive to cancer patients’ heart problems, they acknowledge that few West Coast hospitals have created cardio-oncology centers, like those popping up on the East Coast and in the Mid-west.
“We have not delved into this realm yet,” says Barbara Jagels, Vice President of Quality, Safety & Value at the Seattle Cancer Care Alliance.
There are steps that cancer survivors and their physicians may take to lower their risk, even when sophisticated care isn’t available, Moslehi says. For instance, doctors at Vanderbilt have developed a simple checklist for patients and their doctors that offers basic guidelines for monitoring and treatment.
“Many people think, ‘Oh my God, my breast cancer is taken care of,'” adds Moslehi. “But there’s so much more we can do.”
By Steve Sternberg