Surviving Cancer, But at a Cost: Radiation & Chemo-induced Cardiovascular Diseases

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Wars leave damage in their wake, and the war on cancer may be no exception. Radiation therapy and chemotherapy have greatly improved survivorship in some cancers, but they also may leave the heart and cardiovascular system battle scarred. In the absence of clinical trials, cardio-oncologists are building a case for the need to monitor survivors at risk of developing radiation- and chemo-induced cardiovascular diseases, but how and how often remains unclear.

Changing landscape

In the mid to late 1970s, the five-year survival rate for a child diagnosed with cancer was 58 percent and for a woman with invasive breast cancer it was 75 percent, according to the National Cancer Institute. Until then, the heart was thought to be safe from the damaging effects of two mainstay cancer treatments, radiation therapy and anthracyclines, a belief that was turned on its head with evidence of treatment-induced cardiomyopathy and heart failure. That prompted changes in protocol, including lowering doses, shielding the heart during radiation and measuring left ventricular ejection fraction (LVEF) at baseline and follow-up to identify at-risk patients and modify treatments if needed.

Patient with Radiation-induced Valvular Heart Disease
RadCardDisease.jpg - Patient with Radiation-induced Valvular Heart Disease
This echocardiogram shows extensive calcification of the aortic and mitral valves (arrows) and of the left ventricle. There is significant aortic stenosis and regurgitation.
Source: This figure originally appeared in the European Heart Journal - Cardiovascular Imaging, 2013 Aug;14(8):721-740, in the report "Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography." Used with permission of EACVI.

Those five-year survival figures changed dramatically over the decades, jumping to 82 percent for pediatric cancers and 91 percent for breast cancer by the mid-2000s. Today, almost 59,000 childhood cancer survivors and 3 million breast cancer survivors live in the U.S. That has been a victory on the cancer front, but as survivors live longer, they face another life-threatening specter: the possibility that over time cardiovascular injury from anticancer treatments may manifest into a host of diseases.    

“You have children now who are survivors who are living into their 30s and they are starting to experience cardiovascular events,” says W. Gregory Hundley, MD, a cardiologist at Wake Forest Baptist Medical Center in Winston-Salem, N.C. “For breast cancer patients, it is a very similar story. Twenty to 30 years ago, there was a relatively high morbidity and mortality. … But women who survive beyond five years from treatment of their cancer are now beginning to experience cardiovascular events.”

One assessment of 1,713 adult childhood cancer survivors treated between 1962 and 2001 found that 56 percent who had been exposed to cardiotoxic therapies had cardiac abnormalities, and most of these abnormalities were revealed during the study evaluation (JAMA 2013;309[22]:2371-2381). In a scientific statement on long-term cardiovascular toxicity, the American Heart Association (AHA) reported that cardiovascular disease in childhood cancer survivors is now second only to cancer as a cause of death (Circulation online Sept. 30, 2013). Cardiovascular disease also ranks as the second leading cause of morbidity and mortality in women who have lived five years or more after a breast cancer diagnosis.

Some of those patients were treated in an era of high-dose anthracycline treatments, though. To better assess the early effect of the current low-dose protocol, Hundley and his colleagues evaluated 53 cancer survivors who received low to moderate doses of anthracycline chemotherapy (JACC Cardiovasc Imaging 2013:6[8]:877-885). Using cardiac magnetic resonance (CMR) imaging and biomarker tests at baseline and at one, three and six months, they found LVEF diminished and aortic stiffening increased over six months.

“Are the early changes meaningful? Do they indicate down that road that someone may or may not be at risk? Or are they transient and we don’t need to necessarily react to them? We don’t know,” Hundley says.

Navigating unknowns

Another study that looked at the risk of ischemic heart disease in women irradiated for cancer in Sweden and Denmark between 1958 and 2001 found the rate of MI, coronary revascularization and death from ischemic heart disease increased by 7.4 percent for each increase in Gy of mean dose to the heart (N Engl J Med  2013;368[11]:987-998). The risk grew in the first five years after exposure and persisted for at least 20 years. “The other determinant is prior risk of heart disease,” adds lead author Sarah C. Darby, PhD, of the University of Oxford in the U.K.   

Cost-effectiveness of Echo
Echocardiography has one advantage over many other modalities under consideration for detecting and monitoring cardiotoxicity in childhood cancer survivors: It's been proven to be cost-effective for detecting left ventricular dysfunction. Using long-term follow-up guidelines developed by the Children's Oncology Group, Wong et al of the City of Hope Medical Center in Duarte, Calif., determined that echo screening was cost-effective for childhood cancer survivors who received more than 300 mg/m2 of anthracyclines, whether or not they also underwent radiation therapy and regardless of their age at diagnosis. Echo screening also was cost-effective in patients diagnosed between the ages of 1 and 4 who were treated with less than 300 mg/m2 of anthracyclines and radiotherapy. Their findings were presented at the American Society of Clinical Oncology meeting in 2012.
 
Children's Oncology Group screening guidelinesCost-effectiveness results
Age DiagnosisChest RTAnthracycline dose (mg/m2)Recommended echo interval (years)Delay in CHF onset age (years)Cost per QALY gained (2010 US$)
1-4 yearsYesAny11.08$30,048
<30010.79$49,750
≥ 30011.44$15,821
No<10050.35$17,798
100 to < 30020.36$29,415
≥30011.17$25,065
≥5 yearsYes<30020.38$36,874
≥30010.80$28,093
No< 20050.13$50,750
200 to <30020.24$86,867
≥30010.72$36,401
CHF=congestive heart failure and QALY=quality-adjusted life-years
Source: F. Lennie Wong, City of Hope Medical Center, Duarte, Calif.

In the emerging field or cardio-oncology, most physicians argue there is a need for early detection and monitoring of at-risk patients for latent radiation- or chemotherapy-induced cardiovascular disease, but without the underpinnings of data from clinical trials there is little consensus on the particulars. “It is clear they need to be followed but we don’t know what the right frequency is or even what tests should be done,” says Joseph R. Carver, MD, a cardiologist and chief of staff at the University of Pennsylvania Abramson Cancer Center in Philadelphia. “Should they have echo or blood tests [for] biomarkers? Or should they just be examined by someone who understands what the risks are and what the incidence of cardiotoxicity is? We are still grappling with that.”

Carver likens cardio-oncology to a toddler, still in early stages of development as researchers raise awareness and build a solid base of knowledge. In the absence of evidence-based guidelines, he proposes a surrogate: to view all patients who had been exposed to potentially cardiotoxic radio- or chemotherapy as having Stage A heart failure (Semin Oncol 2013;40:229-238). Following well-established guidelines for heart failure may prevent or slow progression to later-stage disease in cancer survivors.

“It fits all the criteria of Stage A heart failure,” he explains. “You don’t have symptoms [or] any tangible evidence of heart failure but you are at increased risk. There are clear guidelines for what you do for people who are at increased risk. You modify risk factors. You monitor them.”

Several societies also have joined the cause. The AHA lobbied in its statement on childhood cancer survivors for “an optimal monitoring regimen” to detect radiation- and chemo-induced cardiac complications in an effort to prevent, halt or reverse damage to the heart. But it shied away from offering specific recommendations. The American Society of Echocardiography and the European Association of Cardiovascular Imaging went further by publishing an expert consensus describing multiple modalities for evaluating adults for radiation-induced cardiovascular complications and proposed recommendations (J Am Soc Echocardiogr 2013;26:1013-1032).

Most of the literature available includes small, single-center, observational or retrospective evaluations plus some larger and prospective studies, says co-author Vuyisile T. Nkomo, MD, a cardiologist at Mayo Clinic in Rochester, Minn. But the cumulative weight of evidence points toward radiation affecting the heart. “If someone has received radiation before, then there should be a high index of suspicion of some form of cardiovascular disease, maybe five to 10 years after exposure to the radiation,” he says.

A role for imaging

Many oncologists order baseline echo or multigated acquisition scans before starting cancer treatment to identify cardiovascular abnormalities that might alter the course of care. The societies also recommend a baseline echocardiogram, an annual clinical history and physical exam, and screening echo every five to 10 years, depending on risk factors. For instance, a patient irradiated on the left side of the chest, who received a high cumulative dose,  radiation as well as cardiotoxic chemotherapy or who has cardiovascular risk factors is considered high risk. If the physician suspects heart disease during an annual exam,  then he or she should investigate using echo alone or with other modalities, depending on the suspected disease. 

Why echo? First, a baseline exam often already exists, Nkomo says. Plus, “echocardiography is a noninvasive, portable tool. It is quick to use and it gives you a lot of information.” Still, the call for routine testing, especially in asymptomatic patients, may meet with resistance given past criticism of overuse in imaging in general. But he emphasizes that early detection allows for early intervention. While evidence may be lacking on outcomes for cancer survivors specifically, many studies on patients with various cardiac diseases show benefits from early intervention. 

“People survive the cancer, they survive the radiation, they survive chemotherapy and then later they develop cardiovascular diseases,” Nkomo says. “And it is the cardiovascular diseases that account for the loss of life.” 

While echo plays a large role in the recommendations, the authors also detail other modalities that offer additional information. They suggest CMR for suspected pericardial constriction, but Hundley makes a case for much broader use.  He points out that it characterizes myocardial tissue, offers a good 3D assessment of size and shape and includes factors outside the heart that influence cardiac function.

“You can more precisely measure function,” he says. “You can understand when there is dysfunction, what is causing it. And you can look at other factors that are very important in the cardiovascular system.”

Going global

Anticancer therapies also potentially damage arteries and veins, which may contribute to heart failure, ischemia, stroke and vascular problems. “Understanding the vascular disease that occurs as a result of the administration of these treatments for cancer is just as important as understanding the heart dysfunction,” Hundley says. “With MRI, you can do both at the same time in one sitting.”

But MRI also has its drawbacks. It is not appropriate for most patients with metal implants such as defibrillators. Patients who are claustrophobic may not tolerate being in the machines. Obese patients pose challenges. Physicians may need to seek preauthorization for tests in order to receive reimbursement and not all centers offer the technology. But the larger issue, Hundley and others agree, is availability of skilled professionals to perform and interpret the scans.

“Not that many places do it well enough to provide that incremental utility,” says Michel G. Khouri, MD, a cardiologist at Duke University Medical Center in Durham, N.C., adding that Hundley’s group is among the best. “There is a very defined skill set that goes with that and will continue to be a limitation. That being said, it does provide added information that echo cannot provide.”

By looking beyond the heart and even the cardiovascular system, physicians may be able to detect early signs of injury. Khouri and colleagues are exploring the use of cardiopulmonary exercise tests to measure aerobic capacity during and after cancer treatments. “There doesn’t seem to be one tool that does a great job of detecting and following cardiovascular toxicity specifically,” Khouri says. “The injury is diverse, and a way of assessing that global injury is cardiopulmonary exercise testing.” Physicians also might use cardiopulmonary exercise testing to monitor patients.  

Khouri also advocates using technologies beyond traditional two-dimensional evaluation of LVEF, including 3D echo and strain, but adds that evidence of their clinical utility is still accruing. Carver’s group, for instance, demonstrated that myocardial strain was a predictor of later cardiotoxicity in breast cancer patients treated with anthracyclines followed by taxanes and trastuzumab, a monoclonal antibody that also affects the heart (Circ Cardiovas Imaging 2012;5:596-603). It was a better predictor than LVEF, but it is not likely to be the silver bullet, Carver cautions.

Physicians may disagree about methods and frequency of testing but they all concur that early detection may make the difference between a good and a grim outcome. “We need to bring this process that hasn’t been updated since the 1980s to the forefront,” Hundley says, emphasizing that the burden is extensive. “A woman who becomes disabled from heart failure due to [cardiotoxicities] is an issue for herself, her family, economically, socially, on many fronts.”