Childhood survivors treated with high doses of anthracyclines, high doses of chest radiation, or a combination of both, should undergo lifelong surveillance for cardiomyopathy. That is the conclusion of a large-scale review of the medical literature by an international group that attempted to coordinate existing recommendations and reconcile and understand what had been differing conclusions.
The study (Lancet Oncol 2015;16:e123-e136), by the International Late Effects of Childhood Cancer Guideline Harmonization Group, also advised that children treated with moderate or low doses should be considered for surveillance depending on other cardiac risk factors.
“We have seen tremendous advances in childhood cancer treatment, with more than 80 percent of children expected to be survivors for at least five years, but childhood cancer survivors, regardless of their current age, should be aware of their increased risk of cardiovascular problems,” said the chair of the consortium's cardiomyopathy working group, Saro Armenian, DO, Director of the Childhood Cancer Survivorship Clinic at City of Hope.
“This is a lifelong risk, and many of these problems don't appear until 10 or 20 years after treatment, so surveillance and monitoring should continue throughout their life.”
According to American Cancer Society estimates, there are more than 400,000 childhood survivors in the United States, and the number is expected to reach half a million by 2020.
The panel recommended echocardiography as the primary method of surveillance, although other forms of screening, such as magnetic resonance imaging, should also be considered. Screening is advised starting two years after the completion of therapy and should be repeated every five years, although more frequent testing is reasonable for those at higher risk.
As described in the study, the authors conducted a comprehensive review of all available literature to assess risk and make recommendations on how best to protect the hearts of childhood cancer survivors. Even with all the treatment advances, more than 40 percent of childhood cancer survivors who are still alive 30 years after their diagnosis have a severe or life-threatening chronic health disorder, including heart disease.
Cardiovascular complications—coronary artery disease, stroke, and congestive heart failure—have emerged as a leading cause of illness or death in survivors. The investigators also said that childhood cancer survivors should be especially careful to manage their risk of high blood pressure and diabetes, both of which raise the likelihood of heart disease.
Armenian noted that some of this is uncharted territory, since survivors of childhood cancer reaching their 50s and 60s is a fairly new phenomenon. But if they are screened early, even if asymptomatic, there is a chance to mitigate the problems.
The study showed that survivors have 10 times the risk for atherosclerosis, 5.9 times the risk of congestive heart failure, 6.3 times the risk of pericardial disease, and 4.8 times of the risk for heart valve disease. The risks were especially high for those treated with anthracycline drugs, such as doxorubicin, or high-dose radiation therapy to the heart.
“We are trying to develop uniform guidelines. Health care groups around the world have recommended different screening parameters and definitions for these children, and there is some discordance, which can result in confusion,” he said. “We found compelling evidence that the use of anthracyclines and chest radiation can raise the risk of later cardiovascular issues in long-term survivors, and that this requires regular monitoring.”
While there has been increased uniformity in monitoring and screening in the United States and Europe, many other countries lack guidelines. This is especially true for certain subsets of survivors who might have other cardiovascular risk factors.
“As we get more information, we will continue to update these guidelines,” Armenian said. “It is important to emphasize that this has been an exhaustive effort as well as a transparent process of evaluation. We relied on only high-impact, high-quality research.”
Nonetheless, he said that there is a relative lack of research on such survivors and long-term heart issues. When only little evidence was available, the researchers extrapolated data from other populations at risk of congestive heart failure. “Importantly, there are key gaps in our knowledge of the frequency of screening in different risk groups, the role of cardiac MRI, myocardial strain testing, three-dimensional echocardiography, and the use of cardiac blood biomarkers in primary surveillance.
“More research is also needed in the prognostic value of changes in intermediate echocardiographic indices of left ventricular systolic and diastolic function as well as the efficacy of early intervention strategies for congestive heart failure prevention.” Answers to these and other key questions can be addressed only through a comprehensive and systematic approach requiring multidisciplinary and international collaborations in order to access large patient populations, he noted.
Asked for her perspective, Kirsten K. Ness, PT, PhD, Associate Member in the Departments of Epidemiology and Cancer Control NS Pediatric Medicine at St. Jude Children's Research Hospital, said the effort at harmonization by the researchers at many medical facilities across the globe is impressive.
“This paper provides a solid reason that such harmonization is necessary. It emphasizes that there is no safe length of time after childhood cancer after treatment with anthracyclines or radiotherapy that such patients should not be monitored for cardiovascular problems.”
In a 2011 study published in Pediatric Blood Cancer (2011;57:467-472), she and her colleagues evaluated the effectiveness of surveillance echocardiograms given according to the Children's Oncology Group's long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers after one year of treatment—notably the frequency of abnormal echocardiograms. A total of 16.8 percent of survivors had abnormal echocardiograms at a median of 2.9 years, and treatment with an anthracycline dose higher than 300 mg/m2 and radiation to a field involving the heart predicted an increased risk of an abnormal echocardiogram. However, even survivors in the lower-risk groups showed abnormalities up to four years after treatment.
The researchers concluded that periodic echocardiographic surveillance of childhood cancer survivors can uncover abnormalities that can appear even one year after treatment that require further evaluation. Moreover, cardiac issues can occur even in survivors considered to be at low risk.
“I think that oncologists and especially cardio-oncologists are aware of the risk, especially if patients are seen at survivorship clinics. But among the general public this is not the case, and young adult survivors may not have an understanding of the risk unless they get a care plan. Further, general pediatricians and general practitioners need greater awareness.”
Regarding lifestyle factors that can predispose individuals to cardiac problems such as smoking, hypertension, physical inactivity, and diabetes, Ness said that this presents an opportunity for survivors: “I think most of them receive counseling about lifestyle factors. This is important because survivors have some control over these factors and it can be an opportunity for them to improve their long-term survival.”
Group Started in 2010
The International Late Effects of Childhood Cancer Guideline Harmonization Group, started in 2010, is a worldwide effort by several national guideline groups and the Cochrane Childhood Cancer Group, in partnership with the PanCare Childhood and Adolescent Cancer Survivor Care and Follow-up Studies consortium of 16 European institutions to collaborate on developing guidelines.