The effective treatment of childhood cancers has been one of the biggest success stories of the past 50 years in pediatric medicine, Lipshultz says. Childhood leukemia, for example, one of the most common childhood cancers, had a five-year survival rate of about 10% in 1970; today that number is more than 90%. Recent National Cancer Institute estimates suggest that by the year 2010, one in every 500 young adults aged 20 to 45 will have survived a childhood cancer.

"The main difference in this miraculous transformation has been the advent of effective multiagent chemotherapeutic regimens," Lipshultz said. Of these, some of the most effective regimens use agents called anthracyclines, with doxorubicin (Adriamycin^®, Pharmacia) being the most commonly used. While effective, these drugs are not specific, killing other types of tissues as well, including cells in the heart.

Other childhood cancers such as Hodgkin's disease result in tumor masses in the chest. They are treated with radiation, which is also known to affect the heart and coronary vasculature, he noted. While it has been recognized that these treatments can be cardiotoxic, the extent and longer-term effects of treatment have not been known.

In one paper here, the Rochester group, in collaboration with researchers at Children's Hospital, Boston, prospectively studied a cohort of cancer survivors followed by the National Cancer Institute (Bethesda, MD). Survivors, who had had various malignancies including leukemia, lymphoma, Hodgkin's disease, and Wilms's tumor, were 15 to 18 years old and averaged 11 to 15 years' posttreatment.

They were grouped by whether they had received treatments known to be cardiotoxic such as anthracyclines or chest radiation (Group A, n=132) or other treatments thought not to produce these effects (Group B, n=41). Control subjects were then drawn from the siblings of these subjects to control for genetic CAD tendencies (Group C, n=59). All underwent cardiac evaluation by echo, ECG, and various biochemical markers, including pro-brain natriuretic peptide (proBNP) and high-sensitivity C-reactive protein (hs-CRP).

"What we found was that both groups of cancer survivors, whether they had cardiotoxic therapy or not, had abnormalities suggesting cardiomyopathy and accelerated atherosclerosis," Lipshultz said, although the abnormalities were more marked in those who had received treatment considered cardiotoxic.

Left ventricular fractional shortening was reduced in Group A relative to both Group B and Group C (-1.38 SD, -0.43 SD, and 0 SD, respectively, p<0.001 for the comparison of A vs C). Fractional shortening related to both reduced LV contractility and elevated LV afterload due to reduced LV wall thickness. In addition, other markers of cardiomyopathy were present in both treated groups vs controls, including significant prolongation of the QTc interval and elevation of serum pro-BNP.

The risk of accelerated atherosclerosis was suggested as well by an elevation in other known risk factors for CAD in Group A vs Group C. Group B subjects had intermediate values.

There was also some suggestion of growth-hormone reduction in the cancer survivors, including significantly reduced somatomedin C and reduced height. Survivors also tended to have more fat in measures of body composition and have a more sedentary lifestyle than controls.

"The average age of a child when diagnosed with leukemia is about four years, and this group of patients are, on average, 10 years after treatment, but that still makes them teenagers," Lipshultz said. "The concern is where they'll be in their 20s and 30s."

In a second paper, Lipshultz and colleagues assessed a group of 48 Hodgkin's disease survivors treated with radiation. Subjects were a median of 14.3 years' postdiagnosis, having received treatment at a median age of 16.5 years, and so were largely in their early 30s.

None of them see cardiologists, and none of them get regular cardiac care, and we found that not a single one of them was normal.

"These are people who are getting on with their lives; they said their health overall is fine. None of them see cardiologists, and none of them get regular cardiac care, and we found that not a single one of them was normal," Lipshultz told heartwire. "When we look carefully at their hearts, we find that the late effects of radiation to the heart and blood vessels around it result in progressive fibrosis of all of those structures."

Restrictive cardiomyopathy was suggested by echo, with normal mean LV fractional shortening and contractility but significant reductions in mean LV dimension, wall thickness, mass, and afterload.

Trivial to moderate valvular defects were seen in 65%, including mitral, aortic, and tricuspid valve regurgitation, sufficient that they should probably have antibiotic subacute bacterial endocarditis (SBE) prophylaxis with dental and surgical procedures, Lipshultz said. Almost 60% showed a prolonged QTc interval or intracardiac conduction defects. One patient developed complete heart block after the study visit, and another had already had a clinically silent MI. Finally, the average peak myocardial oxygen uptake (VO₂ max) during exercisea predictor of mortality in heart failurewas decreased in many of the patients. Of the patients, "30% had myocardial oxygen consumption values that, if they were adult heart failure patients, might make you want to consider listing them for transplant," he said.

Again, Lipshultz stressed that "if you don't look, you don't know. Late abnormalities are common, but if you know about it, it can lead to use of some effective preventive strategies."