Cranial irradiation as an additional risk factor for anthracycline cardiotoxicity in childhood cancer survivors: an analysis from the cardiac risk factors in childhood cancer survivors study

Abstract

Anthracycline-treated childhood cancer survivors experience cardiac damage that results in decreased left ventricular (LV) mass, leading to increased LV wall stress, which underlies their greater risk of cardiomyopathy. Many of these survivors also are at risk of growth hormone (GH) abnormalities from cranial irradiation exposure, although it is unknown whether such exposure is associated with cardiotoxicity. Echocardiograms and insulin-like growth factor-1 (IGF-1), a marker of GH, were measured in 130 anthracycline-treated childhood cancer survivors, 59 of whom had been exposed to cranial irradiation, a mean 10 years after their cancer diagnosis. Echocardiographic parameters and IGF-1 were standardized relative to age or body surface area using data from sibling control subjects and expressed as the percentage difference from normal values. The results showed that after adjustment for other risk factors, survivors exposed to cranial irradiation had an additional 12 % decrease in LV mass compared with unexposed survivors (P < 0.01) and an additional 3.6 % decrease in LV dimension (P = 0.03). Survivors exposed to cranial irradiation also had a 30.8 % decrease in IGF-1 relative to normal values, which was greater than the 10.5 % decrease in unexposed survivors (P < 0.01). The above findings led us to conclude that in anthracycline-treated childhood cancer survivors a mean 10 years after their diagnosis, those with cranial irradiation exposure had significantly greater decreases in LV mass and dimension. Because cranial irradiation also was associated with decreased IGF-1, it is possible that GH deficiencies mediated this effect, suggesting that GH replacement therapy may help to prevent the development of cardiotoxicity.

Figure 1

Box plots of the distribution of left ventricular (LV) parameters of 130 childhood cancer survivors treated with anthracyclines by exposure to cranial irradiation (CR). LV parameters included mass, end-systolic posterior wall thickness (wall thickness), end-diastolic dimension (dimension), end-systolic wall stress (afterload), and fractional shortening. All LV parameters are expressed as % change relative to normal. The Wilcoxon rank-sum test was used to compare the LV parameters across CR exposure groups with the resulting P values reported.

Figure 2

Box plots of the distributions of IGF-1 and height of 130 childhood cancer survivors treated with anthracyclines by exposure to cranial irradiation (CR). IGF-1 and height expressed as the % change relative to normal. P values reported based on Wilcoxon rank-sum test.

Figure 3

Scatter plots depicting the association between IGF-1 and left ventricular (LV) parameters in 59 childhood cancer survivors treated with anthracyclines and exposed to cranial irradiation. LV parameters included mass, end-systolic posterior wall thickness (wall thickness), end-diastolic dimension (dimension), end-systolic wall stress (afterload), and fractional shortening. All LV parameters and IGF-1 are expressed as % change relative to normal. Spearman’s Rho was used to assess the association between LV parameters and IGF-1, with P values reported, and a linear trend line has been added.