Cardiotoxicity in childhood cancer survivors: strategies for prevention and management

Abstract

Advances in cancer treatment have greatly improved survival rates of children with cancer. However, these same chemotherapeutic or radiologic treatments may result in long-term health consequences. Anthracyclines, chemotherapeutic drugs commonly used to treat children with cancer, are known to be cardiotoxic, but the mechanism by which they induce cardiac damage is still not fully understood. A higher cumulative anthracycline dose and a younger age of diagnosis are only a few of the many risk factors that identify the children at increased risk of developing cardiotoxicity. While cardiotoxicity can develop at anytime, starting from treatment initiation and well into adulthood, identifying the best cardioprotective measures to minimize the long-term damage caused by anthracyclines in children is imperative. Dexrazoxane is the only known agent to date, that is associated with less cardiac dysfunction, without reducing the oncologic efficacy of the anthracycline doxorubicin in children. Given the serious long-term health consequences of cancer treatments on survivors of childhood cancers, it is essential to investigate new approaches to improving the safety of cancer treatments.

Figure 1. Mechanism of anthracycline toxicity within the cardiomyocyte

Anthracyclines enter cardiomyocytes by passive diffusion and spur the generation of free radicals, leading to cell damage. Anthracyclines also directly and indirectly inhibit gene transcription, mitochondrial functioning, and energy production within the cell. β1ADR: β1 adrenergic receptor; Ca: Calcium; cTn: Cardiac troponin; DOX: Doxorubicin; Fe²⁺: Iron; MLC2: Myosin light chain; MM-CK: Muscular creatine kinase; MT-CK: Mitochondrial creatine kinase; NO: Nitric oxide; ROS: Reactive oxygen species; TOPII: Topoisomerase II; Trans reg: Transcriptional regulatory. Reproduced with permission from [28].

Figure 2. Probability of depressed contractility as a function of the cumulative dose of doxorubicin by sex

Adapted from [60], with permission from Massachusetts Medical Society.

Figure 3. Percentage of patients with at least one elevated cardiac troponin T level overall, before treatment with doxorubicin and during treatment

An elevated level of troponin T was defined as one that exceeded 0.01 ng/ml. The number of patients in whom troponin T was measured at least once during the specified intervals is shown in each bar. Adapted with permission from [84].

Figure 4. Model-based estimated probability of having an increased cardiac troponin T level at each depicted time point in patients treated with doxorubicin, with or without dexrazoxane

Vertical bars show 95% CIs. Increased cTnT is defined as a value greater than 0.01 ng/ml. *p-value versus dexrazoxane group ≤0.05; **p-value versus dexrazoxane group ≤0.001. An overall test for dexrazoxane effect during treatment was significant (p < 0.001). cTnT: Cardiac troponin T. Adapted with permission from [70].

Figure 5. Mean left ventricular echocardiographic Z scores in boys and girls (n = 134)

Plots are adjusted for age *p ≤ 0.05 for comparison of the mean Z score of the doxorubicin plus dexrazoxane group with zero. **p ≤ 0.05 for comparison of the mean Z score for the doxorubicin group with zero. ***p ≤ 0.05 for comparisons of mean Z scores between the doxorubicin and doxorubicin plus dexrazoxane groups. Adapted with permission from [166].