Cardiotoxicity in childhood cancer survivors
Authors:   , de Baat Esmée Christina 
Published: August 2023

Long-term health effects in the growing population of childhood cancer survivors are of major concern. Cardiac disease, because of treatment with anthracyclines, mitoxantrone or radiotherapy involving the heart region, can manifest as myocardial dysfunction and heart failure. Ten percent of the survivors exposed to cardiotoxic cancer treatment will develop this within 40 years after their cancer diagnosis. Heart failure is currently the most common non-cancer-related cause of mortality in survivors and significantly compromises the quality-of-life.

This thesis delves into the current state of cardiac diseases in childhood cancer survivors (Chapter 2) and presents new insights into risk stratification, early detection, and primary cardioprotection of cardiac dysfunction and heart failure.

Risk stratification studies demonstrated that high doses of cardiotoxic treatments increase the risk of heart failure, but limited evidence existed about risks associated with lower doses. Chapter 3 describes a study involving over 30,000 European childhood cancer survivors that demonstrated a 2% prevalence of heart failure by age 50. Recent decades' survivors had lower heart failure mortality. Additionally, investigations into lower doses of chemotherapy and radiotherapy showed that even survivors exposed to low mean heart radiotherapy doses (5-<15 Gray) had increased heart failure risk. However, survivors treated with low cumulative anthracycline doses (<100 mg/m2) did not show significantly increased heart failure risk. These results potentially impact future treatment protocols and monitoring guidelines.

Current assessment strategies involve echocardiography every 2-5 years (depending on cumulative dose) combined with a single ECG. Chapter 4 analyzes the possibilities of ECG in cardiomyopathy surveillance. A systematic review in Chapter 4.1 highlights various ECG abnormalities with potential clinical implications among survivors, but there was a lack of studies in large cohorts. In Chapter 4.2, a national cohort study found major ECG abnormalities mainly in survivors treated with radiotherapy involving the heart region. Worse cardiac function correlated with more ECG abnormalities, suggesting limited efficacy in early detection. Yet, specific abnormalities could aid excluding relevant cardiac dysfunction, possibly reducing the need for echocardiography. Further research is required for clarity.

There is a growing focus on primary prevention of heart failure. One way to prevent or reduce anthracycline-induced cardiac damage is to protect the heart with medication. Dexrazoxane is one such medication, and a systematic review in Chapters 5.1 addresses its effectiveness and safety. Chapter 5.2 provides a guideline for its use in children, recommending its consideration for those expected to receive high anthracycline doses.

The studies in this thesis contribute to the improvement of cardiac care for both survivors and future childhood cancer patients. The studies have led to improved identification of survivors at increased risk of cancer-related heart failure, increased knowledge of the use of ECG in the monitoring of cardiac dysfunction, and clear guidance on the use of dexrazoxane in children. The studies also identified gaps in knowledge that could potentially make a difference to the care of pediatric cancer survivors in the future.