Children with cancer who are under the age of 10 are more likely to contract congestive heart failure after receiving cancer therapy.
Developments in cancer therapies have led to overall survival rates exceeding 80% after cancer diagnosed at childhood and early adulthood (YA). Today, there is a growing survivor population at higher risk for morbidity and mortality than the general population.
Premature heart disease after childhood and YA cancer therapy (see Fig. 1) has been recognised as one of the most serious non-malignant complications of cancer treatments. Survivors of childhood cancer also may have earlier development of conventional cardiovascular risk factors such as hypertension, dyslipidemia, and diabetes, which further increase their risk of serious cardiovascular disease.
In a study conducted by Mulrooney et al (2009), the following risk factors for congestive heart failure were identified: aged below 10 years at cancer diagnosis, female gender, cumulative anthracycline exposure >250mg/m2 and the cardiac radiation dose >5 Gy. With respect to myocardial infarction, the only risk factor was radiation >35 Gy, while increasing cardiac radiation doses, cyclophosphamide administration and anthracycline doses >250mg/m2 accounted for the risk factors of pericardial disease.9 The risk of suffering from anthracycline-induced clinical heart failure in childhood cancer survivors has been reported to rise with increasing time after the first anthracycline dose from 2% after two years to 5.5% after 20 years.
A wide range of additional chemotherapeutic drugs such as alkylating agents, antimetabolites, antimicrotubule agents, preoteasome and Tyrosine kinase inhibitors have been reported as further causes for negative cardiovascular effects. Furthermore, other drugs used in chemotherapy such as cytokines (Interleukin-2), all-trans retinoic acid, arsenic trioxide, thalidomide, etoposide and bleomycin have been recognised as risks for cardiac morbidity. Additionally, radiation therapy has shown to predispose to atherosclerosis, vascular stenosis, thromboembolism, transient ischemic attack and strokes. Paediatric cancer treatments including bone marrow transplantation has been identified as a risk factor for the development of metabolic syndrome in addition to the generally known causes, such as physical inactivity and obesity.
Mechanisms for cardiotoxicity are most probably multifactorial and individual sensitivity may vary. Although the precise pathomechanisms leading to acute heart failure and cardiotoxicity remain yet to be revealed, various hypotheses have been proposed including lipid peroxidation, excess oxidative stress, reduced levels of antioxidant and sulphhydryl groups, and the increased release of reactive oxygen species. Separately, the wide range of inter-individual susceptibility to anthracycline-related cardiac failure has led to the hypothesis that genetic variation may contribute to individual susceptibility. To date, genetic variation in more than 20 candidate genes have been described.
A look at home-based physical activity interventions
The focus of research has shifted from optimising cancer therapies for a cure, to managing and possibly preventing late effects after childhood cancer. In addition to cancer therapy, modifiable cardiovascular risk factors after childhood cancer have been shown to add on to the excess risk for premature death and cardiovascular conditions. Current surveillance guidelines are based on the recommendations of the International Late Effects of Childhood Cancer Guideline Harmonization Group. There is new, recently published evidence for the need of changing dose equivalence ratios when comparing other anthracyclines and mitoxantrone to doxorubicin.
Primary prevention strategies include the evolution of oncology treatment protocols to reduce the exposure to anthracyclines, radiation, and other agents known to be cardiotoxic, as well as the development of effective cardioprotective strategies. Secondary prevention strategies are directed towards survivors who have already been exposed to cardiotoxic agents but in whom clinical changes and symptoms have not yet occurred. In our own study, we were able to show positive outcome with a 12-week home-based physical activity intervention in long-term survivors of childhood leukaemia.
As cancer therapy evolves with the adoption of new agents and technology, it remains a challenge to conduct a long-term follow-up of survivors given the long average latency between cancer treatment and cardiotoxicity development. However, leading a healthy lifestyle and regular physical activity are important to reduce and possibly prevent the occurrence of late cardiovascular complications.
MD, PhD, Senior Consultant in Paediatric Haematology/Oncology
Department of Paediatrics and Adolescent Medicine, Turku University Hospital and Turku University
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Please note, this article will feature in the March 2020 issue of our publication.