Cardiotoxicity Induced by Radiotherapy and/or Chemotherapy After Cancer Treatment.

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Background

The therapeutic management of cancer has progressed the last 10 years and allowed a significant increase in patient survival rates. However, the corollary is the development of chronic toxicities that impair patients' quality of life. Cardiovascular diseases induced by chemo and/or radiation are today recognized as concerning side effects of cancer treatment in a patients with breast, childhood or Hodgkin cancer.

1) Radiation-induced cardiotoxicity

Radiation therapy is the second most important treatment modality after surgery in the treatment of cancer. Sixty to seventy percent of cancer patients are treated with radiation therapy, with more than 50 percent achieving complete cure. Radiation therapy is classically applied in a cycle of multiple fractions administered over several weeks to destroy the primary tumor and locoregional lymph node metastases while minimizing as much as possible the toxicity to normal tissue that still occurs. Although effective on cure rates, radiation therapies present some concerns related to the development of delayed cardiac toxicities, particularly in patients treated for childhood cancer or in women treated for left breast tumors.

Although radiation-induced cardiac dysfunction is mostly asymptomatic and heart failure is rare in the first 5 years after radiation, many studies of cardiac function show relatively acute changes (>1 year) in systolic and diastolic function, myocardial perfusion, and conduction defect. Although the use of newer techniques for breast radiotherapy was developed by the desire to reduce the dose to the heart and left anterior descending artery during radiotherapy, late radiation-related side effects on the cardiovascular system still exist. In addition, a few papers have identified a dose-response relationship in a cohort of pediatric patients, in which the relative risk of cardiac death is a linear function of the average radiation dose to the heart (at ERR 1 Gy, 60%).

During a European Cardio-risk project, several teams were able to develop experimental mouse/rat models with local cardiac irradiation at doses between 0.2 and 19 Gy to mimic the side effects of radiotherapy. Under these experimental conditions, several effects are observed such as cardiomyopathy, alteration of physiological parameters (decreased ejection fraction and shortening), amyloid deposition and/or fibrosis at 8 months after low doses of irradiation. Molecular and cellular effects were also observed. These effects were tightly associated with molecular and cellular changes, such as imbalanced oxidative stress homeostasis (e.g. effects on stress response), metabolic changes (e.g. effects on PPAR-alpha signaling and mitochondrial function), vascular dysfunction (e.g. effects on NO signaling) and tissue remodeling (e.g. effects on Roh/Rock and TGF-beta signaling).

2) Cardiotoxicity induced by a combination of chemotherapy and radiotherapy

More recently, treatment with large fraction on small fields and combination of radiotherapy with targeted drugs significantly enhanced anti-tumor efficacy but also cause disabling normal tissue injury. Especially, lethal events have been reported in patients treated by radiotherapy and Avastin. Moreover delayed congestive heart failure occurs in patients who received radiotherapy and anthracycline or Herceptin. Studies of chemotherapy treatment have shown that elderly patients treated with anthracyclines could present 10% increase in the absolute rate of cardiac dysfunction 10 years after treatment. In addition, the association of anthracycline with radiotherapy generates heart disease in patients treated for childhood cancers. Pathological changes include congestive heart failure, myocardial infract, angina pectoris and valvular disorders. Similarly, cardiac toxicity phenomena develop in breast cancer patients treated with targeted therapies, including Herceptin.

Chronic treatment-related cancer toxicities are becoming a major public health problem. However, this field of research remains little studied on the etiology of the development of these cardiac rhythm disorders. Regardless of the technique used, whether it is Formal Radiotherapy, IMRT, Tomotherapy or Cyber-Knife, external radiotherapy irradiates healthy tissues located in the irradiation fields, whatever they may be. Knowledge of the dose-effect relationships for the main organs at risk of iatrogenic pathology is an essential scientific basis for improving radiotherapy techniques and treatment protocols. Epidemiological data underline the importance of the problem of cardiac side effects of radiotherapy, the physiopathological, cellular and molecular bases of which remain unknown. This research project will lead to a scientific breakthrough because these results will allow to better localize the sensitive points in terms of doses to the heart and to identify the signaling pathways of the associated cardio-toxicity in the long term. This project could lead to an additional step in the implementation of new treatment strategies, whether radiotherapy or chemotherapy or even the combination of cancer treatments. In terms of scientific progress, we will be able to establish a list of cellular and molecular signaling pathways that will allow us to advance in the understanding of the occurrence of post-radiotherapy cardiovascular pathologies in these patients treated for cancer. This knowledge greatly facilitates the discovery of biomarkers for cardiotoxicity, the identification of new cardioprotective therapeutic targets and the optimization of prevention and intervention strategies in chemo- and radio-therapy.

Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.

Keywords: Cardiotoxicity, radiotherapy, chemotherapy, cancer treatment

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