What is cardiotoxicity?

Preclinical mechanisms and clinical correlates of cardiotoxicity are pillars of contemporary Cardio-Oncology. The first session of the International Colloquium on Cardio-Oncology (Rome, March 12-14, 2014) asked a provocative question, what is cardiotoxicity? Here we introduce and comment on what the speakers said at that session and discuss in detail in separate articles. In summarizing the strengths and weaknesses of preclinical models and of clinical definitions of cardiotoxicity, we join the experts in concluding that a universal and clinically-integrated definition of cardiotoxicity is in fact lacking. After many years of inquisitive efforts, molecular paths to "cardiotoxicity" remain inadequately characterized. Old generation chemotherapeutics, like anthracyclines, are intuitively different from newer classes of drugs like small-molecule kinase inhibitors. In both cases, however, reported mechanisms of cardiotoxicity need to be put in a wider context that accommodates genetic predisposition or individual modifiable risk factors. In clinical settings, available imaging or biomarkers of cardiotoxicity do not always correlate with patients' cardiac outcome and need to be validated in properly designed studies. Making clinical decisions to change treatment based on one or another biomarker may cause erroneous initiatives that place patients at risk of undertreating the cancer and poor oncologic efficacy. New pragmatic approaches, as exemplified by the concept of actionable cardiotoxicity, should be built on risk:benefit ratio and on balancing oncologic efficacy with cardiac outcomes. Yet, answering the question "what is cardiotoxicity?" remains problematic.