Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention

Abstract

Due to the aging of the populations of developed countries and a common occurrence of risk factors, it is increasingly probable that a patient may have both cancer and cardiovascular disease. In addition, cytotoxic agents and targeted therapies used to treat cancer, including classic chemotherapeutic agents, monoclonal antibodies that target tyrosine kinase receptors, small molecule tyrosine kinase inhibitors, and even antiangiogenic drugs and chemoprevention agents such as cyclooxygenase-2 inhibitors, all affect the cardiovascular system. One of the reasons is that many agents reach targets in the microenvironment and do not affect only the tumor. Combination therapy often amplifies cardiotoxicity, and radiotherapy can also cause heart problems, particularly when combined with chemotherapy. In the past, cardiotoxic risk was less evident, but it is increasingly an issue, particularly with combination therapy and adjuvant therapy. Today's oncologists must be fully aware of cardiovascular risks to avoid or prevent adverse cardiovascular effects, and cardiologists must now be ready to assist oncologists by performing evaluations relevant to the choice of therapy. There is a need for cooperation between these two areas and for the development of a novel discipline, which could be termed cardio-oncology or onco-cardiology. Here, we summarize the potential cardiovascular toxicities for a range of cancer chemotherapeutic and chemopreventive agents and emphasize the importance of evaluating cardiovascular risk when patients enter into trials and the need to develop guidelines that include collateral effects on the cardiovascular system. We also discuss mechanistic pathways and describe several potential protective agents that could be administered to patients with occult or overt risk for cardiovascular complications.

Figure 1

The “sliding doors” concept, an example of diverse outcomes based on first diagnosis. There is a risk for diverse outcomes depending on whether the patient with both cardiovascular disease and cancer first presents to a cardiologist or to an oncologist. The oncologist takes a tumor-centric perspective in diagnosis, and in the past might have been missing the incumbent cardiopathy of the individual. The cardiologist treats the cardiopathy correctly, but may not pick up early signs of cancer, thus the patient risks further progression and oncologic complications. Teamwork should improve patient life expectancy, treating cancer while protecting the heart, or treating the heart and providing a thorough oncologic check up. 5-FU = fluorouracil; FOLFOX = folinic acid (leucovorin), 5-FU and oxaliplatin; GI = gastrointestinal; HF = heart failure.

Figure 2

A possible cardio-oncology team flowchart. In a cardio-oncology team effort, the oncologist and cardiologist should work together, evaluating the patient's cardiovascular risk level as an integral part of the choice of cancer therapy. In addition, the patient is monitored throughout therapy and follow-up so that eventual cardiovascular alterations can be detected in a timely manner and treated either by intervention on the cardiovascular side or by modulation of the cancer therapy. Future trial protocols could include a series of candidate marker measurements, both instrumental and serological, in the initial evaluation stage as well as during the course of therapy to identify those most informative of risk potential. HF = heart failure. *Substantial changes in cardiovascular risk assessment; for example, a reduction in left ventricular ejection fraction (LVEF) from baseline greater than 5% to less than 55% with accompanying signs or symptoms of HF or a reduction in LVEF greater than 10% to less than 55%, without accompanying signs or symptoms.

Figure 3

Examples of major mechanisms causing cardiotoxicity of anticancer treatments (black text), clinically used therapeutic agents (green text), and potential protective agents (blue cursive text). ROS = reactive oxygen species; ACE = angiotensin-converting enzyme, NSAIDs = nonsteroidal anti-inflammatory drugs.