The Role of Cardioprotection in Cancer Therapy Cardiotoxicity

Cardiotoxicity is a relatively frequent and potentially serious side effect of traditional and targeted cancer therapies. Both general measures and specific pharmacologic cardioprotective interventions as well as imaging- and biomarker-based surveillance strategies to identify patients at high risk have been tested in randomized controlled trials to prevent or attenuate cancer therapy–related cardiotoxic effects. Although meta-analyses including early trials suggest an overall beneficial effect, there is substantial heterogeneity in results. Recent randomized controlled trials of neurohormonal inhibitors in patients receiving anthracyclines and/or human epidermal growth factor receptor 2–targeted therapies have shown a lower rate of cancer therapy–related cardiac dysfunction than previously reported and a modest or no sustained effect of the interventions. Data on preventive cardioprotective strategies for novel cancer drugs are lacking. Larger, prospective multicenter randomized clinical trials testing traditional and novel interventions are required to more accurately define the benefit of different cardioprotective strategies and to refine risk prediction and identify patients who are likely to benefit.

The term cardiotoxicity is not uniformly or universally defined. According to the National Cancer Institute, cardiotoxicity is broadly defined as "toxicity that affects the heart." 2 The term may thus include toxicity not only to the myocardium but also the pericardium, endocardium, and coronary vasculature.
However, the term has commonly been used in a narrower sense to mean a reduction in LV systolic function and/or the development of clinical heart failure, on the basis of the classical observations that anthracycline therapy, in a dose-dependent fashion, is associated with the risk for developing an irreversible cardiotoxic cardiomyopathy. 3 Accordingly, the term cardiotoxicity has often been used interchangeably with the more recent term cancer therapy-related cardiac dysfunction (CTRCD).
In this state-of-the-art review, our emphasis is on the role different cardioprotective strategies play in mitigating the cardiotoxic effects of both conventional and targeted cancer therapies in adults. We include a review of the available evidence with an emphasis on recently published randomized controlled trials (Tables 1 and 2) and meta-analyses, but we also provide an overview of the objectives of important ongoing randomized trials (Table 3).
Finally, we briefly summarize some practical guidance for clinicians treating patients receiving conventional and targeted anticancer therapies ( Table 4).

GENERAL CARDIOPROTECTIVE STRATEGIES TO PREVENT CANCER THERAPY CARDIOTOXICITY
General cardioprotective strategies to prevent cancer therapy cardiotoxicity include both strategies that are common to other forms of cardiovascular disease and some that are specific to cancer and cancer therapy.
The multiple-hit model of heart failure is based on the observation that heart failure often is a multifactorial condition. 4 Extrapolating this theory to the cardiotoxicity setting, patients with established or subclinical cardiovascular disease will have less cardiac functional reserve and therefore tolerate less additional injury before symptoms and signs of cardiotoxicity become clinically apparent. Accordingly, many traditional modifiable and nonmodifiable cardiovascular risk factors are associated with increased risk for CTCRD. Strategies aimed at reducing the risk associated with modifiable risk factors, such as smoking cessation, weight loss, exercise and reduction of sedentary time, and pharmacologic interventions including lipid-lowering, antihypertensive, and antidiabetic therapy, thus have the potential to improve general cardiovascular health status and thereby reduce risk for cardiotoxicity. 5 These insights provide a strong argument for oncology patients with established cardiovascular disease or those at substantially increased risk for unrecognized subclinical cardiovascular disease to be evaluated by a cardiologist or cardio-oncologist prior to the initiation of potentially cardiotoxic cancer therapy.
Cancer-associated risk markers for cardiotoxicity include the site (eg, pancreatic, kidney, lung, lymphoma) and stage (ie, advanced) of cancer. Cancer associated factors that can increase the risk for cardiovascular disease include hypercoagulability and cancer invasion in the heart and blood vessels, as well as high-output states. Cancer therapy-associated risk factors include prior radiotherapy, especially if directed at the heart and mediastinum, and prior exposure to anthracyclines or hormone therapy. 6 Although the risk associated with some of these factors is not modifiable, strategies to reduce radiation exposure to the heart and the use of alternative HIGHLIGHTS Traditional and targeted cancer therapies are associated with risk of cardiotoxicity.
There is incomplete evidence of the effect of cardioprotective pharmacotherapy.
Treatment of reversible cardiovascular risk factors is highly recommended.
Close collaboration between oncologists and cardiologists is essential.     survival appeared to be unaffected in patients with early or metastatic breast cancer receiving anthracyclines with or without trastuzumab. 15 However, the evidence in early-stage breast cancer is limited, and in the meta-analysis <10% of the cohort had early-stage breast cancer. Notably, none of the included randomized trials were considered to be at low risk for bias across bias domains. Several studies were classified as being at high risk for performance bias because of the unblinded design and attrition bias because of the amount and handling of incomplete outcome data.
The investigators appropriately concluded that because of the low quality of the available evidence, further randomized trials are warranted before   Blinded 128 High-sensitivity troponin T AUC before and after each chemotherapy cycle and at 1-, 3-, 6-, and 12-mo follow-up Selected ongoing randomized trials of cardioprotection interventions in patients with cancer identified at ClinicalTrials.gov among randomized interventional studies that had not been completed, suspended, terminated, or withdrawn and ClinicalTrialsRegister.eu among randomized trials without results, using the following search terms: "cardiotoxicity," "cancer and heart failure," "cancer and cardioprotection," "cancer and cardiomyopathy," "cardiovascular toxicity," and "heart failure and radiotherapy." In addition, we included selected ongoing trials presented in methods or design papers and recent reviews.
2D ¼ 2-dimensional; ACE ¼ angiotensin-converting enzyme; AUC ¼ area under the curve; CREC ¼ Cardiac Review and Evaluation Committee of trastuzumab-associated cardiotoxicity; CVD ¼ cardiovascular disease; FAC ¼ fractional area change; GDF ¼ growth differentiation factor; HER2 ¼ human epidermal growth factor receptor 2; NYHA ¼ New York Heart Association; PIGF ¼ placental growth factor; PWV ¼ pulse-wave velocity; RV ¼ right ventricular; other abbreviations as in Tables 1 and 2. for neurohormonal antagonists for treatment and prevention of heart failure with beta-adrenergic receptor blockers, angiotensin-converting enzyme  In patients with moderate to high cardiovascular risk profile (including but not limited to elevated cardiac troponins and high cumulative anthracycline dose), consider treatment with beta-blockers and/or ACE inhibitors/ARBs.
If cardiac function deteriorates during cancer treatment, suggest treatment with beta-blockers and/or ACE inhibitors/ARBs.
The optimal cardioprotective duration is unknown but should as a minimum be continued during cancer treatment.
If the patient develops signs or symptoms of heart failure, the ability to continue cancer therapy should be discussed with the oncologist/hematologist. Temporary cessation may be necessary, and heart failure treatment should be initiated according to guidelines.
MRAs are considered safe to use.
Sacubitril-valsartan has been associated with beneficial outcomes, but RCTs are lacking.
Reintroduction of cancer therapy under close monitoring and heart failure therapy may be considered after multidisciplinary deliberation depending on cancer type, prognosis, therapy options, severity of cardiotoxicity, and patient preferences.
Optimal treatment duration is unknown.   Several classes of anticancer therapies, including anthracyclines, human epidermal growth factor receptor 2 (HER2)-targeted therapy (eg, trastuzumab), radiotherapy, and fluoropyrimidines may cause cardiotoxicity. Whereas the principal cardiotoxic problem associated with anthracyclines and HER2-targeted therapy is left ventricular dysfunction, fluoropyrimidines have been associated with vasospasm and subsequent myocardial ischemia. Radiotherapy may cause a variety of cardiovascular diseases, including ischemic heart disease, valvular and pericardial disease, and cardiomyopathy. Preventive strategies include treatment of modifiable cardiovascular risk factors, modification of cancer treatments, and potentially preventive cardioprotective interventions, but there is need for additional research.    The observation that aldosterone is stimulated by  sparse, but this research question will be addressed in ongoing studies ( Table 3).   inconsistent. This may be due to slightly differing focus of interest and reflect the time they were written. A summary of practical clinical recommendations is presented in Table 4. In general, an important strategy is to treat modifiable cardiovascular risk factors. 51 Other preventive measures are modifications of cancer therapy dose and administration method and the administration of potentially cardioprotective drugs such as beta-blockers and or ACE inhibitors or ARBs. The long-term beneficial effects of cardioprotection with these drugs remain unclear, hence a risk-based cardioprotective approach rather than universal implementation may be appropriate at this point. 52  Two second-generation antiandrogen agents deserve to be mentioned specifically: enzalutamide (an androgen receptor antagonist) and abiraterone (a CYP17 inhibitor). Enzalutamide has in randomized controlled trials been associated with an increased risk for hypertension but not cardiac events. 76,77 Abiraterone has been associated with increased risk for both cardiac events and hypertension. 77,78 Antiestrogen therapy, including tamoxifen or aromatase inhibitors, may mimic a postmenopausal state but has not been shown to aggravate cardiovascular disease in patients with breast cancer. 79