Cancer Therapy and Myocardial Dysfunction: 5 Things to Know

Douglas J. Leedy, MD; Richard K. Cheng, MD, MSc; Sofia Carolina Masri, MD; Suma H. Konety, MD


July 26, 2021

Editorial Collaboration

Medscape &

In the United States, there are an estimated 17 million cancer survivors, a number projected to increase to 26 million by 2040. Unfortunately, some cancer treatments can cause cardiotoxicity. Left ventricular (LV) dysfunction in the setting of cancer therapy, also known as "cancer therapy–related cardiac dysfunction" (CTRCD), affects approximately 10% of patients receiving chemotherapy. CTRCD remains a common referral in cardiology and cardio-oncology clinics. Therefore, it is essential that clinicians have thorough knowledge of the therapies associated with CTRCD.

Here are the five things to know about cancer therapy and myocardial dysfunction.

1. Assessing a patient's baseline cardiovascular risk before initiating treatment is key to preventing CTRCD.

As with any disease, prevention is essential when it comes to CTRCD. With the number of shared modifiable risk factors between cancer and cardiovascular disease (CVD), prevention should start with a baseline CV risk assessment, especially in patients whose treatment plan includes therapies associated with CV toxicity. A CV assessment helps guide not only the oncologist's therapeutic approach but also the ongoing CV management needed during and after cancer therapy, because these patients are considered to have stage A heart failure. The risk assessment includes evaluation of traditional CVD risk factors; preexisting CVD; and cancer treatment–related considerations, such as previous treatment with anticancer therapy or planned cancer therapies (eg, high-dose anthracyclines, trastuzumab, mediastinal radiation). Both established CVD and the presence of risk factors for CVD are associated with increased risk for CTRCD and should be managed according to the American College of Cardiology/American Heart Association guidelines to mitigate risk during cancer treatment.

Assessment of high-risk patients includes a baseline cardiac examination, 12-lead electrocardiography, echocardiography (to calculate left ventricular ejection fraction [LVEF] and global longitudinal strain [GLS]), and cardiac biomarkers (eg, troponin, B-type natriuretic peptide). Baseline cardiac biomarkers and LVEF can help classify patients at high risk for CTRCD and identify those who may benefit from cardioprotective strategies.

In a prospective study of 555 patients with cancer by Pavo and colleagues, elevated cardiac biomarker levels before treatment with anticancer therapy were strongly associated with all-cause mortality. Moreover, Zardavas and colleagues found that patients with breast cancer who had elevated troponin I and troponin T levels before receiving trastuzumab were at increased risk for cardiac dysfunction. Similarly, in a study by Ky and colleagues, patients receiving doxorubicin and trastuzumab for breast cancer were at increased risk for subsequent cardiac dysfunction. The corollary is also true: A study by Cardinale and colleagues found a relatively low risk (1%) for CV events in patients undergoing high-dose chemotherapy who had no elevations in troponin I from baseline.

There are several risk-prediction tools to help assess a patient's risk for LV dysfunction. Though not validated in prospective studies, the cardiotoxicity risk score has been utilized at some institutions to assess a patient's risk by considering baseline CV risk factors in combination with the intended cancer therapy. Patients found to be at elevated risk for CTRCD should be identified before starting treatment and their care coordinated through a multidisciplinary approach between hematology-oncology and cardiology teams.

2. Early identification of CTRCD can be challenging.

A major challenge of identifying CTRCD early is the lack of a consistent, standard definition of myocardial dysfunction. The criteria used to define myocardial dysfunction vary across studies. Perhaps the most widely accepted definition comes from an expert consensus statement published by the American Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACVI). In that statement, the ASE/EACVI defines CTRCD as a decrease in LVEF > 10% percentage points to a value below the lower limit of normal (LVEF < 53%), as confirmed by repeat two-dimensional echocardiography (2DE) studies 2-3 weeks after initial findings. However, this definition has not been validated with clinical outcomes, and 2DE has inherent limitations, such as interobserver variability and the inability to detect small changes reliably. Therefore, further refinements, including novel imaging techniques and biomarkers, may be useful to help to define CTRCD more accurately.

3. Heart failure medications may be effective in preventing cardiotoxicity.

Conventional heart failure therapy with neurohormonal blockade (eg, beta-blockers, angiotensin-converting enzyme [ACE] inhibitors, and angiotensin-receptor blockers [ARBs]) as primary prevention of CTRCD has been the focus of recent clinical trials. Overall, studies show a possible modest benefit from neurohormonal therapy, though the clinical significance is unclear. Many of the trials to date are limited by small sample size, study populations with a relatively low risk for CVD, short-term follow-up, and the use of imaging or biomarker surrogates rather than clinical events. Most of the studies on ACE inhibitors and ARBs (eg, candesartan, lisinopril, enalapril) suggest a small attenuation in LVEF reduction during exposure to cancer treatment.

PRADA was a 2 × 2 factorial randomized controlled trial of candesartan and metoprolol in women with early breast cancer undergoing anthracycline therapy with or without trastuzumab. In the primary analysis of 130 women who underwent 10-61 weeks of adjuvant therapy, candesartan, but not metoprolol, was associated with an attenuated decline in LVEF. However, the recently published 2-year extended follow-up study showed that candesartan did not prevent significant reductions in LVEF when given during adjuvant therapy. In the extended study, candesartan was associated with modest reduction in LV end-diastolic volume and preserved GLS.

In the MANTICORE trial, there was an attenuated decline in LVEF associated with bisoprolol compared with perindopril and placebo in 99 patients treated with trastuzumab for breast cancer. In addition, the rate of therapy interruption in the trial due to LV dysfunction was significantly lower in the bisoprolol group (10%) than the control group (30%). Findings from the neurohormonal trials showed that cardioprotective medications are well tolerated by patients, possibly attenuate LVEF decline, and decrease the rate of interruptions in chemotherapy. Therefore, the use of beta-blockers and/or ACE inhibitors/ARBs during cardiotoxic therapy may be reasonable in patients at risk for CTRCD. Several ongoing cardio-oncology trials funded by the National Institutes of Health will hopefully lend more insight into the complex CV care of patients with cancer.

4. Anthracyclines and HER2-targeted therapies are not the only agents associated with LV dysfunction.

LV dysfunction due to chemotherapy has been well described over the decades, with extensive experience with anthracyclines. Despite the introduction of targeted cancer therapies, anthracyclines (eg, doxorubicin, epirubicin) remain the backbone of treatment for many types of cancer, such as breast cancer, hematologic cancers, and sarcomas. Cumulative exposure to anthracyclines increases the risk for potentially nonreversible CTRCD, with LV dysfunction occurring in 5%-26% of patients on cumulative doses of doxorubicin 400 mg/m2 and 550 mg/m2, respectively. Extremes of age (< 5 years or > 65 years); presence of known CVD risk factors or preexisting coronary artery disease; and concomitant therapy with thoracic radiation, cyclophosphamide, or trastuzumab are additional risk factors for CTRCD in patients receiving anthracyclines. Though most anthracycline-induced cardiotoxicities occur within the first year of treatment and are partially reversible, irreversible LV dysfunction can manifest years to decades after treatment.

Another well-known culprit in CTRCD is trastuzumab, a human epidermal growth factor receptor 2 (HER2)–targeted therapy. LV dysfunction associated with trastuzumab is not dose-dependent and is reversible upon discontinuation. The risk for LV dysfunction is 3%-7% in patients receiving trastuzumab monotherapy and increases to 27% when trastuzumab is given concomitantly with doxorubicin and cyclophosphamide.

Alkylating agents (eg, cyclophosphamide, ifosfamide) used to treat solid tumors, leukemia, and lymphomas are also associated with CTRCD. The risk for CTRCD is 7%-28% in patients taking cyclophosphamide and up to 17% in patients taking ifosfamide combination chemotherapy. Cardiotoxicity associated with these agents is dose-dependent, and risk for CRTCD increases with advanced age, higher daily doses, and concurrent radiation and/or anthracycline therapy.

Targeted cancer therapies, such as vascular endothelial growth factor (VEGF) signaling pathway inhibitors, are increasingly being utilized in cancer treatment. Among these, small-molecule tyrosine kinase inhibitors (eg, axitinib, sorafenib, sunitinib, pazopanib) are frequently associated with hypertension (or worsening of existing hypertension) and a high incidence of LV dysfunction. In addition, monoclonal antibodies targeting VEGF, such as bevacizumab, can be associated with nearly a fivefold increase in risk for heart failure.

5. Early detection of LV dysfunction and prompt initiation of therapy is essential.

At many medical centers, 2DE is the modality of choice to assess LVEF owing to its relatively low cost, wide availability, and lack of radiation. When available, advanced imaging modalities, such as endocardial border enhancement with ultrasonic contrast and 3D-echocardiography (3DE), should be used in addition to 2DE to improve the detection of CTRCD. On the basis of studies demonstrating increased accuracy and reproducibility of 3DE compared with 2DE, the ASE/EACVI expert consensus supports the routine use of 3DE to assess LVEF. However, declining LVEF is typically a late manifestation of CTRCD, and echocardiography is unable to detect small (< 10%) changes in LVEF.

For this reason, measuring LV GLS through echocardiography has emerged as a readily available modality. LV GLS can detect subclinical LV dysfunction earlier than LVEF in patients undergoing chemotherapy and is endorsed by the ASE/EACVI and the American Society of Clinical Oncology. A decrease > 15% in GLS from baseline can be considered subclinical CTRCD if the definition by LVEF criteria has not been met. In addition, recent studies, including a retrospective analysis by Ali and colleagues, demonstrated that abnormal baseline GLS before starting anthracycline therapy may serve as a predictor for CTRCD.

Other imaging modalities, such as multiple-gated acquisition scans (MUGA) and cardiac magnetic resonance imaging (CMR), have superior accuracy and serial reproducibility compared with 2DE. Despite excellent reproducibility and availability, MUGA has fallen out of favor owing to radiation exposure (5-10 mSv per scan) and lack of global assessment beyond LVEF. CMR is considered the gold standard for measuring ventricular volumes, mass, and function. It also provides additional characteristics, including myocardial edema, inflammation, scar tissue, and fibrosis. Although the use of CMR is increasing, limitations in cost, availability, and expertise limit widespread adoption. Regardless of the imaging modality chosen, serial assessment of LV function should be consistent within that modality.

Cardiovascular care of patients with cancer can be challenging and complex. Through enhanced recognition and awareness, cardiologists and oncologists can develop effective strategies to facilitate the prevention, early detection, and co-management of CTRCD.

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