Cardiovascular Toxicity of Newer Chemotherapeutic Agents: The Heart of the Matter

In this issue of ONCOLOGY, Bhave and colleagues provide a comprehensive review of the cardiovascular toxicities of the newer targeted chemotherapeutic agents, and insight into the prevention and treatment of chemotherapy-related cardiac dysfunction (CRCD).[1] In addition to the details of toxicities provided in their review, it is worthwhile highlighting several important points. First, cardiotoxicity resulting from targeted cancer therapy is more common than originally thought. Cardiac side effects related to many newer agents were, in many instances, not fully appreciated because of the way in which cardiac surveillance has traditionally been conducted. Second, robust data are lacking on the optimal strategy for surveillance and treatment of CRCD.[2] Guidance from major cardiology societies, including the American Heart Association, the American College of Cardiology, and the Heart Failure Society of America are inexplicably absent. However, newer strategies for surveillance and randomized trials looking at treatment are appearing, and these may provide much-needed direction. Finally, a collaborative approach is clearly needed to optimize strategies for surveillance, prevention, and treatment. A burgeoning cardio-oncology field has emerged out of necessity to tackle the cardiac side effects of these increasingly sophisticated chemotherapy agents.

Since trastuzumab’s approval by the US Food and Drug Administration in 1998, there has been a steady increase in the use of this agent as adjuvant therapy in breast cancer. Earlier clinical trials, as outlined in the review, likely underestimated the true incidence of CRCD associated with trastuzumab therapy. Medicare Surveillance, Epidemiology and End Results (SEER) data show a 3-year incidence of 32.1 per 100 patients, which is in contrast to earlier clinical trial data.[3] In addition, while it has been widely believed that type II cardiac toxicity from trastuzumab was reversible, this is not always the case, and significant long-term morbidity and mortality can result. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial, roughly 15 of 69 patients with 6-month echocardiographic data had persistent reductions in their ejection fraction (EF).[4] Many more patients than this remained on heart failure (HF) medications long-term despite improvement in EF.

The recent explosion in the development of small molecule tyrosine kinase inhibitors, particularly those targeting the VEGF pathway, has certainly revolutionized treatment of certain cancers. However, reports of cardiac toxicity were unexpected and not well predicted by early-phase preclinical studies. For example, in an initial randomized trial of sunitinib for renal cancer, 21% of patients experienced a decline in EF.[5] Subsequent analyses of retrospective data suggest a much higher incidence-up to 47% demonstrating a decline in EF.[6] The apparent increase in incidence of CRCD is likely due to many factors, including reporting governance by the Common Terminology Criteria for Adverse Events,[7] but the important point is that the incidence of CRCD for many targeted therapies is higher than was recognized in earlier-phase clinical trials.

The most effective treatment for chemotherapy-induced cardiotoxicity is likely prevention.[8] Much current effort in the realm of cardioprotection focuses on the early detection of left ventricular (LV) impairment, either by noninvasive imaging modalities or with biomarkers.[9] The rationale for such a strategy is that early recognition permits an intervention: either modifications to chemotherapy, institution of a cardioprotective agent to ameliorate or prevent cardiotoxic manifestations, or early aggressive HF management to prevent further clinical progression. Early initiation of HF treatment and low New York Heart Association functional class are major critical predictors of LVEF recovery, and there is evidence that the potential for cardiac recovery may decrease significantly with longer time to detection.[10]

While transthoracic echocardiography (TTE) and radionuclide ventriculography have traditionally been utilized to measure EF and identify LV dysfunction, a decrease in EF lacks sensitivity in diagnosing subclinical cardiotoxicity. Once symptoms of overt heart failure manifest, the response to medical therapy is frequently less robust and the prognosis generally worse.[11] Contemporary studies have shown that a decrease in LV deformation parameters such as global longitudinal strain and strain rate precede reduction in EF and are independent predictors of delayed clinical cardiotoxicity.[12] Strain and strain rate can be measured using speckle tracking echocardiography or tissue Doppler imaging on a standard two-dimensional TTE. Todaro and colleagues[8] have proposed a cardiac surveillance algorithm for patients receiving trastuzumab that involves monitoring of LV function using EF and longitudinal strain. Additionally, biomarkers such as ultrasensitive troponin I, myeloperoxidase, and N-terminal pro-B-type natriuretic peptide have been shown to be predictors of delayed cardiotoxicity, and abnormal levels of these markers could prompt earlier treatment.[13]

Unfortunately, the effectiveness of treatments for CRCD has been poorly studied to date. Standard HF treatment with angiotensin-converting enzyme (ACE) inhibitors and beta-blockers is recommended but is not based on large randomized clinical trials. The ongoing Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research Trial (MANTICORE 101 - Breast) will evaluate the effects of perindopril (an ACE inhibitor) and bisoprolol (a beta-blocker) on cardiac MRI evidence of remodeling and, it is hoped, will provide much-needed data related to efficacy.[14]

As outlined in the review by Bhave and colleagues, a multitude of targeted chemotherapy agents are now available to treat a wide variety of cancers, and each agent has the potential for a unique profile of cardiac side effects. To address this emerging problem, oncologists and cardiologists are increasingly collaborating, forming cardio-oncology clinics. These collaborative clinics are important for addressing not only cardiac toxicity from traditional chemotherapeutic agents, but especially the toxicities of newer targeted agents. Long-term follow-up of patients is needed to survey for potential late cardiotoxic effects, since experience with traditional chemotherapy and radiation therapy has shown it can sometimes take years for cardiac injury to manifest.

As newer targeted agents are developed and traditional agents remain in use, the possibility of adverse cardiac side effects from cancer therapy unfortunately continues to increase. Current reporting issues with clinical trials for chemotherapy agents may result in continued underestimation of the risks involved. Cardio-oncology specialists are therefore in high demand to address these problems. Standard heart failure regimens remain the mainstay of therapy for CRCD until newer randomized trials suggest otherwise, and earlier detection of toxicity through judicious surveillance with biomarkers and noninvasive imaging remains the cornerstone of management for the foreseeable future.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

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2. Shaikh AY, Shih JA. Chemotherapy-induced cardiotoxicity. Curr Heart Fail Rep. 2012;9:117-27.

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4. Romond EH, Jeong JH, Rastogi P, et al. Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2012;30:3792.

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14. Pituskin E, Haykowsky M, Mackey J. Rationale and design of the Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research Trial (MANTICORE 101 - Breast): a randomized, placebo-controlled trial to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer using cardiac MRI. BMC Cancer 2011;11:318.