Take-aways Heart failure and cardiomyopathy are commonly seen in patients following cancer therapy. In older patients, risk of cardiac events is substantially higher than that reported from clinical trials enrolling younger, healthier women. A number of agents have shown significant and similar efficacy for reducing cardiotoxicity related to cancer therapy, including dexrazoxane, beta-blockers, statins, and angiotensin antagonists.

The prognosis of patients with hematologic malignancies has improved in the last years due to the use of new chemotherapeutic and antineoplastic drugs as well as more dose-intensive regimens. However, it's become better appreciated in the last few years that many cancer therapies confer an increased risk of adverse cardiac outcomes such as HF and cardiomyopathy (CM).

For example, several widely used agents for the adjuvant therapy of breast cancer can cause abnormalities in LV function, leading to HF or CM that can persist many years after the conclusion of chemotherapy. While early investigation focused on the anthracyclines, long known for their cardiotoxic effects, newer agents, too, put patients at risk for myocardial injury.

Because 40.8% of women diagnosed with breast cancer in the United States are at least 65 years of age and because risk for CV events increases with age, it is crucial to better understand the risk of cardiotoxicity associated with newer biologic agents used for treating older adults with cancer outside of clinical trials.

Recently, Chen et al. used Medicare data to estimate HF and CM rates following chemotherapy and adjuvant trastuzumab in older women for breast cancer.¹ In female Medicare beneficiaries with breast cancer, use of this HER2/neu-targeted therapy increased by more than 8-fold from 2000 through 2007 among patients receiving any form of adjuvant therapy. That might make this group an important target for preventing and managing cancer therapy–induced cardiotoxicity.

Almost 50,000 women aged 67-94 years with early-stage breast cancer were identified. Adjusted 3-year HF/CM incidence rates were higher for patients receiving trastuzumab (32 per 100 patients) and anthracycline plus trastuzumab (42 per 100 patients) compared with no adjuvant therapy (18 per 100 patients). In terms of adjusted risk, compared to patients who received no adjuvant chemotherapy or trastuzumab, use of trastuzumab was associated with a higher absolute adjusted incidence rate for HF or CM over 3 years.

Importantly, in this analysis, the cardiac complication rates after trastuzumab therapy for older women were higher than those reported from clinical trials.

Other so-called "targeted" cancer drugs can increase the risk of fatal cardiac events, too. A recent meta-analysis led by scientists at Dana-Farber Cancer Institute evaluated data from 4,679 patients participating in 10 randomized controlled trials.² The study looked at three drugs: sorafenib, sunitinib, and pazopanib, which block the vascular endothelial growth factor (VEGF) tyrosine kinase receptors in cancer cells. These agents have become the cornerstone of therapy for a number of cancers. Investigators analyzed the incidence of arterial thrombotic events, bleeding, HF, and other events. The incidence of fatal complications was 1.5% in patients who received any of the three drugs, compared to a 0.7% incidence in patients given standard treatments or placebos.

Other types of agents, including 5-fluoruracil and anti-VEGF therapy, now have acknowledged CV effects, too. Thus, whether evaluating older established therapies or newer biologics and so-called targeted therapies, pretty much all of them now have recognized cardiotoxic effects.

What Can Be Done About It?

The damaging cardiac effects of modern cancer therapy manifest through a diversity of mechanisms including endothelial toxicity and direct myocyte injury. Angiotensin-converting enzyme inhibitors (ACE-I) have been demonstrated to slow the progression of LV systolic dysfunction and to prevent HF in asymptomatic high-risk patients. These drugs have also been shown to decrease mortality in post-infarction patients with LV dysfunction or heart failure, including anthracycline-induced CM. Also, ACE-Is have preventive effects against chemotherapy-induced cardiotoxicity in animal models and in adults with early cardiotoxicity.

Similar results have been obtained with the administration of beta-blockers in patients with post-infarction LV dysfunction or HF in animal models of cardiotoxicity and in patients treated with anthracyclines. In addition, the administration of both ACE-Is and beta-blockers has additive beneficial effects in patients with LV dysfunction and are the recommended treatment in current ACC/AHA HF guidelines.

Here are some of the recent studies looking at preventing or diminishing the cardiotoxic effects of cancer therapies.

• Investigators from the Cleveland Clinic and Case Western Reserve University evaluated the effect of continuous statin treatment on development of new-onset HF in 628 patients with breast cancer receiving anthracycline-based chemotherapy.³ Incident HF and cancer-related mortality were significantly lower in the statin group, with only four cases of HF in patients treated with statins compared with 23 cases in the control group. Additionally, there were 15 cancer-related deaths in the group not receiving statins, compared with no deaths in the statin group. In an accompanying commentary, Daniel J. Lenihan, MD, wrote, "In a manner similar to athletes training to become 'fit for battle' and perform at their peak, statins appear to be a necessary component for patients with cancer to ready themselves for their cancer war."⁴
• In a paper to be published in JACC, investigators report the results of a pilot randomized trial suggesting that the combination of enalapril and carvedilol prevented LVEF reduction in patients with diverse hematological malignancies undergoing intensive chemotherapy.⁵
• In a systematic review of the evidence, investigators collated data for 2,015 pediatric and adult patients, including 12 randomized controlled trials and two observational studies.⁶ Prophylactic treatment with dexrazoxane, beta-blocker, statin, or angiotensin antagonists all had similar significant efficacy for reducing cardiotoxicity.

Clearly, therapies used in both oncology and cardiology are intimately intertwined at the vascular level.

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References

1. Chen J, Long JB, Hurria A, et al. J Am Coll Cardiol. 2012;60:2504-12. http://content.onlinejacc.org/article.aspx?articleid=1389699
2. Schutz FA, Je Y, Richards CJ, Choueiri TK. J Clin Oncol. 2012;30:871-7.
3. Seicean S, Seicean A, Plana JC, et al. J Am Coll Cardiol. 2012;60:2384-90. http://content.onlinejacc.org/article.aspx?articleid=1389315
4. Lenihan DJ. J Am Coll Cardiol. 2012;60;2391-2 http://content.onlinejacc.org/article.aspx?articleid=1389317
5. Bosch X, Rovira M, Sitges M, et al. J Am Coll Cardiol. 2013;61:2355-62. http://content.onlinejacc.org/article.aspx?articleid=1677827
6. Kalam K, Marwick TH. Eur J Cancer. 2013 May 22. [Epub ahead of print]

To listen to an interview with Daniel J. Lenihan, MD, about heart safety during chemotherapy, visit youtube.cswnews.org.  The interview was conducted by Peter A. McCullough, MD.

Keywords: Prognosis, Infarction, Vascular Endothelial Growth Factor A, Cardiomyopathies, Heart Failure, Breast Neoplasms, Chemotherapy, Adjuvant, Anthracyclines

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