Anthracycline Cardiotoxicity: Why Are We Still Interested?

This article is a review of: Anthracycline  Cardiotoxicity After Breast Cancer Treatment

Anthracycline cardiotoxicity has been of clinical concern for more than 3 decades. Many hundreds of papers have been written about this unusual form of toxic cardiomyopathy, and yet, we are still putting pieces of the puzzle together. Our cumulative knowledge helps us to predict the risk of cardiac damage with fair accuracy for most patients, but others demonstrate an unpredictable sensitivity to anthracyclines and suffer devastating consequences. Strategies to prevent anthracycline cardiotoxicity have been developed but are underutilized.

Then, just as we thought we had reached a plateau in our knowledge base, new agents entered the scene, and we are now challenged by complex interactions between these agents and the anthracyclines. While evolving treatment strategies may someday render anthracyclines less essential (perhaps presaged by the Breast Cancer International Research Group [BCIRG] 006 results),[1] for a variety of cancers the proven oncologic efficacy of anthracyclines remains robust. The timely review by Hershman and Shao in this issue of ONCOLOGY adds perspective with regard to breast cancer, but the quandary of anthracycline cardiotoxicity is still with us, and is likely to remain so for the foreseeable future.

Cumulative Damage

Anthracycline cardiotoxicity might be more understandable if it could be recognized in its early stages, and if it consistently produced the same degree of cardiac dysfunction in all exposed patients. The unfortunate limitation of trying to use ejection fraction to monitor patients during treatment is that systolic dysfunction is a late finding, and substantial irreversible damage on the cellular level has already occurred by the time decreases in ejection fraction are appreciated. By then, we have missed our window of opportunity to use preventive measures.

The fact that anthracycline cardiotoxicity is cumulative-dose–related suggests that damage starts with the first administration, and additional exposure-as far as the heart is concerned-is an additive stress. Indeed, data from endomyocardial biopsies has confirmed cell death at cumulative dosages below those associated with ejection fraction decreases.

In the modern era of cardiac imaging and biomarkers, it should be possible to recognize early toxicity noninvasively, but we have not yet reached that juncture. Progress is being made on this front: In a study of 204 patients, early increase in troponin I was found to significantly predict a drop in left-ventricular ejection fraction at 7 months.[2] Given what we now know about the pathophysiology, it seems increasingly likely that acute manifestations of anthracycline cardiotoxicity are directly and causally linked to the late cardiomyopathy that previously had been thought of as a separate entity. Even with this knowledge, problems remain.

More Sensitive Detection Techniques

After the myocyte insult occurs, subtle changes in cardiac performance and hemodynamics gradually ensue. This may provide an opportunity for early detection prior to the onset of symptoms or frank systolic dysfunction. Echocardiography is able to detect several parameters of left-ventricular dysfunction beyond ejection fraction. Indeed, diastolic function and indirect measurements of elevated left-atrial pressure that generally precede a fall in systolic function in a variety of conditions can be detected.

Yet, how are we to use these more sensitive techniques? If we limit anthracyclines in those with any marker for toxicity, are we compromising the oncologic treatment? Newer nonanthracycline regimens make this less likely for some tumors, but the concern still exists. Perhaps the most useful scenario would be to institute cardioprotection earlier for the high-risk or compromised patient identified by early-detection techniques.

Complicating Factors

Part of the problem, of course, is that doxorubicin does not affect all hearts equally, and notwithstanding the tremendous strides made in the early recognition of cardiac damage, early toxicity is often silent. These facts conspire to confuse us and give us a false level of security with regard to some of our patients.

Our dilemma is in recognizing that the cardiotoxicity taking place is, at least in part, related to the considerable cardiac reserves, without which we could not run marathons, and perhaps would have difficulty living at high altitudes. After more than 30 years, our current tools for assessing toxicity still incorporate a decline in ejection fraction to an abnormal value or a decrease in the ejection fraction compared with the baseline level. It is now known that in cases of subclinical cardiotoxicity, the heart compensates, and that changes in the ejection fraction do not reflect this early compensation. Only when sufficient damage has taken place do we see declines in the ejection fraction, and this may be a relatively late sequela of the initial damage.

This helps to explain why traditional cardiac risk factors increase the likelihood of anthracycline-related damage. Conditions such as advancing age, hypertension, and diabetes (all associated with increased left-ventricular wall stress and elevated filling pressures) have necessitated tapping into those cardiac reserves, thus leaving the heart more vulnerable to any additional insult, including anthracycline administration.

Anthracycline-Trastuzumab Interactions

The interaction of anthracyclines with other breast cancer agents such as trastuzumab (Herceptin) adds yet another layer of complexity. By itself, trastuzumab causes a cardiomyopathy that appears to be fundamentally different from that of anthracyclines; there is no relationship with cumulative dose, there are minimal pathologic changes by electron microscopy, and cardiac dysfunction is largely reversible.[3] Unfortunately, the clinical manifestations of congestive heart failure or decreased ejection fraction are indistinguishable from those caused by doxorubicin. Algorithms for dealing with this on a practical level involve serial imaging studies and are probably overly conservative, but are based on the clinical trials that included both agents.

As Hershman and Shao note, the trastuzumab interaction is unique in its mechanism. Trastuzumab appears to prevent the myocyte’s adaptive response to and repair of anthracycline injury. This explains why trastuzumab, in the absence of anthracycline, is generally benign, but when given concurrently with anthracyclines, markedly increases the risk of cardiomyopathy.[4] Analysis of the adjuvant trastuzumab trials further suggests that the timing between anthracycline and trastuzumab administration also may be a factor in the expression of cardiotoxicity.

The incidence of congestive heart failure in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31[5] and BCIRG 006[1] trials (both gave trastuzumab 21 days postanthracycline) was 4% and 2%, respectively. The HERceptin Adjuvant (HERA) trial (89 days between agents) reported an incidence of 0.6%.[6] In the smaller Finland Herceptin (FinHer) trial, trastuzumab was given prior to anthracycline, and the incidence of heart failure was 0%.[7] Flushing out these types of interactions will be an important component of minimizing anthracycline toxicity, especially as a multitude of newer agents become available.

Conclusions

In the end, we can safely treat the majority of our patients with anthracyclines by assessing their pretreatment risk, monitoring them during their treatment, and incorporating strategies to mitigate toxicity for higher-risk individuals or those in whom a greater anthracycline dose is essential. For the present, anthracyclines remain an integral part of the oncologic armamentarium. The common goal of oncologists and cardiologists must be to optimize cancer survival; we strive to kill the cancer while at the same time minimizing the destruction of myocytes and the dysfunction of cardiac contractile elements.

We are not there yet, but we are making progress. For now, and for these reasons, we remain highly interested in the clinical spectrum of anthracycline cardiotoxicity.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Slamon D, Eiermann W, Robert N, et al: Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study (abstract 1). Breast Cancer Res Treat 94(suppl 1):S5, 2005.
2. Cardinale D, Sandri MT, Martinoni A, et al: Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy. J Am Coll Cardiol 36:517-522, 2000.
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