“Therapy Insight: anthracyclines and trastuzumab—the optimal management of cardiotoxic side effects”

Arising from: Sanjay Popat and Ian E Smith (2008) Therapy Insight: anthracyclines and trastuzumab—the optimal management of cardiotoxic side effects. Nat Clin Pract Oncol 5: 324–335 doi:10.1038/ncponc1090

Although optimization of adjuvant therapy reduces the risk of breast cancer recurrence, recognizing and managing the toxic effects caused by such treatment is also important. Cardiac toxicity is an important long-term complication of adjuvant therapy, but most of the recent studies regarding assessment of this adverse effect have a certain number of shortcomings. Assessing the exact quantification of the excess risk of cardiovascular mortality is not straightforward,¹ and studies analyzing cardiac toxicity only assess the treatment modalities in isolation (i.e. systemic treatments and radiotherapy). This approach is unable to produce complete data that addresses the effects of each modality in terms of the side effects.

Doxorubicin and trastuzumab are known to cause cardiomyopathy and congestive heart failure upon chronic administration. In a recent high-quality Review, Popat and Smith focused on the potential for cardiotoxicity in patients treated with trastuzumab and who had received anthracycline-based chemotherapy.² These authors highlight the underlying biological mechanisms and described the optimal usage of these drugs to minimize the risk of cardiotoxicity.² They should be congratulated for having advocated the potential role of adjuvant radiotherapy to such cardiotoxicity in patients receiving trastuzumab and anthracyclines. Popat and Smith suggest that further data and longer follow-up on the safety of radiotherapy given concurrently or sequentially with trastuzumab are required. We fully agree with the conclusions of the authors, who reported a high-quality assessment taking into account a number of known risk factors for cardiotoxicity.

While the toxicity of radiotherapy in the adjuvant setting should be further assessed, heart dosimetry data from breast cancer radiotherapy are scarce in most reports that have focused on systemic agents. One major obstacle to doxorubicin-containing multiagent therapies pertains to the possible development of cardiomyopathy and congestive heart failure at lower than expected cumulative doses of doxorubicin. The cardiac toxicity of epirubicin may be notably aggravated by postoperative radiotherapy. Ryberg et al. collected data from 1,097 anthracycline-naive patients treated for metastatic breast cancer with epirubicin, and took into consideration a number of known risk factors for cardiotoxicity.³ The authors determined the maximum cumulative dose of epirubicin that avoids cardiotoxicity for patients with different cardiotoxicity risk backgrounds. The mechanisms by which radiotherapy can aggravate doxorubicin-induced cardiotoxicity, however, are not discussed.

The major question is why avoid attributing a potential role of radiation in heart toxicity? One could postulate that the protocols of radiotherapy in breast conservation or post mastectomy studies are not explained sufficiently. There are several questions that remain. What is the best scheme of radiotherapy (i.e. dose, fractionation, involved fields, energy, 2D or 3D radiotherapy or IMRT)? Could brachytherapy be employed for radiotherapy boost? Moreover, the consequences of irradiating internal mammary node fields in the right or left side of breast cancer patients are never debated. Although it is unknown which quantitative measures of the heart dose or volume are most relevant to subsequent heart disease risk,⁴ information is also needed concerning the effect of irradiating different cardiac structures, especially the coronary arteries.⁵

Today's assessment of heart toxicity needs tomorrow's treatments thinking. To provide safety data for chemotherapy drugs or new targeted agents, including trastuzumab, further studies should not separate chemotherapy and radiotherapy in analyzing cardiac morbidity but rather look at its whole in the setting of cardiac adverse effects, with focus on potential additive toxicity.