The impact of radiotherapy, trastuzumab and hormonal therapy on cardiac fibrosis. More is worse?

Abstract

The impact of radiotherapy, trastuzumab and hormonal therapy on cardiac fibrosis. More is worse?334 Radiotherapy (RT) for early breast cancer (EBC) has proven capable of reducing the rates of recurrence and death from the disease. Similarly, trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2) antibody, has significantly improved the prognosis of breast cancer patients in both the adjuvant and metastatic settings. However, major concerns have arisen about these treatments because both have been linked to cardiac toxicity, the former increasing the risk of ischemic heart disease, the latter, heart failure.Before the era of 3-dimensional CT-based treatment planning it was observed that rates of major coronary events increased linearly for the first 5 years after radiotherapy (1). It has also been seen that cardiac side-effects may occur after adjuvant treatment with trastuzumab, with an absolute 12.0% higher adjusted incidence rate for heart failure over 3 years (2). Although preclinical data originally pointed towards a radiosensitizing effect of trastuzumab, more recent clinical studies have demonstrated that concurrent RT and trastuzumab for EBC is not associated with increased acute adverse events, including those of a cardiological nature (3, 4).Having said that, cardiotoxicity is becoming an increasingly important issue in modern medical practice as more and more patients are being treated with RT or chemotherapy and targeted therapies and are surviving longer. Moreover, the widely used definition of cardiotoxicity, originally created by oncologists decades ago and based on the development of heart failure symptoms and/or left ventricular ejection fraction reduction, has become obsolete. In fact, it refers to the detection of cardiac damage only after the onset of cardiac dysfunction and does not take into consideration the possibility of taking timely preventive measures. Finally, the survival rate of cancer patients has greatly increased over the past twenty years (5), making those who recover at higher risk for cardiovascular events.In this context, Cihan et al. (6) published in this issue evaluated the effect of RT, trastuzumab and hormone therapy sequencing on cardiac function in animal models. A single 12-Gy fraction to the rats caused increased fibrosis of the atrium, left ventricle and aorta after 6 months with respect to the control group. The trastuzumab-only treated arm also had higher fibrosis scores than the control group. Interestingly, this study highlighted a difference in the effect of the hormonal agents used, i.e. anastrozole and exemestane reduced the severity of the fibrosis, whereas letrozole and tamoxifen showed no impact on the myocardial damage induced after RT and trastuzumab administration.In Azria et al. (7) preclinical study of breast cancer cells transfected with an aromatase gene, letrozole showed a strong radiosensitising effect. However, the same authors did not observe a clinically meaningful effect in terms of the occurrence of acute or late adverse events w...

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“…Trastuzumab can be safely used after or concurrently with conventionally fractionated radiotherapy after breast-conserving surgery or mastectomy [32] at least if no radiotherapy for the treatment of the internal mammary chain lymph nodes is administered. In the palliative setting, trastuzumab was administered in combination with hypofractionated radiotherapy in different clinical situations [33,34,35]. No relevantly enhanced acute or late toxicity has been reported.…”

Adjuvante hypofraktionierte Strahlentherapie beim frühen Mammakarzinom. Übersicht und Meta-Analyse randomisierter kontrollierter Studien

“…Trastuzumab ist sicher für die Anwendung nach oder während einer konventionell fraktionierten Strahlentherapie nach brusterhaltender Operation oder Mastektomie [32], zumindest wenn keine Bestrahlung der Lymphknoten der Mammaria-interna-Kette durchgeführt wird. Im palliativen Setting ist Trastuzumab in Kombination mit hypofraktionierter Strahlentherapie in verschiedenen klinischen Situationen angewandt worden [33,34,35]. Hierbei wurde keine relevant erhöhte akute oder späte Toxizität beobachtet.…”