Detection of defects in myocardial perfusion imaging in patients with early breast cancer treated with radiotherapy

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Abstract

Background and purpose: To evaluate radiation-induced defects in myocardial perfusion imaging in early breast cancer patients treated with modern technique radiotherapy.

Patients and methods: Twenty-four patients with left-breast tumours and 12 control patients with right-breast tumours, relapse-free since treatment for primary disease, who had undergone radiotherapy at least 5 years previously and with no history of ischaemic heart disease prior to radiotherapy underwent study. In left-breast patients, at least 1 cm of heart was required to have been in the treatment field. Patients underwent cardiac assessment and single photon emission computerized tomography myocardial perfusion imaging.

Results: Myocardial perfusion tracer uptake was abnormal in 17 (70.8%) left-breast and two (16.7%) right-breast patients (P=0.002). Of the 17 abnormal scans in left-breast patients, abnormalities were confined to the cardiac apex in 16 patients, and perfusion defects were reversible (n=7), fixed (n=7) or mixed (n=3). Reversible perfusion defects that were not confined to the cardiac apex were observed in two right-breast patients. Left ventricular ejection fraction was normal in all 33 patients in whom it was measured, and no myocardial perfusion abnormalities were judged to require treatment or follow-up.

Conclusions: In this selected study population modern technique radiotherapy to the left breast was associated with a significantly greater number of myocardial perfusion abnormalities than radiotherapy to the right breast. These abnormalities were both reversible and irreversible, suggesting that radiotherapy can lead to both myocardial damage and to epicardial coronary disease. With a minimum of 5 years follow-up since treatment, no abnormalities were considered to be clinically significant.

Introduction

Radiotherapy is an integral component of the local management of early breast cancer. It is used after breast-conserving surgery [10], [34], and following mastectomy in selected high-risk patients [28], [34]. The efficacy of radiotherapy in these contexts is now well-established, reducing local disease recurrence from 30.1 to 10.4% at 20 years, and reducing breast cancer deaths by 4.8% at 20 years [7]. Furthermore, recent studies of high-risk patients post-mastectomy demonstrated that the use of radiotherapy is associated with an increase in overall survival [25], [26].

Despite these clear benefits, breast and chest wall radiotherapy are also associated with long-term cardiac toxicity. Population-based cancer registry studies demonstrate increased mortality due to myocardial infarction for patients treated for left- compared with right-sided tumours [27], [29]. In an overview of eight trials of post-mastectomy radiotherapy started before 1975 [6], the use of radiotherapy was associated with an excess of cardiac deaths when compared with no radiotherapy (standardized mortality ratio for heart disease 1.62, P<0.001). The most recent published update of the Early Breast Cancer Trialists' Collaborative Group [7], which now has 20 years of follow-up, shows that while the use of radiotherapy is associated with a reduction in breast cancer deaths, this is offset by an increase in non-breast cancer deaths. Analysis of the causes of these deaths reveals that they were confined to vascular events, which were significantly increased in patients treated with radiotherapy, although information was not collected centrally on site of vessel irradiation or laterality of tumour.

A number of factors have been identified that are of potential significance in radiation-induced cardiac toxicity, including use of orthovoltage radiation [17], [20], the volume of irradiated heart [14], [17], [20], [30], and the use of large fraction sizes [7], [20]. However, it should be noted that studies identifying these factors and the majority of those included in the two overviews were commenced between the 1950s and 1970s. At that time, target volumes were extensive, often routinely encompassing internal mammary chain lymph nodes, which were treated by extension of the medial tangent beyond the midline [13], [30], or by matching of a direct photon field to the medial tangent [20]. This frequently resulted in irradiation of significant volumes of heart. In contrast, current treatment techniques reflect efforts to reduce the volume of heart in the treatment volume, either by treating the internal mammary chain nodes with a direct electron field [25], [26], or by omitting their treatment altogether. However, it is difficult to avoid cardiac irradiation completely [5], [21], and even the use of standard tangents alone will frequently include a segment of the left anterior descending coronary artery within the treatment volume [8], [13]. Nevertheless, in two studies using modern techniques and with sufficient follow-up (median follow-up of at least 9 years), no increase in deaths due to ischaemic heart disease (IHD) has been demonstrated in patients receiving radiotherapy [18], [31].

Thus, while evidence from a large number of studies conducted two or more decades ago clearly links the use of radiotherapy used in the treatment of early breast cancer to an excess of cardiac deaths, it is less clear at present what impact current treatment techniques will have on reducing cardiac morbidity and mortality. In this study, the effects of modern technique breast radiation on the heart have been assessed by myocardial perfusion imaging using single photon emission computed tomography (SPECT), allowing assessment of both myocardial perfusion and function. A cohort of patients treated for left-sided tumours, all of whom are known to have a clinically significant volume of heart within the radiotherapy target volume, are compared with a matched cohort of patients treated for right-sided tumours. Furthermore, attempts are made to classify myocardial perfusion imaging abnormalities aetiologically in terms of myocardial damage and epicardial coronary disease.

Section snippets

Patients

This study was designed as a retrospective study to compare cardiac damage in patients who had received radiotherapy to the left breast with matched controls who had received radiotherapy to the right breast. Patients entered into the study were required to fulfil a number of eligibility criteria (Fig. 1): to have received radiotherapy performed at least 5 years previously, following either breast-conserving surgery or neoadjuvant chemotherapy for early stage unilateral breast cancer; to have

Eligibility characteristics

The median age of study participants was 62.5 (inter-quartile range (IQR) 54.5–69.0) years for patients with left-sided tumours and 59.0 (IQR 51.0–69.5) years for those with right-sided tumours. Median follow-up post-radiotherapy was 6.65 (IQR 5.75–8.75) years for patients with left-sided tumours and 8.30 (IQR 6.30–10.05) years for those with right-sided tumours. Although this suggests that there may be a difference in median follow-up post-radiotherapy between the two groups, this was not

Discussion

The role of radiotherapy in the aetiology of late cardiac damage sustained during the treatment of early breast cancer is now well-established on the basis of long-term follow-up of clinical studies conducted at least 20 years ago [7]. This is of particular concern since breast cancer is the commonest cancer in women world-wide and hundreds of thousands of women have breast or chest wall radiotherapy every year. It has been suggested that modern radiotherapy treatment techniques may decrease

Acknowledgements

We would like to thank Peter Seddon for preparation of the figures, and Judith Bliss for help and advice with the manuscript.

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