Abstract
PurposeExternal beam radiotherapy (EBRT) is the gold standard adjuvant treatment after breast conserving surgery although a recent phase 3 trial has shown the non-inferiority of intraoperative radiotherapy (IORT).Radiation exposure of the heart and cardiac vessels causes an increase in morbidity and mortality following EBRT for breast cancer.We have used γ-H2AX foci formation in peripheral blood lymphocytes as a surrogate marker of dose delivered to the heart and great vessels and have assessed the feasibility of using this technique for biological dosimetry.Methods34 patients were recruited, having either EBRT or IORT as part of a randomised controlled trial (TARGIT). Blood samples were taken prior to and after first fraction of radiotherapy, and the γ-H2AX biomarker then quantified.ResultsData were available for 31 patients. Following TARGIT-IORT there was an increase of 0.203 foci per cell (range −1.436 to 1.275) compared with 0.935 foci per cell (range −0.679 to 2.216) in the EBRT group; this difference was highly significant (p = 0.009). As TARGIT-IORT treatment is completed with a single fraction, whilst EBRT requires at least 15 fractions, the actual difference is estimated to be many times more.ConclusionsThese data show a significantly greater change in γ-H2AX foci number per cell following one fraction of EBRT compared to TARGIT-IORT. This is the first study to demonstrate this effect using a biomarker and demonstrates a proof of concept methodology for similar applications.
Highlights
Postoperative radiotherapy to the breast is regarded as an essential adjunct to breast cancer conservation surgery as there is overwhelming evidence that adjuvant radiotherapy decreases the risk of local recurrence and improves survival (Fisher et al 1991; EBCTCG et al 2011)
This study aims to quantify the difference in exposure using a biomarker of radiation exposure: the phosphorylated histone H2AX protein (γ-H2AX). γ-H2AX is expressed after induction of DNA double strand breaks caused by ionising radiation (Valdiglesias et al 2013), created as lymphocytes in the circulation pass through, and adjacent to, the irradiated field
34 patients were recruited to this study of which 20 received External beam radiotherapy (EBRT) and 14 received TARGIT-intraoperative radiotherapy (IORT). 3 patients (2 EBRT and 1 TARGIT-IORT) were not evaluable due to technical errors in the laboratory transport or processing meaning γ-H2AX foci results were unavailable
Summary
Postoperative radiotherapy to the breast is regarded as an essential adjunct to breast cancer conservation surgery as there is overwhelming evidence that adjuvant radiotherapy decreases the risk of local recurrence and improves survival (Fisher et al 1991; EBCTCG et al 2011). Known adverse events include early skin erythema and desquamation as well as late skin fibrosis and telangiectasia, acute fatigue, late lung fibrosis, rib fractures, secondary malignancy and ischaemic heart disease (START Trialists’ Group et al 2008). A recent publication on the risk of ischaemic heart disease after radiotherapy for breast cancer (Darby et al 2013) showed that the overall average of the mean doses to the whole heart was 4.9 Gy, and that the risk of a subsequent coronary event increased linearly with doses at a rate of 7.4% per Gy. It concluded that the risk increase begins within a few years after exposure, and continues for at least 20 years. Data on whole body exposure has shown an elevated risk of stroke and heart disease with doses over 0.5 Gy (Shimizu et al 2010) and the association between breast radiotherapy and ischaemic heart disease is widely accepted (Sardaro et al 2012)
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