Biological dosimetry for breast cancer radiotherapy: a comparison of external beam and intraoperative radiotherapy
David K Woolf
0
Norman R Williams
2
Raheleh Bakshi
1
Seyed Yazdan Madani
1
David J Eaton
0
Sara Fawcitt
0
Katharine Pigott
0
Susan Short
3
Mohammed Keshtgar
1
0
Department of Academic Oncology, Royal Free Hospital
,
London, UK
1
The Academic Breast Unit, University College London
,
London, UK
2
Clinical Trials Group, University College London
,
London, UK
3
Leeds Institute of Cancer and Pathology, St James University Hospital
, Leeds,
UK
Purpose: External 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 -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. Methods: 34 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 -H2AX biomarker then quantified. Results: Data 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. Conclusions: These data show a significantly greater change in -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.
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Introduction
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). However, whole breast radiotherapy is not
without risk or side effects. 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).
Cardiac toxicity is the most likely of these to result in
serious morbidity as well as mortality. 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 also 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 also
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).
Modern radiotherapy techniques are safer than those
used in the past due to more accurate planning using
computed tomography enabling an element of cardiac
sparing, augmented by the existence of heart atlases to
avoid structures such as the left anterior descending
coronary artery (Feng et al. 2011), an area at particular risk
(Taylor et al. 2007). There are also data to show that
using hypofractionated regimes result in a lower
biological dose to the heart when compared with
conventional schedules, due to the presumed relatively high
fraction sensitivity of the heart (Appelt et al. 2013).
Methods of reducing cardiac dose without
compromising target coverage include shielding with multileaf
collimation or breath-hold techniques (Bartlett et al. 2013a)
but are not widely utilized (Bartlett et al. 2013b).
There has been growing interest in accelerated partial
breast irradiation (APBI) allowing treatment to be
delivered safely over a shorter duration. There are several
APBI techniques available, which include linac-based
intensity-modulated radiotherapy, multicatheter
interstitial brachytherapy, balloon-based APBI, intra-operative
radiotherapy using a mobile linear accelerator (ELIOT)
or a miniature X-ray generator in the operating theatre
(TARGIT) (Williams et al. 2011).
With the TARGIT technology, radiation is produced
when accelerated electrons strike a gold target at the tip
of a 10-cm-long drift tube with a diameter of 3 mm,
resulting in the emission of low-energy X-rays (50 kV)
in an isotropic dose distribution around the tip (Vaidya
et al. 2001; Vaidya et al. 2002). The irradiated tissue is
kept at a fixed, kn (...truncated)