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• W2051446412 abstract "Breast cancer is the most common malignancy in the UK, with over 42 000 new cases diagnosed each year [[1]Toms J.R. CancerStats monograph. Cancer Research UK, 2004: 21-30Google Scholar]. Over the last three decades the incidence has increased, although mortality has decreased due to earlier detection, improved surgical and radiotherapeutic techniques and more effective systemic therapies [2Early Breast Cancer Trialists' Collaborative GroupEffects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials.N Engl J Med. 1995; 333: 1444-1455Crossref PubMed Scopus (1054) Google Scholar, 3Coombes R.C. Kilburn L.S. Snowdon C.F. et al.Survival and safety of exemestane versus tamoxifen after 2–3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial.Lancet. 2007; 369: 559-570Abstract Full Text Full Text PDF PubMed Scopus (745) Google Scholar]. Consequently, the number of breast cancer survivors is rising and is projected to reach 1.7 million by 2040 [[4]Maddams J. Utley M. Moller H. Projections of cancer prevalence in the United Kingdom, 2010–2040.Br J Cancer. 2012; 107: 1195-1202Crossref PubMed Scopus (286) Google Scholar]. In view of this surge in survivor numbers, the late side-effects of treatment, including radiotherapy, are of increasing concern to patients and healthcare commissioners alike. We know that the survival benefit from radiotherapy after breast-conserving surgery is offset by a 1% increase in non-breast cancer mortality at 15 years, 90% of which is cardiovascular in origin [[5]Clarke M. Collins R. Darby S. et al.Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.Lancet. 2005; 366: 2087-2106Abstract Full Text Full Text PDF PubMed Scopus (3914) Google Scholar]. There is increasing evidence that irradiation of the left anterior descending coronary artery (LAD) is a significant factor in this [6Lind P.A. Pagnanelli R. Marks L.B. et al.Myocardial perfusion changes in patients irradiated for left-sided breast cancer and correlation with coronary artery distribution.Int J Radiat Oncol Biol Phys. 2003; 55: 914-920Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 7Correa C.R. Litt H.I. Hwang W.T. Ferrari V.A. Solin L.J. Harris E.E. Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer.J Clin Oncol. 2007; 25: 3031-3037Crossref PubMed Scopus (282) Google Scholar, 8Nilsson G. Holmberg L. Garmo H. et al.Distribution of coronary artery stenosis after radiation for breast cancer.J Clin Oncol. 2012; 30: 380-386Crossref PubMed Scopus (257) Google Scholar], and its situation on the most anterior portion of the heart makes it particularly susceptible to high doses of radiation from tangential field radiotherapy. Improvements in radiotherapy techniques (including cardiac shielding using multileaf collimation) have reduced normal tissue doses [[9]Taylor C.W. Nisbet A. McGale P. Darby S.C. Cardiac exposures in breast cancer radiotherapy: 1950s–1990s.Int J Radiat Oncol Biol Phys. 2007; 69: 1484-1495Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar], correlating with reductions in non-breast cancer-related mortality over the last three to four decades [[10]Darby S.C. McGale P. Taylor C.W. Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries.Lancet Oncol. 2005; 6: 557-565Abstract Full Text Full Text PDF PubMed Scopus (776) Google Scholar]. Nonetheless, doses to the heart, LAD and lung from current standard supine breast and chest wall radiotherapy remain clinically significant [[11]Taylor C.W. Povall J.M. McGale P. et al.Cardiac dose from tangential breast cancer radiotherapy in the year 2006.Int J Radiat Oncol Biol Phys. 2008; 72: 501-507Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar]. It has been difficult to incorporate our knowledge of radiation-related heart disease (RRHD) from breast radiotherapy into the clinic because until now there has been no practical method of quantifying the dose–effect relationship between heart dose and late cardiac effects. Recent work from Darby et al. [[12]Darby S.C. Ewertz M. McGale P. et al.Risk of ischemic heart disease in women after radiotherapy for breast cancer.New Engl J Med. 2013; 368: 987-998Crossref PubMed Scopus (2265) Google Scholar] has addressed this as well as other important issues, greatly enhancing our understanding of the interaction between breast radiotherapy and heart disease. Their work, published in the New England Journal of Medicine in March 2013, was a population-based case–control study of major coronary events (MCE) in over 2000 women who received breast radiotherapy in Denmark and Sweden between 1958 and 2001. MCE were defined as a diagnosis of myocardial infarction, coronary revascularisation or death from ischaemic heart disease (IHD). Strict selection and matching criteria were applied and, wherever possible, hospital cardiology or autopsy records were reviewed. In terms of radiation dosimetry, individual patient radiotherapy treatment charts were copied (including treatment fields, photographs, diagrams and treatment plans, where available) and used to reconstruct each radiotherapy treatment using computed tomography-based virtual simulation of a women with typical anatomy. They found a strong linear relationship between the mean heart dose (Gy) and the subsequent rate of MCE, which increased at 7.4% per Gy of the mean heart dose. Importantly, there was no threshold dose below which IHD did not occur. The overall rate of MCE was over six times greater in women with a history of IHD than in those with no such history (13 times greater in the first 9 years after exposure). However, the percentage increase in MCE per Gy mean heart dose was the same whether or not the women had this risk factor. The overall rate of MCE was also increased by other risk factors, including diabetes, chronic obstructive pulmonary disease, smoking and raised body mass index. For most women, however, absolute risks of radiation-related IHD are low: for example, the absolute risks (%) of a radiation-related acute coronary event by age 80 years in women with no cardiac risk factors who are irradiated with a mean heart dose of 3 Gy at aged 40, 50 and 60 years (at least one cardiac risk factor in brackets) are 1.0 (1.7), 0.9 (1.7) and 0.8 (1.4), respectively, and for 1 Gy are 0.3 (0.6), 0.3 (0.5) and 0.3 (0.5), respectively. Another interesting finding from the study was the relationship between rates of MCE and the time since radiation exposure. Until now, it has been widely presumed that excess cardiac morbidity and mortality secondary to breast radiotherapy do not present until at least 10–15 years after exposure. However, the Darby et al. paper [[12]Darby S.C. Ewertz M. McGale P. et al.Risk of ischemic heart disease in women after radiotherapy for breast cancer.New Engl J Med. 2013; 368: 987-998Crossref PubMed Scopus (2265) Google Scholar], shows that MCE not only occur earlier than previously thought, with a 16.4% increase per Gy of radiation between 0 and 4 years, but also that the increase continues into the third decade after radiotherapy. By using computed tomography of a patient with typical anatomy, the authors have found a pragmatic solution to the problem of interpreting cardiac doses from treatment charts of a pre-computed tomography era. However, it is clearly a limitation, and further work using clinical computed tomography-based plans is likely to be more representative and may allow modelling of the relationship between anatomical features, cardiac doses and cardiac late effects. The historical nature of much of the data also meant that the number of women in the study who received chemotherapy was not representative of the modern era: the number of women receiving anthracyclines was small, and no women received taxanes or trastuzumab. However, the use of chemotherapy in the treatment of breast cancer has increased markedly over the past 20 years, as has the proportion of patients receiving cardiotoxic agents [13Kemetli L. Rutqvist L.E. Jonsson H. Nystrom L. Lenner P. Tornberg S. Temporal trends in the use of adjuvant systemic therapy in breast cancer: a population based study in Sweden 1976–2005.Acta Oncol. 2009; 48: 59-66Crossref PubMed Scopus (9) Google Scholar, 14Tataru D. Robinson D. Møller H. Davies E. Trends in the treatment of breast cancer in Southeast England following the introduction of national guidelines.J Public Health. 2006; 28: 215-217Crossref Scopus (12) Google Scholar, 15Mariotto A. Feuer E.J. Harlan L.C. Wun L.-M. Johnson K.A. Abrams J. Trends in use of adjuvant multi-agent chemotherapy and tamoxifen for breast cancer in the United States: 1975–1999.J Natl Cancer Inst. 2002; 94: 1626-1634Crossref PubMed Google Scholar, 16van Herk-Sukel M.P. van de Poll-Franse L.V. Creemers G.J. et al.Major changes in chemotherapy regimens administered to breast cancer patients during 2000–2008 in the Netherlands.Breast J. 2013; 19: 394-401Crossref PubMed Scopus (9) Google Scholar]. There is concern about the effect of these trends in systemic therapy practice on RRHD in the breast cancer population and further work is required to assess this. At the very least, we can assume that radiation-induced cardiac disease will remain relevant in this context. Given the widely held belief (and substantial evidence) that irradiation of the LAD is a major causative factor in the development of RRHD, it is surprising that inclusion of the mean LAD dose to the mean heart dose failed to improve the prediction of MCE rates. One reason is that LAD dose estimates may be inaccurate due to difficulties in localising this structure. Finally, although the dose–effect relationship observed in the study is highly statistically significant, the relationship is linear and not the sigmoidal dose–effect relationship for late effects that would be predicted by the Poisson dose–response model. This is an unexpected finding and as yet unexplained. Although for most women the absolute risks of IHD from breast cancer radiotherapy are low, the Darby et al. paper [[12]Darby S.C. Ewertz M. McGale P. et al.Risk of ischemic heart disease in women after radiotherapy for breast cancer.New Engl J Med. 2013; 368: 987-998Crossref PubMed Scopus (2265) Google Scholar] suggests that all women stand to benefit from heart-sparing radiotherapy. The increasing incidence of breast cancer and improved survivorship mean that these small absolute risks will translate into significant numbers at risk across the breast cancer population. For example, assuming the number of breast cancer survivors is, as predicted, 1.7 million by 2040, that the proportion of patients with at least one cardiac risk factor is similar to that in the Darby et al. paper [[12]Darby S.C. Ewertz M. McGale P. et al.Risk of ischemic heart disease in women after radiotherapy for breast cancer.New Engl J Med. 2013; 368: 987-998Crossref PubMed Scopus (2265) Google Scholar] control population (i.e. approaching 50%) and that 90% of these patients receive radiotherapy, reducing mean heart doses from 3 to 1 Gy could be expected to reduce the number of radiation-related acute coronary events in this population from around 19 500 to 6000 and the number of deaths from IHD from around 9000 to 2000. However, given that breast radiotherapy accounts for 30% of radiotherapy treatments, any heart-sparing radiotherapy techniques must be simple and inexpensive in order to avoid an unsustainable burden on healthcare systems. The use of heart-sparing breast radiotherapy in the UK is currently rather limited. The 2012 Royal College of Radiologists' audit into UK breast radiotherapy practices showed that in nearly 50% of cases with ‘heart in the field’, no cardiac shielding was used and that in most of the remainder, either multileaf collimation was used to shield cardiac tissue or target tissue coverage was compromised. Breath-holding techniques, in which the heart is pulled down and away from the treatment field, were used in only 4% of cases. A major advantage of breath-holding techniques is that they minimise the trade-off between target and non-target tissue coverage that is commonplace with standard supine free-breathing breast radiotherapy. A current UK study (The HeartSpare Study) has shown that a simple, inexpensive breath-holding technique (voluntary deep-inspiratory breath-hold) is reproducible and effective at heart sparing [[17]Bartlett F.R. Colgan R.M. Carr K. et al.The UK HeartSpare Study: randomised evaluation of voluntary deep-inspiratory breath-hold in women undergoing breast radiotherapy.Radiother Oncol. 2013; https://doi.org/10.1016/j.radonc.2013.04.021Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar]. The feasibility of using this technique in a multicentre setting is now being assessed in the context of the UK NCRI FAST-Forward trial (HeartSpare II). It is hoped that this study will facilitate the UK-wide uptake of heart-sparing breast radiotherapy. Despite some remaining unanswered questions, we have a dose–effect relationship between the mean heart dose and the risk of subsequent IHD, for the first time. It is no longer safe to presume that older patients will not live long enough to experience the late cardiac effects of breast radiotherapy, nor that there is a mean heart dose below which women have no risk. It is clear that we need to exercise particular caution when treating women with pre-existing cardiac risk factors, whose absolute risk of radiation-related MCE is far greater than those without. Managing cardiac risk factors in this group of patients will be important to minimise their cardiac risk, and as such education of and integration with cardiology and general practice colleagues will be vital. Although heart-sparing breast radiotherapy has the potential to benefit all women, only techniques that minimise the burden on resources can realistically become part of standard breast radiotherapy. Response to D. Woolf and M. Keshtgar's reply to: Breast Radiotherapy and Heart Disease – Where Are We Now?Clinical OncologyVol. 26Issue 2PreviewSir — We thank Woolf and Keshtgar [1] for their response to our editorial [2]. In keeping with other partial breast radiotherapy techniques, intraoperative radiotherapy may offer heart-sparing benefits, and dosimetric data to support this would be welcomed. As Woolf and Keshtgar point out, whole breast radiotherapy remains the current UK standard. However, partial breast irradiation may have a role to play in the treatment of patients at low risk of recurrence, and the long-term results of a number of partial breast radiotherapy trials are awaited with interest. Full-Text PDF Intraoperative Radiotherapy for Breast Cancer Deserves a MentionClinical OncologyVol. 26Issue 2PreviewSir — We read with interest the editorial by Bartlett and colleagues [1] addressing the issue of cardiac toxicity from breast radiotherapy. Although techniques to reduce cardiac dose, including cardiac shielding and breath-holding techniques, are discussed we note that the use of intraoperative radiotherapy techniques are not mentioned. These technologies include the TARGIT system, where a miniature X-ray generator in the operating theatre produces low energy X-rays (50 kV) in an isotropic dose distribution around the tip. Full-Text PDF" @default.
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