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Journal of Clinical Oncology Skip to main page content Search GO Advanced Search » User Name Password Sign In HOME Search Browse BY TOPIC ARCHIVE Early Release PODCASTS Meeting Abstracts Resources ALERTS Advertisement © 2011 by American Society of Clinical Oncology Breast Cancer Radiotherapy and Coronary Artery Stenosis: Location, Location, Location 1. Timothy M. Zagar⇓ and 2. Lawrence B. Marks + Author Affiliations 1. University of North Carolina, Chapel Hill, NC 1. Corresponding author: Timothy M. Zagar, MD, Campus Box 7512, 101 Manning Dr, Chapel Hill, NC 27514; e-mail: [email protected]. Radiation therapy (RT) plays an integral role in the treatment of breast cancer. Lumpectomy followed by whole breast RT provides equivalent outcomes to mastectomy.1 In a meta-analysis of nearly 42,000 women who were treated within clinical trials, the use of RT after mastectomy or lumpectomy improved local control, breast cancer–specific survival, and overall survival.1 Unfortunately, the use of RT also has a dark side. In that same Oxford metaanalysis, the hazard ratio for death secondary to heart disease, presumably radiation related, was 1.27.1 Although the incidence of cardiac events was low in the first 5 years of follow-up, it increased over time and persisted after year 15. In the article that accompanies this editorial, Nilsson et al2 provide the oncology community with another useful and elegantly performed study that addresses radiation-associated heart disease. Previous studies from this group and others have suggested that RT for breast cancer can clearly increase the risk of cardiovascular disease, including pericarditis, coronary artery disease (CAD), conduction abnormalities, congestive heart failure, and valvular disease.3–6 In addition, essentially all of the increased risk of clinically meaningful cardiac events is not manifest until more than 10 years after RT. Given this long latency, prospective studies with clinical end points have been difficult; therefore, much of the current data is derived from population-based studies and a few clinical trials with long follow-up. Additionally clouding the issue is that RT techniques have been improved during the last several decades and much of the cardiac toxicity data come from older series. 7,8 RT is also associated with reductions in regional perfusion as assessed by single photon emission computed tomography (SPECT) scans, in a manner consistent with microvascular injury, relatively soon after RT (eg, 6 months to 5 years).9,10 These perfusion defects seem to largely persist with longer follow-up,11–13 but their clinical relevance is not yet known.11,14 Previous studies have not clearly defined the anatomic distribution of RTassociated CAD. One would reasonably hypothesize that the increased risk of CAD would be dose dependent and would manifest largely in the coronary arteries that are directly within the radiation portal. In the few studies that have considered a dose response, doses are typically described as those received by the entire heart, left ventricle, and/or left anterior descending artery (LAD). Doses to the individual branches/portions of the coronary arteries are not typically considered. Nilsson et al2 took a meaningful step to address this lack of data in a systematic and logical manner. They examined a Swedish cohort of patients with breast cancer who were identified through their national registry and who had been treated between 1970 and 2003. They then cross referenced this with their coronary angiography registry and found 199 women who were treated for breast cancer and who went on to have coronary angiography at some point after their treatment. A comparison group of patients who were not treated for breast cancer was also identified. A radiologist who was blinded to the radiation information reviewed the angiographies and scored the degree of coronary artery stenosis within 18 segments of the major coronary arteries. Because detailed, three-dimensional dose data were not available for the patients, the authors defined coronary subsegments that were most likely to be directly included within the RT beams for the patients with left- versus right-sided disease, and for the different RT techniques (eg, with or without a separate anterior internal mammary nodal [IMN] field). Among all of the women who received RT, those with left-sided breast cancer had a statistically significant increased rate of stenosis in the coronary artery branches on the left-anterior surface of the heart (the mid, distal, and distal diagonal branch of the LAD) when compared with those with right-sided cancer. This makes perfect sense given the location of typical RT fields. Interestingly, there was not an increased risk of stenosis in the left main coronary artery or in the proximal LAD, likely because of their relatively posterior locations. This is illustrated nicely in Figure 2A of the article by Nilsson et al.2 The rate of stenosis in the proximal right coronary artery is (nonstatistically significantly) slightly higher in the patients with right- versus left-sided disease—again, a logical finding given the location of the proximal right coronary artery relative to the typical RT fields. The lack of a more dramatic difference may be a result of the frequent use of an anterior IMN field in patients for whom the right and left-sided arteries are both at risk. The patients who received RT were additionally subdivided into those who received high-risk (as termed by the authors2) versus low-risk RT beams, on the basis of the location of the beams relative to the coronary arteries at risk. High-risk beams included any anterior IMN field or left-sided tangents. Among the patients with coronary lesions, the distribution of lesions was similar in the reference subjects (no breast cancer and no RT) to the patients with breast cancer who either received no RT or received RT using low-risk beams. Conversely, in the patients who were treated with high-risk beams, the distribution of coronary lesions differed from that of the reference subjects. There was a marked increase in right-main disease in those patients who were treated with a right IMN field, and there was a somewhat more subtle increase in mid and distal left main and distal diagonal disease in the patients with left-sided disease who received RT using high-risk beams. Again, the RT seems to alter the distribution of coronary lesions. There are several shortcomings that might limit the interpretation of the data. For example, there may have been biases with respect to which patients were sent for an angiogram, on the basis of their previous RT exposure. Patients with potential cardiac symptoms and a previous history of RT might have been more likely to be sent for an angiogram than those who had not received previous RT. This effect might be influenced by the laterality of the RT as well. Furthermore, patients with severe coronary disease who succumbed to a sudden cardiac event were obviously not included in the study and potentially could have suffered from RT-induced stenosis. Nevertheless, this study was carefully conducted, clever, and addresses an important clinical challenge. The results lend additional support to the mounting evidence that RT can cause CAD and that there seems to be an association between the location of the RT beam and the location of the excess coronary events. This observation provides hope that altering the RT dose distribution will alter the risks. Indeed, studies suggest that the risks of CAD are less with more modern techniques that reduce the degree of cardiac exposure (compared with less modern approaches).8 Thus, radiation oncologists should exploit available tools/techniques to reduce doses to cardiovascular structures (eg, more judicious use of nodal RT, careful selection of gantry angles that maximally spare the heart, respiratory maneuvers to increase physical separation between the breast/chest wall and the heart). Conformal field shaping (ie, a heart block) is an easy way to markedly reduce cardiac exposure when using left-sided tangents; intensity modulated radiation therapy does not provide any additional advantage compared with a heart block when traditional tangent fields are used. Thus, cardiac avoidance is not typically a justification for intensity modulated radiation therapy unless a more complex set of beams is considered. However, for many patients with breast cancer and other intrathoracic malignancies, the RT beams will necessarily traverse the heart. In these instances, we might be able to exploit knowledge of cardiac substructure anatomy to avoid the coronary arteries and other critical targets. Most radiation oncologists do not define the coronary arteries as structures to be avoided, but perhaps we should. This issue is not limited to patients with breast cancer. There is clearly an increased risk of heart disease in patients who receive RT for lymphoma involving the mediastinum,15–17 and perhaps for those who receive RT for lung cancer as well.18 The situation for patients with lung cancer is somewhat analogous to the situation with breast cancer 25 years ago. The addition of (large field) postoperative RT in patients with non–small-cell lung cancer reduces overall survival, despite a marked improvement in local control.19 RT seems to increase the rate of noncancer deaths, presumably cardiopulmonary in nature, and this overshadows the potential improvements in cancer-specific survival.20 One can reasonably hypothesize that better RT fields/techniques that reduce the risks of such toxicities might yield an improvement in overall survival,21 as suggested by two more recent studies22,23 that used smaller/conformal RT fields. Given the long natural history of RT-associated CAD, investigators who have conducted prospective clinical studies to address RT-associated heart disease have often looked to surrogate end points such as biochemical findings or imaging. Serum biomarker studies have evaluated numerous candidates for markers of cardiac injury, such as troponins, creatine kinase– myocardial band, or pro-brain natriuretic peptide, although to date these have not proven useful in clinical practice.24–27 Recently, the coronary calcium score—sometimes used to predict for CAD in patients without cancer who are thought to be at increased risk for CAD—has been evaluated in patients treated with RT for Hodgkin's lymphoma, with some suggestion that it might be predictive in certain patients.28 SPECT cardiac imaging has been used to assess for early post-RT subclinical cardiac injury in patients treated with RT for left-sided breast cancer. In a prospective study of more than 130 patients treated with RT at Duke University, new cardiac SPECT abnormalities were noted in close to 50% of patients. The incidence of such SPECT abnormalities was largely dependent on the volume of left ventricle irradiated.9 The abnormalities were primarily limited to the confines of the RT beam (eg, they did not follow the territory of a named coronary artery), and thus seem to reflect microvascular injury. To date, these SPECT abnormalities have not been linked to any clinical events and thus their clinical relevance is unclear.11 It is challenging to place these short-term imaging findings in context with the longer-term CAD findings. In concert, a reasonable hypothesis regarding interplay between RT-associated micro- and macrovascular damage may be as follows (Figs 1 A and 1B).29 RT causes a loss of capillary density and a loss of collateral flow reserve in the territory of myocardium within the radiation portal. A subsequent coronary stenosis might be more likely to lead to a clinical cardiac event because of the reduced collateral flow. Furthermore, one might expect that the degree of myocardium that is affected by a coronary lesion of a given location/severity might be larger in a patient who has had previous RT compared with a patient with a similar coronary lesion who has not received RT. This would be an area of interesting additional study. View larger version: In this page In a new window PowerPoint Slide for Teaching Fig 1. A depiction of how microvascular and macrovascular radiation–related cardiac injury could theoretically combine to cause myocardial ischemia after RT.29 (A) Coronary angiogram demonstrating significant stenosis in the LAD artery; (B) SPECT images of a patient with left-sided breast cancer before and after treatment with tangential RT. LAD, left anterior descending; RT, radiotherapy; SPECT, single photon emission computed tomography. The present study, in a well-designed fashion, again emphasizes the potential ill effects of RT on the heart. The location of dose is important, as is the location of the target structures. Furthermore, the location(s) where we look for injury is important. For example, angiograms demonstrate excess coronary lesions, SPECT scans suggest myocardial microvascular injury, and echocardiograms detect pericardial and valvular abnormalities. Therefore, fairly comprehensive evaluations may be needed to understand the full spectrum of cardiac effects and their potential interactions. An improved definition of the various target tissues will help us to design better RT treatment plans. Fortunately, radiation oncologists have an increasing array of techniques to manipulate the RT dose. These should be exploited to additionally improve the therapeutic ratio of RT for patients who receive RT for breast cancer and other thoracic diseases. Next Section AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Lawrence B. Marks, TomoTherapy, Siemens Expert Testimony: None Other Remuneration: None Previous SectionNext Section AUTHOR CONTRIBUTIONS Manuscript writing: All authors Final approval of manuscript: All authors Previous SectionNext Section Acknowledgment Supported in part by Grant No. CA 69579 from the National Institutes of Health (L.B.M.) for the study of radiation-associated cardiopulmonary injury. Previous SectionNext Section Footnotes See accompanying article on page 380 Previous Section REFERENCES 1. 1.↵ 1. 2. 3. 4. Clarke M, Collins R, Darby S, et al. (2005) 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 366:2087–2106. Medline 2. 2.↵ 1. 2. 3. 4. Nilsson G, Holmberg L, Garmo H, et al. (2012) Distribution of coronary artery stenosis after radiation for breast cancer. J Clin Oncol 30:380–385. Abstract/FREE Full Text 3. 3.↵ 1. 2. 3. 4. McGale P, Darby SC, Hall P, et al. (2011) Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden. Radiother Oncol 100:167–175. CrossRefMedline 4. 4. 1. 2. 3. 4. Hooning MJ, Botma A, Aleman BM, et al. (2007) Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst 99:365–375. Abstract/FREE Full Text 5. 5. 1. 2. 3. 4. Correa CR, Litt HI, Hwang WT, et al. (2007) Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer. J Clin Oncol 25:3031– 3037. Abstract/FREE Full Text 6. 6.↵ 1. 2. 3. 4. Patt DA, Goodwin JS, Kuo YF, et al. (2005) Cardiac morbidity of adjuvant radiotherapy for breast cancer. J Clin Oncol 23:7475–7482. Abstract/FREE Full Text 7. 7.↵ 1. 2. 3. 4. Demirci S, Nam J, Hubbs JL, et al. (2009) Radiation-induced cardiac toxicity after therapy for breast cancer: Interaction between treatment era and follow-up duration. 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(2010) Relation of coronary artery calcium score to premature coronary artery disease in survivors > 15 years of Hodgkin's lymphoma. Am J Cardiol 105:149–152. CrossRefMedline 29. 29.↵ 1. 2. 3. 4. Darby SC, Cutter DJ, Boerma M, et al. (2010) Radiation-related heart disease: Current knowledge and future prospects. Int J Radiat Oncol Biol Phys 76:656–665. CrossRefMedline CiteULike Connotea Delicious Digg Facebook Google+ Reddit Technorati Twitter What's this? Related Article ORIGINAL REPORTS - Breast Cancer: Distribution of Coronary Artery Stenosis After Radiation for Breast Cancer o Greger Nilsson, o o o o o o Lars Holmberg, Hans Garmo, Olov Duvernoy, Iwar Sjögren, Bo Lagerqvist, and Carl Blomqvist JCO Feb 1, 2012:380-386; published online on December 27, 2011; o o o [Abstract] [Full Text] [PDF] « Previous | Next Article » Table of Contents This Article 1. Published online before print December 27, 2011, doi: 10.1200/JCO.2011.38.9304 JCO February 1, 2012 vol. 30 no. 4 350-352 1. » Full Text 2. PDF 1. Purchase Article 2. View Shopping Cart - Classifications 1. o EDITORIALS - Services 1. 2. 3. 4. 5. 6. 7. 8. Email this article to a colleague Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in PubMed Add to My File Cabinet Download to citation manager Rights & Permissions + Google Scholar + PubMed + Related Content + Social Bookmarking Navigate This Article 1. 2. 3. 4. 5. 6. Top AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST AUTHOR CONTRIBUTIONS Acknowledgment Footnotes REFERENCES Current Issue 1. May 20, 2012, 30 (15) 1. 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