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© 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.
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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
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ORIGINAL REPORTS - Breast Cancer: Distribution of Coronary Artery
Stenosis After Radiation for Breast Cancer
o Greger Nilsson,
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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;
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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
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