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Coronary Artery Findings After Left-Sided Compared With Right-Sided Radiation Treatment for Early-Stage Breast Cancer

Candace R. Correa, Harold I. Litt, Wei-Ting Hwang, Victor A. Ferrari, Lawrence J. Solin, Eleanor E. Harris

From the Department of Radiation Oncology, Radiology-Cardiovascular Imaging Section, Medicine-Division of Cardiovascular Medicine, and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA

Address reprint requests to Candace R. Correa, MD, Department of Radiation Oncology, University of Michigan, 1500 E Medical Center Dr, UH B2C490, Box 0010, Ann Arbor, MI 48109; e-mail: ccorrea{at}mail.med.umich.edu

	ABSTRACT

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Purpose To compare the incidence and distribution of coronary artery disease after left-sided versus right-sided irradiation in patients treated with breast conservation for early-stage breast cancer who subsequently underwent cardiac stress testing and/or catheterization for cardiovascular symptoms.

Patients and Methods The medical records of 961 stage I-II breast cancer patients treated from 1977 to 1995 at the University of Pennsylvania with conventional tangential beam radiation treatment (RT) were screened for cardiac stress tests and catheterizations performed after RT. The results of these tests were analyzed by laterality of RT and compared with baseline cardiovascular risk.

Results At diagnosis, patients with left-sided and right-sided breast cancer had the same estimated 10-year risk (both 7%) of developing coronary artery disease. At a median time of 12 years post-RT (range, 2 to 24 years), 46 patients with left-sided and 36 patients with right-sided breast cancer (total, N = 82) had undergone cardiac stress testing. A statistically significant higher prevalence of stress test abnormalities was found among left (27 of 46; 59%) versus right-side irradiated patients (three of 36; 8%; P = .001). Furthermore, 19 of 27 of left-sided abnormalities (70%) were in the left anterior descending artery territory. Thirteen left-side irradiated patients also underwent cardiac catheterization revealing 12 of 13 with coronary stenoses (92%) and eight of 13 with coronary stenoses (62%) solely in the left anterior descending artery.

Conclusion Patients treated with left-sided radiation as a component of breast conservation have an increased risk of late, radiation-associated coronary damage. Treatment with modern radiation techniques may reduce the risk of cardiac injury.

	INTRODUCTION

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Between 1975 and 2002, more than 2 million women in the United States were diagnosed with invasive breast cancer.¹ Today, approximately two thirds of invasive breast cancer cases are discovered at an early, localized stage, and thus can be treated with breast conservation surgery and definitive radiation treatment (RT).² A recent meta-analysis of randomized clinical trials showed that compared with surgery alone, the addition of RT to breast cancer therapy both reduced the rate of local cancer recurrence and improved overall survival.³ However, among irradiated patients, there was a significant excess of nonbreast cancer deaths and mortality from heart disease.⁴ In addition, several epidemiologic investigations have reported increased rates of radiation-associated cardiac mortality by laterality.^5-8

Despite this evidence, the long-term cardiovascular effects of modern RT for breast cancer are not well-established. We have previously demonstrated a higher rate of chest pain, coronary artery disease (CAD), and myocardial infarction diagnosis among left-, as compared with right-side, irradiated early-stage breast cancer patients.⁹ These results suggest that one possible mechanism of radiation-associated cardiac sequelae is coronary artery damage. Cardiac stress testing and cardiac catheterization are commonly used to evaluate for CAD. In this study, we compare the results of these tests among symptomatic left- versus right-side irradiated early-stage breast cancer patients.

	PATIENTS AND METHODS

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All available inpatient and outpatient medical records from our health system for 1,212 consecutive patients treated with conventional tangential-beam RT for stage I-II breast cancer from 1977 to 1995 were reviewed. Forty-one patients had pre-existing cardiac disease and were excluded from further analysis. Of the remaining 1,171 patients, 961 who had at least 2 years of follow-up were further screened for cardiac tests which evaluated for CAD: single photon emission computed tomography (SPECT) myocardial perfusion stress tests, stress echocardiograms, and cardiac catheterizations. In terms of length of follow-up, 854 had five or more, 658 had 10 or more, 332 had 15 or more, and 108 patients had 20 or more years of follow-up. Institutional review board approval was granted for this study.

At a median time of 12 years post-RT (range, 2 to 24 years), 46 patients with left-sided and 36 patients with right-sided breast cancer (total, N = 82) had undergone cardiac stress testing at our institution. Patients were treated with radiation techniques described previously.^10-12 The whole breast was treated to 44 to 50 Gy (median 46 Gy) with standard coplanar tangent fields via 6 or 15 MV photons in 1.8 to 2.0 Gy fractions (Table 1). The median central lung distance (CLD) of the 82 patients who underwent cardiac stress testing was 2.5 cm. All patients received a 12.6 to 20 Gy (median, 18 Gy) electron boost to the tumor bed. Total radiation dose was 60 to 66 Gy (median, 64 Gy). Internal mammary node (IMN) fields were treated in 13% of left-sided (n = 6) and 17% of right-sided patients (n = 6). Techniques used to treat the IMNs were extended tangents (50%), electrons (42%), and photons (8%). IMN fields were used to treat to a depth of less than 4 cm in 50% (n = 6), of 4 to 5 cm in 42% (n = 5), and to more than 5 cm in 8% (n = 1). All patients were treated using fluoroscopic simulation before the era of routine computed tomography (CT) -based treatment planning. There was no statistically significant difference between left- and right-sided patients with respect to total radiation dose, CLD, IMN, supraclavicular, or posterior axillary irradiation (all P .07). When analyzed by treatment era, the median CLD was larger in the earlier era as compared with the more recent era (2.73 cm for 1977 to 1984 v 2.40 cm for 1985 to 1994; P = .02; Appendix Table A1, online only). Most patients were treated in the era of cyclophosphamide, methotrexate, and fluorouracil chemotherapy (Table 1). For primary breast cancer treatment, only two left- and three right-sided patients received doxorubicin-based chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil). The total doxorubicin dose was 240 mg/m² for these five patients. Patients were not censored for cardiac testing for breast cancer recurrences. Subsequent chemotherapies and hormone therapies administered at time of cancer recurrence are listed in Table 1.

Comparisons between left- and right-sided patients were conducted by Pearson's ² statistic and Fisher's exact test for discrete variables, and t-test for continuous variables. Univariate logistic regression was used to test for association between test abnormalities and patient characteristics. Statistical tests were two sided, and P .05 was considered significant.

	RESULTS

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Patient Characteristics
Among the 961 screened patients, a total of 46 left- and 36 right-sided breast conservation patients underwent cardiac stress testing at our institution. As presented in Table 1, the left- versus right-sided patients had similar cardiovascular risk factors at the time of breast cancer diagnosis. No significant differences in cardiovascular risk factors of age, systolic blood pressure, total cholesterol, high density cholesterol, and number of smokers and diabetics in each group were demonstrated (all P > .65). Left-sided patients had higher total cholesterol (242 mg/dL) than right-sided patients (219 mg/dL; P = .06). The Framingham risk model incorporates all of the listed cardiovascular risk factors and estimates the probability of developing CAD over the next 10 years.²⁰ Symptomatic, tested left- and right-sided breast conservation patients both had the same 10-year Framingham risk (7%) at breast cancer diagnosis. The Framingham risk at time of breast cancer diagnosis among 284 patients with complete data (of the entire screened group of 961 patients) who did not undergo cardiac testing was also 7%.

Cardiac Stress Tests
A total of 46 of 485 left- (9%) and 36 of 476 right-sided patients (8%; total N = 82 of 961; 9%) from our screened population underwent either SPECT myocardial perfusion stress testing (n = 72), or M-mode, two-dimensional, transthoracic stress echocardiographic testing (n = 10). The proportion of left- versus right-sided patients undergoing testing was not significant (P = .99). There was no significant difference in the type of stress test, or the indication for testing between the left- and right-sided groups (Table 2). The details of stress tests protocols are available in Appendix Table A2 (online only).

A statistically significant higher proportion of stress test abnormalities was found among left- (27 of 46; 59%) versus right-side irradiated patients (three of 36; 8%; P = .001; Table 2). When analyzed by treatment era, there was a nonsignificant trend toward a higher proportion of defects among left-side irradiated patients treated in the earlier treatment era (9 of 11; 82%; 1977 to 1984 v 18 of 35; 54%; for 1985 to 1994; P = .10; Appendix Table A3, online only). The median time until stress test defects after RT among left-side irradiated patients was 15 years.

The majority of left-sided stress test abnormalities (19 of 27; 70%) were described as being in the left anterior descending artery territory. Among the left-sided patients, four of 27 abnormalities (15%) involved the left anterior descending coronary artery plus other vessels. All three of three of the right-sided patient's abnormalities (100%) were in the left anterior descending coronary artery territory.

A similar proportion of patients who received IMN irradiation (12 of 123; 10%) versus patients who did not receive IMN irradiation (70 of 838; 8%; P = .99) underwent cardiac stress testing. Six left- and six right-sided patients who received IMN irradiation underwent stress testing. Among this group, more left-side irradiated patients had cardiac stress test abnormalities, six of six (100%), as compared with one of six right-side irradiated patients (17%; P = .17).

Cardiac Catheterizations
Fourteen patients, 13 left and one right sided, who had stress tests also underwent cardiac catheterization. The median time post-RT of catheterization was 15 years (range, 2 to 24 years). The proportion of catheterization among the total group of left- (13 of 485; 3%) versus right-sided patients (one of 476; 0.2%; P = .01) was statistically significant. However, among the patients with stress test abnormalities, a similar proportion, 13 of 27 left-sided patients (48%) and one of three right-sided patients (33%), underwent catheterization (P = .99).

Of the 13 patients with left-sided radiation who underwent catheterization, 12 of 13 (92%) had coronary abnormalities. In 11 of 13 (85%), the left anterior descending coronary artery was affected. In eight of 11 of these patients, it was the sole vessel affected; in one patient, the left anterior descending and the left circumflex were diseased, and in one other patient, all three main coronary vessels were diseased. One patient had left circumflex and right coronary stenoses without evidence of left anterior descending artery disease (Table 3 and Fig 1). The one right-sided patient who underwent catheterization had no evidence of coronary disease.

View larger version (42K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. (A) Lateral and (B) medial views of left-side irradiated patient's catheterization findings. Counts in locations of coronary stenoses: proximal left circumflex (LCx), n = 1; distal LCx, n = 1; proximal left anterior descending (LAD), n = 2; mid LAD, n = 6; distal LAD, n = 4; proximal right coronary artery (RCA), n = 1; mid RCA, n = 2; distal RCA, n = 0.

Four left-sided patients who had IMN irradiation had catheterization. All four of these patients had coronary stenoses at catheterization: three (two treated with extended tangents and one treated with electrons) had midvessel left anterior descending artery stenoses, and one (treated with electrons) had three vessel coronary disease. None of the right-sided patients who had IMN irradiation underwent catheterization.

	DISCUSSION

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In this study, patients treated with left-sided radiation for early-stage breast cancer with conventional tangential-beam RT had an increased risk of late, radiation-associated coronary damage. There was an excess of cardiac stress test abnormalities among left- as compared with right-side irradiated patients. Most of these abnormalities appeared more than one decade after RT and were located in the anterior heart, the region at greatest risk of being included in tangential radiation fields, with 85% of abnormalities involving the left anterior descending coronary artery territory. Because many more left-sided patients had stress test abnormalities, a statistically significant higher number of these patients underwent cardiac catheterization. Catheterization confirmed stress test results among left-sided patients, showing coronary stenoses involving the left anterior descending coronary artery in 85% of patients, and in 62% it was the sole vessel affected. These findings vary from the expected distribution of CAD among women: 46% for left anterior descending, 38% for right coronary, and 15% for left circumflex disease.²¹

We have previously reported an increased risk of late cardiac effects: a higher incidence of chest pain, CAD, myocardial infarction diagnosis, and nearly double the rate of late ( 20 years post-RT) cardiac deaths among left- versus right-side irradiated breast cancer patients.⁹ This study has demonstrated a small but important excess of late coronary disease visualized on cardiac catheterization among left- versus right-side irradiated symptomatic breast cancer patients. The long-term cardiac mortality associated with contemporary RT for breast cancer is not well-defined. Several population-based mortality by laterality investigations revealed an increased cardiac mortality from myocardial infarctions and ischemic heart disease among left-side irradiated patients.^5-8 The updated overview from Early Breast Cancer Trialists' Collaborative Group demonstrated an excess mortality from heart disease among irradiated women as compared with nonirradiated women (rate ratio, 1.27; SE, 0.07; 2P = .0001).³ The ultimate clinical consequences of this study's findings are unknown, but it is possible that the findings among left-sided patients may translate into increased cardiac morbidity and mortality with longer follow-up.

Technical analyses of modern RT plans suggest that some irradiated patients may be at risk for late adverse cardiac events.²² Recent prospective investigations have demonstrated cardiac damage via resting myocardial perfusion imaging after RT among asymptomatic left- versus right-side irradiated patients at 6 to 18 months after radiation.^23-25 Moreover, resting myocardial perfusion and wall motion abnormalities in left-side irradiated breast cancer patients in the left anterior coronary artery distribution have been associated with the amount of irradiated left ventricle.^23,24 The long-term clinical outcomes from these studies are unknown, but the investigators concluded that the mechanism of damage was likely microvascular (fibrotic) and not macrovascular (coronary atherosclerosis) in nature.²⁴ It is possible that radiation-associated cardiac damage occurs by both methods, with macrovascular damage occurring after a longer latency period.

The majority of stress test abnormalities in this study were found in the anterior portion of the heart in the left anterior descending coronary artery. Adjustments in RT treatment parameters can alter the amount of radiation delivered to cardiac structures.^26-30 Because relatively few patients in this study received IMN irradiation for breast cancer treatment (12 of 82; 15%), there was inadequate statistical power to evaluate the cardiovascular effects of IMN irradiation. However, analyses of the irradiated volume of the left anterior descending coronary artery of left-sided patients have shown significant variation with increasing CLD.³⁰ We have previously reported an increased incidence of anterior myocardial perfusion defects in left- versus right-side irradiated breast cancer patients, and correlated CLD with the development of congestive heart failure.^31,32 In this study, the CLD, as well as the presence of abnormalities on stress tests, decreased over time, reflecting the potential to avoid radiation-associated cardiac damage via modification of treatment parameters.

Advances in RT planning allow for both visualization of cardiac structures and potential avoidance of cardiac irradiation via field border modification, modulation of dose around critical structures, placement of heart blocks, breathing techniques, and intensity-modulated RT.^33-36 Left-sided patients commonly undergo three-dimensional CT-based treatment planning that typically allows for improved heart delineation and quantification of irradiated heart volumes. As compared to conventional techniques, three-dimensional CT-based planning frequently results in a reduction in the volume of heart irradiated.³³ The posterior border of conventional tangents may be modified if large myocardial volumes are included in the planned radiation field. Irradiation of coronary arteries, and the left anterior descending artery in particular, may be reduced. The placement of partial cardiac shielding and the use of intensity-modulated RT reduced the radiation dose received by the heart from conventional tangents without compromise of target coverage in treatment planning studies.³⁴ Breathing techniques, such as deep-inspiratory breath hold, may play a role in reducing irradiated heart volumes, as the heart is displaced posteriorly during inspiration as the lung expands.³⁶

In this study, 6% of screened left-side irradiated patients (27 of 485) had cardiac test abnormalities. However, this study only evaluated cardiac test findings among symptomatic patients who had cardiac testing at our institution, thus the overall prevalence of cardiac findings among the entire group of left-sided patients is unknown. Eighteen percent of patients were lost to follow-up soon after the completion of RT, and others may have received cardiac care by cardiologists at other institutions.

Patients in this study were treated in an era of cyclophosphamide, methotrexate, and fluorouracil chemotherapy. The long-term cardiac effects of modern, doxorubicin-based breast cancer chemotherapy regimens and RT are unknown, but several investigators have reported an increased risk of cardiac disease with the use of doxorubicin plus RT.^37,38 In addition, trastuzumab in combination with doxorubicin-based chemotherapy is associated with an increased risk of cardiac dysfunction.³⁹ However, recent data with short-term follow-up (median, 1.5 years) suggests that there are no significant differences in cardiac events among patients receiving chemotherapy including trastuzumab with versus without adjuvant RT.⁴⁰ This study could not assess the possible interaction of RT plus trastuzumab and doxorubicin-based chemotherapy.

In this study, the patients at greatest risk for radiation-associated cardiac disease were symptomatic left-side irradiated breast cancer patients at 10 years post-RT. In 2002, the estimated number of women survivors in the United States who were diagnosed with left-sided invasive breast cancer 10 to 27 years ago was approximately 350,000 to 400,000.¹ Many of these patients underwent definitive RT for left-sided breast cancer. Thus, there are substantial numbers of breast cancer survivors at risk for radiation-associated cardiovascular disease. Radiation remains an integral part of breast conservation therapy which is associated with a local control benefit as well as improved survival. This study's findings highlight the importance of careful follow-up and assessment of left-side irradiated patients. These patients could potentially benefit from screening, cardiac risk factor modification, lifestyle changes, and cardiac intervention. This study also emphasizes the need for careful RT planning that minimizes the irradiated volume of heart, which is increasingly performed with newer RT techniques.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Candace R. Correa, Harold I. Litt, Wei-Ting Hwang, Victor A. Ferrari, Lawrence J. Solin, Eleanor E. Harris

Financial support: Eleanor E. Harris

Administrative support: Candace R. Correa, Eleanor E. Harris

Provision of study materials or patients: Lawrence J. Solin, Eleanor E. Harris

Collection and assembly of data: Candace R. Correa, Harold I. Litt, Eleanor E. Harris

Data analysis and interpretation: Candace R. Correa, Harold I. Litt, Wei-Ting Hwang, Victor A. Ferrari, Lawrence J. Solin, Eleanor E. Harris

Manuscript writing: Candace R. Correa, Harold I. Litt, Wei-Ting Hwang, Victor A. Ferrari, Lawrence J. Solin

Final approval of manuscript: Candace R. Correa, Harold I. Litt, Wei-Ting Hwang, Victor A. Ferrari, Lawrence J. Solin, Eleanor E. Harris

	Appendix

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	Rationale for noninvasive cardiac stress tests for assessing coronary artery disease.

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	NOTES

 
Supported by a grant from the Breast Cancer Research Foundation.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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32. Correa CR, Harris EE, Das IJ, et al: Prediction of cardiac test abnormalities and diagnoses from tangential beam treatment parameters in primary radiotherapy for left-side breast cancer. Proceedings Radiological Society of Northern America, November 28-December 3, 2004, Chicago, IL http://rsna2004.rsna.org/rsna2004/V2004/conference/event_display.cfm?em_id=4407886

33. Muren LP, Maurstad G, Hafslund R, et al: Cardiac and pulmonary doses and complication probabilities in standard and confromal tangential irradiation in conservative management of breast cancer. Radiother Oncol 62:173-183, 2002[CrossRef][Medline]

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Submitted August 11, 2006; accepted April 24, 2007.

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