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Int. J. Radiation Oncology Biol. Phys., Vol. 68, No. 1, pp. 82–93, 2007Copyright © 2007 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/07/$–see front matter

doi:10.1016/j.ijrobp.2006.12.019

LINICAL INVESTIGATION Breast

RADIATION THERAPY, CARDIAC RISK FACTORS, AND CARDIACTOXICITY IN EARLY-STAGE BREAST CANCER PATIENTS

JOHN J. DOYLE, DR.P.H.,* ALFRED I. NEUGUT, M.D., PH.D.,*†‡

JUDITH S. JACOBSON, DR.P.H., M.B.A.,*‡ JIAN WANG, M.D., M.S.,* RUSSELL MCBRIDE, M.P.H.,*ALISON GRANN, M.D.,§ VICTOR R. GRANN, M.D., M.P.H.,*†‡

AND DAWN HERSHMAN, M.D., M.S.*†‡

*Department of Epidemiology, Mailman School of Public, and the †Department of Medicine, and the ‡Herbert IrvingComprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York Presbyterian Hospital, New

York, NY; and §Department of Radiation Oncology, Saint Barnabas Medical Center, Livingston, NJ

Purpose: The benefits of adjuvant radiation therapy (RT) for breast cancer may be counterbalanced by the riskof cardiac toxicity. We studied the cardiac effects of RT and the impact of pre-existing cardiac risk factors(CRFs) in a population-based sample of older patients with breast cancer.Methods and Materials: In the Surveillance, Epidemiology and End-Results (SEER)–Medicare database ofwomen >65 years diagnosed with Stages I to III breast cancer from January 1, 1992 to December 31, 2000, weused multivariable logistic regression to model the associations of demographic and clinical variables withpostmastectomy and postlumpectomy RT. Using Cox proportional hazards regression, we then modeled theassociation between treatment and myocardial infarction (MI) and ischemia in the 10 or more years afterdiagnosis, taking the predictors of treatment into account.Results: Among 48,353 women with breast cancer; 19,897 (42%) were treated with lumpectomy and 26,534(55%) with mastectomy; the remainder had unknown surgery type (3%). Receipt of RT was associated with lateryear of diagnosis, younger age, fewer comorbidities, nonrural residence, and chemotherapy. Postlumpectomy RTwas also associated with white ethnicity and no prior history of heart disease (HD). The RT did not increase therisk of MI. Presence of MI was associated with age, African American ethnicity, advanced stage, nonruralresidence, more than one comorbid condition, a hormone receptor-negative tumor, CRFs and HD. Amongpatients who received RT, tumor laterality was not associated with MI outcome. The effect of RT on the heartwas not influenced by HD or CRFs.Conclusion: It appears unlikely that RT would increase the risk of MI in elderly women with breast cancer, regardlessof type of surgery, tumor laterality, or history of CRFs or HD, for at least 10 years. © 2007 Elsevier Inc.

Radiation therapy, Cardiotoxicity, Breast cancer, Elderly, SEER-Medicare.

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INTRODUCTION

adiation therapy (RT) improves survival among patientsith early-stage breast cancer, but may also lead to late

ardiac toxicity (1–10). More than 30 years ago, Fajardond Stewart hypothesized that RT might cause ischemia byamaging the endothelial cells of myocardial capillaries11). Meta-analyses of randomized controlled trials by thearly Breast Cancer Trialists’ Group confirmed that patientsho received RT had a higher risk of vascular mortality

Reprint requests to: Dawn Hershman, M.D., M.S., Herbert Irv-ng Comprehensive Cancer Center, 161 Ft Washington Room068, New York, NY 10032; E-mail: dlh23@columbia.eduThis study used the linked Surveillance, Epidemiology and

nd-Results (SEER)-Medicare database. The interpretation andeporting of these data are the sole responsibility of the authors.he authors acknowledge the efforts of the Applied Researchranch, Division of Cancer Prevention and Population Science,CI; the Office of Information Services, and the Office of Strate-ic Planning, HCFA; Information Management Services (IMS),

nc; and the SEER Program tumor registries in the creation of the

82

han those who did not, and that this association was stron-est among older patients (12).Although some small studies have not found higher car-

iac mortality in women undergoing left-sided RT (13–18),iordano et al. recently reported a hazard ratio of 1.5 (95%I, 1.19–1.87) for ischemic heart disease among elderlyomen diagnosed with left-sided vs. right-sided breast can-

er during 1979 to 1989. The association of laterality witheart disease was not observed among patients diagnosedore recently; this change was attributed to improved RT

EER-Medicare database.Conflict of interest: none.Supported by the following: an American Society of Clinical

ncology Career Development Award and a K07 Award from theCI (CA95597) (to D.H.); a K05 Award from the NCI (CA89155)

nd a grant from the American Cancer Society (RSGT-01-024-04-PHPS) (to A.I.N.); and a T32 fellowship from NCI (CA09529)nd an R25 fellowship (CA94061) (to R.McB.).

Received Sept 27, 2006, and in revised form Nov 13, 2006.ccepted for publication Dec 6, 2006.

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83Radiation therapy and cardiac risk in breast cancer ● J. J. DOYLE et al.

echnique and lowered RT dose (19, 20) because RT doseractionation and the dose–volume of heart irradiated influ-nce the degree of cardiotoxicity (21). A recent study alsouggested that hypertension might interact with left-sidedT to increase its cardiotoxic effects (22).Many women are treated with both RT and chemother-

py, but data are not available on the interactive long-termffects of these treatments (23, 24). Chemotherapy, espe-ially doxorubicin, has been thought to exacerbate the car-iac toxicity of RT. Conflicting reports on this interactionave been published (15, 25–29). Although the mechanismsy which RT and chemotherapy may cause cardiotoxicityiffer, both treatments may result in myocardial fibrosis29).

Studies by our group have shown that postmastectomyadiation is more likely to result in secondary radiation-nduced malignancies of the lung (30) and esophagus (31).

e therefore studied the long-term cardiac effects of RT inpopulation-based sample of elderly breast cancer patients,

ocusing on laterality, type of surgery and prior history ofardiovascular disease risk factors.

METHODS AND MATERIALS

tudy databaseThe study database was co-developed by the US National Can-

er Institute and the Center for Medicare/Medicaid Services. Theurveillance, Epidemiology and End-Results (SEER) program is aetwork of tumor registries covering roughly 14% of the USopulation. The Medicare program covers hospital services, phy-ician services, some drug therapy, and other medical services forore than 97% of persons 65 years or more of age. The linkedEER-Medicare database contains clinical, demographic, andedical claims data on patients more than 65 years of age who

ave been diagnosed with cancer since 1990 (32).

atient selection criteriaWe conducted a retrospective cohort study of female Medicare

ecipients, aged 65 years and older, who were diagnosed withreast cancer from 1992 to 2000. We excluded: (1) women whoere enrolled in a health maintenance organization during anyonth of the study period because treatment data were unavailable

or these periods; (2) women who did not participate in bothedicare Part A and Part B during any month of the study period

ecause data were partially unavailable for these periods; (3)omen diagnosed with American Joint Committee on Cancer

AJCC) Stage 0 or Stage 4 because our evaluation was focused ondjuvant treatment; (4) women who had end-stage renal disease;5) women who died or were censored within 12 months of theiriagnosis of breast cancer; (6) women who had other histologicallyonfirmed primary diagnosis of cancer at breast, such as sarcoma;nd (7) women who could not be classified as having had aastectomy or lumpectomy. For each patient, information was

ollected from 12 months before her breast cancer diagnosis to hereath or censoring at December 31, 2003.

easurement of treatmentsSurgery, radiation therapy, and chemotherapy exposures

ere defined according to previously published criteria using n

he SEER-Medicare linked databases (33). Du et al. found thatnternational Classification of Disease (ICD)-9-CM procedure,urrent Procedures Coding (CPT)-4, and Healthcare Commonrocedure Coding System (HCPCS) codes capture 99% ofreast cancer cases, and that revenue center and ICD-9-CM Vodes capture the rest (33).

Surgery codes in the SEER file and ICD-9-CM codes and CPTodes in the Medicare files were used to identify procedures.atients were classified as having a mastectomy if they had a total,ubcutaneous, radical, or modified radical mastectomy. Patientsere classified as having a lumpectomy if they had segmentalastectomy, lumpectomy, quadrantectomy, tylectomy, wedge re-

ection, excisional biopsy, nipple resection, or partial mastectomynspecified. To be consistent with the literature, we used bothurgery codes from the SEER file and ICD-9-CM (lumpectomy:5.12, 85.20, 85.21, 85.22, 85.23, 85.25; mastectomy:5.41,85.42,85.43,85.44,85.45,85.46,85.47,85.48) and CPT codeslumpectomy: 19110,19120,19125,19160,19162; mastectomy:9180, 19182, 19200, 19220, 19240) from the Medicare files tolassify patients by surgical procedure. This methodology has beenreviously described (34). Because we wanted to study the effectsf RT as adjuvant therapy in relation to an initial surgical proce-ure, we classified patients as having had lumpectomy or mastec-omy only if their surgery was performed within 12 months of thenitial diagnosis. Patients who had RT more than 12 months afteriagnosis (2207, 4%) were excluded from the analysis. It was notossible to determine the site of RT, so this was done to avoidisclassification bias. The analyses were performed classifying

hese patients in the RT group, and the results did not change.atients who had no surgery or later surgical procedures werexcluded from this analysis.

We categorized patients as receiving RT if they had the SEERodes for beam radiation, radioactive implants, radioisotopes orther radiation documented by SEER, but not if they had onlyodes for radiation planning, hyperthermia, or nuclear medicine35). We also ascertained RT from the Medicare files using ICD--CM Diagnosis codes (V58.0, V66.1, V67.1), ICD-9-CM Proce-ural codes (92.2–92.29), CPT and HCPCS codes (77400-77499;7750-77797), DRG code (409), and Revenue Center codes (330,33, 339). We categorized patients as receiving radiation only ifhey did so within 12 months after their initial diagnosis of breastancer.

Chemotherapy exposure was ascertained from the Medicareles using ICD-9-CM Diagnosis codes (V58.1, V66.2, V67.2,933.1, E930.7), ICD-9-CM Procedural codes (99.25), CPT andCPCS codes (964xx, 965xx, Q0083-Q0085, J9000-J9999), DRG

ode (410), and Revenue Center codes (331, 332, 335).Because the SEER-Medicare database does not include data on

ral therapies, such as tamoxifen, we used hormone-receptor (es-rogen receptor/progesterone receptor [ER/PR]) status to controlor the effect of tamoxifen on cardiac risk.

easurement of outcomesWe developed a database coding algorithm using diagnosis and

rocedure codes in the Medicare files to identify myocardial in-arction and cardiac arrest (MI), ischemia, congestive heart failurend cardiomyopathy (CHF), and other heart disease (HD). OtherD included ICD-9, DRG and CPT codes for myocarditis/peri-

arditis; arrhythmia and valvular heart disease. Cardiac diagnosesefore or during the 12 months after the breast cancer diagnosisere considered to be pretreatment cardiac events; cardiac diag-

oses more than 12 months after the breast cancer diagnosis were

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84 I. J. Radiation Oncology ● Biology ● Physics Volume 68, Number 1, 2007

Table 1. Baseline characteristics of patients who received radiation therapy (RT) by surgical procedure

Mastectomy Lumpectomy Total

RT4,986 (18.8%)

Total26,534

RT15,202 (76.4%)

Total19,897

RT21,502 (44.5%)

Total48,353

ear of diagnosis1992 552 (15.0) 3,457 1,027 (67.8) 1514 1808 (34.2) 5,279 (10.9)1993 492 (15.7) 3,137 1,098 (70.4) 1,560 1,790 (36.0) 4,970 (10.2)1994 497 (16.9) 2,941 1,152 (71.5) 1,611 1,868 (38.7) 4,822 (9.9)1995 480 (17.1) 2,812 1,368 (74.7) 1,831 2,042 (41.7) 4,897 (10.1)1996 453 (17.8) 2,543 1,410 (74.7) 1,887 2,066 (44.0) 4,693 (9.7)1997 507 (20.7) 2,452 1,550 (75.9) 2,043 2,270 (47.5) 4,775 (9.8)1998 497 (20.6) 2,320 1,862 (78.8) 2,363 2,354 (49.5) 4,747 (9.8)1999 489 (21.3) 2,293 2,467 (79.7) 2,467 2,471 (51.3) 4,817 (9.9)2000 1,037 (22.6)* 4,579 3,768 (81.5)* 4,621 4,833 (51.6)* 9,353 (19.3)

ge at diagnosis (y)65–69 1,255 (24.7) 5,076 3,607 (93.1) 3,874 5,242 (55.8) 9,384 (19.4)70–74 1,575 (21.7) 7,248 4,881 (90.6) 5,390 6,910 (52.4) 13,175 (27.2)75–79 1,263 (19.3) 6,535 3,995 (82.2) 4,859 5,550 (47.0) 11,800 (24.4)80–84 638 (13.9) 4,588 1,984 (63.2) 3,139 2,755 (34.5) 7,986 (16.5)�85 255 (8.3)* 3,086 735 (27.9)* 2,635 1,045 (17.3)* 6,008 (12.4)

thnicityWhite 4,417 (18.6) 23,698 13,802 (76.6) 18,026 19,406 (44.7) 43,407 (89.7)AA 331 (22.8) 1,452 726 (70.3) 1,033 1,118 (42.5) 2,628 (5.4)Other 238 (17.2)* 1,384 674 (80.4)* 782 978 (42.1)* 2,318 (4.7)arital statusUnmarried 2,570 (17.3) 14,842 7,393 (69.0) 10,711 10,529 (39.6) 26,549 (54.9)Married 2,231 (20.8) 10,743 7,281 (86.7) 8,396 10,233 (51.1) 19,991 (41.3)Unknown 185 (19.5)* 949 528 (66.8)* 790 740 (40.8)* 1,813 (3.7)

esidenceRural 407 (13.1) 3119 732 (63.9) 1145 1196 (27.4) 4362 (9.0)Urban/suburban 4579 (19.6)* 23415 14479 (77.2)* 18752 20306 (46.1)* 43991 (90.9)

ateralityRight 2403 (18.6) 12897 7449 (76.4) 9747 10494 (44.5) 23582 (48.7)Left 2583 (18.9) 13637 7753 (76.4) 10150 11008 (44.4) 24771 (51.2)

JCC stageI 1411 (11.6) 12124 11023 (77.0) 14322 13274 (48.3) 27441 (56.7)II 2376 (19.9) 11911 3944 (75.8) 5204 6676 (37.7) 17704 (36.6)III 1199 (48.0)* 2499 235 (63.3)* 371 1552 (48.3)* 3208 (6.6)

R/PR statusER–/PR– 1593 (22.7) 7011 3645 (79.7) 4574 5537 (46.3) 11960 (24.7)ER� and/or PR� 2620 (18.1) 14448 9296 (78.3) 11865 12705 (46.5) 27267 (56.3)Unknown 773 (15.2)* 5075 2261 (65.4)* 3456 3260 (35.7)* 9126 (18.8)

ositive lymph nodes0 1771 (11.6) 15267 9049 (92.8) 9755 11763 (45.1) 26051 (53.8)1–3 912 (19.3) 4730 1659 (923) 1798 2735 (40.6) 6726 (13.9)�4 2119 (35.0) 6061 4397 (53.4) 8231 6713 (44.8) 14972 (30.9)Unknown 184 (38.7)* 476 97 (85.8)* 113 291 (48.1)* 604 (1.2)

omorbidity score0 3,837 (20.2) 18,996 11,316 (80.7) 14,029 16,819 (47.0) 34,429 (71.2)1 778 (15.7) 4,954 2,634 (68.9) 3,825 3,619 (39.6) 9,124 (18.8)�1 371 (14.4)* 2,584 1,252 (61.3)* 2,043 1,694 (35.2)* 4,800 (9.9)

re-existing MI risk factorsDiabetes 1,430 (17.9) 7,991 4,152 (73.5)* 5,649 5,864 (41.5)* 14,118 (29.2)Hypertension 3,723 (18.3)* 20,354 11,719 (75.3)* 15,565 16,363 (43.8)* 37,299 (77.1)Hyperlipidemia 2,651 (19.6)* 13,506 9,572 (81.6)* 11,733 12,846 (49.3)* 26,047 (53.8)Atherosclerosis 1,290 (15.7)* 8,189 4,290 (68.0)* 6,305 3,092 (35.9)* 8,613 (17.8)1 Risk factor 1,434 (18.6)* 7,692 4,184 (76.8)* 5,448 6,055 (44.0)* 13,753 (28.4)2 Risk factors 1,650 (18.5)* 8,935 5,552 (77.4)* 7,176 7,650 (45.6)* 16,761 (34.7)�2 Risk factors 1,192 (18.1)* 6,599 3,892 (74.4)* 5,233 5,284 (43.5)* 12,160 (25.2)

re-existing HDNone 2,382 (20.4) 11,675 7,245 (84.3) 8,597 10,381 (48.9) 21,227 (43.9)MI 193 (15.4)* 1,252 680 (62.6)* 1,086 925 (37.8)* 2,446 (5.0)CHF 1577 (17.3)* 9,133 4,311 (65.0)* 6,624 6,141 (37.6)* 16,321 (33.7)Other HD 2,047 (17.2)* 11,923 6,547 (70.5)* 9,286 9,063 (41.2)* 21,999 (45.5)

(Continued)

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85Radiation therapy and cardiac risk in breast cancer ● J. J. DOYLE et al.

onsidered to be posttreatment cardiac events. All MIs were de-ected from hospital discharge codes. The diagnosis of ischemiaas detected in both hospital discharge and outpatient billing

odes. Patients who were alive and free of posttreatment HD at thend of follow-up in our dataset in 2003 were censored.

omorbiditiesWe used a comorbidity index developed by Klabunde et al. (36)

ased on conditions identified by Charlson et al. (37) to search foriagnosis and procedure claims in the inpatient and outpatientedicare data. The Charlson scale is considered to be a reliableeasure of comorbidity in cancer trials of older patients (38) and

as been found to be predictive of hospitalization in breast canceratients using the SEER-Medicare linked database (39). We usedhe comorbidity score without diabetes included, and other demo-raphic and clinical factors to control for baseline differencesetween groups in our multivariate analysis. In addition, weearched for diagnosis and procedure codes for cardiac risk factorsCRFs) and included patients with diagnoses of hypertension,yperlipidemia/hypercholesterolemia, diabetes, and atherosclero-is. We classified risk factors as none, one, two, or more than twoRFs in the analysis.

tatistical analysisWe compared frequency distributions of categorical variables

epresenting baseline demographic and clinical characteristics be-ween patients who received RT and those who did not, andetween those who received right-sided RT and left-sided RT,sing Chi-square tests of statistical significance.To analyze the association of demographic and clinical variables

nd risk factors with receiving RT, we used logistic regressionodeling. To estimate the association of treatment with a subse-

uent cardiac event, while controlling for the other covariates andccounting for differences in follow-up time, we used Cox pro-ortional hazards models. We excluded from each of the modelsatients who had a prior history of the outcome being analyzedMI or MI/ischemia) because it is not possible to distinguish newvents from prior events with billing codes. We generated Kaplan-eier cumulative incidence curves and applied log-rank tests to

ompare cardiac disease events across groups. All analyses wereonducted using SAS, version 8.02 (SAS Institute, Cary, NC).

RESULTS

The cohort consisted of 48,353 breast cancer patients;

Table 1. Baseline characteristics of patients who receiv

Mastectomy

RT4,986 (18.8%)

Total26,534 15

hemotherapyNone 2,912 (13.5) 21,613 13Any 2,074 (42.1)* 4,921 1

Abbreviations: AA � African American; AJCC � Americaardiomyopathy; HD � heart disease; MI � myocardial infarctionherapy.

“Total” column includes 1922 patients with unknown surgery t* p � 0.05, Chi-square statistic.

9,897 (42%) had lumpectomy, 26,534 (55%) had a mas- a

ectomy, and the remainder had unknown surgery type3%). Of the total cohort, 21,502 patients (45%) receiveddjuvant RT alone, 7,219 (15%) received adjuvant chemo-herapy alone, and 4,151 (9%) received both.

Table 1 shows the distribution of breast cancer patientsy RT exposure and surgical type. Patients who received RTere younger, had cancer diagnosed in a later year, andere more likely to be married, to live in nonrural areas,ave hormone receptor-negative cancers, and to have hadhemotherapy as compared to patients who did not receiveT. Patients of African American ethnicity were less likely

o undergo postlumpectomy RT but more likely to undergoostmastectomy RT than were those of white ethnicity.atients with pre-existing HD, cardiovascular disease riskactors, or other comorbidities were less likely to receiveT. Advanced stage at diagnosis was associated with re-eiving RT only among patients who had had a mastectomy.aterality of breast cancer was not associated with RT orny other baseline demographic or clinical factors (Table 2).

In a multivariable logistic regression analysis, patientsiagnosed in more recent years were more likely than pa-ients diagnosed earlier to receive RT. Older patients andhose with comorbid conditions were less likely to receiveT (Table 3) than were younger and healthier patients. The

nverse relationship of age with RT was stronger amongatients who had undergone a lumpectomy than amonghose who had undergone a mastectomy. Patients diagnosedith Stage 3 were 5 times as likely to receive postmastec-

omy RT as patients diagnosed with Stage 1 cancer. Africanmerican ethnicity was associated with a decreased likeli-ood of receiving RT. Patients with pre-existing MI or CHFnd were less likely than patients without those diagnoses toeceive RT, but patients with hypertension or other cardiacisease risk factors were not. Patients who underwent aumpectomy were nine times as likely to receive RT ashose who underwent a mastectomy, and patients who re-eived chemotherapy were more than twice as likely toeceive RT as patients who did not.

After adjusting for pre-existing CRFs and prior heartisease, we found no significant association between RTnd MI (HR, 0.93; 95% CI, 0.84–1.02) or the combined MI

iation therapy (RT) by surgical procedure (Continued)

umpectomy Total

6.4%)Total

19,897RT

21,502 (44.5%)Total

48,353

74.5) 17,844 17,351 (42.1) 41,134 (85.0)92.6)* 2,053 4,151 (57.5)* 7,219 (14.9)

t Committee on Cancer; CHF � congestive heart failure andestrogen receptor; PR � progesterone receptor; RT � radiation

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86 I. J. Radiation Oncology ● Biology ● Physics Volume 68, Number 1, 2007

Table 2. Baseline characteristics of patients who received radiation, by laterality

Left11,008 (51.2%)

Right10,494 (48.8%)

Total21,502 (%)

ear of diagnosis1992 937 (51.8) 871 (48.1) 1,808 (8.4)1993 945 (52.7) 845 (47.2) 1,790 (8.3)1994 937 (50.1) 931 (49.8) 1,868 (8.6)1995 1,036 (50.7) 1,006 (49.3) 2,042 (9.5)1996 1018 (49.2) 1,048 (50.7) 2,066 (9.6)1997 1,172 (51.6) 1,098 (48.3) 2,270 (10.5)1998 1,183 (50.2) 1,171 (49.7) 2,354 (10.9)1999 1,272 (51.4) 1,199 (48.5) 2,471 (11.4)2000 2,508 (51.9) 2,325 (48.1) 4,833 (22.4)

ge at diagnosis (y)65–69 2,735 (52.1) 2,507 (47.8) 5,242 (24.3)70–74 3,514 (50.8) 3,396 (49.1) 6,910 (32.1)75–79 2,848 (51.3) 2,702 (48.7) 5,550 (25.8)80–84 1,402 (50.8) 1,353 (49.1) 2,755 (12.8)�85 509 (48.7) 536 (51.3) 1,045 (4.8)

thnicityWhite 9,934 (51.1) 9,472 (48.8) 19,406 (90.2)AA 548 (49.0) 570 (50.9) 1,118 (5.2)Other 526 (53.8) 452 (46.2) 978 (4.5)arriedYes 5,418 (51.4) 5,111 (48.5) 10,529 (48.9)No 5,214 (50.9) 5,019 (49.0) 10,233 (47.5)Unknown 376 (50.8) 364 (49.1) 740 (3.4)

esidenceRural 635 (53.0) 561 (46.9) 1,196 (5.6)Urban/suburban 10,373 (51.0) 9,933 (48.9) 20,306 (94.4)

JCC stageI 6,824 (51.4) 6,450 (48.6) 13,274 (61.7)II 3,379 (50.6) 3,297 (49.4) 6,676 (31.0)III 805 (51.8) 747 (48.1) 1,552 (7.2)

R/PR statusER�/PR� 2,888 (52.1) 2,649 (47.8) 5,537 (25.7)ER� and/or PR� 6,438 (50.6) 6,267 (49.3) 12,705 (59.0)Unknown 1,682 (51.6) 1,578 (48.4) 3,260 (15.1)

ymph nodes positive0 6,081 (51.7) 5,682 (48.3) 11,763 (54.7)1-3 1,425 (52.1) 1,310 (47.9) 2,735 (12.7)�4 3,361 (50.0) 3,352 (49.9) 6,713 (31.2)Unknown 141 (48.4) 150 (51.5) 291 (1.3)

omorbidity score0 8,319 (51.3) 7,870 (48.6) 16,189 (75.2)1 1,837 (50.7) 1,782 (49.2) 3,619 (16.8)�1 852 (50.3) 842 (49.7) 1,694 (7.8)

re-existing MI risk factorsNone 1,256 (49.9) 1,257 (50.0) 2,513 (11.6)Diabetes 2,966 (50.5) 2,898 (49.4) 5,864 (27.2)Hypertension 8,437 (51.5) 7,926 (48.4) 16,363 (76.1)Hyperlipidemia 6,612 (51.4) 6,234 (48.5) 12,846 (59.7)Atherosclerosis 1,546 (50.0) 1,546 (50.0) 3,092 (14.3)1 Risk factor 3,117 (51.5) 2,938 (48.5) 6,055 (28.2)2 Risk factors 3,938 (57.5) 3,712 (48.5) 7,650 (35.6)�2 Risk factors 2,697 (51.0) 2,587 (49.0) 5,284 (24.6)

re-existing HDNo 5,306 (51.1) 5,075 (48.8) 10,381 (48.28)Yes 5,702 (51.2) 5,419 (48.0) 11,121 (51.72)

Abbreviations: AA � African American; AJCC � American Joint Committee on Cancer; HD � heart disease; MI � myocardialnfarction; ER � estrogen receptor; PR � progesterone receptor.

No significant association by univariate Chi-square statistic.

“Total” column includes 1922 patients with unknown surgery type.

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87Radiation therapy and cardiac risk in breast cancer ● J. J. DOYLE et al.

Table 4). Both MI and MI-associated outcomes were as-

Table 3. Adjusted odds ratios (OR) for the association of demogtherapy after b

Mastectomy

OR 95%CI

ear of diagnosis1992 Reference1993 0.99 0.85–1.141994 1.05 0.91–1.211995 1.07 0.93–1.241996 1.11 0.96–1.261997 1.29* 1.12–1.491998 1.29* 1.12–1.501999 1.32* 1.14–1.522000 1.41* 1.24–1.60

ge (y)65–69 Reference70–74 0.98 0.88–1.0875–79 0.92 0.85–1.0580–84 0.65* 0.58–0.73�85 0.35* 0.58–0.41

JCC StageI ReferenceII 1.49* 1.38–1.61III 5.39* 4.84–6.01

esidenceUrban/suburban ReferenceRural 0.62* 0.58–0.75

omorbidity score0 Reference1 0.84* 0.76–0.93�2 0.75* 0.71–0.94

thnicityWhite ReferenceAA 1.05 0.89–1.21Other 0.79 0.71–0.99

ormone receptorER� and/or PR� ReferenceER�/PR� 1.03 0.87–1.03Unknown 0.79* 0.67–0.85

hemotherapyNone ReferenceAny 2.79* 2.73–3.25

ateralityRight ReferenceLeft 1.01 0.92–1.06

rior MI risk factorNone Reference1 Risk factor 0.96 0.85–1.082 Risk factors 0.96 0.82–1.05�2 Risk factors 0.96 0.82–1.07

rior HDNone ReferenceMI/ischemia 0.85* 0.76–0.96CHF 0.97 0.89–1.06Other HD 1.08 0.96–1.20

Abbreviations: AA � African American; AJCC � Americaardiomyopathy; MI � myocardial infarction.

The ORs for each variable are adjusted for all the other variabTotal model controls for surgery (OR for mastectomy to get ra“Total”column includes 1922 patients with unknown surgery ty* p � 0.05.

ociated with advanced age, African American ethnicity, t

dvanced stage, nonrural residence, increased comorbidi-

and clinical characteristics with propensity to receive radiationancer surgery

Lumpectomy Total

OR 95%CI OR 95%CI

Reference Reference1.16 0.95–1.36 1.06 0.94–1.181.11 0.93–1.33 1.09 0.95–1.201.40* 1.15–1.65 1.21* 1.04–1.311.40* 1.17–1.64 1.24* 1.03–1.301.50* 1.24–1.77 1.38* 1.19–1.491.82* 1.57–2.28 1.53* 1.33–1.691.97* 1.81–2.63 1.59* 1.43–1.812.20* 1.96–2.73 1.74* 1.58–1.94

Reference Reference0.74* 0.62–0.85 0.93* 0.85–0.990.38* 0.33–0.45 0.71* 0.66–0.770.15* 0.13–0.17 0.34* 0.31–0.370.04* 0.03–0.04 0.08* 0.07–0.09

Reference Reference1.01 0.92–1.11 1.25* 1.18–1.330.58* 0.45–0.79 4.75* 4.29–5.27

Reference Reference0.45* 0.38–0.53 0.56* 0.52–0.63

Reference Reference0.68* 0.63–0.77 0.76* 0.71–0.820.55* 0.48–0.62 0.63* 0.59–0.71

Reference Reference0.67* 0.57–0.80 0.87* 0.77–0.970.97 0.82–1.25 0.84 0.75–0.94

Reference Reference1.08 0.96–1.18 1.05 0.99–1.120.54* 0.49–0.61 0.66* 0.61–0.72

Reference Reference2.06* 1.66–2.45 2.46* 2.40–2.81

Reference Reference0.98 0.90–1.05 0.99 0.93–1.04

Reference Reference1.27* 1.07–1.44 1.08 0.97–1.171.41* 1.19–1.60 1.11 1.02–1.201.44* 1.21–1.67 1.32 1.03–1.25

Reference Reference0.91 0.80–1.02 0.87* 0.80–0.92

0.74* 0.69–0.83 0.86* 0.81–0.920.98 0.85–1.08 1.04 0.96–1.12

t Committee on Cancer; CHF � congestive heart failure and

he model.therapy, 0.03; 95% CI, 0.02–0.03).

raphicreast c

n Join

les in tdiationpe.

ies, ER/PR-negative tumors, pre-existing CRFs, and prior

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88 I. J. Radiation Oncology ● Biology ● Physics Volume 68, Number 1, 2007

istory of HD. Neither chemotherapy nor type of surgery

Table 4. Cox proportional hazards model for the association betand

Variable

MI (2717

HR

adiationNo RefereYes 0.93

ear1992 Refere1993 0.82*1994 0.75*1995 0.61*1996 0.51*1997 0.50*1998 0.43*1999 0.31*2000 0.30*

ge (y)65–69 Refere70–74 1.23*75–79 1.68*80–84 2.05*�85 2.34*

thnicityWhite RefereAA 1.33*Other 1.02

JCC stageI RefereII 1.29*III 1.55*

esidenceUrban/suburbanUrban 1.21*

omorbidity score0 Refere1 1.35*�2 1.95*

ormone ReceptorER�/PR� RefereER� and/or PR� 0.86*Unknown 0.94

isk factorsNone Refere1 Risk factor 1.26*2 Risk factors 1.56*2 Risk factors 1.89*

re–existing HDNone RefereCHF 1.59*Other HD 1.32*

hemotherapyNone RefereAny 0.99

urgeryLumpectomy RefereMastectomy 1.00

Abbreviations: AA � African American; AJCC � Americaardiomyopathy; CI � confidence interval; HD � heart disease;

†Interaction of risk factors or pre–existing heart disease and la* Hazard ratio (HR) is statistically significant (p � 0.05).

as associated with MI outcomes. t

Among those patients who underwent RT, we analyzed

adiation therapy (RT) exposure and myocardial infarction (MI)ia

) MI � ischemia (4356, 14.4%)

95% CI HR 95% CI

Reference0.84–1.02 1.02 0.94–1.10

Reference0.72–0.93 0.74* 0.67–0.810.66–0.86 0.62* 0.56–0.690.53–0.70 0.53* 0.47–0.590.44–0.59 0.43* 0.38–0.480.43–0.59 0.42* 0.37–0.470.37–0.51 0.36* 0.31–0.410.21–0.38 0.26* 0.23–0.310.25–0.35 0.26* 0.26–0.34

Reference1.07–1.40 1.04 0.96–1.141.48–1.91 1.33* 1.22–1.461.78–2.33 1.47* 1.33–1.632.00–2.73 1.71* 1.51–1.92

Reference1.16–1.54 1.23* 1.08–1.390.85–1.21 0.89 0.78–1.04

Reference1.18–1.39 1.08* 1.01–1.151.31–1.84 1.28* 1.11–1.46

1.05–1.41 1.25* 1.12–1.39

Reference1.23–1.49 1.40* 1.29–1.521.74–2.20 1.65* 1.47–1.85

Reference0.79–0.95 0.93* 0.86–0.990.84–1.06 1.03 0.94–1.12

Reference1.08–1.47 1.35* 1.21–1.491.34–1.81 1.66* 1.49–1.841.61–2.22 2.28* 2.03–2.56

Reference1.46–1.73 1.54* 1.43–1.651.21–1.44 1.31* 1.22–1.41

Reference0.87–1.13 0.97 0.87–1.08

Reference0.92–1.08 1.03 0.97–1.10

t Committee on Cancer; CHF � congestive heart failure andhazard ratio.were nonsignificant.

ween rischem

, 6.5%

nce

nce

nce

nce

nce

nce

nce

nce

nce

nce

nce

n JoinHR �terality

he association of left-sided vs. right-sided RT. We found

no

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89Radiation therapy and cardiac risk in breast cancer ● J. J. DOYLE et al.

o significant association of laterality with the outcomes

Table 5. Cox proportional hazards model for the association beexposure and myocardial infarction (MI)

Variable

MI (1090, 5.4%)

HR 95

ateralityRightLeft 0.99 0.8

ear19921993 0.90* 0.71994 0.74* 0.51995 0.57* 0.41996 0.52* 0.31997 0.49* 0.31998 0.41* 0.31999 0.26* 0.12000 0.27* 0.2

ge category65–69 Reference70–74 1.26* 1.075–79 1.56* 1.380–84 2.21* 1.7�85 2.68* 2.0

thnicityWhite ReferenceAA 1.30* 1.0Other 1.09 0.8

esidenceUrban/suburbanRural 1.13 0.8

JCC StageI ReferenceII 1.44* 1.2III 2.14* 1.7

ormone receptorER�/PR� ReferenceER� and/or PR� 0.87* 0.7Unknown 0.94 0.7

omorbidity score0 Reference1 1.50* 1.2�2 2.03* 1.6

isk factorsNone Reference1 Risk factor 1.51* 1.12 Risk factors 1.68* 1.2�2 Risk factors 2.18* 1.6

re–existing HDNone ReferenceCHF 1.44* 1.2Other HD 1.31* 1.1

hemotherapyNone ReferenceAny 1.05 0.8

urgeryLumpectomy ReferenceMastectomy 1.13* 1.0

Abbreviations: AA � African American; AJCC � Americaardiomyopathy; CI � confidence interval; HD � heart disease;

†Interaction of risk factors or pre–existing HD and laterality w* HR was statistically significant (p � 0.05).

f MI (HR, 0.99; 95% CI, 0.87–1.11) or MI/ischemia w

HR, 1.03; 95% CI, 0.93–1.13) (Table 5). In this group of

left–sided radiation therapy (RT) exposure vs. right–sided RThemia among women with breast cancer

MI � ischemia (1979, 13.1%)

HR 95% CI

1.03 0.93–1.13

0.71* 0.60–0.830.58* 0.49–0.690.47* 0.40–0.560.43* 0.36–0.510.41* 0.34–0.490.35* 0.30–0.430.26* 0.21–0.320.23* 0.19–0.27

Reference1.01 0.89–1.131.19* 1.05–1.341.42* 1.21–1.671.50* 1.18–1.91

Reference1.23* 1.01–1.490.87 0.70–1.08

1.19* 0.96–1.48

Reference1.10 0.99–1.221.29* 1.07–1.57

Reference0.93 0.84–1.041.00 0.87–1.15

Reference1.48* 1.32–1.671.67* 1.39–1.99

Reference1.38* 1.17–1.631.61* 1.37–1.882.32* 1.95–2.75

Reference1.50* 1.34–1.671.36* 1.22–1.51

Reference0.93 0.81–1.08

Reference1.05 0.97–1.15

t Committee on Cancer; CHF � congestive heart failure andhazard ratio.nsignificant.

tweenand isc

% CI

7–1.11

3–1.119–0.926–0.729–0.668–0.621–0.539–0.350–0.35

5–1.513–1.922–2.622–3.54

3–1.633–1.46

3–1.54

3–1.686–2.59

5–0.998–1.13

7–1.766–2.50

7–1.989–2.188–2.82

5–1.655–1.52

7–1.27

1–1.27

n JoinHR �ere no

omen, the risk of MI was lower in patients who were

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90 I. J. Radiation Oncology ● Biology ● Physics Volume 68, Number 1, 2007

iagnosed later, and higher among older women, Africanmerican women, and women who resided in rural lo-

ations. Patients with pre-existing HD risk factors andith CHF and other HD were more likely to have anI-related outcome compared with those without these

onditions. The risk of MI increased with increasingRFs and among patients who underwent mastectomy.he interactions between laterality and surgery type,

aterality and pre-existing CRFs, laterality and pre-exist-ng heart disease, and laterality and chemotherapy useere not significant.Figures 1a and 1b present the Kaplan-Meier incidence

urves of MI and MI/ischemia by tumor laterality. Thennual incidences of MI related outcomes for right-sidednd left-sided tumors were not significantly different duringhe 13-year follow-up period.

DISCUSSION

Our analysis shows that although elderly breast canceratients with pre-existing MI and CHF were less likely toeceive RT than patients without those diagnoses, RT wasot associated with MI events during the follow-up period.urthermore, among patients who underwent RT after 1992,omen with left-sided tumors were not more likely than

hose with right-sided tumors to experience MI. In addition,lthough the presence of CRFs increased the likelihood ofn MI, these factors did not increase the likelihood ofT-induced cardiac toxicity or left-sided cardiac toxicity.

Fig. 1. (a) Kaplan-Meier incidence curves for myocardright-sided radiation therapy (RT). (b) Kaplan-Meier incleft-sided and right-sided RT.

lthough patients who received chemotherapy were more t

ikely to receive RT than patients who did not, chemother-py also did not increase the RT-associated risk of MI.

Several studies have found an association between RT,pecifically left-sided RT, and increased cardiac morbiditynd mortality (12, 19, 22, 40, 41). In their 2005 update, thearly Breast Cancer Trialists’ Group found that RT reducedreast cancer–specific mortality but increased the risk ofeath from other, mainly cardiac, causes by 27% during 15ears of follow-up (12, 40). A study by Darby et al. alsoeported a cardiac mortality ratio for left-sided vs. right-ided tumor laterality of 1.20 (95%CI, 1.04–1.38) in therst decade of follow-up and higher ratios thereafter (41).ost of these studies have the benefit of long follow-up and

nclude patients with cancer diagnosed in the 1970s and980s. These studies suggest that independent of length ofollow-up, the risk of cardiac toxicity decreased over theears as radiation techniques evolved (19, 41).Our findings are consistent with other studies that have

ound no risk of cardiac morbidity or mortality after radia-ion therapy for early-stage breast cancer (13, 18). Perhapsn our elderly population, RT-related risks are small byomparison to competing causes of morbidity and mortality.

prior study using the SEER-Medicare database found aisk of MI-related mortality only in patients �60 years after0 to 15 years of follow-up (8). Another recent evaluation ofatients from the SEER-Medicare database who were diag-osed with breast cancer between 1986 and 1993 also didot demonstrate an association of HD requiring hospitaliza-ion with left-sided radiation (20). The accompanying edi-

rction (MI) among women treated with left-sided andcurves for MI and ischemia among women treated with

ial infaidence

orial (42) noted that radiation techniques during that time

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91Radiation therapy and cardiac risk in breast cancer ● J. J. DOYLE et al.

eriod were more likely than those used later in the 1990s toesult in exposure to the heart among patients undergoingight-sided radiation. Hence, the results of that study mayave been biased toward the null.Previous studies have suggested that RT is an indepen-

ent risk factor for anthracycline-induced cardiotoxicity29, 43, 44). Many women are treated with both RT andhemotherapy; yet few long-term data are available on thenteractive effects of these treatments (23, 24). Controllingor baseline risk for HD, we did not find RT associated withverall HD or CHF, nor did we find chemotherapy associ-ted with risk of MI after radiation, although we previouslyeported that radiation exacerbated the effects of chemo-herapy-induced CHF (45). We were surprised that we didot see an association of MI with postmastectomy radiation;e believed that patients who receive RT postmastectomyight have higher radiation exposure to the myocardium

han patients who receive RT postlumpectomy. Our nullndings are consistent with a recent study of cardiovasculareath after postmastectomy radiation and doxorubicin-ased chemotherapy conducted by Woodward et al. (46). Inheir retrospective review of 1,101 patients, the investiga-ors found, after 10 years of follow-up, low rates of myo-ardial infarction for patients who had and had not under-one radiation (2.4% vs. 0.5%, respectively, p � 0.06). Theack of an association may reflect the high risk of breastancer–related mortality among women who receive post-astectomy RT.The SEER population is not a random sample; SEER

egions are chosen for local or state registry quality andinority representation. However, the age distribution of

he SEER-Medicare linked data set is comparable to that ofhe US population of person 65 or more years of age (32).

Newschaffer et al. reported that increased age and co-orbidities are associated with less aggressive treatment in

arly-stage breast cancer (47). We found that patients whoere older, resided in rural locations, or had more comorbid

onditions were less likely than younger, urban-dwelling, orealther patients to receive RT. We expected patients withre-existing HD to be less likely than others to receive RT5). However, pre-existing HD was less predictive of treat-ent than comorbid conditions. The association of rural vs.

rban residence with RT may reflect difficulties in travelingo a radiation facility.

Advanced age and comorbidities also represent estab-ished risk factors for heart disease (39). By including age,omorbidity score, and pre-existing heart disease status inur multivariable analysis, we attempted to control for bias.s expected, increased age, comorbidities and presence ofre-existing heart disease and CRFs were associated withorse cardiac outcomes. Unfortunately, neither SEER noredicare collects data on other known CRFs such as smok-

ng history, family history, and obesity. If these factors werelso associated with receipt of RT, our inability to controlor them would lead to residual confounding and might haveiased our results toward the null.

Another limitation of our study was lack of individual i

nformation on radiation fields and dose schedule. Althoughadiation dose is likely to be an important predictor ofyocardial damage (4), neither technique nor dose is likely

o have been associated with laterality. To the extent thatadiation oncologists treated patients with left-sided breastancers with lower doses than those with right-sided dis-ase, again our results would be biased toward the null.owever, improvements in technique may partially explain

he decline in risk observed in patients treated since 1994.Radiation dosing in breast cancer has remained relatively

onstant over the past 30 years, but techniques havehanged significantly. In the late 1980s and early 1990s, itas more common than it is now to irradiate regional lymphodes. Radiation to the internal mammary chain would havencreased the radiation exposure of the heart regardless ofaterality (48). The similar exposure of the heart in patientsho undergo chest wall radiation may explain why MI risk

s increased after postmastectomy RT (49). Recently, radi-tion oncologists began using techniques, such as three-imensional conformal radiation and intensity-modulatedadiation, to protect the heart (50, 51). In a recent study of7 Stage II and Stage III breast cancer patients followed foryears, Niwinska et al. found that modern RT did not cause

linically significant heart damage but that anthracyclinesaused reversible myocardial damage (52).

Receipt of adjuvant chemotherapy and hormonal therapys associated with the receipt of RT. In our data, patientsho received chemotherapy were more likely to receive RT

han patients who did not, but receiving chemotherapy didot increase the RT-associated risk of MI, nor was lateralityssociated with other cardiac outcomes. Tamoxifen haseen believed to protect the heart, but in an NSABP trial,atients who received tamoxifen did not have lower risk oforonary disease than other patients (53). Because the Medi-are files do not contain data on tamoxifen use, we usedR/PR status as a surrogate for tamoxifen exposure. We didnd that among all women, patients with hormone-sensitive

umors were slightly less likely to have an MI than patientsith ER/PR tumors. Unfortunately, 22% of records wereissing data on hormonal status, and using ER/PR positive

tatus as a surrogate marker for tamoxifen use may haveesulted in some misclassification.

To our knowledge, our analysis is the first to evaluate theffect of radiation on the heart accounting for pre-existingeart disease, cardiovascular disease risk factors, surgicalrocedure, and chemotherapy use in an elderly patient pop-lation. Our study of more than 45,000 breast cancer pa-ients, with up to 13 years of follow-up, did not find anncreased risk of cardiac morbidity associated with RT oreft-sided RT in patients treated after 1992.

The observational nature of the research and incompleteeasurement of risk factors predisposing patients to receiveT limits our findings. However, our data support thergument that the benefits of RT in elderly breast canceratients outweigh the cardiac risks, regardless of pre-exist-

ng CRFs.

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92 I. J. Radiation Oncology ● Biology ● Physics Volume 68, Number 1, 2007

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