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Originally published as JCO Early Release 10.1200/JCO.2005.05.1037 on August 14 2006 © 2006 American Society of Clinical Oncology. Late Cardiac Mortality and Morbidity in Early-Stage Breast Cancer Patients After Breast-Conservation Treatment
From the Department of Radiation Oncology; Department of Biostatistics and Epidemiology; Cardiovascular Imaging Section, Department of Radiology; and Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA Address reprint requests to Eleanor E.R. Harris, MD, Moffitt Cancer Center and Research Institute, Division of Radiation Oncology, 12902 Magnolia Dr, Tampa, FL 33612; e-mail: HarrisE{at}moffitt.usf.edu
Purpose Several studies have reported increased cardiac mortality related to the use of left-sided breast or chest-wall irradiation. This study was undertaken as a comprehensive examination of the long-term cardiac mortality and morbidity after breast irradiation using contemporary irradiation techniques. Methods The medical records of 961 consecutive patients presenting between 1977 and 1994 with stage I or II breast cancer treated with breast conservation treatment were reviewed. Data was recorded on baseline pretreatment patient, tumor and treatment characteristics and on subsequent cancer or cardiac related events. The median follow-up time was 12 years.
Results There was no difference in overall mortality from any cardiac cause (P = .25). Death from any cardiac cause occurred in 2% of right-sided patients and 3.5% of left-sided patients. However, in the second decade after treatment, there was a higher rate of cardiac deaths in left-sided patients, with a cumulative risk of 6.4% (95% CI, 3.5% to 11.5%) for left-sided compared with 3.6% (95% CI, 1.8% to 7.2%) for right-sided patients at 20 years. There were statistically higher rates of chest pain, coronary artery disease, and myocardial infarction diagnosed in left-sided patients (all P Conclusion Irradiation to the left breast is not associated with a higher risk of cardiac death up to 20 years after treatment, but is associated with an increased rate of diagnoses of coronary artery disease and myocardial infarction compared with right breast treatment.
A number of randomized trials comparing breast-conservation therapy, including lumpectomy and breast irradiation, with mastectomy have demonstrated equivalent survival outcomes between these two treatment modalities for women with early-stage breast cancer.1-3 Several studies have raised concerns that cardiac morbidity and mortality may be increased by the use of left-sided breast or chest wall irradiation, which often includes some of the myocardium and coronary arteries.4-8 Many such studies used irradiation techniques that exposed larger volumes of heart to greater doses than current treatment standards, such as anterior photon beams and treatment with cobalt-60 or orthovoltage therapy. During the last two decades, megavoltage linear accelerator–based therapy to tangential fields has resulted in a lower volume of heart exposed to radiation in left-sided patients. Such techniques have been employed at the University of Pennsylvania (Philadelphia, PA) since 1977, with infrequent prophylactic treatment of the internal mammary nodes. This study was therefore undertaken to perform a comprehensive examination of the long-term sequelae to the heart and coronary vessels after left-sided irradiation compared with right-sided treatment using contemporary irradiation techniques. Cardiac morbidity and mortality as well as potential contributing medical and therapeutic factors were examined to determine the long-term risk of cardiac damage in early-stage breast cancer patients.
Medical records were reviewed for all women presenting between 1977 and 1994 with an American Joint Committee on Cancer9 stage I or II breast cancer who were treated with breast-conservation treatment. Institutional review board approval was granted for this study. Patients were ineligible for the study if they had a prior or synchronous contralateral breast cancer, other prior malignancy, or noninvasive breast cancer. Patients who died within 2 years of diagnosis or who were lost to follow-up less than 2 years after treatment were excluded (n = 210). Also excluded were patients with known pre-existing cardiac disease at the time of breast cancer diagnosis (n = 42). Breast conserving surgery was defined as complete excision of a primary, unilateral invasive breast cancer. In all cases, radiation was delivered to the whole breast via tangential coplanar fields using 6 MV to 15 MV photons, followed by a boost to the tumor bed to a median total tumor bed dose of 64 Gy (range, 59.75 to 71.60 Gy). In both groups, 74% of patients were treated with tangents alone, and 26% were also treated with regional nodal fields (a supraclavicular photon field with or without a posterior axillary field). Internal mammary node (IMN) fields were used in 14% (n = 68) of left-sided patients and 11% (n = 54) of right-sided patients (P = .20). Techniques used to treat the IMNs were either wide tangents (82%) or medial electron strip (16%). Technique was unknown in 2%. IMN fields were used to treat to a depth of less than 4 cm in 82% (n = 100), of 4 to 5 cm in 14% (n = 17), and to more than 5 cm in 4% (n = 5). This study largely predated the use of adjuvant doxorubicin-based chemotherapy, which was administered in 26 (6%) of 477 right-sided patients and 32 (7%) of 484 left-sided patients. Doxorubicin was administered for recurrence in 48 (10%) of 477 right-sided patients and 47 (10%) of 484 left-sided patients, at a median time from initial breast cancer diagnosis of 5 and 4 years, respectively. Only eight patients ever received trastuzumab, all for recurrence. Of 81 patients who developed coronary artery disease, two (2%) had doxorubicin at initial diagnosis and two (2%) for subsequent relapse. Among 39 patients with myocardial infarction (MI), one (2%) in the left-sided group received doxorubicin at initial diagnosis. Of 65 patients with congestive heart failure (CHF), eight (12%; five right sided and three left sided) received doxorubicin at initial diagnosis, and nine (14%; six right sided and three left sided) received doxorubicin for subsequent relapse. Data was collected on patient, tumor and treatment characteristics, and other relevant baseline diagnoses and behaviors including smoking history, alcohol use, thyroid disease, diabetes, hypertension, and hypercholesterolemia. The definitions used and the comparison of baseline cardiac risk factors may be found in the Appendix (online only). There were 961 women eligible for analysis, 477 (49.6%) with right-sided breast cancers and 484 (50.4%) with left-sided breast cancers. The median follow-up time for all patients and for left- and right-sided patients was 12 years (range, 2 to 27 years). The patient and tumor characteristics at pretreatment baseline were comparable, as shown in Table 1. The number of patients at risk in the right-/left-sided groups were, respectively, as follows: 5 years, 421 and 433; 10 years, 313 and 345; 15 years, 159 and 173; 20 years, 51 and 57.
Overall survival analyses included all causes of death. Cardiac death analyses included death as a result of MI or CHF. Patients with unknown cause of death were excluded from this analysis (n = 32; 3.3%). Relapse-free survival was defined as recurrence of breast cancer (local, regional, or distant recurrence) or death as a result of breast cancer. Morbidity end points included all diagnoses of chest pain, coronary artery disease, MI, CHF and chronic ischemic heart disease, arrhythmia and palpitations, and valvular disorders. Survival probability of overall survival, time to cardiac death, and relapse-free survival was evaluated by the Kaplan-Meier method and compared by log-rank test.10,11 Cumulative incidence of cardiac death was also calculated such that the death from other causes was treated as a competing-risk event, and this analysis gave very similar results (data not shown).12 Incidence of mortality and morbidity end points were also compared between the right- and left-sided breast cancer patients using Poisson (for morbidity) or Cox (for mortality) regression analysis.13 All regression analyses were also adjusted for year of treatment (1977 to 1985 v 1986 to 1994) and baseline cardiac risk factors that were associated with the laterality of cancer, and these results were not different from the unadjusted analyses (data not shown). Then patients were censored at the time of distant metastases to account for the sequelae of metastatic disease or the use of chemotherapy for relapse, and the incidence of cardiac mortality and morbidity end points in the remaining patients who did not suffer a relapse was not different than the overall group (data not shown). To assess the risk of death from any cardiac cause over time, the cumulative hazard function for cardiac death was calculated using Nelson-Aalen estimators.14,15 Univariate association between the baseline cardiac risk factors and mortality and morbidity end points were examined using Cox proportional hazard regression models.16 All possible confounding and interaction effects of the baseline risk factors with laterality of cancer were analyzed using multivariate Cox regression models.
Mortality Analyses All mortality analyses were performed comparing right-sided patients with left-sided patients. The actuarial survival rates are shown in Table 2. There were no statistically significant differences in the actuarial rates of death from any cause (P = .41; Fig 1) or in death from any cardiac cause (P = .25) between the right- and left-sided breast cancer patients. Death as a result of any cardiac cause occurred in 10 (six MI, six CHF; 2%) right-sided patients and 17 (12 MI, five CHF; 3.5%) left-sided patients. Relapse-free survival was 72% for right-sided and 75% for left-sided patients (P = .22). Survival end points were analyzed adjusting for year of treatment (1977 to 1985 v 1986 to 1994) to account for any possible change in treatment technique over time, and there was no difference compared with the unadjusted analyses (Appendix). Cumulative incidence was analyzed using a competing-risks model, which also showed no statistically significant difference in cardiac deaths between the two groups (data not shown; all P  .09).
To specifically examine whether the risk of cardiac death was higher in the second decade after radiation than at earlier follow-up times, a cumulative hazard risk was estimated (Table 3). At 10 years after radiation, the cumulative risk of cardiac death was similar, at 1.9% (95% CI, 0.09% to 3.9%) for left-sided and 1.5% (95% CI, 0.07% to 3.4%) for right-sided patients. However, by 20 years, the risk in the left-sided patients appeared to be greater than that of the right-sided patients: 6.4% (95% CI, 3.5% to 11.5%) for left-sided compared with 3.6% (95% CI, 1.8% to 7.2%) for right-sided patients.
When baseline risk factors for cardiac disease were analyzed for an association with the risk of cardiac mortality, univariate analysis showed an association between death from any cardiac cause and age, pack-years of tobacco smoking, blood pressure, high serum triglycerides, hypertension, diabetes, and Framingham risk assessment score.17,18 When laterality was also considered, radiation treatment to the left breast did not modify the association between any of these baseline risk factors for cardiac disease and subsequent death as a result of cardiac disease. An analysis comparing the study population to the United States female population was performed, showing that this study population had lower than expected rates of coronary artery disease and MI, but a somewhat higher than expected rate of CHF which was not related to laterality or breast cancer therapy (data not shown).
Morbidity Analyses There were significant differences in the development of chest pain, and in any diagnosis of coronary artery disease and MI, all of which were more likely to occur in left-sided patients (Table 4). The 20-year actuarial freedom from coronary artery disease was 90% in right-sided patients and 75% in left-sided patients (P < .001; Fig 2). The 20-year actuarial freedom from MI was 95% in right-sided patient and 85% in left-sided patients (P = .002; Fig 3).
When the risk of cardiac morbidity was adjusted for baseline risk factors and examined for any interaction with laterality, hypertension demonstrated an interaction effect with laterality in patients who developed coronary artery disease. The hazard ratio (HR) for developing coronary artery disease was elevated for all patients with hypertension, and the highest HR was seen in left-sided patients with hypertension. The HRs were as follows: right sided, no hypertension, HR = 1.0 (reference); right sided, with hypertension, HR = 7.2 (95% CI, 2.9 to 17.9); left sided, no hypertension, HR = 4.6 (95% CI, 2.0 to 10.4); left sided, with hypertension, HR = 11.4 (95% CI, 5.0 to 26.2). Thus among patients with hypertension, the risk ratio for the development of coronary artery disease is 1.59 for left- versus right-sided patients (for absolute rates, see Appendix.) There were no interactions between the baseline risk factors and left-sided cancer and the risk of developing a MI. The impact on morbidity of the use of IMN fields was examined, comparing patients of either laterality who did or did not receive IMN radiation. Coronary artery disease was significantly associated with the use of IMN fields: 7% without IMN compared with 18% with IMN (P < .001). MIs were significantly more common after the use of an IMN field: 3% without IMN versus 9% with IMN (P = .01). IMN use was not associated with any other morbidity end points.
This study was undertaken to examine whether there was an association between the use of left- versus right-sided breast tangent irradiation as part of breast-conservation treatment for early-stage breast cancer and the subsequent development of cardiac disease 10 years or more after irradiation. This study examined both mortality and morbidity end points and assessed the impact of baseline risk factors for cardiac disease on the development of late cardiac effects. The Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute (National Institutes of Health, Bethesda, MD) estimates that there are approximately 2,156,000 breast cancer survivors in the United States, approximately 35% of whom have received radiation therapy.19 Among these women, there are approximately 740,000 women, or 370,000 with left-breast cancer, who are alive 10 years or more after diagnosis.20 There have been significant improvements in the management of ischemic heart disease in the last decade, which has likely contributed to fewer cardiac deaths over time.21 However, nonfatal events including MI and chronic ischemic heart disease can lead to significant symptomatology, expense, and increased risk of subsequent death. Therefore, characterizing the risk of cardiac disease attributable to breast cancer treatments and other factors is important for the follow-up care of long-term breast cancer survivors. A meta-analysis by the Early Breast Cancer Trialists' Collaborative Group4 that included 78 randomized trials of breast or chest wall irradiation after surgery examined the risk of death from breast cancer and non–breast cancer causes. In this analysis, there was an excess of non–breast cancer deaths among women who received radiation, mainly due to heart disease and lung cancer. The excess mortality was seen only after 5 years after treatment, and was not age dependent. The studies included were conducted between 1961 and 1995, and many of the older trials used outdated radiation techniques that exposed more volume of heart and lung to larger doses of irradiation than current standard tangential beams,22 accounting for the excess cardiovascular mortality. Other studies from this era have also shown an increased risk of cardiac deaths in patients receiving radiation.5-8 There are few long-term studies in patients treated with contemporary tangential beam technique. Such data are beginning to accumulate for the second decade after treatment, during which time cardiac effects may increase.1,23 Several such studies with median follow-up of 9 to 10 years found no increased risk of MI in the radiated patients compared with controls and no relationship between MI and laterality.24-27 In contrast, population-based data from the Ontario Cancer Registry (Ontario, Canada) on breast cancers treated with lumpectomy from 1982 to 1987 showed a rate of fatal MI of 2% in left-sided patients and 1% in right-sided patients (P = .02).28 Using the United States SEER database from 1973 to 1992 of women with local and regional breast cancer, this group reported an increased risk of fatal MI for left-sided patients who were treated before the age of 60.29 More recently, the SEER database was examined for changes over time in the risk of cardiac death after adjuvant radiation.23 Death from ischemic heart disease was higher in left-sided compared with right-sided patients among the earlier cohort (1973 to 1979; 13% v 10%; P = .02), whereas there was no difference by laterality in two subsequent time periods examined. The authors attribute the reduction in mortality to changes in radiation technique over time, although length of follow-up and improvements in the management of heart disease could also have contributed to the observed trends. In the current study, there was no significant difference in outcomes by era of treatment. This likely reflects the fact that the study cohort is from a single institution where relatively uniform treatment techniques were utilized throughout the study period. The SEER database has also been used to examine cardiac morbidity, using International Classification of Diseases (ninth edition; ICD-9) codes from hospital discharges for breast cancer patients who had received adjuvant radiation.30 The investigators found no difference between right- and left-sided patients discharged with diagnoses of ischemic heart disease, valvular disease, conduction abnormalities, or heart failure. This study did not examine comorbidities, baseline risk factors, subsequent events, or morbidities, and had no details on radiation dose or technique. Problematically, the SEER database records only information on cancer therapy delivered within the first 4 months of initiation of treatment, has no information on the radiation technique, and has been shown to underidentify the use of radiation in breast cancer patients, especially in women receiving breast-conserving surgery, so the potential inaccuracies in these data must be considered.31 In the present study, detailed information regarding radiation treatment parameters of dose and field arrangements, adjuvant therapy, subsequent cancer therapy, comorbidities, and cardiac risk factors was known. Mortality analyses showed no significant difference in the actuarial rate of death from MI or CHF between right and left-sided patients at 20 years. There was no interaction between laterality of cancer and the presence of any known cardiac risk factors and death. There may be an increasing risk of cardiac death in the second decade after treatment. This study found nearly double the rate of cardiac deaths at 20 years that was not seen at earlier time points for left-sided compared with right-sided patients (6.4% v 3.6%). Similar latency has been seen in other studies, emphasizing the importance of long-term follow-up for breast cancer survivors.4,23,28,32 One limitation of the present study is the infrequent use of cardiotoxic chemotherapy in the study period. Only 6% of patients in the study cohort received adjuvant doxorubicin. Because the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-15 trial showed improved outcomes with doxorubicin-based chemotherapy in 1990,33 the use of this regimen has increased substantially, and may have an impact on the rates of cardiac sequelae after radiation. In addition, trastuzumab has known cardiac toxicity and is often administered concurrently with radiation.34 Recent reports of randomized trials looking at the use of trastuzumab in the adjuvant setting have shown improved outcomes compared with chemotherapy alone, so use of this drug will increase substantially in the coming years.35,36 The impact of these systemic therapies on the risk of long-term cardiac mortality and possible interactions with radiation therapy must continue to be studied. When morbidity outcomes in the present study were analyzed, there was a significant increase in complaints of chest pain and diagnoses of coronary artery disease and MI in left-sided patients. These diagnoses were more common in patients who had received IMN radiation. We have previously reported a higher percentage of perfusion abnormalities in left-sided patients who underwent cardiac testing. Among those who underwent cardiac catheterization after irradiation, 85% had documented disease in the left anterior descending artery.37 These data suggest that there is damage to the left side of the heart and coronary arteries, which corresponds to the irradiated heart volume, and which leads to an increased risk of symptomatic cardiac disease. We have previously reported that even when using contemporary tangential field technique, there is an association between the volume of heart irradiated and the presence of perfusion abnormalities.38 When other baseline risk factors were examined, there was an interaction between the risk of development of coronary artery disease and hypertension, such that the highest relative risk of developing coronary artery disease was seen in those with left-sided cancer and hypertension (HR = 1.59). Hypertension alone is associated with a three-fold increased risk for developing coronary artery disease, representing a much greater risk factor than radiation exposure.39 Hypertension is easily screened for and treatable, thus monitoring women after left-sided irradiation for hypertension and treating it appropriately may help reduce their risk of developing cardiac disease. To our knowledge, no other study of long-term cardiac effects after breast tangent irradiation has examined the association of baseline risk factors and the subsequent development of cardiac disease. In a study conducted at Duke University (Durham, NC), in which new perfusion defects within the first 2 years after treatment were characterized, perfusion defects within the radiation field at up to 24 months were associated with percent of irradiated left ventricle, the use of hormone therapy and hypercholesterolemia.40,41 These data indicate that other known risk factors for cardiac disease may interact with the coronary artery damage induced by irradiation to further increase the patient's risk of developing ischemic heart disease after treatment. Overall, in this study of patients treated with contemporary tangential breast irradiation, there was a significant increase in the post-treatment development of ischemic cardiac disease in left-sided patients, although no increase in mortality from cardiac disease. Women treated for left-sided breast cancer should be monitored long term for hypertension and other risk factors and treated appropriately. Radiation therapy remains an important modality in the multidisciplinary treatment of breast cancer. Radiation significantly reduces the risk of local and regional recurrence after breast-conserving surgery and imparts a long-term survival benefit.4 These data emphasize the need for further refinements in the radiation techniques for treatment of left-sided breast cancers that consistently reduce the volume of irradiated heart to minimize the risk of late toxicities in this patient population with a substantial opportunity for long-term survival.
Definitions of Cardiac Risk Factors and Diagnoses Alcohol use was defined per patient report in the history as follows: none, rare (less than one drink per week), occasional (one to three drinks per week), moderate (more than three drinks per week, fewer than six drinks per day), abuse (alcoholic or more than six drinks per day). Patients were considered to have a particular cardiac diagnosis if that condition was documented by a physician in the medical record, and/or if the corresponding ICD-9 diagnosis code was associated with their medical record. In addition to these parameters, the following criteria were used to define each of the cardiac diagnoses: (1) coronary artery disease: history of MI, cardiac catheterization proven significant coronary artery stenoses, regional wall motion abnormalities on transthoracic echocardiogram, and/or perfusion abnormalities on myocardial perfusion imaging; (2) MI: chest pain and electrocardiogram confirmation of MI, and/or two sets of positive cardiac enzymes, and/or cardiac catheterization demonstrating coronary artery occlusions; (3) CHF and chronic ischemic heart disease: documented diagnosis in medical record; (4) valvular abnormality: moderate or severe aortic, mitral, tricuspid, or pulmonary regurgitation on echocardiogram; (5) hypercholesterolemia: fasting total serum cholesterol more than 240, and/or taking antilipid medications; (6) high low-density lipoprotein cholesterol (LDL): fasting serum LDL more than 130; (7) high high-density lipoprotein (HDL): fasting serum HDL more than 60; (8) hypertriglyceridemia: fasting serum triglycerides more than 200, and/or taking antitriglyceride medications; (9) hypertension: blood pressure more than 140/90 on two separate occasions, and/or taking antihypertensive medications; (10) diabetes mellitus, hemoglobin A1C more than 6.2, fasting blood sugar more than 200, and/or taking antihyperglycemics or insulin; (11) hyper/hypothyroidism: serum indicators of hyper- or hypothyroidism and/or taking thyroid hormone or other medications for thyroid disease; and (12) chest pain: symptoms of chest pain as documented in the medical record with an attempt to exclude overtly noncardiac causes of chest pain. The following diagnoses were primarily documented by a physician in the medical record and/or ICD code: palpitations, arrhythmia, cerebrovascular accident, peripheral vascular disease.
Framingham Score Comparison of Baseline Cardiac Risk Factors
Baseline cardiac risk factors compared available information between the two groups including amount of alcohol use, smoking history, family history of cardiac disease, serum LDL and HDL levels, hypertension, diabetes, thyroid disease, stroke, peripheral artery disease, bilateral oophorectomy, and Framingham score. None of these baseline cardiac risk factors showed any statistically significant difference between right- and left-sided patients (data not shown; all P
Absolute Rates of Cardiac Morbidity and Mortality for Era of Treatment and Cardiac Risk Factors The absolute (or crude) rates for each cardiac end point with respect to era of treatment and the presence of hypertension (which was the only baseline risk factor found to interact with radiation to increase the risk of cardiac disease in left-sided patients) are presented in Table A1. The actuarial rates are presented in the Results section of the article. The absolute rates were generated from the probability that a subject without a particular diagnosis at time zero will have that diagnosis at the subsequent time point examined. The data for MI, coronary artery disease, and CHF include both fatal and nonfatal events. All analyses were competed for noncardiac deaths, and compared left- versus right-sided patients. Because these are crude rates, P values are not provided, and it should be noted that there are relatively few patients at risk for each subgroup, particularly at the 20-year follow-up times. When considering the presence of hypertension, the absolute rates of cardiac morbidity increase in both groups over time and appear to be more likely in left- versus right-sided patients with hypertension, especially for development of MI or coronary artery disease. In addition, left-sided patients without hypertension appear to have higher rates of these two diagnoses as well.
When considering era of treatment, although the risk of cardiac diagnoses appears to be higher in left- versus right-sided patients, there does not appear to be much difference in the incidence of each event based on year of treatment. Specifically, the risk of cardiac diagnoses does not appear to be higher in those treated in the earlier era of the study. This study represents a single institutional experience and as such is less subject to changes in treatment technique based on institutional preferences or era of treatment than multi-institutional series or those based on national databases. Although the tangent field technique has undergone refinements over time, the University of Pennsylvania has used a relatively similar technique throughout the study period.
The authors indicated no potential conflicts of interest.
published online ahead of print at www.jco.org on August 14, 2006. Supported in part by US Army Medical Research and Material Command under DAMD17-03-1-0309 (E.E.R.H., J.L.) and Breast Cancer Research Foundation (E.E.R.H., W.-T.H., L.J.S.). These funding sources had no role in the collection, analysis, interpretation or reporting of the data presented, or in the decision to submit the data for publication. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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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. Presented at the 90th Scientific Assembly and Annual Meeting of the Radiological Society of North America, Chicago, IL, November 28-December 3, 2004 http://rsna2004.rsna.org/rsna2004/v2004/conference/event_display.cfm?id=66601&p_navID=272&em_id=4407886 39. Kannel WB: Hypertension as a risk factor for cardiac events–epidemiologic results of long-term studies. J Cardiovasc Pharm 21:27-37, 1993 40. Marks LB, Yu X, Prosnitz RG, et al: The incidence and functional consequences of RT-associated cardiac perfusion defects. Int J Radiat Oncol Biol Phys 63:214-223, 2005[CrossRef][Medline] 41. Yu X, Prosnitz RR, Zhou S, et al: Symptomatic cardiac events following radiation therapy for left-sided breast cancer: Possible association with radiation therapy-induced changes in regional perfusion. Clin Breast Cancer 4:193-197, 2003[Medline] Submitted November 25, 2005; accepted June 8, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
.002). The presence of hypertension was associated with a higher risk of coronary artery disease in left-sided patients. 
