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Assessment of Coronary Heart Disease Morbidity and Mortality After Radiation Therapy for Early Breast Cancer

From the Departments of Radiation Oncology and Biostatistics, Princess Margaret Hospital/University Health Network and University of Toronto, and Cancer Care Ontario, Toronto; Ottawa General Hospital, Ottawa, Ontario, Canada; and Beth Israel Hospital and Harvard Medical School, Boston, MA.

Address reprint requests to Katherine A. Vallis, MD, PhD, Department of Radiation Oncology, Princess Margaret Hospital/University Health Network, 610 University Ave, Toronto, Ontario M5G 2M9, Canada; email: katherine.vallis{at}rmp.uhn.on.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To assess the risk of fatal and nonfatal myocardial infarction (MI) after breast-conserving surgery (BCS) and radiation therapy (RT) for left-sided breast cancer.

PATIENTS AND METHODS: A hospital-based retrospective cohort linkage study of all breast cancer patients registered at the Princess Margaret Hospital (PMH), Toronto, Canada, between 1982 and 1988 who were treated with postlumpectomy RT was performed. Available identifiers for the study cohort were linked to two province-wide health files: the Canadian Institute for Health Information Hospitalization File and the Ontario Mortality Database. Admissions to hospital for MI and deaths attributable to MI were identified. The relevant original health records were abstracted to verify the diagnosis of MI according to diagnostic criteria used in the World Health Organization multinational monitoring of trends and determinants in cardiovascular disease (MONICA) project. We compared incidence of MI in the study cohort with the general population and incidence of MI after therapy for left- versus right-sided breast cancer.

RESULTS: A cohort of 2,128 patients was identified. The median length of follow-up was 10.2 years. The incidence of MI in the study cohort was comparable to that in an age-matched general population of women in Ontario. There were 70 coronary events among 56 patients after breast irradiation. According to MONICA criteria, 53 and six events were characterized as definite and possible MIs, respectively. Eleven events did not satisfy MONICA criteria for MI. Twenty-six patients treated for left-sided and 23 patients treated for right-sided breast cancer experienced at least one definite or possible MI (log-rank test, P = .66). There were eight fatal MIs among the left-sided group and six among the right-sided group. There was no excess of other cardiac diseases among patients who received left-sided radiotherapy compared to the right-sided group.

CONCLUSION: We have found no evidence for excess morbidity and mortality from coronary artery disease among women treated with RT to the left breast after BCS at 10.2 years of follow-up. Longer follow-up is required to confirm that excess cardiac disease has been completely avoided.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
BREAST-CONSERVING surgery (BCS) and radiation therapy (RT) is accepted as standard treatment for patients with early breast cancer and is equivalent to mastectomy in terms of overall survival.¹ Although serious treatment-related morbidity of postlumpectomy RT is unusual,² there is concern that it may lead to an increased risk of cardiac disease because of inclusion of part of the heart in the irradiated volume. Irradiation of the heart resulting from treatment of mediastinal tumors such as lymphoma³ and seminoma⁴ is associated with an elevated risk of long-term cardiac mortality. The pathophysiology and clinical manifestations of radiation-induced heart disease, including accelerated coronary disease, have been described,⁵ and the risk of cardiac damage correlates with radiation dose-volume⁶ and fractionation.⁷ It is particularly important to quantify radiation-associated cardiac toxicity in early breast cancer patients because other aspects of treatment may also result in cardiac morbidity. For example, anthracycline-based adjuvant chemotherapy is frequently used and is associated with a dose-dependent cumulative risk of cardiomyopathy. Chemotherapy may cause premature menopause, which carries a greater risk of coronary artery disease than natural menopause.⁸ This risk is further compounded because hormone replacement therapy is not generally recommended for patients with breast cancer.⁹ Early detection through mammographic screening and the introduction of more effective adjuvant systemic therapy have resulted in improved prognosis for some breast cancer patients who will therefore be at risk for radiation-induced heart disease for a long time.

Meta-analyses of randomized clinical trials^10-12 and studies of population-based cancer registry data^13,14 indicate an increased risk of death from cardiac disease among breast cancer patients exposed to RT, particularly among those who received treatment to the left side. Conversely, two institutional case series have shown no evidence for a differential risk of myocardial infarction (MI) among patients treated with BCS + RT for left- and right-sided breast cancer.^15,16

These studies have all relied on death certificates or physician records to identify cases of MI and are therefore subject to the well-recognized lack of validity in reporting cause of death¹⁷ and diagnosis of MI.^18,19 With the exception of one case series,¹⁶ the published reports have included only fatal MIs. The influence of RT on the incidence of nonfatal, but possibly clinically important, cardiac disease therefore remains to be determined. To address some of these issues, we have identified a large cohort of patients treated with BCS + RT who were treated at a single center in a consistent manner. We have identified individuals who experienced fatal and nonfatal MIs and have verified the cardiac diagnoses by reexamining the original clinical data.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Study Design and Patients
A hospital-based retrospective cohort linkage study design was used. Patients with a diagnosis of unilateral invasive or intraductal breast cancer treated by BCS + RT with no prior history of malignant disease, who received treatment at the Princess Margaret Hospital (PMH) between 1982 and 1988 and were resident in Ontario throughout the follow-up period, were included. A cohort of 2,128 patients who met these criteria was identified through a review of patient records. Demographic details were recorded, as were tumor size, location, stage, and histology. Note was made of the smoking history and of any prior history of heart disease or hypertension. Treatment details including radiation dose and technique were abstracted.

Ascertainment of Cardiac Events
Hospital discharge records for female residents of Ontario for the period 1979 to 1998 were used to identify all cases with a diagnosis of MI, International Classification of Diseases, 9th Revision (ICD-9) code 410 or other cardiac diagnoses (ICD-9 codes 411 to 417 and 420 to 429). Discharge records based on a review of patient charts and containing up to 16 diagnoses are transmitted from all public hospitals in Ontario to the Canadian Institute for Health Information (CIHI). They include identifiers that allow accurate record linkage. All death records of female residents of Ontario, covering the period 1982 to 1998, were obtained from the Registrar General of Ontario. Information from the death certificate is coded and entered into the Ontario Mortality Database (OMDB). This file includes identifiers for record linkage. Events in the CIHI file and the OMDB were sorted according to individual patient through the use of computerized probabilistic record linkage relying on available identifying information. For the electronic linkage of the data, the software application Automatch (Matchware Technologies, Inc, Silver Spring, MD) was used in a UNIX environment at the Ontario Cancer Registry. The linked patient-specific records of hospitalizations and deaths were then matched to the breast cancer cohort.

Since concordance between standard diagnostic criteria and clinical diagnoses of MI on death certificates and in hospitalization abstracts is not particularly high, we validated all fatal and nonfatal MIs through review of hospital records. We restricted this part of the study to ICD-9 code 410, as this is the only cardiac diagnosis for which standardized diagnostic criteria are available. Trained abstractors visited hospitals across Ontario to collect data that included presenting symptoms, cardiac enzyme test results, and postmortem findings if available. The study cardiologist (A.W.), who was blinded to the laterality of RT, reviewed the electrocardiograms. The information abstracted from medical records was processed according to the World Health Organization criteria used in the multinational monitoring of trends and determinants in cardiovascular disease (MONICA) project.²⁰ Electrocardiograms were interpreted using the Minnesota coding criteria.^21,22 Events were classified as definite or possible MI or as not satisfying MONICA criteria for MI. Possible MIs were categorized as MI for statistical analyses. All coronary events recorded within a period of 28 days were regarded as a single episode. All MIs were classified as fatal or nonfatal.

Data Management and Quality Control
Data were entered directly into the study database. Automated range and logic checks were performed at the time of data entry. Periodic reabstraction and data entry of a representative sample of patient charts was performed for quality control. For the purpose of linkages with the CIHI and the OMDB, an electronic file of linkable identifiers for the breast cancer cohort was transferred to the Ontario Cancer Registry.

Statistical Analysis
Time of follow-up was calculated as the time between start of RT and date of first MI, date of death, or last recorded follow-up. We compared the time to MI among patients who received RT for left- and right-sided cancers by generating Kaplan-Meier curves and applying the log-rank test. Overall survival for the left- and right-sided groups was compared to test whether the two groups differed with respect to cause of death other than MI. Some patients experienced more than one MI and so the numbers of MI events were compared using Poisson regression with the laterality of RT as explanatory variable. These analyses were repeated after exclusion of patients who received thoracic radiation therapy after their primary treatment for breast cancer. Subsequent thoracic radiation therapy was given as treatment for contralateral breast cancer, for metastatic disease, or for second malignancy. The incidence of MI for the breast cancer cohort was compared with the expected number of MIs calculated for the normal population on the basis of records for 1982 to 1996 according to 5-year age groups and adjusting for length of follow-up.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Clinical Characteristics
Between 1982 and 1988, 6,680 patients with breast cancer were registered at the Princess Margaret Hospital. Patients were excluded from the current analysis for one or more of the following reasons: mastectomy (n = 2,625), biopsy only or other surgical procedure (n = 247), no postlumpectomy radiotherapy given (n = 1,154), metastatic disease at presentation (n = 78), emigration from the province during follow-up (n = 230), and RT given at another hospital (n = 68). A cohort of 2,128 patients met the inclusion criteria. The median length of follow-up was 10.2 years (range, 7.7 to 15.1 years). The median age was 54 years (range, 22 to 86 years). A total of 1,074 patients received left-sided breast irradiation and 1,054 received right-sided breast irradiation. Patient characteristics are listed in Table 1. There was no significant difference in the distribution of clinical, pathologic, and treatment variables between patients treated for left- and right-sided cancers.

Risk Factors for Cardiac Disease
The incidence of risk factors for cardiac disease (smoking, hypertension, and previous history of cardiac disease) was similar among patients who were treated for left- and right-sided breast cancer (Table 1). We found that hyperlipidemia and family history of cardiac disease were not reliably recorded in the hospital charts and so data regarding these cardiac risk factors were not collected. There was no significant difference in the distribution of cardiac risk factors between patients treated for left- and right-sided cancers.

Treatment Outcome
The overall survival rates for the whole group at 5, 10, and 15 years were 81%, 67%, and 60%, respectively. Sites of first recurrence were breast (243 [11%]), regional lymph nodes (160 [8%]), distant sites (405 [19%]), or a combination of these (122). One hundred forty-seven patients (7%) developed contralateral breast cancer. Overall survival comparison for patients who received treatment for left- and right-sided cancers is shown in Fig 1.

View larger version (12K): [in this window] [in a new window]   Fig 1. Survival curves according to laterality of breast cancer.

There were 70 verifiable events among 56 patients. Of these, 11 (15.7%) did not meet the MONICA criteria for MI. Six (8.6%) were consistent with the MONICA definition of possible MI and the remaining 53 events (75.7%) were confirmed as definite MI. Forty-nine patients experienced at least one definite or possible MI after the treatment of breast cancer; 23 had received treatment for right-sided and 26 had received treatment for left-sided tumors. There were eight fatal MIs among the left-sided group and six among the right-sided group. There was no significant difference in the incidence of MI among patients treated for left- and right-sided cancers (log-rank test, P = .66) (Fig 2). Because some patients experienced more than one MI, the data were also analyzed according to the number of events each patient experienced taking into account the follow-up time. Again, no significant difference was found between those who received left-sided and those that received right-sided radiotherapy (P = .25). We dichotomized the cohort into two age groups: 20 to 59 and more than 60 years. As expected, the incidence of MI was higher in the older age group. However, there was no significant difference in incidence of MI in those treated for left- or right-sided cancer (Table 3). We also dichotomized the cohort into groups according to the extent of RT: those that received RT to the breast only versus those that also received RT to regional lymph nodes. There were three MIs among the 86 patients treated with regional radiotherapy for left-sided breast cancer and none among the 96 patients that were treated for right-sided breast cancer (Table 3). However, these small numbers did not allow a meaningful statistical evaluation. None of the patients who had received radiation therapy to the internal mammary lymph nodes developed MI.

View larger version (15K): [in this window] [in a new window]   Fig 2. Time to occurrence of MI according to laterality of breast cancer.

Comparison With the General Female Population of Ontario
Using age-matched data for the general female population of Ontario for the incidence of MI for the years 1982 to 1996, we calculated the number of expected cardiac events to be 93. Because these were not validated, the appropriate comparison was with the unvalidated data from our cohort. The total number of cardiac events was 92. Therefore, we conclude that there was no increase in incidence of MI in the breast cancer population compared to the general population of Ontario.

Other Cardiac Diagnoses
Linkage with the CIHI file and OMDB generated links between 229 cardiac events (ICD-9 codes 414 to 417 and 420 to 429) and the breast cancer cohort. The numbers of patients with left- and right-sided cancer who experienced cardiac disease other than MI were 124 and 105, respectively (P = .24). There was no evidence for a preponderance of other cardiac diseases among patients with left-sided breast cancer compared to those with right-sided breast cancer.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We did not observe an increase in the incidence of fatal or nonfatal MI among patients treated with postlumpectomy RT for left-sided breast cancer compared to those treated for right-sided breast cancer during 10.2 years of follow-up. This is consistent with the findings of two other institutional studies that have reported the incidence of cardiac mortality after BCS + RT. Nixon et al¹⁵ reviewed 745 patients who had been followed up for a minimum of 12 years. The cause of death was ascertained from medical records, only fatal events were considered, and all cardiac causes of death were included in this study. There was no evidence for increased mortality from cardiac disease in patients treated for left-sided breast cancer compared to those treated for right breast cancer. Similarly, in a study reported by the Stockholm Breast Cancer Group, there was no excess of fatal or nonfatal MI at a median follow-up of 9 years among 684 patients treated with BCS + RT compared to a control group of patients treated by mastectomy without RT.¹⁶ The incidence of MI was similar irrespective of tumor laterality.

Conversely, in a large population-based study, Rutqvist et al¹³ reported the cause-specific mortality by laterality of the primary tumor among 55,000 breast cancer patients included in the Swedish Cancer Registry between 1970 and 1985. After a median follow-up of 9 years, patients with left-sided cancers had an increased mortality resulting from MI (P < .01),¹³ and it was postulated that this was because of radiation-induced heart disease. However, the RT details and dose were not available and so the impact of RT technique could not be assessed. In particular, it was not known how many patients had received treatment to the IM lymph nodes. This particular field arrangement is associated with a large cardiac dose. Paszat et al¹⁴ studied the risk of fatal MI among women with breast cancer registered in the American Surveillance, Epidemiology, and End-Results cancer registries from 1973 to 1992. After a median follow-up of 6 years 2 months, stratified analysis showed the highest relative risk for fatal MI was in women treated for left-sided breast cancer, who were aged less than 60 at the time of RT and who had survived more than 10 years after exposure. However, only those with "regional" stage disease, who were likely treated with more extensive RT fields, showed a significant excess mortality from MI.

Several meta-analyses have also indicated an increased risk of MI after breast irradiation. Cuzick et al¹⁰ reviewed data from trials of postoperative RT for breast cancer initiated before 1975 in which RT was the randomized option. An excess of cardiac deaths among those treated with RT was apparent (P < .001), although this was offset by a decrease in breast cancer deaths, giving a nonsignificant net benefit in overall mortality associated with RT. The ratio of standardized mortality rates for left-sided versus right-sided tumors was 1.34, suggesting that cardiac risk was higher after irradiation for left- compared with right-sided cancer, although this value did not reach statistical significance. The patients included in this meta-analysis had undergone mastectomy and so the results may not be applicable to patients treated with breast-conserving therapy. Outdated RT techniques were used and included low energy sources, overlapping field arrangements, and large fraction sizes. More recently, a meta-analysis of 40 randomized trials of RT involving 20,000 women with early breast cancer has been reported by the Early Breast Cancer Trialists’ Collaborative Group.¹² Adjuvant RT was associated with a statistically definite reduction in the annual death rate from cancer, but this was offset by an increase in mortality attributable to vascular causes (death rate ratio, 1.3; SE = 0.09). The proportional excess of vascular deaths during the first decade of follow-up was similar to afterwards (ratio, 1.32; SE = 0.12 v 1.27; SE = 0.13), but the absolute rates were about three times as great in the latter period. Although the results of the meta-analysis strongly suggest a vascular hazard from RT, it should be noted that only 7% of the patients were participants in trials in which RT was limited to the breast, and such trials do not yet involve prolonged follow-up. Indeed, most of the nonbreast cancer deaths were in trials in which RT involved all three locoregional sites (breast or chest wall, axilla or supraclavicular fossa, and IM). Because very few patients in our study received regional RT, our observation that RT was not associated with excess cardiac mortality is consistent with the result of the meta-analysis. That the addition of regional RT to breast or chest wall RT may be associated with excess cardiac risk is of particular concern, given the increasing use of regional RT. This trend has followed the publication of randomized trials that demonstrate postmastectomy RT in women with node-positive breast cancer who were treated with adjuvant chemotherapy is associated with improved survival.^23,24

Recently, Paszat et al²⁵ have reported the results of a population-based study of women treated with postlumpectomy RT in Ontario from 1982 to 1987. There was an increased risk of fatal MI associated with left-sided compared with right-sided RT. When age-stratified analyses were performed, the increased likelihood of mortality from MI was evident only among women aged more than 60 years. This was a registry-based study using administrative records of health services originally created for other purposes, and no attempt was made to validate the diagnosis of fatal MI or to study nonfatal MI events. Despite an overlap in the population of patients included in the study reported by Paszat et al²⁵ and our cohort, we did not find a significant increase in the incidence of MI in general or among women aged 60 or greater in particular. There were significant differences in the selection of subjects for the two studies that may explain this apparently contradictory result. The PMH study included patients treated for ductal carcinoma-in-situ as well as invasive breast cancer and, on average, the patients included were slightly younger than those in the province-wide study (54.0 v 55.7 years). Thirty-two percent of the patients referred to the PMH during the study period were treated with BCS + RT. In contrast, the percentage of patients treated with BCS + RT was only 12% for the province as a whole. This likely reflects the referral bias to a specialized cancer center, differences in patterns of care at PMH compared with the rest of the province, a difference in the stage distribution of patients referred to the PMH, or a combination of these factors. We cannot rule out the possibility that subtle differences in RT practice at PMH compared with other centers might have led to reduced cardiac dose or volume, because the volume of cardiac tissue irradiated is not known for the PMH or provincial cohorts. We know from the work of Paszat et al²⁵ that patients residing in the Toronto area were more likely to receive treatment using a linear accelerator rather than cobalt RT and to receive fractions of more than 2.00 Gy. The proportion of patients that received regional RT at PMH during the study period was low at 8.5%. Information regarding the frequency of use of regional RT was not available for the province-wide study. With the number of events observed in our study (49), we could have detected a hazard ratio of 2 with 68% power (representing an increase in probability of MI from 1.32% to 2.73%), which is similar to the difference seen in the provincial study for women over 60 years.

All previously published reports of cardiac disease after RT for breast cancer have relied on death certification or unvalidated physician records for the diagnosis of MI, and only fatal MI events were considered. We identified and validated nonfatal as well as fatal coronary events in a large cohort of patients treated for early breast cancer with BCS + RT. We found that 15% of cases recorded as MI in hospital discharge files or on death certificates were inaccurate. This emphasizes the need to review original clinical data pertaining to specific cardiac events in retrospective studies of this kind.

The median RT dose and number of fractions received by patients in our cohort reflects the most commonly used dose/fractionation practice in Ontario during the 1980s. A similar fractionation schedule (42.5 Gy in 16 fractions, 2.65 Gy per fraction) has recently been compared with a more traditional fractionation scheme of 50.0 Gy in 25 fractions in a randomized clinical trial conducted by the Ontario Clinical Oncology Group.²⁶ The two fractionation schedules were found to be equivalent in terms of recurrence rates and cosmetic outcome, and the shorter 3-week fractionation schedule is now widely used in Canada. Thus, the results of our study that indicate an absence of excess cardiac morbidity after treatment with a similar protocol are reassuring and are pertinent to contemporary breast cancer patients in Canada and other countries where shorter fractionation schedules are favored.

The results of the current study suffer from the inherent problems of retrospective analysis, and the statistical power of the study is constrained by the rarity of the outcome (MI after RT). There is concern that breast cancer patients treated with RT and anthracycline-based chemotherapy may have an increased risk of cardiac toxicity. We are not able to comment on this possibility because anthracycline-based chemotherapy was used infrequently during the 1980s and only 3% of patients in this study received an anthracycline. The results of the Early Breast Cancer Trialists’ Collaborative Group meta-analysis suggest that 10 years of follow-up may be insufficient to definitively rule out late cardiac mortality after adjuvant RT for breast cancer, and we intend to review our cohort at later time points.¹²

In summary, we have studied a large group of early breast cancer patients treated with BCS + RT in a consistent manner at a single center. We found that RT to the left breast is not associated with excess mortality or morbidity from acute myocardial infarction at a median of 10.2 years of follow-up. Further follow-up and analysis of this group of patients is planned, as very late manifestations of radiation-induced heart disease may yet occur.

	ACKNOWLEDGMENTS

 
Supported by a grant from the Canadian Breast Cancer Foundation.

We thank J. Gariépy and V. Meehan for data abstraction, B.M. Wielgosz for assistance with validation of cardiac events, and L. Paszat, MD, for reviewing the manuscript.

	REFERENCES

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Submitted February 1, 2001; accepted October 5, 2001.

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