Cardiac Morbidity of Adjuvant Radiotherapy for Breast Cancer
http://www.100md.com
《临床肿瘤学》
the Departments of Medical Oncology, Radiation Oncology, and Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston
Department of Internal Medicine and Sealy Center on Aging, University of Texas Medical Branch at Galveston, Galveston, TX
ABSTRACT
PURPOSE: Adjuvant breast irradiation has been associated with an increase in cardiac mortality, because left-sided breast radiation can produce cardiac damage. The purpose of this study was to determine whether modern adjuvant radiotherapy is associated with increased risk of cardiac morbidity.
PATIENTS AND METHODS: Data from the Surveillance, Epidemiology, and End Results–Medicare database were used for women who were diagnosed with nonmetastatic breast cancer from 1986 to 1993, had known disease laterality, underwent breast surgery, and received adjuvant radiotherapy. The Cox proportional-hazards model was used to compare patients with left- versus right-sided breast cancer for the end points of hospitalization with the following discharge diagnoses (International Classification of Diseases, 9th Revision codes): ischemic heart disease (410-414, 36.0, and 36.1), valvular heart disease (394-397, 424, 35), congestive heart failure (428, 402.01, 402.11, 402.91, and 425), and conduction abnormalities (426, 427, 37.7-37.8, and 37.94-37.99).
RESULTS: Eight thousand three hundred sixty-three patients had left-sided breast cancer, and 7,907 had right-sided breast cancer. Mean follow-up was 9.5 years (range, 0 to 15 years). There were no significant differences in patients with left- versus right-sided cancers for hospitalization for ischemic heart disease (9.9% v 9.7%), valvular heart disease (2.9% v 2.8%), conduction abnormalities (9.7% v 9.6%), or heart failure (9.7% v 9.7%). The adjusted hazard ratio for left- versus right-sided breast cancer was 1.05 (95% CI, 0.94 to 1.16) for ischemic heart disease, 1.07 (95% CI, 0.89 to 1.30) for valvular heart disease, 1.07 (95% CI, 0.96 to 1.19) for conduction abnormalities, and 1.05 (95% CI, 0.95 to 1.17) for heart failure.
CONCLUSION: With up to 15 years of follow-up there were no significant differences in cardiac morbidity after radiation for left- versus right-sided breast cancer.
INTRODUCTION
Adjuvant radiotherapy is an important component of therapy for many women with early-stage breast cancer. The addition of radiotherapy to the care of women treated with breast-conserving surgery produces outcomes equivalent to those seen in women treated with mastectomy and allows the patient to retain her breast.1,2 Radiotherapy after mastectomy also decreases the risk of local recurrence and may improve overall survival.3-10 Both postlumpectomy radiation and postmastectomy radiation result in lower breast cancer mortality.11 However, radiotherapy is not without long-term toxicities. Historically, patients who received adjuvant radiotherapy had an increased risk of cardiovascular mortality. Yet, some recent studies have suggested that this risk has decreased over time.12-14 The potential long-term cardiovascular morbidity of modern adjuvant breast irradiation has not been well characterized. Defining the relationship between radiation and cardiac morbidity is important, because morbidity should be an earlier and more sensitive indicator of cardiac damage than cardiovascular death rates.
Cardiac irradiation can result in significant pathologic damage to the heart as manifested by diffuse myocardial interstitial fibrosis, microcirculatory damage leading to ischemia and fibrosis, fibrous thickening of the pericardium, valvular fibrosis, and accelerated atherosclerosis.15-19 These pathologic changes can produce multiple clinical complications including coronary artery disease,14,20 pericarditis,21 cardiomyopathy,22 valvular heart disease,23 and conduction disturbances.24,25 Patients who have been treated with left-sided adjuvant radiotherapy for breast cancer can have clinically significant cardiac radiation exposure26 and may be at higher risk of these complications than patients with right-sided breast cancer. Little is known about potential long-term cardiac morbidity after radiotherapy for breast cancer. Some studies have reported no difference in the risk of acute myocardial infarction between patients who did and did not receive radiation27 or patients who received radiation for left- versus right-sided breast cancer,28 but these studies were underpowered to detect less than a doubling of risk. A small Swedish study of 90 patients evaluated abnormalities in ECG, exercise tests, myocardial scintigraphy, and valvular dysfunction in premenopausal women 45 to 64 years of age and demonstrated no serious cardiac sequelae after 13 years.29 To our knowledge, the long-term morbidity of cardiovascular end points has not been assessed in an adequately powered study.
Over the last several decades there have been many advances in radiation treatments for breast cancer. The improved treatment-planning tools and techniques have decreased both the volume of cardiac tissue exposed to radiation and the dose of radiation delivered to the heart.30 Therefore, the increase in ischemic heart disease mortality reported among patients treated in the 1970s may not be an accurate assessment of cardiac risk for patients who are treated with more modern techniques. This study was undertaken to determine the cardiac morbidity of adjuvant breast irradiation for patients over a time period more reflective of modern radiotherapy.
PATIENTS AND METHODS
Data Source
We used the merged Surveillance, Epidemiology, and End Results (SEER)–Medicare database for our analysis. The SEER database program is a population-based tumor registry sponsored by the National Cancer Institute consisting of tumor registries that collect information on all newly diagnosed cancer cases that occur in persons residing in SEER-participating areas.30 The areas included in the registry since 1973 are the states of Connecticut, Hawaii, New Mexico, Iowa, and Utah and the metropolitan areas of San Francisco–Oakland, CA, and Detroit, MI, with registries in Seattle, WA, and Atlanta, GA, added in 1974. San Jose and Los Angeles, CA, joined the SEER program in 1992. Over the years of this study, the SEER database included approximately 14% of the US population. The SEER registry routinely collects information on patient demographics, tumor characteristics, stage at diagnosis, date of diagnosis, treatment within 4 months of diagnosis, and date and cause of death.
The Medicare program is administered by the Centers for Medicare and Medicaid Services (formerly the Health Care Financing Administration) and is the primary insurer for 97% of the US population 65 years of age.31 All Medicare beneficiaries receive Part A benefits, which cover inpatient hospitalizations and stays in skilled nursing facilities (SNFs). The Medicare claims data used in this study were from the Medicare Provider Analysis and Review (MEDPAR) file, which contains inpatient hospital- and SNF-stay records. Each record represents a beneficiary stay in an inpatient hospital or SNF. The information includes beneficiary demographics, dates of admission and discharge, up to 10 diagnoses codes (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] format), and up to 10 procedure codes (ICD-9-CM). These data are available for all beneficiaries starting in 1986, which is the year in which we began our analysis.
Under an agreement between the National Cancer Institute and the Centers for Medicare and Medicaid Services, SEER subjects who are eligible for Medicare have been linked to their Medicare records by using the method described by Potosky et al.31
Study Population
The study population included all Medicare part A–eligible women who were diagnosed with in situ, localized, or regional stage breast cancer between 1986 and 1993. To be eligible for this study, patients must have been treated with primary surgical therapy and adjuvant radiotherapy as documented in the SEER database. Women with bilateral disease, unknown laterality, another primary cancer, or unstaged disease were excluded. Women who belonged to a health maintenance organization (HMO) were also excluded, because their claims data may be incomplete. Follow-up in Medicare claims was available through 2001.
Cardiac morbidity was ascertained by the presence of the following discharge diagnosis ICD-9 codes in the first or second position for hospital or SNF stays and was categorized as follows: (1) ischemic heart disease: ischemic heart disease (410-414), percutaneous transluminal coronary angioplasty (36.0), and coronary artery bypass graft (36.1); (2) valvular disease: valvular heart disease (394-397 and 424) and operations on valves of the heart (35); (3) conduction abnormalities: conduction abnormalities (426), dysrhythmias (427), pacemaker-related procedures (37.7-37.8), and implantation of an automatic cardioverter/defibrillator (37.94-37.99); and (4) heart failure and cardiomyopathy: congestive heart failure and cardiomyopathy (428, 402.01, 402.11, 402.91, and 425).
Data Analysis
Patient characteristics were compared between those patients with left and right breast cancers by using the 2 test for categoric variables and t test for continuous variables. Education was characterized by percentage of individuals who lived in a census tract area with fewer than 12 years of education. Poverty was measured by percentage of individuals living in a given census tract living below the poverty level. The cutoff points for education and poverty were selected as the integers that were closest to the quartile of education and poverty. Comorbidities, including the cardiovascular outcomes of interest, were evaluated in the year before diagnosis and did not differ by patient laterality. The proportion of patients who were hospitalized at least 1 month after cancer diagnosis with the ICD-9 diagnosis and procedure codes (as previously detailed) was determined. The different outcomes were compared by tumor laterality using the 2 test.
Time-to-event curves were calculated by using the conditional Kaplan-Meier method for each diagnostic outcome by tumor laterality. Because some patients were not eligible for Medicare at the time of diagnosis, we used left truncation, or "delayed entry," to allow these patients to enter as they become Medicare eligible.32 In these analyses, we assume that patients did not develop any cardiac events before they became eligible for Medicare; therefore, all the estimators were conditional given no event at entry time. Of note, analyses performed without delayed entry yielded similar results to the delayed-entry models. Patients were censored at time of death, Medicare ineligibility, or receipt of care through an HMO. Cox left-truncated proportional-hazards models were used to calculate the hazard of hospitalization with an ICD-9 diagnosis code indicating (1) ischemic heart disease, (2) valvular disease, (3) conduction abnormalities, and (4) cardiomyopathy/heart failure. The final models included the cardiac morbidity outcome, age at diagnosis, race, education, income, SEER region, stage, year of diagnosis, and type of surgery. Based on survival analyses with a .05 two-sided significance level, an attrition rate of 0.02 per year, an accrual period of 8 years, and a maximum of 15 years' follow-up, a sample size of 8,000 in each group will be able to detect a hazard ratio (HR) of 1.10 with a power of 89. Statistical analyses were performed by using SAS software (version 8.02, SAS Institute, Cary, NC).
RESULTS
Of the 16,270 patients who were included in this study, 8,363 had left-sided breast cancer and 7,907 had right-sided breast cancer. Mean follow-up was 9.5 years (median, 9.7 years) for both groups (range, 0 to 15 years) and median age was 66 years. Among surviving patients, the mean follow-up was 11.1 years (range, 8 to 15 years). Patient characteristics did not differ between patients with left- and right-sided breast cancer (Table 1). The mean age at diagnosis was 65.9 years for women with left-sided cancer and 66.0 years for women with right-sided breast cancer (P = .66). Stage at diagnosis was similar between those patients with left- and right-sided breast cancer (P = .93), with approximately 8% presenting with in situ disease, 66% with localized (lymph node–negative) disease, and 26% with regional (lymph node–positive) cancers. Surgical treatment also did not differ by tumor laterality (P = .12). Overall, 83% of the patients received radiation after breast-conserving surgery, and 17% were treated with postmastectomy radiation.
Time to event was compared for patients with right- and left-sided tumors for the following cardiac end points: hospitalization with a diagnosis of ischemic heart disease; valvular disease; conduction disturbances; and heart failure/cardiomyopathies (Fig 1). No significant differences by tumor laterality were seen in cardiac morbidity for any of the end points with up to 15 years of follow-up. Table 2 lists the proportion of patients hospitalized with the cardiac outcomes of interest. Among patients with left-sided tumors, 9.9% were hospitalized with a diagnosis of ischemic heart disease versus 9.7% of patients with right-sided tumors (P = .77). Similarly, no differences were seen in hospitalization for valvular disease (2.9% v 2.8%; P = .93), conduction abnormalities (9.7% v 9.6%; P = .98), or heart failure/cardiomyopathy (9.7% v 9.7%; P = 1.00).
Cox left-truncated proportional-hazards models then were used to determine the independent risk of cardiac morbidity, adjusting for age at diagnosis, race, education, income, SEER region, stage, year of diagnosis, and type of surgery. The left-versus-right HR for hospitalization with any cardiac event was 1.06 (95% CI, 0.99 to 1.14) and for a diagnosis of ischemic heart disease was 1.05 (95% CI, 0.94 to 1.16). There was no interaction between patient age (P = .65), tumor stage (P = .68), year of diagnosis (P = .83), or type of surgery (P = .11) and tumor laterality. No significant differences by laterality were seen for the diagnoses indicating valvular disease (HR, 1.07; 95% CI, 0.89 to 1.30), conduction abnormalities (HR, 1.07; 95% CI, 0.96 to 1.19), or heart failure/cardiomyopathy (HR, 1.05; 95% CI, 0.95 to 1.17). In addition, as Figure 1 illustrates, the time-to-event analysis is similar for left versus right breast cancer for all cardiac morbidity end points measured.
Because the risk of ischemic heart disease is known to increase over time, we did an additional analysis among those patients with 10 to 15 years of follow-up (Table 3). In this cohort of 7,303 patients with a mean of 12.5 years of follow-up, there still was no difference in left versus right cardiac morbidity. For instance, 3.9% of the patients with left-sided tumors were hospitalized with a diagnosis of ischemic heart disease versus 3.7% of those with right-sided tumors (P = .43). None of the other end points showed a significant difference between those patients with left- and right-sided breast cancer.
DISCUSSION
In this study of more than 16,000 women, we found no difference in the risk of hospitalization for ischemic heart disease, valvular heart disease, conduction disturbances, and heart failure between women with left- versus right-sided breast cancer. To our knowledge, this is the first study to evaluate long-term cardiovascular morbidity of adjuvant radiation for these various cardiac end points. By using ICD-9 codes to identify hospitalizations for various diagnosis and procedures, we were able to evaluate multiple potential cardiovascular end points. With up to 15 years of follow-up, no differences are apparent in any of these end points, and the Kaplan-Meier curves do not suggest any separation of the curves among the patients with the longest follow-up times. Our data are reassuring in that adjuvant radiotherapy for breast cancer does not seem to be causing significant cardiovascular disease.
An increased risk of ischemic heart disease has been demonstrated previously to be associated with adjuvant radiation for breast cancer.11,33 In a meta-analysis performed by the Early Breast Cancer Trialists' Collaborative Group, which included 20,000 women, an increase in cardiovascular mortality was seen among women who received adjuvant radiation to the breast.11 Similarly, in a meta-analysis of eight randomized trials, there was an excess of cardiac deaths in the treatment groups receiving radiotherapy.34 Fatal myocardial infarctions have also been associated with adjuvant radiotherapy to the breast.35 However, these studies predominantly included patients treated in the 1970s or earlier, and recent studies have suggested that the increase in cardiovascular deaths may not be present among women treated with radiation in the 1980s and later.12,36,37
Valvular heart disease, conduction abnormalities, and heart failure have been demonstrated to be a consequence of radiotherapy in animal models and among patients treated with mediastinal radiation for Hodgkin's disease.23,38 Whether breast cancer patients treated with adjuvant radiotherapy are at increased risk of these long-term complications has been unclear, because previous studies have only evaluated ischemic heart disease.
Recent studies that evaluated patients with breast cancer who were treated for left breast cancers with radiation have found that many of them develop perfusion defects in the left ventricle in regions included in the irradiated field. These data likely represent microvascular damage that can lead to diastolic dysfunction.39 The long-term clinical significance of these defects remains unknown. The data from our study suggest that radiation effects on a small volume of the heart, which is possible with current treatments, may not increase the risk of cardiac events in patients with left-sided breast cancers versus those with right-sided disease.
One possible explanation for our findings compared to those reported in the initial meta-analyses is that adjuvant breast radiation may now be safer than in the past. There have been changes over time that have decreased radiation dose and volume to the heart. Two such improvements that occurred were the increased effort made to avoid the heart in the radiation fields and elimination of an en face photon/gamma radiation field that was used to treat the internal mammary lymph nodes. In addition, most breast cancer patients are currently treated with linear accelerators, whereas historically some had been treated with orthovoltage equipment. This change in delivery alone has been shown to substantially decrease radiation to the heart.30 Radiotherapy techniques and technologies have continued to improve over time, with three-dimensional imaging being incorporated into treatment planning. However, many of these improvements, such as the use of computed tomography simulation, were developed after the time period relevant to this study. Despite the low risk of cardiac morbidity seen in our study, additional reduction of myocardial exposure to radiation is likely to be beneficial, because there is a strong correlation between doses of radiation to the myocardium and risk of death resulting from myocardial disease.26
Although our data suggest that modern radiotherapy is not causing significant cardiac morbidity, we cannot be certain that differences would not emerge with longer follow-up. In previous studies, significant increases in cardiac mortality caused by radiation did not emerge until 8 to 10 years after radiation and have increased with longer follow-up.11,12 However, prior studies have shown differences in ischemic heart disease mortality with a length of follow-up that was similar to that in our study.40,41 In addition, our subanalysis among patients with more than 10 years of follow-up indicated no emerging differences between women with left- and right-sided cancers. Finally, we would expect that cardiac morbidity would be both a more sensitive and earlier predictor of cardiac damage from radiation; thus, the apparent lack of cardiac morbidity is encouraging.
Our rates of cardiac morbidity are likely to be an underestimate of all cardiac illnesses. We ascertained cardiac morbidity by inpatient hospitalization, and thus milder toxicities, which would be treated on an outpatient basis, would be missed. We also allowed patients to be included into this study as they became Medicare eligible (delayed entry); thus, early events might be missed. However, on the basis of a subset analyses among 9,412 patients whose cancer was diagnosed after enrollment onto Medicare (mean age at diagnosis, 71.7; mean follow-up time, 8.6 years), none of the study outcomes were significantly different between patients with left- and right-sided breast cancer.
Other important limitations include potential coding errors and lack of information on the technical aspects of radiation such as field arrangements and use of cobalt. Although our study did not specifically address techniques of radiotherapy, physician adherence to standard recommendations for radiation treatment parameters was high during the treatment time studied.42 Nonetheless, the lack of technical details on radiotherapy limits the ability to define specific subsets of patients who could be at increased risk. Our patient population could have had a low risk of cardiac toxicity, because the majority of the patients in this study were not candidates for nodal radiation and thus would not have gotten anterior internal mammary node irradiation. Even using old techniques, the amount of heart in the field for most patients should have been relatively modest. Finally, it should also be recognized that our data set is from an older patient population receiving Medicare, and the generalizability of our data to a younger population or those who are enrolled in HMOs is unknown.
We had the advantage of a large population-based cohort of patients with complete billing records of all inpatient care. The size of our study population gave us adequate power to detect a relatively small (10%) increase in cardiac risk. In addition, by looking at cardiac morbidity we have a more sensitive and earlier predictor of cardiac damage than mortality. We also were able to analyze a variety of cardiac end points including ischemic heart disease, valvular heart disease, heart failure, and conduction disturbances. Finally, because our enrollment began with patients diagnosed in 1986, our data are more reflective of the modern radiation techniques than other studies have been previously.
In conclusion, in this study we found no significant differences in cardiac morbidity for left- versus right-sided breast cancer. These data are reassuring and suggest that modern adjuvant radiotherapy is not causing substantial clinically relevant cardiac disease. By making adjuvant radiotherapy a safer process, women can feel more confident about their treatment for breast cancer and their decision for breast-conserving surgery.
Authors' Disclosures of Potential Conflicts of Interest
The authors have indicated no potential conflicts of interest.
NOTES
Supported by National Institutes of Health Grant No. 1K07 CA 109064-01 (S.H.G.).
Presented at the 2004 San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004 (abstr 4063).
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
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van Dongen JA, Bartelink H, Fentiman IS, et al: Factors influencing local relapse and survival and results of salvage treatment after breast-conserving therapy in operable breast cancer: EORTC trial 10801, breast conservation compared with mastectomy in TNM stage I and II breast cancer. Eur J Cancer 28A:801-805, 1992
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Giordano SH, Kuo YF, Freeman JL, et al: Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 97:419-424, 2005
Darby S, McGale P, Peto R: Mortality from cardiovascular disease after radiotherapy for breast cancer in 298,885 women registered in the SEER cancer registries. 27th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004 (abstr 32)
Cuzick J, Stewart H, Rutqvist L, et al: Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 12:447-453, 1994
Fajardo LF, Stewart JR, Cohn KE: Morphology of radiation-induced heart disease. Arch Pathol 86:512-519, 1968
Stewart JR, Fajardo LF: Radiation-induced heart disease: Clinical and experimental aspects. Radiol Clin North Am 9:511-531, 1971
Stewart JR, Fajardo LF, Gillette SM, et al: Radiation injury to the heart. Int J Radiat Oncol Biol Phys 31:1205-1211, 1995
Brosius FC 3rd, Waller BF, Roberts WC: Radiation heart disease: Analysis of 16 young (aged 15 to 33 years) necropsy patients who received over 3,500 rads to the heart. Am J Med 70:519-530, 1981
Bradley EW, Zook BC, Casarett GW, et al: Coronary arteriosclerosis and atherosclerosis in fast neutron or photon irradiated dogs. Int J Radiat Oncol Biol Phys 7:1103-1108, 1981
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Stewart JR, Fajardo LF: Radiation-induced heart disease: An update. Prog Cardiovasc Dis 27:173-194, 1984
Burns RJ, Bar-Shlomo BZ, Druck MN, et al: Detection of radiation cardiomyopathy by gated radionuclide angiography. Am J Med 74:297-302, 1983
Adams MJ, Lipsitz SR, Colan SD, et al: Cardiovascular status in long-term survivors of Hodgkin's disease treated with chest radiotherapy. J Clin Oncol 22:3139-3148, 2004
Orzan F, Brusca A, Gaita F, et al: Associated cardiac lesions in patients with radiation-induced complete heart block. Int J Cardiol 39:151-156, 1993
Cohen SI, Bharati S, Glass J, et al: Radiotherapy as a cause of complete atrioventricular block in Hodgkin's disease: An electrophysiological-pathological correlation. Arch Intern Med 141:676-679, 1981
Rutqvist LE, Lax I, Fornander T, et al: Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary breast cancer. Int J Radiat Oncol Biol Phys 22:887-896, 1992
Hojris I, Overgaard M, Christensen JJ, et al: Morbidity and mortality of ischaemic heart disease in high-risk breast-cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: Analysis of DBCG 82b and 82c randomised trials. Radiotherapy Committee of the Danish Breast Cancer Cooperative Group. Lancet 354:1425-1430, 1999
Vallis KA, Pintilie M, Chong N, et al: Assessment of coronary heart disease morbidity and mortality after radiation therapy for early breast cancer. J Clin Oncol 20:1036-1042, 2002
Gustavsson A, Bendahl PO, Cwikiel M, et al: No serious late cardiac effects after adjuvant radiotherapy following mastectomy in premenopausal women with early breast cancer. Int J Radiat Oncol Biol Phys 43:745-754, 1999
Fuller SA, Haybittle JL, Smith RE, et al: Cardiac doses in post-operative breast irradiation. Radiother Oncol 25:19-24, 1992
Potosky AL, Riley GF, Lubitz JD, et al: Potential for cancer related health services research using a linked Medicare-tumor registry database. Med Care 31:732-748, 1993
Cuzick J, Stewart H, Rutqvist L, et al: Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 12:447-453, 1994
Klein JP, Moeschberger ML: Survival Analysis: Techniques for Censored and Truncated Data. New York, NY, Springer-Verlag, 1997
Haybittle JL, Brinkley D, Houghton J, et al: Postoperative radiotherapy and late mortality: Evidence from the Cancer Research Campaign trial for early breast cancer. BMJ 298:1611-1614, 1989
Paszat LF, Mackillop WJ, Groome PA, et al: Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries. J Clin Oncol 16:2625-2631, 1998 [Erratum: J Clin Oncol 1999;17:740]
Nixon AJ, Manola J, Gelman R, et al: No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques. J Clin Oncol 16:1374-1379, 1998
Rutqvist LE, Liedberg A, Hammar N, et al: Myocardial infarction among women with early-stage breast cancer treated with conservative surgery and breast irradiation. Int J Radiat Oncol Biol Phys 40:359-363, 1998
Hull MC, Morris CG, Pepine CJ, et al: Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin's lymphoma treated with radiation therapy. JAMA 290:2831-2837, 2003
Gyenes G, Fornander T, Carlens P, et al: Myocardial damage in breast cancer patients treated with adjuvant radiotherapy: A prospective study. Int J Radiat Oncol Biol Phys 36:899-905, 1996
Woodward WA, Strom EA, McNeese MD, et al: Cardiovascular death and second non-breast cancer malignancy after postmastectomy radiation and doxorubicin-based chemotherapy. Int J Radiat Oncol Biol Phys 57:327-335, 2003
Paszat LF, Mackillop WJ, Groome PA, et al: Mortality from myocardial infarction following postlumpectomy radiotherapy for breast cancer: A population-based study in Ontario, Canada. Int J Radiat Oncol Biol Phys 43:755-762, 1999
Shank B, Moughan J, Owen J, et al: The 1993-94 patterns of care process survey for breast irradiation after breast-conserving surgery: Comparison with the 1992 standard for breast conservation treatment—The Patterns of Care Study, American College of Radiology. Int J Radiat Oncol Biol Phys 48:1291-1299, 2000(Debra A. Patt, James S. G)
Department of Internal Medicine and Sealy Center on Aging, University of Texas Medical Branch at Galveston, Galveston, TX
ABSTRACT
PURPOSE: Adjuvant breast irradiation has been associated with an increase in cardiac mortality, because left-sided breast radiation can produce cardiac damage. The purpose of this study was to determine whether modern adjuvant radiotherapy is associated with increased risk of cardiac morbidity.
PATIENTS AND METHODS: Data from the Surveillance, Epidemiology, and End Results–Medicare database were used for women who were diagnosed with nonmetastatic breast cancer from 1986 to 1993, had known disease laterality, underwent breast surgery, and received adjuvant radiotherapy. The Cox proportional-hazards model was used to compare patients with left- versus right-sided breast cancer for the end points of hospitalization with the following discharge diagnoses (International Classification of Diseases, 9th Revision codes): ischemic heart disease (410-414, 36.0, and 36.1), valvular heart disease (394-397, 424, 35), congestive heart failure (428, 402.01, 402.11, 402.91, and 425), and conduction abnormalities (426, 427, 37.7-37.8, and 37.94-37.99).
RESULTS: Eight thousand three hundred sixty-three patients had left-sided breast cancer, and 7,907 had right-sided breast cancer. Mean follow-up was 9.5 years (range, 0 to 15 years). There were no significant differences in patients with left- versus right-sided cancers for hospitalization for ischemic heart disease (9.9% v 9.7%), valvular heart disease (2.9% v 2.8%), conduction abnormalities (9.7% v 9.6%), or heart failure (9.7% v 9.7%). The adjusted hazard ratio for left- versus right-sided breast cancer was 1.05 (95% CI, 0.94 to 1.16) for ischemic heart disease, 1.07 (95% CI, 0.89 to 1.30) for valvular heart disease, 1.07 (95% CI, 0.96 to 1.19) for conduction abnormalities, and 1.05 (95% CI, 0.95 to 1.17) for heart failure.
CONCLUSION: With up to 15 years of follow-up there were no significant differences in cardiac morbidity after radiation for left- versus right-sided breast cancer.
INTRODUCTION
Adjuvant radiotherapy is an important component of therapy for many women with early-stage breast cancer. The addition of radiotherapy to the care of women treated with breast-conserving surgery produces outcomes equivalent to those seen in women treated with mastectomy and allows the patient to retain her breast.1,2 Radiotherapy after mastectomy also decreases the risk of local recurrence and may improve overall survival.3-10 Both postlumpectomy radiation and postmastectomy radiation result in lower breast cancer mortality.11 However, radiotherapy is not without long-term toxicities. Historically, patients who received adjuvant radiotherapy had an increased risk of cardiovascular mortality. Yet, some recent studies have suggested that this risk has decreased over time.12-14 The potential long-term cardiovascular morbidity of modern adjuvant breast irradiation has not been well characterized. Defining the relationship between radiation and cardiac morbidity is important, because morbidity should be an earlier and more sensitive indicator of cardiac damage than cardiovascular death rates.
Cardiac irradiation can result in significant pathologic damage to the heart as manifested by diffuse myocardial interstitial fibrosis, microcirculatory damage leading to ischemia and fibrosis, fibrous thickening of the pericardium, valvular fibrosis, and accelerated atherosclerosis.15-19 These pathologic changes can produce multiple clinical complications including coronary artery disease,14,20 pericarditis,21 cardiomyopathy,22 valvular heart disease,23 and conduction disturbances.24,25 Patients who have been treated with left-sided adjuvant radiotherapy for breast cancer can have clinically significant cardiac radiation exposure26 and may be at higher risk of these complications than patients with right-sided breast cancer. Little is known about potential long-term cardiac morbidity after radiotherapy for breast cancer. Some studies have reported no difference in the risk of acute myocardial infarction between patients who did and did not receive radiation27 or patients who received radiation for left- versus right-sided breast cancer,28 but these studies were underpowered to detect less than a doubling of risk. A small Swedish study of 90 patients evaluated abnormalities in ECG, exercise tests, myocardial scintigraphy, and valvular dysfunction in premenopausal women 45 to 64 years of age and demonstrated no serious cardiac sequelae after 13 years.29 To our knowledge, the long-term morbidity of cardiovascular end points has not been assessed in an adequately powered study.
Over the last several decades there have been many advances in radiation treatments for breast cancer. The improved treatment-planning tools and techniques have decreased both the volume of cardiac tissue exposed to radiation and the dose of radiation delivered to the heart.30 Therefore, the increase in ischemic heart disease mortality reported among patients treated in the 1970s may not be an accurate assessment of cardiac risk for patients who are treated with more modern techniques. This study was undertaken to determine the cardiac morbidity of adjuvant breast irradiation for patients over a time period more reflective of modern radiotherapy.
PATIENTS AND METHODS
Data Source
We used the merged Surveillance, Epidemiology, and End Results (SEER)–Medicare database for our analysis. The SEER database program is a population-based tumor registry sponsored by the National Cancer Institute consisting of tumor registries that collect information on all newly diagnosed cancer cases that occur in persons residing in SEER-participating areas.30 The areas included in the registry since 1973 are the states of Connecticut, Hawaii, New Mexico, Iowa, and Utah and the metropolitan areas of San Francisco–Oakland, CA, and Detroit, MI, with registries in Seattle, WA, and Atlanta, GA, added in 1974. San Jose and Los Angeles, CA, joined the SEER program in 1992. Over the years of this study, the SEER database included approximately 14% of the US population. The SEER registry routinely collects information on patient demographics, tumor characteristics, stage at diagnosis, date of diagnosis, treatment within 4 months of diagnosis, and date and cause of death.
The Medicare program is administered by the Centers for Medicare and Medicaid Services (formerly the Health Care Financing Administration) and is the primary insurer for 97% of the US population 65 years of age.31 All Medicare beneficiaries receive Part A benefits, which cover inpatient hospitalizations and stays in skilled nursing facilities (SNFs). The Medicare claims data used in this study were from the Medicare Provider Analysis and Review (MEDPAR) file, which contains inpatient hospital- and SNF-stay records. Each record represents a beneficiary stay in an inpatient hospital or SNF. The information includes beneficiary demographics, dates of admission and discharge, up to 10 diagnoses codes (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] format), and up to 10 procedure codes (ICD-9-CM). These data are available for all beneficiaries starting in 1986, which is the year in which we began our analysis.
Under an agreement between the National Cancer Institute and the Centers for Medicare and Medicaid Services, SEER subjects who are eligible for Medicare have been linked to their Medicare records by using the method described by Potosky et al.31
Study Population
The study population included all Medicare part A–eligible women who were diagnosed with in situ, localized, or regional stage breast cancer between 1986 and 1993. To be eligible for this study, patients must have been treated with primary surgical therapy and adjuvant radiotherapy as documented in the SEER database. Women with bilateral disease, unknown laterality, another primary cancer, or unstaged disease were excluded. Women who belonged to a health maintenance organization (HMO) were also excluded, because their claims data may be incomplete. Follow-up in Medicare claims was available through 2001.
Cardiac morbidity was ascertained by the presence of the following discharge diagnosis ICD-9 codes in the first or second position for hospital or SNF stays and was categorized as follows: (1) ischemic heart disease: ischemic heart disease (410-414), percutaneous transluminal coronary angioplasty (36.0), and coronary artery bypass graft (36.1); (2) valvular disease: valvular heart disease (394-397 and 424) and operations on valves of the heart (35); (3) conduction abnormalities: conduction abnormalities (426), dysrhythmias (427), pacemaker-related procedures (37.7-37.8), and implantation of an automatic cardioverter/defibrillator (37.94-37.99); and (4) heart failure and cardiomyopathy: congestive heart failure and cardiomyopathy (428, 402.01, 402.11, 402.91, and 425).
Data Analysis
Patient characteristics were compared between those patients with left and right breast cancers by using the 2 test for categoric variables and t test for continuous variables. Education was characterized by percentage of individuals who lived in a census tract area with fewer than 12 years of education. Poverty was measured by percentage of individuals living in a given census tract living below the poverty level. The cutoff points for education and poverty were selected as the integers that were closest to the quartile of education and poverty. Comorbidities, including the cardiovascular outcomes of interest, were evaluated in the year before diagnosis and did not differ by patient laterality. The proportion of patients who were hospitalized at least 1 month after cancer diagnosis with the ICD-9 diagnosis and procedure codes (as previously detailed) was determined. The different outcomes were compared by tumor laterality using the 2 test.
Time-to-event curves were calculated by using the conditional Kaplan-Meier method for each diagnostic outcome by tumor laterality. Because some patients were not eligible for Medicare at the time of diagnosis, we used left truncation, or "delayed entry," to allow these patients to enter as they become Medicare eligible.32 In these analyses, we assume that patients did not develop any cardiac events before they became eligible for Medicare; therefore, all the estimators were conditional given no event at entry time. Of note, analyses performed without delayed entry yielded similar results to the delayed-entry models. Patients were censored at time of death, Medicare ineligibility, or receipt of care through an HMO. Cox left-truncated proportional-hazards models were used to calculate the hazard of hospitalization with an ICD-9 diagnosis code indicating (1) ischemic heart disease, (2) valvular disease, (3) conduction abnormalities, and (4) cardiomyopathy/heart failure. The final models included the cardiac morbidity outcome, age at diagnosis, race, education, income, SEER region, stage, year of diagnosis, and type of surgery. Based on survival analyses with a .05 two-sided significance level, an attrition rate of 0.02 per year, an accrual period of 8 years, and a maximum of 15 years' follow-up, a sample size of 8,000 in each group will be able to detect a hazard ratio (HR) of 1.10 with a power of 89. Statistical analyses were performed by using SAS software (version 8.02, SAS Institute, Cary, NC).
RESULTS
Of the 16,270 patients who were included in this study, 8,363 had left-sided breast cancer and 7,907 had right-sided breast cancer. Mean follow-up was 9.5 years (median, 9.7 years) for both groups (range, 0 to 15 years) and median age was 66 years. Among surviving patients, the mean follow-up was 11.1 years (range, 8 to 15 years). Patient characteristics did not differ between patients with left- and right-sided breast cancer (Table 1). The mean age at diagnosis was 65.9 years for women with left-sided cancer and 66.0 years for women with right-sided breast cancer (P = .66). Stage at diagnosis was similar between those patients with left- and right-sided breast cancer (P = .93), with approximately 8% presenting with in situ disease, 66% with localized (lymph node–negative) disease, and 26% with regional (lymph node–positive) cancers. Surgical treatment also did not differ by tumor laterality (P = .12). Overall, 83% of the patients received radiation after breast-conserving surgery, and 17% were treated with postmastectomy radiation.
Time to event was compared for patients with right- and left-sided tumors for the following cardiac end points: hospitalization with a diagnosis of ischemic heart disease; valvular disease; conduction disturbances; and heart failure/cardiomyopathies (Fig 1). No significant differences by tumor laterality were seen in cardiac morbidity for any of the end points with up to 15 years of follow-up. Table 2 lists the proportion of patients hospitalized with the cardiac outcomes of interest. Among patients with left-sided tumors, 9.9% were hospitalized with a diagnosis of ischemic heart disease versus 9.7% of patients with right-sided tumors (P = .77). Similarly, no differences were seen in hospitalization for valvular disease (2.9% v 2.8%; P = .93), conduction abnormalities (9.7% v 9.6%; P = .98), or heart failure/cardiomyopathy (9.7% v 9.7%; P = 1.00).
Cox left-truncated proportional-hazards models then were used to determine the independent risk of cardiac morbidity, adjusting for age at diagnosis, race, education, income, SEER region, stage, year of diagnosis, and type of surgery. The left-versus-right HR for hospitalization with any cardiac event was 1.06 (95% CI, 0.99 to 1.14) and for a diagnosis of ischemic heart disease was 1.05 (95% CI, 0.94 to 1.16). There was no interaction between patient age (P = .65), tumor stage (P = .68), year of diagnosis (P = .83), or type of surgery (P = .11) and tumor laterality. No significant differences by laterality were seen for the diagnoses indicating valvular disease (HR, 1.07; 95% CI, 0.89 to 1.30), conduction abnormalities (HR, 1.07; 95% CI, 0.96 to 1.19), or heart failure/cardiomyopathy (HR, 1.05; 95% CI, 0.95 to 1.17). In addition, as Figure 1 illustrates, the time-to-event analysis is similar for left versus right breast cancer for all cardiac morbidity end points measured.
Because the risk of ischemic heart disease is known to increase over time, we did an additional analysis among those patients with 10 to 15 years of follow-up (Table 3). In this cohort of 7,303 patients with a mean of 12.5 years of follow-up, there still was no difference in left versus right cardiac morbidity. For instance, 3.9% of the patients with left-sided tumors were hospitalized with a diagnosis of ischemic heart disease versus 3.7% of those with right-sided tumors (P = .43). None of the other end points showed a significant difference between those patients with left- and right-sided breast cancer.
DISCUSSION
In this study of more than 16,000 women, we found no difference in the risk of hospitalization for ischemic heart disease, valvular heart disease, conduction disturbances, and heart failure between women with left- versus right-sided breast cancer. To our knowledge, this is the first study to evaluate long-term cardiovascular morbidity of adjuvant radiation for these various cardiac end points. By using ICD-9 codes to identify hospitalizations for various diagnosis and procedures, we were able to evaluate multiple potential cardiovascular end points. With up to 15 years of follow-up, no differences are apparent in any of these end points, and the Kaplan-Meier curves do not suggest any separation of the curves among the patients with the longest follow-up times. Our data are reassuring in that adjuvant radiotherapy for breast cancer does not seem to be causing significant cardiovascular disease.
An increased risk of ischemic heart disease has been demonstrated previously to be associated with adjuvant radiation for breast cancer.11,33 In a meta-analysis performed by the Early Breast Cancer Trialists' Collaborative Group, which included 20,000 women, an increase in cardiovascular mortality was seen among women who received adjuvant radiation to the breast.11 Similarly, in a meta-analysis of eight randomized trials, there was an excess of cardiac deaths in the treatment groups receiving radiotherapy.34 Fatal myocardial infarctions have also been associated with adjuvant radiotherapy to the breast.35 However, these studies predominantly included patients treated in the 1970s or earlier, and recent studies have suggested that the increase in cardiovascular deaths may not be present among women treated with radiation in the 1980s and later.12,36,37
Valvular heart disease, conduction abnormalities, and heart failure have been demonstrated to be a consequence of radiotherapy in animal models and among patients treated with mediastinal radiation for Hodgkin's disease.23,38 Whether breast cancer patients treated with adjuvant radiotherapy are at increased risk of these long-term complications has been unclear, because previous studies have only evaluated ischemic heart disease.
Recent studies that evaluated patients with breast cancer who were treated for left breast cancers with radiation have found that many of them develop perfusion defects in the left ventricle in regions included in the irradiated field. These data likely represent microvascular damage that can lead to diastolic dysfunction.39 The long-term clinical significance of these defects remains unknown. The data from our study suggest that radiation effects on a small volume of the heart, which is possible with current treatments, may not increase the risk of cardiac events in patients with left-sided breast cancers versus those with right-sided disease.
One possible explanation for our findings compared to those reported in the initial meta-analyses is that adjuvant breast radiation may now be safer than in the past. There have been changes over time that have decreased radiation dose and volume to the heart. Two such improvements that occurred were the increased effort made to avoid the heart in the radiation fields and elimination of an en face photon/gamma radiation field that was used to treat the internal mammary lymph nodes. In addition, most breast cancer patients are currently treated with linear accelerators, whereas historically some had been treated with orthovoltage equipment. This change in delivery alone has been shown to substantially decrease radiation to the heart.30 Radiotherapy techniques and technologies have continued to improve over time, with three-dimensional imaging being incorporated into treatment planning. However, many of these improvements, such as the use of computed tomography simulation, were developed after the time period relevant to this study. Despite the low risk of cardiac morbidity seen in our study, additional reduction of myocardial exposure to radiation is likely to be beneficial, because there is a strong correlation between doses of radiation to the myocardium and risk of death resulting from myocardial disease.26
Although our data suggest that modern radiotherapy is not causing significant cardiac morbidity, we cannot be certain that differences would not emerge with longer follow-up. In previous studies, significant increases in cardiac mortality caused by radiation did not emerge until 8 to 10 years after radiation and have increased with longer follow-up.11,12 However, prior studies have shown differences in ischemic heart disease mortality with a length of follow-up that was similar to that in our study.40,41 In addition, our subanalysis among patients with more than 10 years of follow-up indicated no emerging differences between women with left- and right-sided cancers. Finally, we would expect that cardiac morbidity would be both a more sensitive and earlier predictor of cardiac damage from radiation; thus, the apparent lack of cardiac morbidity is encouraging.
Our rates of cardiac morbidity are likely to be an underestimate of all cardiac illnesses. We ascertained cardiac morbidity by inpatient hospitalization, and thus milder toxicities, which would be treated on an outpatient basis, would be missed. We also allowed patients to be included into this study as they became Medicare eligible (delayed entry); thus, early events might be missed. However, on the basis of a subset analyses among 9,412 patients whose cancer was diagnosed after enrollment onto Medicare (mean age at diagnosis, 71.7; mean follow-up time, 8.6 years), none of the study outcomes were significantly different between patients with left- and right-sided breast cancer.
Other important limitations include potential coding errors and lack of information on the technical aspects of radiation such as field arrangements and use of cobalt. Although our study did not specifically address techniques of radiotherapy, physician adherence to standard recommendations for radiation treatment parameters was high during the treatment time studied.42 Nonetheless, the lack of technical details on radiotherapy limits the ability to define specific subsets of patients who could be at increased risk. Our patient population could have had a low risk of cardiac toxicity, because the majority of the patients in this study were not candidates for nodal radiation and thus would not have gotten anterior internal mammary node irradiation. Even using old techniques, the amount of heart in the field for most patients should have been relatively modest. Finally, it should also be recognized that our data set is from an older patient population receiving Medicare, and the generalizability of our data to a younger population or those who are enrolled in HMOs is unknown.
We had the advantage of a large population-based cohort of patients with complete billing records of all inpatient care. The size of our study population gave us adequate power to detect a relatively small (10%) increase in cardiac risk. In addition, by looking at cardiac morbidity we have a more sensitive and earlier predictor of cardiac damage than mortality. We also were able to analyze a variety of cardiac end points including ischemic heart disease, valvular heart disease, heart failure, and conduction disturbances. Finally, because our enrollment began with patients diagnosed in 1986, our data are more reflective of the modern radiation techniques than other studies have been previously.
In conclusion, in this study we found no significant differences in cardiac morbidity for left- versus right-sided breast cancer. These data are reassuring and suggest that modern adjuvant radiotherapy is not causing substantial clinically relevant cardiac disease. By making adjuvant radiotherapy a safer process, women can feel more confident about their treatment for breast cancer and their decision for breast-conserving surgery.
Authors' Disclosures of Potential Conflicts of Interest
The authors have indicated no potential conflicts of interest.
NOTES
Supported by National Institutes of Health Grant No. 1K07 CA 109064-01 (S.H.G.).
Presented at the 2004 San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004 (abstr 4063).
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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