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Originally published as JCO Early Release 10.1200/JCO.2006.06.5516 on November 6 2006 © 2006 American Society of Clinical Oncology. Decreased Risk of Stroke Among 10-Year Survivors of Breast Cancer
From the Departments of Epidemiology, Neuro-oncology, and Radiation Oncology, the Netherlands Cancer Institute, Amsterdam; Department of Neurology, Radboud University Nijmegen Medical Center, Nijmegen; Department of Medical Oncology, Erasmus MC, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands Address reprint requests to Flora E. van Leeuwen, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands; e-mail: f.v.leeuwen{at}nki.nl
PURPOSE: To assess treatment-specific risk of cerebrovascular events in early breast cancer (BC) patients, accounting for cerebrovascular risk factors. PATIENTS AND METHODS: We studied the incidence of cerebrovascular accidents (CVA; stroke and transient ischemic attack [TIA]) in 10-year survivors of early BC (n = 4,414) treated from 1970 to 1986. Follow-up was 96% complete until January 2000. Treatment-specific incidence of CVA was evaluated by standardized incidence ratios (SIRs) based on comparison with general population rates and by Cox proportional hazards regression. RESULTS: After a median follow-up of 18 years, 164 strokes and 109 TIAs were observed, resulting in decreased SIRs of 0.8 (95% CI, 0.6 to 0.9) for stroke and 0.8 (95% CI, 0.7 to 1.0) for TIA. Significantly increased risk of stroke was found in women who had received hormonal treatment (HT; tamoxifen) and in women who had hypertension or hypercholesterolemia, with hazard ratios (HRs) of 1.9, 2.1, and 1.6, respectively. Patients irradiated on the supraclavicular area and/or internal mammary chain (IMC) did not experience a higher risk of stroke (HR = 1.0; 95% CI, 0.7 to 1.6) or TIA (HR = 1.4; 95% CI, 0.9 to 2.5) compared with patients who did not receive radiotherapy or who were irradiated on fields other than the supraclavicular area or IMC. CONCLUSION: Long-term survivors of BC experience no increased risk of cerebrovascular events compared with the general population. HT is associated with an increased risk of stroke. Radiation fields including the carotid artery do not seem to increase the risk of stroke compared with other fields.
The prognosis of patients with early breast cancer (BC) has significantly improved over the past decades as a result of earlier diagnosis and the use of multimodality treatment. Meta-analyses of randomized clinical trials by the Early Breast Cancer Trialists' Collaborative Group have shown an important reduction in local recurrence rate and in BC mortality as a result of the application of postoperative adjuvant radiotherapy (RT)1-3 and adjuvant systemic therapy.4 However, adjuvant RT has also been associated with increased risks of cardiovascular morbidity and second primary cancers.5-7 Exposure to chemotherapy or hormonal therapy (HT) may even further increase the risk of cardiovascular disease.8,9 In BC patients treated with adjuvant RT, the coronary arteries, brachiocephalic trunk, subclavian artery, and common carotid arteries (CCAs) may be exposed, depending on the fields applied. As a result, BC patients are potentially at risk for late vascular sequelae of RT.10-14 So far, nearly all studies on vascular sequelae after BC irradiation have focused on the risk of cardiac disease. RT-related stroke is mediated by accelerated atherosclerosis that can result in enhanced thromboembolism and stenosis of the area of the carotid artery within the RT portal.15,16 Head and neck cancer patients and survivors of Hodgkin's lymphoma treated with local RT on the neck experience an increased risk of stroke during long-term follow-up.17-19 In case of irradiation on the supraclavicular lymph nodes, the proximal part of the CCA is located within the RT portal. Therefore, we hypothesize that BC patients irradiated at the supraclavicular lymph nodes are subject to an increased risk of stroke. Until now, no study has reported on the incidence of ischemic stroke in relation to specific radiation regimens for BC. Therefore, we examined the incidence of cerebrovascular accident (CVA) in the Dutch Late Effects Breast Cancer cohort. Unique features of this study include near-complete and long-term follow-up (median, 18 years), the assessment of cerebrovascular risk according to radiation field, and the incorporation of cerebrovascular risk factors into the analysis.
Data Collection Procedures The Late Effects Breast Cancer cohort consists of 7,425 1-year survivors, younger than 71 years of age at diagnosis, treated for stage I, II, or IIIA female BC in the period from 1970 to 1986 in the Netherlands Cancer Institute or the Erasmus MC, Daniel den Hoed Cancer Center. A detailed description of data collection procedures has been published previously.20 In brief, all patients were identified through the hospital-based cancer registries of the two centers. From the registries and the oncologic records, we collected the following information: date of BC diagnosis, tumor histology, axillary lymph node involvement, dates and treatment modalities of primary BC and of recurrent disease (ie, type of surgery, radiation fields, cytostatic agents, and HT), dates of stroke and transient ischemic attack (TIA), cerebrovascular risk factors, date of most recent medical information or date of death and primary cause of death. Risk factors (such as smoking, hypertension, diabetes mellitus [DM], and hypercholesterolemia) were recorded both at the date of diagnosis of BC and at the end of follow-up. Smoking was scored as positive when the patient was currently smoking or had stopped smoking less than 1 year before. Hypertension, hypercholesterolemia, and DM were scored as positive when stated in the medical information or when treated. We restricted this study to patients who survived BC for at least 10 years (n = 4,414) because the increase in risk of vascular events associated with RT seems to emerge after 10 or more years.2,5,15-17,20 For these patients, we updated information until at least January 1, 2000 on cerebrovascular diagnoses and risk factors by sending questionnaires to their general practitioners (GPs). In the Netherlands, nearly all residents have a GP who receives all medical correspondence from attending physicians. Forty-six patients were excluded from the cohort because their oncologic records did not contain information after 10 years since diagnosis and no additional information on vascular events could be obtained from their GPs. For the remaining 4,368 patients, we collected cerebrovascular data for 83% of the patients from both the medical record and the GP, and for the other 17% of patients, we collected data from the oncologic records only. Complete follow-up information was eventually available for 4,259 patients (96%). For patients who died from a stroke, without prior evidence of a cerebrovascular event, the date of death was recorded as date of diagnosis of stroke.
Treatment
Statistical Analysis We compared the incidence of stroke and TIA in the study population with the incidence in the Dutch female population, taking into account the person-years of observation in the cohort (by age, calendar period, and follow-up interval). Incidence data of the Continuous Morbidity Registration–Nijmegen, derived from several GP practices from representative regions in the Netherlands, were used as reference rates.21 This registry has collected data on the incidence of vascular events (including TIA) for the period from 1972 to 2000, allowing for multiple separate diagnoses per person but recording only the first of a specific diagnosis per person. To assess treatment effects on stroke risk, we distinguished five mutually exclusive treatment categories based on all treatments received (Table 1). Treatments administered in the last year of follow-up were excluded from the analysis because we did not want to take into account all salvage treatments received for recurrent disease during the last period in life. We also analyzed the effects of specific RT fields.
Follow-up time was defined as the period from the date of first treatment until the date of most recent medical information (including date of death). Because the study was restricted to 10-year survivors, time at risk began 10 years after the start of first treatment and ended at date of diagnosis of stroke or TIA, date of death, or date of most recent medical information, whichever came first. Observed numbers were based on all first events of stroke and TIA occurring during time at risk (ie, after at least 10 years since first treatment); patients diagnosed with a cerebrovascular event before BC diagnosis or within 10 years since first treatment were excluded from the analysis. The standardized incidence ratios (SIRs) of the observed and expected numbers of stroke and TIA in the study population were determined, and the CIs of the SIRs were calculated using exact Poisson probabilities of observed numbers.22 P values for tests for trend were calculated according to standard methods. Absolute excess risk was calculated by subtracting the expected number of cerebrovascular events in our cohort from the number observed and dividing by person-years at risk (expressed per 10,000 person-years). The Cox proportional hazards model23 was used to quantify the effects of different treatments on the risk of CVA, taking into account several covariates. To evaluate the independent effects of primary adjuvant treatment, we did a separate analysis where time at risk ended at date of treatment for recurrent disease. Cox models were fitted with the use of SPSS statistical software (SPSS Inc, Chicago, IL).
Patient Characteristics The median age at BC diagnosis in the study population was 49 years, and 32% of patients were younger than 45 years at diagnosis (Table 1). Median follow-up time was 17.7 years, and 31% of the patients were followed for more than 20 years. Fifty-four percent of the patients were treated with a combination of RT and surgery, and 32% received RT and adjuvant chemotherapy and/or HT, the latter mostly for recurrent disease. Fifty-eight percent of patients received IMC RT, usually including the medial supraclavicular area, 50% were irradiated to the chest wall or breast region, and 24% were irradiated to the supraclavicular area. Table 2 displays the information on cerebrovascular risk factors in the study population. We compared the distribution of hypertension, DM, and hypercholesterolemia by age categories in our study to the reference population from Continuous Morbidity Registration–Nijmegen (Table 3). Since this Registry had no data on smoking habits, we used figures from a nationwide survey held in 2000 for comparison.24 At the end of follow-up, the distribution of risk factors was very similar in our study group compared with the control population, with the exception of patients aged more than 75 years, who had a significantly higher prevalence of hypertension (44% v 34%, respectively; P < .001).
Risk of CVA by Age, Follow-Up, and Treatment Regimen Overall, we observed 164 strokes and 109 TIAs (Table 4), including 14 patients with both (TIA preceding stroke). In total, 51 patients died from a stroke. The median age at stroke diagnosis was 75.5 years after a median follow-up of 17.0 years; TIAs were diagnosed at a median age of 73.1 years after a median follow-up of 16.8 years.
With 217.6 strokes expected versus 164 seen, the risk of stroke was significantly decreased by 25% (SIR = 0.75; 95% CI, 0.64 to 0.88; Table 4). Decreased risk of stroke was found for all age groups. For TIA, the risk was increased in patients younger than 45 years old at BC diagnosis, with SIRs showing a consistent decline with older ages at diagnosis of BC (P for trend < .0001; Table 4). There was no trend over follow-up time for risk of stroke or TIA. Risks of stroke and TIA did not differ between patients who were treated with surgery alone and those who received RT in combination with surgery. However, among patients who were treated with RT plus HT, we observed an elevated risk of stroke (SIR = 1.31; 95% CI, 0.87 to 1.88) compared with the general population, whereas risk of TIA was significantly increased in patients treated with RT plus chemotherapy (SIR = 2.90; 95% CI, 1.45 to 5.19).
Risk of CVA by RT Field: Cox Model Analysis
This is the first long-term cohort study assessing the incidence of cerebrovascular events in early BC patients according to RT fields delivered. Overall, the risk of stroke was decreased by 25% in comparison with the general female population. Contrary to our expectation, risk of stroke was not increased in patients treated with adjuvant RT at the carotid arteries compared with nonirradiated patients. Of all treatment modalities, only HT was associated with an increased risk of stroke. Strongest risk factors were hypertension and hypercholesterolemia, but these factors did not modify the risk estimates for treatment.
Data on risk of stroke in BC patients are scarce. Recently, Jagsi et al25 found a nonsignificantly elevated SIR of CVA (1.74; 95% CI, 0.94 to 2.37) in patients with early BC after a median follow-up of 6.8 years. In the Early Breast Cancer Trialists' Collaborative Group meta-analysis on effects of RT, the gain in BC survival from RT was partly offset by an increase of vascular mortality.2 A recent update3 showed that this excess vascular mortality mainly involved heart disease, whereas risk of stroke was not increased in irradiated versus nonirradiated patients. In a large population-based study (median follow-up, 5.4 years), Nilsson et al26 found that BC patients had an overall relative risk (RR) of stroke of 1.12 (95% CI, 1.07 to 1.17) compared with the general population. This increased risk was especially pronounced during the first year after diagnosis (RR = 1.22; 95% CI, 1.06 to 1.39). Possibly, the increase during the first year was caused by tumor-related coagulation disorders.27,28 The effect of specific treatment regimens could not be examined because of lack of information. Retrospective studies of head and neck tumor patients and survivors of Hodgkin's lymphoma irradiated to the carotid region show a significantly increased risk of stroke. In BC patients, both left and right supraclavicular radiation portals include the ipsilateral CCA, with the left artery exposed over a slightly longer stretch than the right one. Therefore, we expected an increased risk of CVA, probably somewhat higher for RT on the left side. Overall, we found no increased risk of CVA. When analyzing by laterality, we observed an increased risk of TIA among women irradiated on the left supraclavicular region (HR = 2.00; Table 5, see HT such as tamoxifen increases the risk of venous thromboembolism, and some recently published studies have investigated risk of stroke associated with tamoxifen.29-31 Results from a meta-analysis by Bushnell and Goldstein8 showed an elevated risk of ischemic stroke (RR = 1.82; 95% CI, 1.41 to 2.36). However, the International Breast Cancer Intervention Study-I prevention study29 and the nested case-control study by Geiger et al31did not demonstrate a significantly increased risk of stroke with tamoxifen. In our study, we observed a nearly two-fold elevated risk of stroke in patients treated with HT. However, tamoxifen is often prescribed for metastasized BC. Therefore, the association with tamoxifen may be confounded by the presence of active disease, which in itself may predispose to thrombosis27 and thereby to ischemic stroke.32 The separate effects of active disease and HT could not be disentangled in earlier studies.29,31 Therefore, we assessed the influence of HT on the risk of stroke separately in patients without signs of relapse and again observed a (nonsignificantly) increased risk of stroke (HR = 2.14). Our recent study on cause-specific mortality in BC patients already showed a (nonsignificant) 16% decrease in overall mortality from stroke.20 Importantly, this study showed no mortality increase from stroke during the first 10 years of follow-up, justifying our decision to focus on 10-year survivors of BC in the current study. There are several explanations for reduced risk of stroke in long-term BC survivors compared with the general population. First, the risk profile for BC (eg, late menopause) may be protective against (cerebro)vascular disease.33 In addition, women may opt for a healthier lifestyle (eg, more exercise, healthier diet) after BC diagnosis, which would reduce their risk profile for stroke even more.34,35 Although we did not observe a more favorable risk profile in the study population compared with the general population, our BC cohort may have been subject to more subtle changes in risk profile during follow-up (eg, dietary changes, less smoking rather than cessation of smoking). Hypertension was even more frequently diagnosed in our BC population than in the general female population, probably as a result of surveillance bias. Paradoxically, this might explain the reduced risk of stroke. BC patients with known hypertension will receive treatment and thus reduce their risk of stroke, whereas a high proportion of the general population with hypertension may not be correctly diagnosed and thus will remain untreated. Finally, particularly in this cancer center–based study population, we may have studied BC patients with higher socioeconomic status, which has been reported to be associated with lower rates of vascular disease.36,37 Strengths of our study include the availability of data on all primary and follow-up treatments, including radiation fields, and on cerebrovascular risk factors. Follow-up was near complete and very long, with over 30% of patients followed for more than 20 years. A potential weakness of our study concerns under-reporting of CVA diagnoses. However, a study on cardiovascular risk in the same study population38 rendered a significant 1.3-fold increased risk of cardiovascular disease, which was comparable to results from other studies.2,5,39 In both studies on vascular events, we obtained information from GPs for the large majority of patients because a pilot study had shown that 20% of vascular events were not registered in oncologic records. Furthermore, since the GP was the source of information for both observed events and the reference rates used for comparison, any underreporting by GPs would not affect the validity of our results. Although we had information on cardiac risk factors at baseline and also at follow-up, it was not always available at the time we were most interested in (ie, at 10 years after first treatment). We used hypertension, DM, and hypercholesterolemia as fixed covariates in the analysis with a positive score obtained at any point in time. Although this approach may have introduced some misclassification, this would be expected to bias our risk estimates to unity. As for smoking, this problem was largely avoided by using separate categories for smokers who continued smoking until the end of follow-up and for ex-smokers (those who stopped at the time of BC diagnosis). In conclusion, no association between stroke risk and irradiation to the supraclavicular nodes was found in our BC population. Although adjuvant HT4 clearly improves BC survival, physicians should be aware of the increased risk of stroke after HT in long-term BC survivors.
Example for the calculation of expected events. A woman diagnosed at age 50 years in 1980 and subsequently observed until 2000, would contribute 10 years time at risk, from 1990 to 2000. Reference rates were available for 3-year calendar periods from 1972 to 2000, covering 5-year age groups ranging from 0 to 85+ years. Consequently, from the years 1990 to 1992, she would contribute all 3 years to age group 60 to 64 in the calendar period 1990 to 1992. For 1993 to 1994 (ages 63-64) 2 years would be allocated to age group 60 to 64 in the calendar period 1993 to 1995. Then 1 year (1995; age 65) would be added to age group 65 to 69 in the calendar period 1993 to 1995. From the years 1996 to 1998 (ages 66-68), she would contribute all 3 years to age group 65 to 69 in the calendar period 1996 to 1998, and so on. Multiplying the total number of years at risk per cell with the specific rate and adding up the outcomes from all cells, would result in the expected number of events. Finally the standardized incidence ratio was calculated by dividing the observed by the expected number of events.
The authors indicated no potential conflicts of interest.
We thank E.H. van de Lisdonk (Continuous Morbidity Registration–Nijmegen); A.A.M. Hart, A.W. van den Belt-Dusebout, V.B. Hartog, S.E. Kraus, and M.A. Kuenen (Netherlands Cancer Institute, Amsterdam, the Netherlands); and more than 3,500 physicians from throughout the Netherlands who provided follow-up data.
published online ahead of print at www.jco.org on November 6, 2006. Supported by Dutch Cancer Society Grant No. NKI 98-1833. Both M.J.H. and L.D.A.D. contributed equally to this work. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Early Breast Cancer Trialists' Collaborative Group: Effects of radiotherapy and surgery in early breast cancer: An overview of the randomized trials. N Engl J Med 333:1444-1455, 1995 2. Early Breast Cancer Trialists' Collaborative Group: Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomised trials. Lancet 355:1757-1770, 2000[CrossRef][Medline] 3. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005[Medline] 4. Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 5. 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[Abstract] 6. Harvey EB, Brinton LA: Second cancer following cancer of the breast in Connecticut, 1935-82. Natl Cancer Inst Monogr 68:99-112, 1985[Medline] 7. Rutqvist LE, Johansson H: Mortality by laterality of the primary tumour among 55,000 breast cancer patients from the Swedish Cancer Registry. Br J Cancer 61:866-868, 1990[Medline] 8. Bushnell CD, Goldstein LB: Risk of ischemic stroke with tamoxifen treatment for breast cancer: A meta-analysis. Neurology 63:1230-1233, 2004 9. Nuver J, Smit AJ, van der Meer J, et al: Acute chemotherapy-induced cardiovascular changes in patients with testicular cancer. J Clin Oncol 23:9051-9052, 2005 10. Atabek U, Spence RK, Alexander JB, et al: Upper extremity occlusive arterial disease after radiotherapy for breast cancer. J Surg Oncol 49:205-207, 1992[Medline] 11. Gyenes G, Rutqvist LE, Liedberg A, et al: Long-term cardiac morbidity and mortality in a randomized trial of pre- and postoperative radiation therapy versus surgery alone in primary breast cancer. Radiother Oncol 48:185-190, 1998[CrossRef][Medline] 12. Hashmonai M, Elami A, Kuten A, et al: Subclavian artery occlusion after radiotherapy for carcinoma of the breast. Cancer 61:2015-2018, 1988[CrossRef][Medline] 13. 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[CrossRef][Medline] 14. Taylor PJ, Cooper GG, Sarkar TK: Upper-limb arterial disease in women treated for breast cancer. Br J Surg 82:1089-1091, 1995[Medline] 15. Cheng SW, Ting AC, Lam LK, et al: Carotid stenosis after radiotherapy for nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg 126:517-521, 2000 16. Dubec JJ, Munk PL, Tsang V, et al: Carotid artery stenosis in patients who have undergone radiation therapy for head and neck malignancy. Br J Radiol 71:872-875, 1998[Abstract] 17. Dorresteijn LD, Kappelle AC, Boogerd W, et al: Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years. J Clin Oncol 20:282-288, 2002 18. Haynes JC, Machtay M, Weber RS, et al: Relative risk of stroke in head and neck carcinoma patients treated with external cervical irradiation. Laryngoscope 112:1883-1887, 2002[CrossRef][Medline] 19. Bowers DC, McNeil DE, Liu Y, et al: Stroke as a late treatment effect of Hodgkin's disease: A report from the Childhood Cancer Survivor Study. J Clin Oncol 23:6508-6515, 2005 20. Hooning MJ, Aleman BMP, van Rosmalen AJM, et al: Cause-specific mortality in long-term survivors of breast cancer: A 25-year follow-up study. Int J Radiat Oncol Biol Phys 64:1081-1091, 2006[CrossRef][Medline] 21. Lisdonk van de EH, Bosch van den WJHM, Huygen FJA, et al: Ziekten in de Huisartsenpraktijk (ed 3). Maarssen, the Netherlands, Elsevier/Bunge, 1999 22. Breslow NE, Day NE: Statistical methods in cancer research, in Volume II: The design and Analysis of Cohort Studies. International Agency for Research on Cancer Press, 1987, pp 1-406 23. Cox DR: Regression models and life-tables. J R Stat Soc B 34:187-202, 1972 24. Nationaal Kompas voor de Volksgezondheid: 12/2004 update. http://www.rivm.nl/vtv/object_documentation/o1210n19085.html 25. Jagsi R, Griffith KA, Koelling T, et al: Stroke rates and risk factors in patients treated with radiation therapy for early-stage breast cancer. J Clin Oncol 24:2779-2785, 2006 26. Nilsson G, Holmberg L, Garmo H, et al: Increased incidence of stroke in women with breast cancer. Eur J Cancer 41:423-429, 2005[CrossRef][Medline] 27. Blom JW, Doggen CJ, Osanto S, et al: Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 293:715-722, 2005 28. Lee AY, Levine MN: Venous thromboembolism and cancer: Risks and outcomes. Circulation 107:I-17–I-21, 2003[Medline] 29. Cuzick J, Forbes J, Edwards R, et al: First results from the International Breast Cancer Intervention Study (IBIS-I): A randomised prevention trial. Lancet 360:817-824, 2002[CrossRef][Medline] 30. Dignam JJ, Fisher B: Occurrence of stroke with tamoxifen in NSABP B-24. Lancet 355:848-849, 2000[Medline] 31. Geiger AM, Fischberg GM, Chen W, et al: Stroke risk and tamoxifen therapy for breast cancer. J Natl Cancer Inst 96:1528-1536, 2004 32. Rogers LR: Cerebrovascular complications in patients with cancer. Semin Neurol 24:453-460, 2004[CrossRef][Medline] 33. Barrett-Connor E, Bush TL: Estrogen and coronary heart disease in women. JAMA 265:1861-1867, 1991 34. Selmer R, Tverdal A: Body mass index and cardiovascular mortality at different levels of blood pressure: A prospective study of Norwegian men and women. J Epidemiol Community Health 49:265-270, 1995 35. Sjostrom L, Lindroos AK, Peltonen M, et al: Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 351:2683-2693, 2004 36. Casper ML, Wing S, Anda RF, et al: The shifting stroke belt: Changes in the geographic pattern of stroke mortality in the United States, 1962 to 1988. Stroke 26:755-760, 1995 37. Manhem K, Dotevall A, Wilhelmsen L, et al: Social gradients in cardiovascular risk factors and symptoms of Swedish men and women: The Goteborg MONICA Study 1995. J Cardiovasc Risk 7:359-368, 2000[Medline] 38. Hooning MJ, Botma A, Aleman BMP, et al: Long-term risk of cardiovascular disease in 10-years survivors of breast cancer. Breast Cancer Res Treat 94:S177, 2005 (abstr 4035)[CrossRef] 39. 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 Submitted March 14, 2006; accepted September 26, 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
footnote), whereas no such risk increase was found for the right side (HR = 0.84). No left–right difference was observed for stroke, however. Although there were some differences in fractionation schedules used in our study population, all schedules had a more or less equivalent biologic effective dose. Consequently, we did not expect any differences in risk between these fractionation regimens. 
