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194 speaker RADIATION-RELATED HEART DISEASE FOLLOWING TREATMENT FOR BREAST CANCER
S 76
S YMPOSIUM
T UESDAY, M AY 10, 2011
194 speaker
30 years of radiation oncology in Breast cancer What is the evidence that ‘we’ have created? - Update on randomized trials and Meta-analyses
RADIATION-RELATED HEART DISEASE FOLLOWING TREATMENT FOR BREAST CANCER C. Taylor1 1 U NIVERSITY OF OXFORD, Clinical Trial Service Unit, Oxford, United Kingdom
193 speaker RADIOTHERAPY AFTER BREAST-CONSERVING SURGERY IN EARLY BREAST CANCER: UPDATE FROM THE EARLY BREAST CANCER TRIALISTS’ COLLABORATIVE GROUP S. Darby1 1
U NIVERSITY OF OXFORD, Clinical Trial Service Unit, Oxford, United Kingdom
Background: For common diseases, including breast cancer, treatments that improve survival by only a few percentage points can save many lives. Individual trials are often not large enough to detect such small differences reliably, so overviews combining data from all trials are necessary. By doing this, it is possible to obtain estimates of the differences between treatments that are more precise than the estimates given by any individual trial. This combination cannot be done satisfactorily from published data alone, as the inclusion of unpublished as well as published data is necessary to avoid bias. Furthermore, the information available from the published trials is not sufficient to allow a uniform analysis of all the available data with appropriate stratification for factors that will affect survival such as age, time since diagnosis, node status, and so on. Thus, analysis based on individual patient data is necessary. Following breast-conserving surgery for early breast cancer, it is known that radiotherapy can reduce the risk of recurrence and of death from breast cancer. The question arises as to whether the absolute benefit is greater for some groups of women than for others. To examine the evidence for any such differences and, where appropriate, to quantify them, collaborative meta-analyses of individual patient data have been undertaken of the relevant randomised trials that began before 1 January 2000. Material and methods: Information was available on 10,801 women in 17 randomised trials of radiotherapy after breast-conserving surgery. Median follow-up for early trials was 12.2 years, but only 6.6 years for recent trials of women judged to be at low risk of recurrence. The 10-yr risks of any recurrence (ie locoregional or distant) with and without radiotherapy were estimated for women with differing values of various predictive factors. 15-yr risks of death from breast cancer and from all causes were also estimated. Women were classified as large, medium, or small predicted absolute benefit by considering the dependence of the rate of first recurrence on predictive factors. Findings: For all women (n=10,801), radiotherapy reduced the absolute 10year risk of any first recurrence by 15.7% (19.3% vs. 35.0%; 2p<0.00001) and the absolute 15-year risk of breast cancer death by 3.8% (21.4% vs. 25.2%; 2p=0.00005). In pN0 disease (n=7287), radiotherapy reduced the absolute 10-year risk of any first recurrence by 15.4% (15.6 vs. 31.0%; 2p<0.00001), and the absolute 15-year risk of breast cancer death by 3.3% (17.2% vs. 20.5%; 2p<0.005). For women with large, medium, and small predicted absolute benefit, 10-year absolute reductions in first recurrence risk were 24.3 % (95% confidence interval 19.6, 29.0), 12.4% (9.7, 15.1) and 6.0% (2.2, 11.6) (2p trend <0.00001) and 15-year absolute reductions in breast cancer death were 7.9% (95% confidence interval 3.1, 12.5), 1.0% (-2.0, 4.2), and 0.1% (-7.5, 7.7) (2p trend 0.03 ). In pN+ disease (n=1050), radiotherapy reduced the absolute 10-year risk of any first recurrence by 21.2% (42.5% vs. 63.7%; 2p<0.00001), and the absolute 15-year risk of breast cancer death by 8.5% (42.8% vs. 51.3%; 2p=0.01). No factor was independently predictive of absolute benefit. Interpretation: Radiotherapy conferred substantial absolute reductions in the risks of recurrence and breast cancer death for pN+ women and for some groups of pN0 women. For other pN0 women, radiotherapy conferred a moderate absolute reduction in recurrence risk and may also confer a small reduction in breast cancer death.
It has been recognized since the 1960s that the heart may be damaged by substantial doses of radiation [>30 Gray (Gy)], such as used to occur during mantle radiotherapy for Hodgkin lymphoma. During the last few years, however, evidence that radiation-induced heart disease can occur following doses below 20 Gy has emerged from several independent sources. These sources include randomized trials of radiotherapy in breast cancer patients who received cardiac doses up to about 20 Gy and studies of survivors of the atomic bombings of Japan who received uniform whole-body doses of up to 4 Gy. Much of our knowledge of the effect of radiation on the heart has come from long-term follow-up of breast cancer patients entered into trials in which all women received similar treatment in terms of surgery and drugs, and then half of the women were allocated at random also to receive adjuvant radiotherapy. One of the first studies to examine the effect of radiotherapy on long-term survival in breast cancer was a meta-analysis of randomized trials published in 1987 which showed that survival beyond 10 years was significantly worse for those receiving radiotherapy. This early study was unable to determine the disease responsible for the detrimental effect on survival, but subsequent meta-analyses by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) have shown that mortality from heart disease was increased by 27% (2p =0.0001) in women randomized to surgery plus radiotherapy compared with women randomized to surgery alone. Most of the increase was due to coronary artery disease. Recently, a preliminary analysis of updated EBCTCG data has related mortality from heart disease to estimated cardiac doses in over 30,000 women followed for up to 20 years. There is clear evidence that the radiation-related increase is higher in trials with larger mean cardiac doses and that the risk of death from heart disease increases by 3% per Gy (95% CI, 2%-5%; 2p < 0.00001). This estimate can only be taken as an approximate indication of the risk, as individual treatment plans were not available for the women in those trials. Nevertheless, the data provide strong evidence that the risk of radiation-related heart disease was related to cardiac dose in these irradiated breast cancer patients. Outside the context of a randomized trial, comparisons of heart disease rates in individuals exposed to radiation at different levels are often misleading because those exposed at different levels may well have had different levels of risk in the absence of any radiation exposure. In breast cancer, however, a reliable indication of the effect of radiotherapy on heart disease can be obtained by comparing the experience of irradiated women with left-sided tumors with that of women with right-sided tumors. This can be done because cardiac radiation doses in women given radiotherapy for left-sided tumors are usually larger than the cardiac radiation doses in women with right-sided tumors, and breast cancer laterality has, in the past, played little part in determining who should be given radiotherapy. The opportunity afforded by the comparison of left-sided and right-sided breast cancer patients paves the way for more detailed studies of the effects of cardiac radiation on subsequent heart disease. For example, a recent study examining the incidence of coronary artery disease following breast irradiation revealed a higher prevalence of stress test abnormalities in leftsided than in right-sided tumor patients (59% vs. 8%; p = 0.001). Among left-sided tumor patients, the disease distribution differed from that expected in women, with a preponderance of left anterior descending artery disease. The anterior portion of the heart and the left anterior descending artery territory are the parts of the heart most often within the tangential radiation fields used to treat breast cancer. Hence, this finding provides direct evidence of a causal effect of radiotherapy on the development of coronary artery disease. Another example is the RACE study in which the remarkable possibilities available in Denmark and Sweden are being used to identify women with breast cancer through the national cancer registries, and then to obtain details of their radiotherapy exposure from the national health care systems and also information on any subsequent cardio-vascular events from the cause of death and hospital discharge registries. Provisional results of this study will be presented.
S YMPOSIUM
T UESDAY, M AY 10, 2011
194 speaker
30 years of radiation oncology in Breast cancer What is the evidence that ‘we’ have created? - Update on randomized trials and Meta-analyses
RADIATION-RELATED HEART DISEASE FOLLOWING TREATMENT FOR BREAST CANCER C. Taylor1 1 U NIVERSITY OF OXFORD, Clinical Trial Service Unit, Oxford, United Kingdom
193 speaker RADIOTHERAPY AFTER BREAST-CONSERVING SURGERY IN EARLY BREAST CANCER: UPDATE FROM THE EARLY BREAST CANCER TRIALISTS’ COLLABORATIVE GROUP S. Darby1 1
U NIVERSITY OF OXFORD, Clinical Trial Service Unit, Oxford, United Kingdom
Background: For common diseases, including breast cancer, treatments that improve survival by only a few percentage points can save many lives. Individual trials are often not large enough to detect such small differences reliably, so overviews combining data from all trials are necessary. By doing this, it is possible to obtain estimates of the differences between treatments that are more precise than the estimates given by any individual trial. This combination cannot be done satisfactorily from published data alone, as the inclusion of unpublished as well as published data is necessary to avoid bias. Furthermore, the information available from the published trials is not sufficient to allow a uniform analysis of all the available data with appropriate stratification for factors that will affect survival such as age, time since diagnosis, node status, and so on. Thus, analysis based on individual patient data is necessary. Following breast-conserving surgery for early breast cancer, it is known that radiotherapy can reduce the risk of recurrence and of death from breast cancer. The question arises as to whether the absolute benefit is greater for some groups of women than for others. To examine the evidence for any such differences and, where appropriate, to quantify them, collaborative meta-analyses of individual patient data have been undertaken of the relevant randomised trials that began before 1 January 2000. Material and methods: Information was available on 10,801 women in 17 randomised trials of radiotherapy after breast-conserving surgery. Median follow-up for early trials was 12.2 years, but only 6.6 years for recent trials of women judged to be at low risk of recurrence. The 10-yr risks of any recurrence (ie locoregional or distant) with and without radiotherapy were estimated for women with differing values of various predictive factors. 15-yr risks of death from breast cancer and from all causes were also estimated. Women were classified as large, medium, or small predicted absolute benefit by considering the dependence of the rate of first recurrence on predictive factors. Findings: For all women (n=10,801), radiotherapy reduced the absolute 10year risk of any first recurrence by 15.7% (19.3% vs. 35.0%; 2p<0.00001) and the absolute 15-year risk of breast cancer death by 3.8% (21.4% vs. 25.2%; 2p=0.00005). In pN0 disease (n=7287), radiotherapy reduced the absolute 10-year risk of any first recurrence by 15.4% (15.6 vs. 31.0%; 2p<0.00001), and the absolute 15-year risk of breast cancer death by 3.3% (17.2% vs. 20.5%; 2p<0.005). For women with large, medium, and small predicted absolute benefit, 10-year absolute reductions in first recurrence risk were 24.3 % (95% confidence interval 19.6, 29.0), 12.4% (9.7, 15.1) and 6.0% (2.2, 11.6) (2p trend <0.00001) and 15-year absolute reductions in breast cancer death were 7.9% (95% confidence interval 3.1, 12.5), 1.0% (-2.0, 4.2), and 0.1% (-7.5, 7.7) (2p trend 0.03 ). In pN+ disease (n=1050), radiotherapy reduced the absolute 10-year risk of any first recurrence by 21.2% (42.5% vs. 63.7%; 2p<0.00001), and the absolute 15-year risk of breast cancer death by 8.5% (42.8% vs. 51.3%; 2p=0.01). No factor was independently predictive of absolute benefit. Interpretation: Radiotherapy conferred substantial absolute reductions in the risks of recurrence and breast cancer death for pN+ women and for some groups of pN0 women. For other pN0 women, radiotherapy conferred a moderate absolute reduction in recurrence risk and may also confer a small reduction in breast cancer death.
It has been recognized since the 1960s that the heart may be damaged by substantial doses of radiation [>30 Gray (Gy)], such as used to occur during mantle radiotherapy for Hodgkin lymphoma. During the last few years, however, evidence that radiation-induced heart disease can occur following doses below 20 Gy has emerged from several independent sources. These sources include randomized trials of radiotherapy in breast cancer patients who received cardiac doses up to about 20 Gy and studies of survivors of the atomic bombings of Japan who received uniform whole-body doses of up to 4 Gy. Much of our knowledge of the effect of radiation on the heart has come from long-term follow-up of breast cancer patients entered into trials in which all women received similar treatment in terms of surgery and drugs, and then half of the women were allocated at random also to receive adjuvant radiotherapy. One of the first studies to examine the effect of radiotherapy on long-term survival in breast cancer was a meta-analysis of randomized trials published in 1987 which showed that survival beyond 10 years was significantly worse for those receiving radiotherapy. This early study was unable to determine the disease responsible for the detrimental effect on survival, but subsequent meta-analyses by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) have shown that mortality from heart disease was increased by 27% (2p =0.0001) in women randomized to surgery plus radiotherapy compared with women randomized to surgery alone. Most of the increase was due to coronary artery disease. Recently, a preliminary analysis of updated EBCTCG data has related mortality from heart disease to estimated cardiac doses in over 30,000 women followed for up to 20 years. There is clear evidence that the radiation-related increase is higher in trials with larger mean cardiac doses and that the risk of death from heart disease increases by 3% per Gy (95% CI, 2%-5%; 2p < 0.00001). This estimate can only be taken as an approximate indication of the risk, as individual treatment plans were not available for the women in those trials. Nevertheless, the data provide strong evidence that the risk of radiation-related heart disease was related to cardiac dose in these irradiated breast cancer patients. Outside the context of a randomized trial, comparisons of heart disease rates in individuals exposed to radiation at different levels are often misleading because those exposed at different levels may well have had different levels of risk in the absence of any radiation exposure. In breast cancer, however, a reliable indication of the effect of radiotherapy on heart disease can be obtained by comparing the experience of irradiated women with left-sided tumors with that of women with right-sided tumors. This can be done because cardiac radiation doses in women given radiotherapy for left-sided tumors are usually larger than the cardiac radiation doses in women with right-sided tumors, and breast cancer laterality has, in the past, played little part in determining who should be given radiotherapy. The opportunity afforded by the comparison of left-sided and right-sided breast cancer patients paves the way for more detailed studies of the effects of cardiac radiation on subsequent heart disease. For example, a recent study examining the incidence of coronary artery disease following breast irradiation revealed a higher prevalence of stress test abnormalities in leftsided than in right-sided tumor patients (59% vs. 8%; p = 0.001). Among left-sided tumor patients, the disease distribution differed from that expected in women, with a preponderance of left anterior descending artery disease. The anterior portion of the heart and the left anterior descending artery territory are the parts of the heart most often within the tangential radiation fields used to treat breast cancer. Hence, this finding provides direct evidence of a causal effect of radiotherapy on the development of coronary artery disease. Another example is the RACE study in which the remarkable possibilities available in Denmark and Sweden are being used to identify women with breast cancer through the national cancer registries, and then to obtain details of their radiotherapy exposure from the national health care systems and also information on any subsequent cardio-vascular events from the cause of death and hospital discharge registries. Provisional results of this study will be presented.