Radiation-Induced Heart Disease After Breast Cancer Treatment: How Big a Problem, and How Much Can-and Should-We Try to Reduce It?

More than 20 years ago, the Early Breast Cancer Trialists’ Collaborative Group found radiotherapy (RT) increased long-term noncancer mortality. Subsequent meta-analyses and registry-based studies reported higher mortality rates for individuals undergoing irradiation of left-sided cancers (whose average exposed cardiac volume and dose are higher) compared with right-sided cancers. However, patients in these studies were largely treated with RT techniques that on average exposedmuch larger cardiac volumes to much higher doses than techniques that came into common use by 1980. The Danish randomized trials of postmastectomy RT, which enrolled more than 3,000 patients from 1982 to 1990, found no difference in cardiac morbidity or mortality between patients who underwent irradiation and those who did not, whether they had leftsided or right-sided cancers, with amedian follow-up of 117months in surviving patients. Several other single-institution studies using modern RT techniques have also not shown increased cardiac morbidity or mortality at median follow-up times of 10 to 20 years, although others have. Finally, large registry studies have not found a significant excess incidence of radiation-induced heart disease (RIHD) for patients undergoing irradiation after approximately 1980 to 1985. There is nonetheless still reason to worry about RIHD, even if population-wide effects are no longer seen. Although the average cardiac exposure has decreased with modern techniques, some patients will still have much greater irradiated cardiac volumes than others. For example, a recent study from the University of California, San Francisco, of 256 patients with left-sided cancers treated from 2007 to 2013 without inclusion of the internal mammary nodes found the mean heart dose (MHD) per patient ranged from 0.91 to 4.45 Gy. Some individuals also have comorbidities that may place them at increased risk of RIHD, even if the irradiated volume is relatively small. However, few studies have examined this issue. Preexisting ischemic heart disease was a risk factor for developing acute cardiac events in a study from Sweden and Denmark. A study from the University of Pennsylvania in Philadelphia found a statistically significant interaction between hypertension and left-breast irradiation for the development of coronary artery disease. However, a study from Amsterdam and Rotterdam found that hypertension was not a significant risk factor, but smoking was. (Of note, excess cardiac events in this study occurred in patients treated with postmastectomy RT, which generally included the internal mammary nodes, but not in patients treated only to the breast after partial mastectomy.) Darby et al recently analyzed how the irradiated volume and patient risk factors interact in causing cardiac disease. Their casecontrol study included more than 2,000 women treated in Sweden and Denmark between 1958 and 2001. They found a linear relationship between MHD and risk of a major coronary event. This relationship was substantially modulated by whether patients had preexisting cardiac risk factors, such as hypertension or diabetes. However, RT techniques and fractionation schemes changed enormously over this study period. (For example, in an analysis of coronary stenosis in Swedish patients with breast cancer, standard fractionation changed from 45Gy in 3-Gy fractions to 46Gy in 2.3-Gy fractions to 50 Gy in 2-Gy fractions between 1970 and 2003.) The investigators tried to overcome this problem by using the linearquadratic model to convert all treatments to an equivalent dose in 2-Gy fractions, but the validity of this approach for cardiac effects has never been proven. Furthermore, patients in this study were treated well before computed tomography (CT) –based simulation became common. Hence, cardiac volumes and doses were calculated based on a reconstruction of each patient’s fields on a single CTscan of a woman with so-called typical anatomy and not measured individually. Therefore, the validity of their findings is uncertain. The superbly conducted and reported study by van den Bogaard et al in Groningen, the Netherlands, that accompanies this editorial is the first to my knowledge to perform such an analysis of cardiac outcomes in a population treated with a uniform RT technique, with CT-based simulation from which individuals’ cardiac dose-volume parameters could be measured, and with thorough data on cardiac risk factors (defined as preexisting ischemic or other heart disease, hypertension, chronic obstructive pulmonary disease, pulmonary embolism, diabetes, current smoking status, and body mass index$ 30 kg/m). With median followup of 7.6 years in 910 patients, there were 30 acute cardiac events (ie, myocardial infarction, coronary revascularization, or death resulting from ischemic heart disease), of which 11 were fatal. The cumulative incidence in the first 9 years after RT was 3.9%; they estimated 1.1% was attributable to RT. Cardiac risk increased by 16.5% per Gy of MHD during this period, almost identical to the