A population-based case-control study reported by Sarah C. Darby, PhD, Professor of Medical Statistics in the Clinical Trial Service Unit and Epidemiologic Studies Unit at the University of Oxford, and colleagues in The New England Journal of Medicine indicates that incidental exposure of the heart to radiation in breast cancer treatment is associated with increased risk of ischemic heart disease.¹ The investigators found that the risk of major coronary events increased linearly with radiation dose to the heart, with increased risk starting within 5 years after radiotherapy, and that women with preexisting cardiac risk factors have a greater absolute risk than other women.

The study involved 2,168 women who underwent radiotherapy for breast cancer between 1958 and 2001 and who were younger than 70 years at the time of breast cancer diagnosis in Sweden or between 1977 and 2000 and who were younger than 75 years at diagnosis in Denmark. The analysis included a total of 963 women with major coronary events, defined as myocardial infarction, coronary revascularization, or death from ischemic heart disease, and 1,205 controls matched for country, age at diagnosis, and year of diagnosis who had no major coronary event prior to an index date defined as the date of breast cancer diagnosis plus time to first major event in the matched case patient. Mean radiation doses to the whole heart and left anterior descending coronary artery were estimated from radiotherapy charts.

Risks for Major Coronary Events

Overall, women irradiated for cancer of the left breast had higher major coronary event rates than women with irradiation to the right breast (rate ratio [RR] = 1.32, P = .002). There were no other strong associations between major coronary events and tumor characteristics or cancer treatments administered in addition to radiotherapy, apart from a borderline significant association with positive nodal status (RR = 1.20, P = .06).

The rate ratio for major coronary events among women with a history of ischemic heart disease was 6.67 compared with the rate in women without such history (overall P < .001). Elevated rates of major coronary events were also associated with a history of other circulatory diseases, diabetes, chronic obstructive pulmonary disease, smoking, high body mass index, and history of regular analgesic use. The rate ratio for major coronary events when one or more of these factors was present in the absence of history of ischemic heart disease was 1.96.

Effects of Radiotherapy

The average of the estimated mean doses of radiation to the heart was 6.6 Gy in women with tumors in the left breast, 2.9 Gy in those with tumors in the right breast, and 4.9 Gy overall. The rate of major coronary events increased by 7.4% for each increase of 1 Gy delivered to the heart (P < .001).

Compared with the estimated major coronary event rate for no radiation dose to the heart, major coronary event rates increased by 10% for doses < 2 Gy, 30% for doses of 2 to 4 Gy, 40% for doses of 5 to 9 Gy, and 116% for doses of 10 Gy or more. The percentage increase per Gy did not differ according to any of the matching factors used in selection of control patients, tumor characteristics (including whether the tumor was in the right or left breast), or cancer treatment in addition to radiotherapy. Although the overall major coronary event rate was higher in women with vs without cardiac risk factors, the percentage increase in rate per Gy was similar for both groups.

The percentage increases in major coronary event rate per Gy according to number of years since radiation exposure were 16.3% for 0 to 4 years, 15.5% for 5 to 9 years, 1.2% for 10 to 19 years, and 8.2% for 20 or more years. Findings were similar when this analysis was repeated separately according to age at time of breast cancer diagnosis, presence or absence of preexisting cardiac risk factors, and whether the case patient had died from ischemic heart disease.

The estimated mean dose of radiation to the heart was a better predictor of major coronary events (P < .001) than the estimated mean dose to the left anterior descending coronary artery (P = .001). The estimated mean dose to the heart remained a significant predictor (P = .04) after adjustment for the estimated mean dose to the left anterior descending coronary artery. The mean dose to the left anterior descending coronary artery was no longer a significant predictor (P = .62) after adjustment for the estimated mean dose to the heart.

Study Limitations

Limitations of the study include the fact that computed tomography (CT)-based information on radiotherapy was not available for the women studied, since they were treated prior to the era of three-dimensional CT-based planning. Further, the study included few women younger than 40 years at the time of radiotherapy; as noted by the authors, “[C]aution is needed in applying our results to women in this age group, and the possibility of larger increases in the rate of major coronary events per gray of radiation for this group cannot be ruled out.”

In addition, few women in the study were treated with anthracyclines and none received taxanes or trastuzumab (Herceptin). All of these drugs are known to have adverse effects on the heart even in the absence of radiotherapy.

The authors concluded:

[W]e found that incidental exposure of the heart to radiotherapy for breast cancer increased the rate of major coronary events by 7.4% per gray, with no apparent threshold. The percentage increase per unit increase in the mean dose of radiation to the heart was similar for women with and women without preexisting cardiac risk factors, which indicates that the absolute increases in risk for a given dose to the heart were larger for women with preexisting cardiac risk factors. Therefore, clinicians may wish to consider cardiac dose and cardiac risk factors as well as tumor control when making decisions about the use of radiotherapy for breast cancer. ■

Disclosure: The study was supported by funding or grants from Cancer Research UK, British Heart Foundation, UK Medical Research Council, European Commission, UK Department of Health, and Oxford National Institute for Health Research Biomedical Research Centre.

Reference

1. Darby SC, Ewertz M, McGale P, et al: Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 368:987-998, 2013.