CVD risks of breast cancer radiation quantified in new study

Fran Lowry

March 13, 2013

Boston, MA - Women exposed to ionizing radiation when they receive radiotherapy as part of their treatment for breast cancer have an increased risk of developing heart disease, and a new study quantifies this risk in the March 14, 2013 issue of the New England Journal of Medicine[1] .

"Oncologists have always suspected that ionizing radiation for breast cancer, particularly for left-sided breast cancer, increases the risk of myocardial infarction, and there have been a couple of studies done over the years, including one that we published nearly 10 years ago," senior author Dr Per Hall (Karolinska Institutet, Stockholm, Sweden) said in an interview. "What we haven't known is at what doses this risk increases. Nor have we understood how previous disorders influence this risk."

Hall and his group conducted a population-based case-control study of major coronary events, including MI, coronary revascularization, or death from ischemic heart disease, in 2168 women who had radiotherapy for breast cancer between 1958 and 2001 in Sweden and Denmark.

Of these, 963 women had major coronary events and 1205 women were controls. Of the coronary events, 44% occurred less than 10 years after breast cancer was diagnosed, 33% occurred 10 to 19 years afterward, and 23% occurred 20 or more years after breast-cancer diagnosis.

Irradiation for cancer of the left breast was associated with higher rates of major coronary events than irradiation of the right breast (p=0.002). However, there was no link between major coronary events and characteristics of the tumor or the chemotherapy received to treat the breast cancer.

The mean radiation dose to the heart was 4.9 Gy (range 0.03-27.72 Gy), and the researchers found that rates of major coronary events increased as the mean dose to the heart increased.

For women with tumors in the left breast, the estimated mean dose of radiation to the heart was 6.6 Gy, and for those with tumors in the right breast, it was 2.9 Gy.

Each Gy of radiation was associated with a 7.4% increase in the occurrence of a subsequent major coronary event (95% CI 2.9-14.5; p<0.001).

The researchers also found that the risk of a major coronary event increased within five years of exposure to radiation, and this risk continued out to three decades after radiotherapy.

Women with a history of ischemic heart disease were at greater risk of having a major coronary event. The overall rate ratio for a major coronary event among women with a history of ischemic heart disease was 6.67 (95% CI 4.37-10.18) compared with women with no such history.

This risk was highest in the first 10 years after the cancer diagnosis, when the rate ratio was 13.43 (95% CI 7.65-23.58). During later years, this rate ratio was 2.09 (95% CI 1.05-4.13; p<0.001).

Women with previous circulatory diseases, diabetes, chronic obstructive pulmonary disease and those who smoked, had a high body-mass index, or a history of regular analgesic use also had higher rates of major coronary events.

Hall pointed out that many people would argue that the radiation doses to the heart are lower today than previously, but although this is true, many of the drugs developed to treat breast cancer are themselves cardiotoxic, including the older chemotherapy compounds such as anthracyclines.

"In this project we were not able to study the combined effect of radiotherapy and cardiotoxic compounds, due to the low number of women who were treated more recently," he said.

Hall also noted some of his study's limitations.

"The major limitations were that, in order to have a long follow-up, we mostly included women who were treated more than 10 years ago. This means that we do not know how today's treatments are affecting women."

The strength of the study is its complete follow-up, the detailed information on doses, a factor that Hall considers to be truly unique, and the thorough verification of outcome. "We are certain that women who developed myocardial infarction did in fact have this diagnosis," he said.

For now, doctors can tell their patients that radiotherapy is a very important treatment and it should be used, he said. However, they should try to lower the dose of radiation to the heart as much as possible. "They should also think twice before they administer radiotherapy to women who previously had a myocardial infarction," he said.

Hall hopes that this study will have an impact on how doctors treat their breast-cancer patients. "Given the increasing incidence of breast cancer and the decreasing mortality, more and more women are living cured of their cancer. Late adverse health effects do become an increasing problem. We hope our data can be used to help clinicians guide their treatment decisions as to whether a woman will actually benefit from radiotherapy or not, especially if she has previous heart disorders or risk factors for myocardial infarction."

The tip of the iceberg?

In an accompanying editorial [2], Dr Javid Moslehi (Harvard Medical School, Boston, MA) writes that the findings by Hall and his group may represent "just the tip of the iceberg."

"In addition to ischemic cardiac disease," Moslehi writes, "radiation therapy has been associated with other cardiac conditions, including pericardial disease, peripheral vascular disease, cardiomyopathy, valvular dysfunction, and arrhythmias—diseases that were not included in this analysis."

He agrees with Hall that newer therapies have increased survival in breast cancer and points out that "cardio-oncology [cardiovascular care of patients with cancer] has emerged as a new discipline in medicine."

Moslehi also calls for greater collaboration between cardiologists and oncologists because the use of radiation therapy in the treatment of breast cancer is so widespread.

"An important lesson for the oncologist may be that the time to address concerns about cardiovascular 'survivorship' is at the time of cancer diagnosis and before treatment rather than after completion of therapy," he suggests.

"Similarly, cardiologists need to assess prior exposure to radiation therapy as a significant cardiovascular risk factor in survivors of breast cancer."

The study was suppo rted by Cancer Research UK , the British Heart Foundation , the UK Medical Research Council , the European Commission , the U K Department of Health , the British Heart Foundation Centre for Research Excellence , and the Oxford National Institute for Health Research Biomedical Research Centre . Hall reports no relevant financial relationships. Disclosures for the coauthors are listed at www.nejm.org . Moslehi reports financial relationships with Novartis and Forest Laboratories.

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