乳腺癌：心脏风险随心脏放射剂量而增加

一项针对43年间接受放疗的瑞典和丹麦女性乳腺癌患者的研究显示，主要缺血性冠状动脉事件(MICE)风险与心脏平均估计放射剂量明显呈线性正相关。MICE风险在治疗5年内开始增加并在20年后仍持续增加。借助该研究结果，我们得以估计女性患者中放射相关缺血性心脏病的绝对风险，并权衡这一绝对风险与无放疗时乳腺癌复发或死亡风险的可能绝对降幅(N. Engl. J. Med. 2013;368:987-98 [doi: 10.1056/NEJMoa1209825])。

这项人群研究由英国牛津大学的Sarah C. Darby博士及其同事进行，研究对象是瑞典国家癌症注册处或丹麦乳腺癌合作组收录的1958~2001年间通过外线束放射治疗浸润性乳腺癌的2,168例女性患者。研究者对963例随后发生MICE(心肌梗死、冠状动脉血运重建、或缺血性心脏病死亡，不包括心绞痛)的女性患者和1,205例对照者进行了比较。

Sarah C. Darby博士

在诊断乳腺癌后的10年、10~19年和20年以上(含20年)，分别有44%、33%和23%的患者发生MICE。在这些患者中，54%死于缺血性心脏病。

总体而言，心脏平均估计放射剂量为4.9 Gy (范围：0.03~27.72 Gy)。在左侧乳腺癌患者中，心脏平均放射剂量为6.6 Gy；在右侧乳腺癌患者中，心脏平均放射剂量为2.9 Gy。在左侧乳腺放疗患者中观察到的MICE发生率显著更高。研究者表示，在目前接受放疗的女性中，心脏估计放射剂量为1~5 Gy。

心脏平均放射剂量每增加1 Gy，MICE发生率增加7.4%，该结果具有高度统计学显著性。与无心脏放射的对照者相比，心脏平均放射剂量＜2 Gy、2~4 Gy、5~9 Gy和≥10 Gy的患者的MICE发生率分别增加10%、30%、40%和116%。

具有缺血性心脏疾病史的女性的MICE风险几乎为无缺血性心脏病史女性的7倍。该风险在治疗后10年内增加12倍，在10年后增加1倍。

研究者表示，在原本就具有危险因素的女性中，某一心脏放射剂量所致的风险绝对增幅较大，因此，临床医生在决定是否适用放射治疗乳腺癌时应考虑心脏放射剂量和心脏危险因素及肿瘤控制。

该研究的优点在于其纳入了两个国家中所有在研究时间内接受放疗的乳腺癌女性患者。由于该研究较少纳入30岁前接受治疗的乳腺癌患者，因此研究结果可能不适用于这类患者。

该研究获牛津大学癌症研究临床试验服务中心、英国心脏基金会和英国医学研究理事会支持。

相关评论：上述风险反映的是过时的放射方案

加州大学旧金山分校海伦·迪勒家庭综合癌症中心的乳腺肿瘤学和临床试验教育处主任Hope Rugo博士指出，该研究结果可能高估了放疗相关冠状动脉事件风险，并且研究结果可能会被误读，导致女性患者放弃接受可潜在挽救生命的治疗。在20世纪80年代诊断的女性患者中观察到的MICE发生率的增幅明显较高(放射剂量每增加1 Gy，发生率增加20%)，但在20世纪90年代诊断的女性患者中观察到的事件发生率的增幅很小(放射剂量每增加1 Gy，发生率增加0.85%)。该研究中的大部分数据来自于放疗技术不甚成熟的时代，在目前的技术条件下，心脏放射剂量明显要少很多。该研究未使用三维CT扫描，研究者承认这是一个局限。此外，众所周知，放疗病历一般不太准确，而在该研究中，放射剂量恰恰是根据放疗病历来估计的。再者，目前对于哪些患者可从放疗中获得生存益处有了更深入的认识。正确靶向放疗可使大部分乳腺癌患者得以存活。

Rugo博士声明无相关经济利益冲突。

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By: ELIZABETH MECHCATIE, Cardiology News Digital Network

The risk of major ischemic coronary events was significantly and proportionately associated with the estimated mean radiation dose to the heart in a study of women in Sweden and Denmark who received radiotherapy for breast cancer over a 43-year period.

"The risk of a major coronary event increased linearly with the mean dose to the heart," reported Sarah Darby, Ph.D., of the University of Oxford (England), and her associates. The risk began to increase within the first 5 years of treatment and continued to increase for at least 20 years.

The findings make it possible for a woman to estimate her absolute risk of radiation-related ischemic heart disease, the authors wrote. "This absolute risk can be weighed against the probable absolute reduction in her risk of recurrence or death from breast cancer that would be achieved without radiotherapy" (N. Engl. J. Med. 2013;368:987-98 [doi: 10.1056/NEJMoa1209825]).

The population-based study included 2,168 women who had been treated with external-beam radiation for invasive breast cancer between 1958 and 2001, and were enrolled in the Swedish National Cancer Register or the Danish Breast Cancer Cooperative Group. The 963 women who were subsequently diagnosed with a major coronary event (myocardial infarction, coronary revascularization, or death from ischemic heart disease, but not angina) were compared with 1,205 controls.

The major coronary events were diagnosed in the first decade after breast cancer diagnosis in 44% of patients; 33% of events were diagnosed 10-19 years after breast cancer diagnosis; and 23% occurred 20 or more years later. Of the cases, 54% died of ischemic heart disease.

The estimated mean radiation dose to the heart overall was 4.9 Gy (range, 0.03-27.72 Gy). For those with cancer in their left breast, the mean dose exposure to the heart was 6.6 Gy; for those with right-breast tumors, it was 2.9 Gy. Major coronary events were significantly higher among the women with radiation to the left breast.

The estimated dose to the heart of women who are currently treated with radiotherapy ranges from 1 to 5 Gy, the authors said.

For each 1-Gy increase in the mean dose of radiation to the heart, the rate of major coronary events increased by 7.4%, which was a highly statistically significant finding. Compared with controls who had no cardiac dose, the rate of major coronary events increased by 10% among those exposed to a mean radiation dose of less than 2 Gy, by 30% among those exposed to 2-4 Gy, by 40% among those exposed to 5-9 Gy, and by 116% in those exposed to 10 Gy or more.

Among women with a history of ischemic heart disease, the risk of major coronary events was almost sevenfold higher than it was in women with no history of ischemic heart disease. This risk was increased by about 13-fold during the first 10 years after treatment and was about twofold higher in later years.

"Absolute increases in risk for a given dose to the heart were larger for women with preexisting risk factors," they wrote, so "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."

Among the strengths of the study was that the analysis included all women who were documented as having received radiotherapy for breast cancer in the two countries during the time period studied. The authors cautioned against applying the results to breast cancer patients who are treated before age 30 because few women in this age group were included in the study.

The study was supported by the Oxford University Clinical Trial Service Unit from Cancer Research UK, the British Heart Foundation, and the UK Medical Research Council. View on the News

Risks reflect outmoded radiation protocols

While the results of the study are interesting, they likely overestimate the risk of coronary events associated with contemporary radiation therapy. Of greater concern, the findings could be misinterpreted and could deter women from having potentially lifesaving treatment.

Increases in the rate of major coronary events – about 20% higher per 1 Gy – were far greater among the women diagnosed in the 1980s, who drive much of the increase in risk. There was barely an increase in the rate of events – 0.85% per 1 Gy – among those diagnosed in the 1990s, for example.

Most of the data are taken from a time when radiation was administered by techniques that differ from those used today, which are associated with a lot less scatter to the heart. Three-dimensional, CT-based planning was not used for the women in the study, which the authors acknowledged was a limitation. Also, the dose was estimated using radiotherapy charts, which are notoriously inaccurate.

Further, there is now a better understanding of which patients are likely to have a survival benefit from radiation. Correctly targeted radiation therapy plays an incredibly important role in the excellent results we see today, with the majority of breast cancer patients surviving their disease.

Dr. Hope Rugo is professor of medicine at the University of California, San Francisco, and director of breast oncology and clinical trials education at the UCSF Helen Diller Family Comprehensive Cancer Center. She had no relevant financial disclosures.