乳腺放疗后25年未见心脏毒性

波士顿——从美国放射肿瘤学会(ASTRO)2012年会上传来了一个振奋人心的好消息：现代乳腺照射似乎并不会导致远期心脏毒性。

Charles B. Simone博士

宾夕法尼亚大学医院的Charles B. Simone Ⅱ博士报告，在20世纪70和80年代随机接受乳房切除术或保乳手术(BCS)+放疗的50例女性患者，如今在弗莱明翰心脏研究危险评分方面并无显著差异。尽管接受保乳手术+放疗者的生存率略低于接受乳房切除术者，但这一差异似乎与心脏受到的辐射剂量无关。在接受保乳手术+放疗的患者中，左侧照射者与右侧照射者的生存率无差异。

本项研究的50例受试者来自237名参与1979~1986年国立癌症研究所保乳试验(79-C-0111)的女性中的102例存活者。在那项试验中，I期或II期乳腺癌患者接受改良的根治性乳房切除术+腋窝淋巴结切开，或接受乳房肿瘤切除术+淋巴结切开+45~50.4 Gy剂量的全乳放疗。后者接受或不接受区域淋巴结处置，序贯15~20 Gy剂量的加强放疗。所有的淋巴结阳性患者均接受6~11轮阿霉素+环磷酰胺化疗，从1985年开始，淋巴结阳性的绝经后女性接受他莫西芬治疗。

Simone博士指出，这项试验在当时是独一无二的，因为它在设计治疗计划和修正剂量不均一性时采用了CT模拟。

分开的生存曲线

在随机分组后中位时间25.7年时，43.8%的乳房切除术组患者仍然健在，而保乳手术组患者的生存率为37.9%。尽管这一差异并无统计学意义，但两组的生存曲线实际上已经呈现出分道扬镳的趋势。这一趋势无法用继发恶性肿瘤、远处转移的改变或任何其他乳腺癌相关因素来解释。为了确定这一趋势是否与放疗的心脏毒性有关，Simone博士及其同事开展了这项心脏毒性研究，共有26例保乳手术组患者和24例乳房切除术患者同意参加。

研究者采集了详细的心脏病史，并对其进行了心脏实验室检查、心脏MRI(采用3特斯拉磁铁)以寻找解剖学和功能学异常，还进行了CT造影以寻找狭窄性冠心病，确定冠脉钙化评分(CSC)和粥样硬化负担。研究者还分析了诸如照射野中心肺厚度、照射野大小、剂量和加强剂量等放疗技术参数。

结果在心脏MRI中，研究者仅发现了2项显著差异。保乳手术组患者的填充率达峰时间显著短于乳房切除术组(487 ms vs. 647 ms；P=0.02)，但填充率峰值本身无明显组间差异。保乳手术组患者的左心室质量明显小于乳房切除术组(平均值：90.5 gm vs. 111 gm)，但在校正收缩压之后，这一差异不再具有统计学意义。

“有趣的是，我们在所有受试者中未发现任何心肌纤维化的证据，而且两组各仅有1例患者有某种程度的心包增厚。”

令人安心的数据

不仅如此，研究者在CT造影中也未发现两组患者在肉眼可见的斑块或明显/严重血管狭窄方面有显著性差异。而且，在身体左侧或右侧接受放疗的患者，在左前降支斑块或狭窄方面也无明显差异。“甚至具体到我们观察的每一根血管，在狭窄程度上都不存在显著差异。”受试者的中位CAC评分较低但仍处于正常范围内，不过接受了化疗的患者有动脉粥样硬化和斑块形成增加的趋势。

Bruce Haffty博士

新泽西癌症研究所放射肿瘤部主任Bruce Haffty博士评论指出：“这项研究将可以使患者们更加放心，因为接受现代放疗技术治疗左侧乳腺癌的患者在25年后并未显示出明显心脏毒性。”

这项研究获得了国立癌症研究所的支持。Simone博士和Haffty博士无利益冲突披露。

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By: NEIL OSTERWEIL, Oncology Practice

BOSTON – Here’s heartening news that physicians can convey to breast cancer survivors: Modern breast irradiation did not appear to cause late-term cardiac toxicity in a study that examined women a quarter of a century after they were treated.

Investigators found no significant differences in Framingham Heart Study risk scores, hemodynamic parameters, pericardial thickening, or heart failure among 50 women who had been randomized in the 1970s and 1980s to either mastectomy or breast-conserving surgery (BCS) and radiation, Dr. Charles B. Simone II reported at the annual meeting of the American Society for Radiation Oncology.
 
Although the survival rate was slightly lower among patients treated with breast-conserving therapy, the difference does not appear to be related to radiation dose to the heart, said Dr. Simone of the Hospital of the University of Pennsylvania in Philadelphia. There were no differences in survival among women treated with BCS and radiation to left- or right-sided tumors.

"Based on this study, in the era of 3D planning, patients with early-stage breast cancer treated with radiotherapy do not have a higher risk of long-term cardiac morbidity compared with patients having mastectomy," he said.

The patients studied included 50 of 102 survivors from an original cohort of 237 women who had participated in the National Cancer Institute’s Breast Conservation Trial (79-C-0111), with randomization from 1979 to 1986. In that trial, women with stage I or II breast cancer received modified radical mastectomy with axillary node dissection or they underwent lumpectomy plus node dissection and a radiation dose of 45-50.4 Gy to the whole breast; the latter came with or without treatment of regional nodes, followed by a boost of 15-20 Gy with either iridium 192 brachytherapy or electrons.

All node-positive patients underwent 6-11 cycles of chemotherapy with doxorubicin and cyclophosphamide, and beginning in 1985 postmenopausal women with positive nodes were given tamoxifen.

The trial was unique at the time in that it used CT simulations for treatment planning and dose inhomogeneity corrections, Dr. Simone noted.

Diverging Survival Curves

At a median of 25.7 years after randomization, 43.8% of mastectomy patients were still alive, compared with 37.9% of BCS patients. Although the difference was not significant, it appeared to represent a divergence of survival curves that had been virtually identical for the first 25 years.

The trend could not be accounted for by secondary malignancies, changes in distant metastasis, or any other breast cancer–related causes, leading the investigators to question whether it might be due to radiation toxicity to the heart, as some studies have suggested.

In all, 26 patients who had had BCS and 24 who underwent mastectomy agreed to come back for the cardiac toxicity study.

The investigators took a detailed cardiac history, and subjected the women to exams, cardiac labs, cardiac MRI with a 3 Tesla magnet to look for anatomic and functional abnormalities, and CT angiogram to look for stenotic coronary disease and determine coronary arterial calcium score (CAC) of atherosclerotic burden.

They also looked at radiation technique parameters such as central lung distance, field size, dose, and boost dose.

On cardiac MRI, they only saw two significant between-group differences. Time to peak filling rate was shorter for BCS patients (487 milliseconds vs. 647 ms for mastectomy patients; P = .02), but there was no difference in the peak filling rate itself. Left ventricular mass was smaller for BCS patients (mean 90.5 gm vs. 111 gm for mastectomy patients), but this difference was no longer significant after adjustment for systolic blood pressure, Dr. Simone noted.

"Interestingly, we didn’t see any evidence of myocardial fibrosis in any patient assessed, and only one patient in each arm had any degree of pericardial thickening," he said.

Reassuring Data

Additionally, investigators saw no significant differences on CT angiography in the presence of visible plaque or significant or severe vascular stenosis. There were also no differences in plaque or stenosis in the left anterior descending arteries of women treated with radiation for tumors on the left or the right side of the body.

"For each and every vessel we looked at, there was no difference in the degree of stenosis," Dr. Simone said.
 

Median CAC scores were low and in the normal range, but patients who had received chemotherapy had a trend toward increased atherosclerosis and plaque formation, Dr. Simone noted.

The study "gives some reassurance to our patients that, after 25 years of follow-up, using modern radiation techniques the delivery of radiation to the left does not cause cardiac toxicity," Dr. Bruce Haffty, chair of radiation oncology at the Cancer Institute of New Jersey, New Brunswick, said at a briefing.

The study was supported by the National Cancer Institute. Dr. Simone and Dr. Haffty reported no relevant disclosures.