Tamoxifen之后转换为芳香酶抑制剂可改善早期乳癌病患存活率

　　February 12, 2007 —一项发表于2月12日癌症期刊合并分析两项前瞻性研究的文献显示，对已经使用tamoxifen二至三年的乳癌病患而言，转换为芳香酶抑制剂（AI）会比继续使用tamoxifen好，因为这样做可以显著提升存活率。
　　
　　义大利Genoa大学与国家癌症研究机构Francesco Boccardo医师表示，许多研究已经证实芳香酶抑制剂在作为早期乳癌的辅助治疗上比tamoxifen好，但并未研究证实其具有提升存活率的好处；透过合并分析两项研究的结果，他们发现转换至AI的妇女相较于继续使用tamoxifen的妇女，其整体死亡率或是与乳癌相关的死亡率都较低，且显然不会增加其他原因造成的死亡。
　　
　　作者的结论是，这项合并分析提供在使用tamoxifen几年后转换至芳香酶抑制剂，相较于继续使用tamoxifen，具有降低死亡率好处的证据，且降低与乳癌相关的死亡率主要是因为转换药物的效应。
　　
　　他们附带表示，这些新的研究数据再次强调了目前正在使用tamoxifen的妇女，早期转换为AI的适应症。
　　
　　其他显示该药物具有降低死亡率好处的研究，也支持这项转换的策略，这些研究包括the Intergroup Exemastane Study与the anastrozole ARNO 95 study，以及来自一项收纳使用anastrazole研究的综合分析（Jonat W等人，Lancet Oncol 2006;7:991-996）。
　　
　　【预先计划合并分析数据】
　　Boccardo医师解释他的团队自1992年已经发展一种“转换流程”，且过去已经针对使用tamoxifen的妇女转换为AI疗法进行两项研究；在早期的研究中（GROCTA 4 B），所使用的药物是aminogluthimide，一种早期的AI药物现在已经不再使用，之后的研究（ITA）使用的是anastrozole (Arimidex，阿斯特捷利康药厂制造)；除此之外，该试验的设计与选择病患条件相似，目前这项综合分析是前瞻性的，且于ITA试验设计时就已经计划好。
　　
　　这两项研究收纳了828位停经后妇女，大部分是雌性激素受体（ER）阳性且为淋巴结阳性的乳癌病患，所有的病患都使用tamoxifen，平均使用三年，之后这些妇女被随机分派使用AI或是继续使用tamoxifen；整体后续追踪平均为78个月（范围自6－141个月），但是较早的GROCTA试验的后续追踪时间（平均104个月）比ITA试验（平均64个月）长。
　　
　　相较于继续使用tamoxifen的妇女，转换为AI的妇女其整体死亡率显著较低，危险比值（HR）为0.61（95% CI为0.42－0.88；P＝0.007），且与乳癌相关的死亡率也显著较低（HR为0.61；95% CI为0.39－0.94；P＝0.025）；在多变项分析校正病患年龄、肿瘤大小与程度、淋巴结状况、与过去是否接受局部以及／或是全身性治疗之后，这样的降低死亡率好处仍然是具显著差异的。
　　
　　【GROCTA 4B与ITA研究综合分析】

结果	继续使用 Tamoxifen (n=415)	转换为 AI (n=413)
不论原因之死亡	74	48
乳癌再发	51	33
第二个原发性肿瘤	3	6
中风	4	1
心血管事件	12	5
其他原因	2	1
资料遗失	2	2

　　
　　研究者表示，两组之间与乳癌无关的死亡率并无显著差异，然而，这些事件数目并不大，且可能并不可靠；他们附带表示，这两个试验的后续追踪时间不一样长，且这可能是很重要的，尽管这些遗憾，他们强调，转换为AI的妇女发生因为中风与心血管疾病，如致命性心脏缺血事件，造成的死亡率较低，他们指出，目前为止其他使用芳香酶抑制剂的辅助疗法研究结果显示心脏缺血性事件并未增加，这点不应该被低估。

Switching to Aromatase Inhibitors After Tamoxifen Improves Survival in Early Breast Cancer

By Zosia Chustecka
Medscape Medical News

February 12, 2007 — For breast cancer patients who have taken tamoxifen for 2 to 3 years, switching to an aromatase inhibitor (AI) is better than staying on tamoxifen, as the switch significantly improves survival. So concludes a pooled analysis of 2 prospective trials in a paper published online February 12 in Cancer.

Several trials have already suggested a superiority of aromatase inhibitors over tamoxifen in the adjuvant treatment of early breast cancer, but not all studies have shown a mortality benefit, say the authors, led by Francesco Boccardo, MD, from the National Cancer Research Institute and University of Genoa, Italy. By pooling the results of 2 trials together, they found that women who switched to an AI had lower mortality from all causes as well as lower mortality related to breast cancer when compared with women who stayed on tamoxifen, and there appeared to be no increase in death from other causes.

"This pooled analysis provides solid evidence that switching to an aromatase inhibitor following a few years of tamoxifen treatment implies a mortality benefit over continued tamoxifen and that the benefit on breast cancer–related mortality is mainly due to the effect of switching," the authors conclude.

These new data reinforce the indication of early switching to an AI in women currently receiving adjuvant treatment with tamoxifen, they add.

Other evidence of mortality benefits that also supports this switching approach has come from the Intergroup Exemastane Study and the anastrozole ARNO 95 study and from a meta-analysis of 3 trials with anastrozole (Jonat W et al. Lancet Oncol 2006;7:991-996).

Pooled Analysis of Data Was Preplanned

Dr. Boccardo explains that his group has been developing the "switching approach" since 1992 and previously conducted 2 trials in which women who were taking tamoxifen were switched over to an AI. In the earlier trial (GROCTA 4 B), the switch was to aminogluthimide, an early AI product that is not used anymore, while the later trial (ITA) allowed a switch to anastrozole (Arimidex, AstraZeneca). Otherwise, the trials were similar in design and in selection criteria. The current pooled analysis was prospectively planned at the time that the ITA trial was designed, the researchers note.

Together, the 2 trials involved 828 postmenopausal women, mostly with estrogen-receptor (ER)-positive and node-positive breast cancer. All the women took tamoxifen for an average of 3 years, after which some were randomized to switch to an AI while the others continued on tamoxifen. The overall median follow-up was 78 months (range, 6 – 141 months), but the women in the earlier GROCTA trial had been followed for longer (median 104 months) than those in the ITA trial (median 64 months).

When compared with the women who stayed on tamoxifen, the women who switched to an AI had significantly lower all-cause mortality, with a hazard ratio (HR) of 0.61 (95% CI, 0.42 – 0.88; P = .007), and significantly lower breast cancer–related mortality (HR, 0.61; 95% CI, 0.39 – 0.94; P = .025). Both of these mortality benefits were still statistically significant even after multivariate analysis by patient age, tumor size and grade, nodal status, and prior local and/or systemic treatment.

Pooled Analysis of the GROCTA 4B and ITA trials

Outcome	Staying on Tamoxifen (n=415)	Switching to AI (n=413)
Death from any cause	74	48
Breast cancer relapse	51	33
Second primary tumor	3	6
Stroke	4	1
Cardiovascular event	12	5
Other causes	2	1
Missing information	2	2

There was no significant difference between the 2 groups in mortality unrelated to breast cancer. However, these numbers were small and are less likely to be reliable, the researchers comment, adding that the median follow-up was different in the 2 trials, which may be crucial. Despite these cautions, they highlight the finding that women who switched to an AI had fewer deaths from stroke and from cardiovascular causes, including lethal cardiac ischemic events. "It should not be underestimated that no increase in cardiac ischemic events was reported in any of the other adjuvant trials with aromatase inhibitors reported so far," they add.

Cancer.Published online February 12, 2007.