Low-dose estradiol shows activity against advanced breast cancer that has acquired resistance to aromatase inhibitors, “and should be further investigated,” according to a report in the Aug. 19 issue of JAMA.
The low-dose regimen provided similar clinical benefit as did higher-dose estradiol, and it caused fewer adverse events in a phase II randomized trial involving 66 postmenopausal women with a mean age of 59 years, said Dr. Matthew J. Ellis of Washington University, St. Louis, and his associates.
They compared the two doses of estradiol in women who had advanced estrogen receptor–positive and/or progesterone receptor–positive breast cancer. These patients had received treatment with an aromatase inhibitor and responded with at least 24 weeks of progression-free survival before their cancer became resistant to that therapy.
In all, 34 women were randomly assigned to receive one oral 2-mg generic estradiol tablet three times daily (total dosage, 6 mg/day) and 32 to receive five 2-mg tablets three times daily (total dosage, 30 mg/day). They underwent tumor radiologic assessment every 12 weeks.
A total of 10 of 34 women (29%) on low-dose estradiol showed clinical benefit, which was not statistically different from the rate in women on high-dose estradiol (9 of 32 women, or 28%). There was no difference between the two groups in progression-free survival or in time to treatment failure.
However, women taking the lower dose had fewer cases of high-grade nausea and vomiting, electrolyte disturbance, and pleural effusion. Their overall adverse event rate was 11%, compared with 34% for women taking the higher dose of estradiol, Dr. Ellis and his colleagues said (JAMA 2009;302:774-80).
Analysis of biomarkers – suppression of serum insulin growth factor I and stimulation of tumor 18fluorodeoxyglucose (FDG) uptake – showed that the lower dose of estradiol was biologically effective.
“After noting a significant number of patients responding to estradiol, the study was extended to address the hypothesis that the acquired aromatase inhibitor resistance exhibited by the trial population might, in some instances, be reversed by an extended period of estradiol therapy,” they said.
“To date, 7 patients have been re-treated with an aromatase inhibitor. Three have experienced clinical benefit (2 partial responses and 1 stable disease lasting 36, 36, and 28 weeks, respectively),” the investigators continued.
This result suggests that retreatment with aromatase inhibitors or other endocrine agents after successful use of estradiol “should be explored further,” they concluded.
This study was sponsored by the U.S. National Cancer Institute and the U.S.-based Avon Foundation. Dr. Ellis reported no financial conflicts of interest.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
《美国医学会杂志》(JAMA) 8月19日刊载的一篇报道称，小剂量雌二醇可有效治疗已对芳香化酶抑制剂产生获得性耐药的晚期乳腺癌患者，该用法值得进一步研究。
美国华盛顿大学圣路易斯分校的Matthew J. Ellis博士及其助手开展了一项II期临床随机试验，试验纳入了66名绝经后妇女，受试者的平均年龄为59岁。结果显示，小剂量雌二醇的临床疗效与大剂量治疗方案的效果相似，且不良事件的发生率更低。
该试验在雌激素受体阳性和/或孕激素受体阳性的晚期乳腺癌患者中对两种剂量的雌二醇进行了对照。所有受试者都曾接受过芳香化酶抑制剂的治疗，并且在对该治疗产生耐药之前都曾获得过治疗应答，无进展生存期至少达到24周。
该试验将受试者随机分成小剂量组和大剂量组，小剂量组的34名受试者每次口服1片2 mg的雌二醇片剂， 每日三次(总剂量：6 mg/日)，大剂量组的32名受试者每次口服5片2 mg的雌二醇片剂， 每日三次 (总剂量，30 mg/日)。受试者每12周接受一次肿瘤放射学评价。
小剂量组的34名受试者中共有10名 (29%)表现出临床获益，与大剂量组相比(9/32或28%)差异无统计学意义。两组受试者的无进展生存期以及治疗失败时间均无差异。
Ellis博士及其同事报告称，“然而小剂量组重度恶心呕吐、电解质紊乱以及胸腔积液的发生率更低。小剂量组不良事件的总发生率为11%，而大剂量组则达到了34%” (JAMA 2009;302:774-80)。
生物标志物的分析结果显示，从血清胰岛素样生长因子-Ⅰ的抑制情况以及肿瘤18氟脱氧葡萄糖(FDG)摄取的激活情况来看，小剂量雌二醇具有生物学效应。
研究者称，“在我们发现对于大部分患者雌二醇治疗都有效之后，便将该试验进一步拓展以验证另一个假设，即延长雌二醇的治疗时间有可能逆转受试人群表现出的芳香化酶抑制剂获得性耐药。”
“到目前为止，有7名患者再次接受了芳香化酶抑制剂的治疗。其中3名已经表现出临床获益(2名部分应答，1名疾病稳定，分别持续36、36和28周)。”
试验结果提示，在雌二醇治疗成功之后可以考虑再次使用芳香化酶抑制剂或其它内分泌制剂，研究者认为“这一做法值得进一步研究”。
该试验受美国国立癌症研究所和美国雅芳 (Avon) 基金会的资助。无经济利益冲突。
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