Lower-Dose vs High-Dose Oral Estradiol Therapy of Hormone Receptor-Positive, Aromatase Inhibitor-Resistant Advanced Breast Cancer A Phase 2 Randomized Study
Lower-Dose vs High-Dose Oral Estradiol Therapy of Hormone Receptor-Positive, Aromatase Inhibitor-Resistant Advanced Breast Cancer A Phase 2 Randomized Study
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DOI：
10.1001/jama.2009.1204
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发表时间：
2009-08-19
影响因子：
120.7
通讯作者：
Siegel, Barry A.
中科院分区：
文献类型：
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作者：
Ellis, Matthew J.;Gao, Feng;Siegel, Barry A.
背景芳香化酶抑制剂的雌激素剥夺疗法被假设为矛盾地使雌激素受体阳性乳腺癌肿瘤细胞对低剂量雌二醇疗法敏感。目的确定6 mg雌二醇（每日）是否是绝经后晚期芳香化酶抑制剂抵抗激素受体阳性乳腺癌的可行疗法。一项每日口服雌二醇6 mg与30 mg的2期随机试验（2004年4月至2008年2月[招募结束]）。符合条件的患者（66例随机分组）患有转移性乳腺癌，用芳香酶抑制剂治疗，辅助芳香酶抑制剂使用后无进展生存期（>= 24周）或复发（>= 2年后）。排除了雌二醇相关不良事件高风险的患者。在1周和2周后检查患者的临床和实验室毒性以及突发反应，此后每4周检查一次。每12周进行一次肿瘤放射学评估。至少1个可测量的病灶或4个可测量的病灶（仅骨疾病）被评估为肿瘤responsibility.Intervention随机接受1口服2毫克通用雌二醇片剂每日3次或5 2毫克片剂每日3次。次要结局：毒性、无进展生存期、至治疗失败的时间、生活质量以及通过正电子发射断层扫描/计算机断层扫描使用氟脱氧葡萄糖F18检测到的代谢爆发反应的预测特性。结果不良事件率30 mg组（11/32 [34%]; 95%置信区间[CI]，23%-47%）中（> 3级）高于6 mg组（4/34 [18%]; 95% CI，5%-22%; P= 0.03）。30 mg组的临床获益率为9/32（28%; 95% CI，18%-41%），6 mg组为10/34（29%; 95% CI，19%-42%）。雌二醇刺激的氟脱氧葡萄糖F18摄取的增加（>= 12%前瞻性定义）预测反应（阳性预测值，80%; 95%CI，61%-92%）。7例雌二醇敏感性疾病的再治疗与芳香化酶抑制剂在雌二醇的进展，其中2个有部分反应和1个稳定的疾病，提示再敏感雌激素deprivation.Conclusions在晚期乳腺癌和获得性耐药芳香化酶抑制剂的妇女，每日剂量为6毫克的雌二醇提供了类似的临床获益率为30毫克，严重不良事件较少。低剂量治疗的有效性应在3期临床试验中进一步检查。试验注册clinicaltrials.gov标识符：NCT 00324259 JAMA。2009; 302（7）：774-780 www.jama.com
Context Estrogen deprivation therapy with aromatase inhibitors has been hypothesized to paradoxically sensitize hormone-receptor-positive breast cancer tumor cells to low-dose estradiol therapy.Objective To determine whether 6 mg of estradiol (daily) is a viable therapy for postmenopausal women with advanced aromatase inhibitor-resistant hormone receptor-positive breast cancer.Design, Setting, and Patients A phase 2 randomized trial of 6 mg vs 30 mg of oral estradiol used daily (April 2004-February 2008 [enrollment closed]). Eligible patients (66 randomized) had metastatic breast cancer treated with an aromatase inhibitor with progression-free survival (>= 24 wk) or relapse (after >= 2 y) of adjuvant aromatase inhibitor use. Patients at high risk of estradiol-related adverse events were excluded. Patients were examined after 1 and 2 weeks for clinical and laboratory toxicities and flare reactions and thereafter every 4 weeks. Tumor radiological assessment occurred every 12 weeks. At least 1 measurable lesion or 4 measurable lesions (bone-only disease) were evaluated for tumor response.Intervention Randomization to receive 1 oral 2-mg generic estradiol tablet 3 times daily or five 2-mg tablets 3 times daily.Main Outcome Measures Primary end point: clinical benefit rate (response plus stable disease at 24 weeks). Secondary outcomes: toxicity, progression-free survival, time to treatment failure, quality of life, and the predictive properties of the metabolic flare reaction detected by positron emission tomography/computed tomography with fluorodeoxyglucose F 18.Results The adverse event rate (> grade 3) in the 30-mg group (11/32 [34%]; 95% confidence interval [CI], 23%-47%) was higher than in the 6-mg group (4/34 [18%]; 95% CI, 5%-22%; P=.03). Clinical benefit rates were 9 of 32 (28%; 95% CI, 18%-41%) in the 30-mg group and 10 of 34 (29%; 95% CI, 19%-42%) in the 6-mg group. An estradiol-stimulated increase in fluorodeoxyglucose F 18 uptake (>= 12% prospectively defined) was predictive of response ( positive predictive value, 80%; 95% CI, 61%-92%). Seven patients with estradiol-sensitive disease were re-treated with aromatase inhibitors at estradiol progression, among which 2 had partial response and 1 had stable disease, suggesting resensitization to estrogen deprivation.Conclusions In women with advanced breast cancer and acquired resistance to aromatase inhibitors, a daily dose of 6 mg of estradiol provided a similar clinical benefit rate as 30 mg, with fewer serious adverse events. The efficacy of treatment with the lower dose should be further examined in phase 3 clinical trials.Trial Registration clinicaltrials.gov Identifier: NCT00324259 JAMA. 2009; 302(7):774-780 www.jama.com