JAMA Oncology
芳香酶抑制剂（AI）可引起明显的泌尿生殖道内萎缩，影响生活质量和药物依从性。
2016年11月10日，《美国医学会杂志肿瘤学分册》在线发表旧金山加利福尼亚大学、塞缪尔梅里特大学的研究报告，评估了阴道内睾酮软膏（IVT）和雌二醇缓释阴道环（7.5μg/d）用于早期乳腺癌患者接受AI期间的安全性。若治疗开始后连续2次间隔至少2周检测有25%以上患者雌二醇持续升高（＞10pg/mL或36.71pmol/L）则认为干预不安全。
该研究入组激素受体阳性I～III期乳腺癌服用AI期间自述出现阴道干燥、性交困难或性欲减退的绝经后女性，随机接受12周IVT或雌二醇阴道环。在第0、4、12周使用市售液相色谱和串联质谱法测量雌二醇水平，在第0、4周测量促卵泡激素水平，在第0、12周完成妇科检查和性生活质量调查问卷。该随机非对照设计允许在同一人群中同时进行2次干预的安全性评估，减少雌二醇测定随时间和2次干预之间变化的可能性。
该研究主要目的是评估IVT和雌二醇阴道环用于早期乳腺癌患者接受AI期间的安全性，次要目的包括评估不良事件、使用癌症康复评估系统性别子量表评估性生活质量变化、使用经过验证的4项量表评估阴道萎缩变化、比较雌二醇水平。
结果共有76位女性签署知情同意书（平均年龄56岁，范围37～78岁），其中75位开始治疗，69位完成12周治疗。平均基础雌二醇水平为20（＜2～127）pg/mL，37%（28/76）的女性雌二醇水平高于绝经后范围（＞10pg/mL）。阴道环组未见雌二醇水平持续升高，IVT组12%（4/34）出现雌二醇水平持续升高。阴道环组、IVT组分别有11%（4/35）、12%（4/34）出现雌二醇水平短暂升高。所有患者阴道萎缩、性欲减退、性功能障碍均改善。
因此，对于接受AI的早期乳腺癌绝经后女性，12周阴道环或IVT治疗满足主要安全性终点。雌二醇基础水平普遍升高，使评估复杂化。阴道萎缩、性欲减退、性功能障碍得到改善。需要进一步研究以了解该情况下雌二醇的多变性。
JAMA Oncol. 2016 Nov 10. [Epub ahead of print]
Vaginal testosterone cream vs estradiol vaginal ring for vaginal dryness or decreased libido in women receiving aromatase inhibitors for early-stage breast cancer: a randomized clinical trial.
Melisko ME, Goldman ME, Hwang J, De Luca A, Fang S, Esserman LJ, Chien AJ, Park JW, Rugo HS.
Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco; Samuel Merritt University, Oakland, California.
Importance: Aromatase inhibitors (AI) are associated with significant urogenital atrophy, affecting quality of life and drug compliance.
Objective: To evaluate safety of intravaginal testosterone cream (IVT) or an estradiol-releasing vaginal ring (7.5 μg/d) in patients with early-stage breast cancer (BC) receiving an AI. Intervention was considered unsafe if more than 25% of patients had persistent elevation in estradiol (E2), defined as E2 greater than 10 pg/mL (to convert to pmol/L, multiply by 3.671) and at least 10 pg/mL above baseline after treatment initiation on 2 consecutive tests at least 2 weeks apart.
Design, Setting, and Participants: Postmenopausal (PM) women with hormone receptor (HR)-positive stage I to III BC taking AIs with self-reported vaginal dryness, dyspareunia, or decreased libido were randomized to 12 weeks of IVT or an estradiol vaginal ring. Estradiol was measured at baseline and weeks 4 and 12 using a commercially available liquid chromatography and tandem mass spectrometry assay; follicle-stimulating hormone levels were measured at baseline and week 4. Gynecologic examinations and sexual quality-of-life questionnaires were completed at baseline and week 12. This randomized noncomparative design allowed safety evaluation of 2 interventions concurrently in the same population of patients, reducing the possibility of E2 assay variability over time and between the 2 interventions.
Main Outcomes and Measures: The primary objective of this trial was to evaluate safety of IVT or an estradiol vaginal ring in patients with early-stage BC receiving an AI; secondary objectives included evaluation of adverse events, changes in sexual quality of life using the Cancer Rehabilitation Evaluation System sexuality subscales, changes in vaginal atrophy using a validated 4-point scale, and comparison of E2 levels.
Results: Overall, 76 women signed consent (mean [range] age, 56 [37-78] years), 75 started treatment, and 69 completed 12 weeks of treatment. Mean (range) baseline E2 was 20 (<2 to 127) pg/mL. At baseline, E2 was above the postmenopausal range (>10 pg/mL) in 28 of 76 women (37%). Persistent E2 elevation was observed in none with a vaginal ring and in 4 of 34 women (12%) with IVT. Transient E2 elevation was seen in 4 of 35 (11%) with a vaginal ring and in 4 of 34 (12%) with IVT. Vaginal atrophy and sexual interest and dysfunction improved for all patients.
Conclusions and Relevance: In PM women with early-stage BC receiving AIs, treatment with a vaginal ring or IVT over 12 weeks met the primary safety end point. Baseline elevation in E2 was common and complicates this assessment. Vaginal atrophy, sexual interest, and sexual dysfunction were improved. Further study is required to understand E2 variability in this setting.
Trial Registration: clinicaltrials.gov Identifier: NCT00698035.
PMID: 27832260
DOI: 10.1001/jamaoncol.2016.3904
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