青蒿琥酯作为附加疗法治疗转移性或局部晚期乳腺癌患者的耳毒性研究：一项前瞻性、开放、非对照、单中心 I 期研究的新听力学结果。
Investigation of ototoxicity of artesunate as add-on therapy in patients with metastatic or locally advanced breast cancer: new audiological results from a prospective, open, uncontrolled, monocentric phase I study.
机构信息
Department of Otolaryngology, Head and Neck Surgery, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Naturopathy and Integrative Medicine, Department of Gynecological Endocrinology and Reproductive Medicine, University Women's Hospital, Heidelberg, Germany.
出版信息
Cancer Chemother Pharmacol. 2016 Feb;77(2):413-27. doi: 10.1007/s00280-016-2960-7. Epub 2016 Jan 21.
PURPOSE
Artesunate (ART) has been used for a long time in the treatment of Plasmodium falciparum malaria and has been considered safe. The present phase I study aimed to determine the daily dose of ART that is well tolerated as add-on therapy in patients with breast cancer for 4 weeks of therapy. Ototoxicity could be a potential safety concern in settings different from malaria. Therefore, comprehensive audiological assessment was essential.
METHODS
The ARTIC M33/2 study was a prospective, open, uncontrolled, monocentric phase I dose-escalation study to evaluate the safety and tolerability of ART in patients with advanced breast cancer. Patients received either 100, 150 or 200 mg oral ART daily for a test phase of 4 weeks as add-on therapy to their ongoing oncological treatment. For the investigation of the safety of ART for hearing, an audiological assessment was performed with each patient before the intake of ART and after 4 weeks of therapy.
RESULTS
Twenty-three female patients were included in the study. During the test phase, four patients had adverse events (AEs) of the auditory system possibly related to the intake of ART. However, none of these AEs was classified as severe AE (SAE) and did not require treatment interruption. Four patients had AEs concerning the vestibular system (vertigo) during the test phase, one of which was classified as SAE. However, the SAE was fully reversible after discontinuation of ART.
CONCLUSION
None of the audiological results after 4 weeks of therapy with ART showed any dose-limiting auditory toxicity. However, audiological monitoring in further clinical studies with prolonged use of oral ART in doses up to 200 mg daily is warranted. The ARTIC M33/2 study is registered at eudract.ema.europa.eu with the Number 2007-004432-23 and at clinicaltrials.gov with the Number NCT00764036.
目的
青蒿琥酯（ART）长期以来一直用于治疗恶性疟原虫疟疾，被认为是安全的。本 I 期研究旨在确定作为附加治疗在乳腺癌患者中使用 4 周的 ART 每日剂量，该剂量能很好耐受。在不同于疟疾的环境中，耳毒性可能是一个潜在的安全问题。因此，全面的听力学评估是必不可少的。
方法
ARTIC M33/2 研究是一项前瞻性、开放性、非对照、单中心 I 期剂量递增研究，旨在评估 ART 对晚期乳腺癌患者的安全性和耐受性。患者接受 100、150 或 200mg 口服 ART 每日治疗，作为其正在进行的肿瘤治疗的附加治疗，测试期为 4 周。为了研究 ART 对听力的安全性，在开始服用 ART 之前和治疗 4 周后对每位患者进行听力评估。
结果
本研究共纳入 23 例女性患者。在测试阶段，4 例患者出现可能与服用 ART 有关的听觉系统不良事件（AE）。然而，这些 AE 均未被归类为严重 AE（SAE），也不需要中断治疗。4 例患者在测试阶段出现与前庭系统（眩晕）相关的 AE，其中 1 例被归类为 SAE。然而，ART 停药后 SAE 完全可逆。
结论
ART 治疗 4 周后的听力结果均未显示任何剂量限制的听觉毒性。然而，需要在进一步的临床研究中进行听力监测，以评估长期使用高达 200mg 每日剂量的口服 ART。ARTIC M33/2 研究在 EudraCT.ema.europa.eu 注册，编号为 2007-004432-23，在 clinicaltrials.gov 注册，编号为 NCT00764036。
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