Overall efficacy and safety of olanzapine 5 mg added to triplet antiemetics for an anthracycline-containing regimen in patients with breast cancer: a phase 3, double-blind, randomised, placebo-controlled trial.

We aimed to investigate if administering 5 mg of olanzapine at home after anthracycline plus cyclophosphamide chemotherapy, rather than before chemotherapy, can maintain efficacy in controlling chemotherapy-induced nausea and vomiting while minimising sedative side-effects and associated risks.

我们旨在研究，在接受葱环类药物加环磷酰胺化疗后，在家中给予5 mg奥氮平，而不是在化疗前，是否可以在维持控制化疗引起的恶心和呕吐的疗效的同时，最小化嗜睡副作用及相关风险。

Methods

This was a phase 3, double-blind, randomised, placebo-controlledtrial, done in 15 hospitals and cancer centres in Japan.

这是一项在日本15家医院和癌症中心进行的3期、双盲、随机、安慰剂对照试验。

Eligible patients were female adults aged 20 years or older with stage I-III breast cancer and an Eastern Cooperative Oncology Group performance status of 0-1, who were scheduled to receive intravenous anthracycline plus cyclophosphamide-based chemotherapy, and were naive to chemotherapy or had never received moderately to highly emetogenic chemotherapy.

符合条件的患者为20岁或以上的女性成年乳腺癌I-III期患者，东部肿瘤协作组（Eastern Cooperative Oncology Group，ECOG）表现状态评分为0-1，计划接受静脉注射的葱环类药物加环磷酰胺为基础的化疗，且为化疗初治或从未接受过中度至高度致吐性化疗。

Eligible patients were randomly assigned 1:1 to oral olanzapine 5 mg or placebo via the central registration system.

符合条件的患者通过中央注册系统随机分配，按1:1的比例接受口服奥氮平5毫克或安慰剂。

Randomisation was performed using blocked stratification, with age (≥55 years vs <55 years) and institution as stratification factors and a block size of two.

随机化采用分层阻塞方法，以年龄（≥55岁与<55岁）和机构作为分层因素，阻塞大小为2。

Allocation was concealed and masking was achieved by using tablets with identical appearance.

分配是保密的，通过使用外观相同的药片来实现盲法。

Treatment was administered at home within 5 h after the end of anthracycline plus cyclophosphamide administration and before the patient's evening meal on day 1 to minimise the risk of sedation during hospital visits and transportation, and on the next 3 days after their evening meal, both with pre-chemotherapeutical application of intravenous dexamethasone 9·9 mg, intravenous palonosetron 0·75 mg, and oral aprepitant 125 mg on day 1 followed by an additional dose of aprepitant 80 mg on days 2 and 3 or intravenous fosaprepitant 150 mg as a premedication on day 1.

治疗在家中进行，从结束多柔比星加环磷酰胺治疗后的5小时内，以及在第1天患者晚餐前进行，以最小化住院访问和运输期间的镇静风险，并在接下来的3天晚餐后进行，均在化疗前应用静脉注射地塞米松9.9毫克，静脉注射帕洛诺司琼0.75毫克，以及口服阿瑞匹坦125毫克在第1天，随后在第2天和第3天额外给予阿瑞匹坦80毫克，或者在第1天使用静脉注射福沙匹坦150毫克作为预处理。

The primary endpoint was the proportion of patients with a complete response, defined as no vomiting and no rescue medication during the overall phase (0-120 h after the initiation of anthracycline plus cyclophosphamide) based on patient diary.

主要终点是完全缓解的患者比例，定义为在整体阶段（从葱环类药物加环磷酰胺治疗开始后的0-120小时内）无呕吐且无需救援药物，基于患者日记记录。

The primary analysis was done by modified intention-to-treat, including all patients who received at least one dose of the study treatment and had at least one efficacy evaluation.

主要分析是通过修改后的意向治疗分析进行的，包括所有至少接受一次研究治疗且至少有一次疗效评估的患者。

Safety was analysed in all patients who received any treatment.

对所有接受治疗的患者进行了安全性分析。

This trial was registered with the Japan Registry of Clinical Trials, jRCT1031200134, and is complete.

该试验已在日本临床试验注册处注册，注册号为jRCT1031200134，并已完成。

Results

Between Oct 26, 2020 and Nov 2, 2022, 500 female patients from 15 medical institutions in Japan were randomly assigned to receive olanzapine (n=251) or placebo (n=249).

2020年10月26日至2022年11月2日期间，来自日本15家医疗机构的500名女性患者被随机分配接受奥氮平(n=251)或安慰剂(n=249)治疗。

Median age at enrolment was 52 years (IQR 45-60) in the olanzapine group and 51 years (46-60) in the placebo group.

入组时，奥氮平组的中位年龄为52岁（四分位数间距45-60岁），安慰剂组的中位年龄为51岁（四分位数间距46-60岁）。

Data on gender and race or ethnicity were not collected.

未收集性别和种族或民族的数据。

The median follow-up was 168 h (IQR 168-168). 480 participants (246 in the olanzapine group and 234 in the placebo group) received at least one dose of study medication and were eligible for the efficacy analysis.

中位随访时间为168小时（四分位数间距168-168）。共有480名参与者（奥氮平组246人，安慰剂组234人）接受了至少一次研究药物治疗，并符合疗效分析的资格。

The complete response rate in the olanzapine group (58·1%, n=143) was significantly higher than in the placebo group (35·5%, n=83; difference 22·7%, 95% CI 14·0-31·4%; p<0·0001) during the overall phase.

在整体阶段，奥氮平组的完全缓解率（58.1%，n=143）显著高于安慰剂组（35.5%，n=83；差异22.7%，95% 置信区间14.0-31.4%；p<0.0001）。

The most frequently reported severe or very severe symptoms based on the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) version 1.0 were anorexia (33 [13%] of 246 patients in the olanzapine group vs 89 [38%] of 235 in the placebo group) and constipation (30 [12%] vs 37 [16%]).

根据患者报告的结果版不良事件通用术语标准（PRO-CTCAE）版本1.0，报告的最常见严重或非常严重的症状是食欲不振（奥氮平组246名患者中有33名[13%]，安慰剂组235名中有89名[38%]）和便秘（奥氮平组30名[12%]，安慰剂组37名[16%]）。

Severe or very severe concentration impairment was reported in 25 (10%) of 246 patients in the olanzapine group and 34 (14%) of 235 patients in the placebo group.

在奥氮平组的246名患者中，有25名（10%）报告了严重或非常严重的注意力集中障碍，在安慰剂组的235名患者中，有34名（14%）报告了同样的问题。

Experimental drug-related grade 3-4 adverse events according to the Common Terminology Criteria for Adverse Events version 5.0 included somnolence (four [2%] of 246 patients in the olanzapine group vs none of 235 in the placebo group), and concentration impairment (two [1%] vs none).

根据不良事件通用术语标准第5.0版，奥氮平组有四名（2%）患者出现与实验药物相关的3-4级不良事件，表现为嗜睡，而在安慰剂组中没有患者出现此症状；注意力集中障碍在奥氮平组有两名（1%）患者出现，安慰剂组则没有。

There were no deaths.

没有出现死亡病例。

interpretation

Post-chemotherapy administration of 5 mg olanzapine in combination with triplet antiemetic therapy before anthracycline plus cyclophosphamide-based chemotherapy significantly improved the complete response rate for chemotherapy-induced nausea and vomiting during the overall phase compared with placebo in female patients with breast cancer receiving outpatient chemotherapy, with an acceptable level of safety.

在乳腺癌女性患者接受门诊化疗期间，化疗后给予5毫克奥氮平联合三药止吐治疗，在接受葱环类药物加环磷酰胺化疗前使用，与安慰剂相比，显著提高了化疗引起的恶心和呕吐在整体阶段的完全缓解率，且安全性可接受。

The findings represent a substantial advancement in managing chemotherapy-induced nausea and vomiting and provide assurance that the safe and effective administration of olanzapine can be achieved at a dosage of 5 mg.

这些发现代表了在管理化疗引起的恶心和呕吐方面取得了重大进展，并确保了以5毫克剂量安全有效地使用奥氮平。

funding

The Capture of Outstanding Clinical Research and Evolution (CORE) project at Juntendo University.

顺天堂大学的杰出临床研究与演变（CORE）项目。