阿瑞匹坦用于晚期乳腺癌化疗的止吐效果观察

姜 敏，迟 峰，曾越灿

阿瑞匹坦用于晚期乳腺癌化疗的止吐效果观察

姜 敏，迟 峰，曾越灿

目的 观察阿瑞匹坦对晚期乳腺癌患者应用含顺铂化疗方案后止吐效果及安全性。方法 选取我院2014年1月—2016年5月使用含顺铂化疗方案的晚期乳腺癌56例，按照随机数字表法分为观察组及对照组，每组各28例。观察组于化疗首日用药前1 h口服阿瑞匹坦125 mg/d，第2、3天晨起口服阿瑞匹坦80 mg/d，同时予格拉司琼、地塞米松各5 mg/d静脉推注；对照组予安慰剂、格拉司琼及地塞米松，剂量及方法与观察组相同。结果 两组急性恶心、迟发性恶心、急性呕吐、迟发性呕吐、急性恶心并呕吐发生率比较差异无统计学意义(P>0.05)；与对照组比较，观察组迟发性恶心并呕吐发生率降低，差异有统计学意义(P=0.043)。观察组无恶心呕吐17例，对照组无恶心呕吐9例，差异有统计学意义(P<0.05)。两组其他不良反应比较差异无统计学意义(P>0.05)，且阿瑞匹坦未发生相关中重度药物不良反应。结论 阿瑞匹坦对应用含顺铂化疗方案的晚期乳腺癌患者止吐效果好，安全性高。

阿瑞匹坦; 血清素5-HT3受体拮抗剂；乳腺肿瘤；止吐

乳腺癌发病率与死亡率位于女性恶性肿瘤首位[1]，且发病年龄逐渐年轻化。目前化疗是乳腺癌内科治疗的主要手段，其中顺铂治疗效果好，但易引起严重恶心呕吐(chemotherapy-induced nausea and vomiting, CINV)，使患者对顺铂望而却步，影响治疗依从性[2]。目前临床主要应用5-羟色胺3受体拮抗剂(5-HT3RA)联合地塞米松防治急性CINV，其对于迟发性恶心呕吐的治疗效果不佳[3]。阿瑞匹坦是2003年美国食品药品监督管理局(FDA)批准上市的第一个神经激肽-1受体拮抗剂，可透过血脑屏障作用于脑干呕吐中枢，对于急性及迟发性恶心、呕吐均有一定的治疗效果。本文研究阿瑞匹坦对使用含顺铂化疗方案的晚期乳腺癌患者恶心、呕吐的预防效果，现将结果报告如下。

1 资料与方法

1.1 研究对象 选择我院2014年1月—2016年5月使用含顺铂化疗方案的晚期乳腺癌56例，均为女性，由细胞学或病理学检查明确诊断为乳腺癌，TNM分期均为IV期；年龄25～73岁，中位年龄55岁；美国东部肿瘤协作组(ECOG)评分均<2分；预测生存期>3个月。所有患者化疗前血常规、生化全项、心电图等检查基本正常，无化疗禁忌证，均予2～8个周期含顺铂的化疗方案化疗,且均签署知情同意书，自愿参与并配合治疗。

1.2 一般资料 将56例按照随机数字表法分为观察组和对照组，每组各28例。化疗方案包括TP方案(多西紫杉醇+顺铂)、GP方案(吉西他滨+顺铂)及NP方案(长春瑞滨+顺铂)。两组一般资料比较差异无统计学意义，具有可比性(P>0.05)，见表1。

表1 采用不同止吐方法的乳腺癌化疗两组一般资料[例(%)]

注：TP方案为多西紧彬醇+顺铂,GP方案为吉西他滨+顺铂,NP方案为长春瑞滨+顺铂;ECOG评分为美国东部肿瘤协作组评分

1.3 治疗方法 所有患者均应用含顺铂的化疗方案，顺铂剂量为75 mg/m2。观察组于化疗首日用药前1 h口服阿瑞匹坦(意美，美国Merck Sharp&Dohme Corp)125 mg/d，第2、3天晨起口服阿瑞匹坦80 mg/d，同时予格拉司琼、地塞米松各5 mg/d静脉推注。对照组予安慰剂、格拉司琼及地塞米松，剂量及用法与观察组相同。

1.4 恶心、呕吐评价标准 参照《美国国家癌症研究所-通用不良反应评价标准》(Common Terminology Criteria for Adverse Events， CTCAE)关于胃肠道不良反应的评价标准，将应用化疗药物24 h内发生的恶心呕吐为急性恶心并呕吐，应用化疗药物24～96 h内出现的恶心呕吐为迟发性恶心并呕吐。记录患者在化疗后96 h内出现恶心、呕吐的情况，统计CINV的发生率及不良反应发生情况。

1.5 统计学处理 采用SPSS 17.0统计学软件对数据进行分析。计数资料采用率(%)表示，组间比较采用χ2检验。以α=0.05为检验水准。

2 结果

2.1 两组CINV发生率比较 两组急性恶心、迟发性恶心、急性呕吐、迟发性呕吐、急性恶心并呕吐的发生率比较差异无统计学意义(P>0.05)；与对照组比较，观察组迟发性恶心并呕吐的发生率明显降低，差异有统计学意义(P=0.043)；观察组无恶心呕吐17例，对照组无恶心呕吐9例，差异有统计学意义(P<0.05)，见表2。

2.2 不良反应评价 两组不良反应均为轻度，差异无统计学意义(P>0.05)，见表3。阿瑞匹坦未发生相关中重度药物不良反应(Ⅲ～Ⅳ度)。

表2 采用不同止吐方法的乳腺癌化疗两组恶心、呕吐发生率比较[例(%)]

注：观察组予阿瑞匹坦、格拉司琼及地塞米松，对照组予安慰剂、格拉司琼及地塞米松

表3 采用不同止吐方法的乳腺癌化疗两组轻度不良反应比较[例(%)]

注：观察组予阿瑞匹坦、格拉司琼及地塞米松，对照组予安慰剂、格拉司琼及地塞米松

3 讨论

化疗是乳腺癌治疗的主要手段之一，易引起恶心、呕吐、便秘等不良反应。按照引起恶心呕吐的概率分为高、中、低和轻微4个风险等级，在无任何干预措施时，风险等级发生的概率分别为>90%、30%～90%、10%～29% 和<10%[4]。铂类、环磷酰胺及表阿霉素类等乳腺癌化疗常用药物均属于高致吐药物，且晚期乳腺癌患者多已进行多种治疗，一般状态较差，对再次化疗的耐受性降低，若不能及时对CINV进行预防和处理，将极大影响患者的信心、依从性和治疗效果。为尽可能保证患者顺利完成化疗，在不增加其他相关不良反应的同时减轻CINV非常重要。

CINV的发生机制较复杂，主要通过5-羟色胺(5-HT)、P物质、组胺等神经递质发挥作用[5]。人体大部分5-HT存在于肠道嗜铬细胞中，机体接受化疗药物刺激后释放大量5-HT，并与5-HT3受体结合，兴奋迷走神经，将信号传递至中枢神经系统，从而引起恶心、呕吐。不同的神经递质可能参与不同类型的CINV，其发挥的作用也不尽相同。P物质是一种神经调节多肽，广泛分布于外周及中枢神经系统，其受体共有3种亚型，分别为神经激肽(neurokinin, NK)-1、NK-2和NK-3，其中NK-1与P物质的结合能力最强，且在脑干呕吐中枢中含量最多，二者结合后可兴奋呕吐中枢从而诱发相应症状[6]。动物实验发现特异性阻断NK-1受体可缓解P物质引起的恶心呕吐[7]。

阿瑞匹坦的作用机制是通过结合NK-1受体达到阻断P物质的作用，且其对NK-1受体具有高选择性及高亲和力，对NK-2、NK-3、5-HT3及地塞米松等其他受体的亲和力较低，故联合其他受体拮抗剂，可明显改善CINV[8]。阿瑞匹坦与蛋白的结合率高，可穿透血脑屏障作用于脑干呕吐中枢的NK-1受体，半衰期长，对急性及迟发性CINV均可发挥作用，且其为口服制剂，服用方便，不受食物影响，多数情况下无需调整剂量，安全性高，患者耐受性良好[9]。

研究发现，阿瑞匹坦对治疗迟发性恶心呕吐具有显著优势，联合5-HT3RA与糖皮质激素可有效防治CINV[10-12]。然而，在不同的临床研究中，阿瑞匹坦三联方案针对不同疾病及化疗方案的急性恶心呕吐完全缓解情况尚无统一结论，尚需大样本临床试验进一步证实[13-14]。随着对阿瑞匹坦研究的不断深入，发现阿瑞匹坦对术后止吐的治疗效果良好[15-16]。体外研究发现，NK-1受体拮抗剂具有促进凋亡、抗血管生成从而抑制黑色素瘤的作用[17]。在急性淋巴细胞白血病的体外研究中亦得出了相似结论，NK-1受体拮抗剂通过作用于Akt/ p53轴从而促进肿瘤细胞凋亡[18]。

本研究结果显示观察组未发生恶心呕吐的例数明显降低，与国外报道的研究结果基本一致[19-21]。本研究应用阿瑞匹坦的患者均未发生其他中重度不良反应，且两组轻度不良反应差异比较无统计学意义，患者耐受性及药物安全性良好。本研究的不足之处在于样本量偏小，未对乳腺癌患者进行长期随访，无法评价药物对乳腺癌无病生存期及总生存率的影响。

综上所述，阿瑞匹坦对应用含顺铂化疗方案的晚期乳腺癌患者止吐效果好，且不良反应轻微，可避免患者因化疗导致的生活质量大幅下降。然而，阿瑞匹坦费用较高，为口服制剂，对于不便服用口服药物的患者，静脉制剂可能是更好的选择，希望日后随着NK-1受体拮抗剂的不断研发和改进，能让更多肿瘤患者摆脱CINV的痛苦。

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Efficacy of Aprepitant in Treatment of Chemotherapy-induced Nausea and Vomiting in Patients with Advance Breast Cancer

JIANG Min, CHI Feng, ZENG Yue-can

(Department of Oncology, Shengjing Hospital Affiliated to China Medical University, Liaoning 110022, China)

Objective To observe efficacy and safety of Aprepitant in treatment of chemotherapy-induced nausea and vomiting in advanced breast cancer patients treated with Cisplatin. Methods A total of 56 advanced breast cancer patients treated with Cisplatin during January 2014 and May 2016 were divided into observation group (n=28) and control group (n=28) according to random digits table method. Observation group was treated with 125 mg/d Aprepitant one hour before medication on the first day of chemotherapy, and 80 mg/d Aprepitant was taken orally in the morning on the 2ndand 3rddays, and 5 mg/d Granisetron and 5 mg/d Dexamethasone were given by intravenous push at the same time. Control group was treated with placebo, Granisetron and Dexamethasone with the same dosage and method. Results There were no significant differences in incidence rates of acute nausea, delayed nausea, acute vomiting, delayed vomiting and acute nausea and vomiting in the two groups (P>0.05). Compared with those in control group, incidence rate of delayed nausea and vomiting was significantly decreased in observation group (P=0.043). There were 17 patients without nausea or vomiting in observation group and 9 patients without nausea or vomiting in control group, and the difference was statistically significant (P<0.05). There were no significant differences in other incidence rates of adverse reaction between the two groups (P>0.05), and no moderate or severe adverse reaction was found by Aprepitant. Conclusion Aprepitant in treatment of chemotherapy-induced nausea and vomiting in advanced breast cancer patients treated with Cisplatin can achieve good effect and safety.

Aprepitant; Serotonin 5-HT3 receptor antagonists; Breast neoplasms; Antiemesis

110022 沈阳，中国医科大学附属盛京医院肿瘤科

曾越灿，E-mail：wellyy2005@hotmail.com

R737.9

A

1002-3429(2017)03-0095-04

10.3969/j.issn.1002-3429.2017.03.035

2016-11-24 修回时间：2016-12-26)