姜 敏，遲 峰，曾越燦

阿瑞匹坦用于晚期乳腺癌化療的止吐效果觀察

姜 敏，遲 峰，曾越燦

目的 觀察阿瑞匹坦對(duì)晚期乳腺癌患者應(yīng)用含順鉑化療方案后止吐效果及安全性。方法 選取我院2014年1月—2016年5月使用含順鉑化療方案的晚期乳腺癌56例，按照隨機(jī)數(shù)字表法分為觀察組及對(duì)照組，每組各28例。觀察組于化療首日用藥前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，同時(shí)予格拉司瓊、地塞米松各5 mg/d靜脈推注；對(duì)照組予安慰劑、格拉司瓊及地塞米松，劑量及方法與觀察組相同。結(jié)果 兩組急性惡心、遲發(fā)性惡心、急性嘔吐、遲發(fā)性嘔吐、急性惡心并嘔吐發(fā)生率比較差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；與對(duì)照組比較，觀察組遲發(fā)性惡心并嘔吐發(fā)生率降低，差異有統(tǒng)計(jì)學(xué)意義(P=0.043)。觀察組無(wú)惡心嘔吐17例，對(duì)照組無(wú)惡心嘔吐9例，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。兩組其他不良反應(yīng)比較差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)，且阿瑞匹坦未發(fā)生相關(guān)中重度藥物不良反應(yīng)。結(jié)論 阿瑞匹坦對(duì)應(yīng)用含順鉑化療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受體拮抗劑；乳腺腫瘤；止吐

乳腺癌發(fā)病率與死亡率位于女性惡性腫瘤首位[1]，且發(fā)病年齡逐漸年輕化。目前化療是乳腺癌內(nèi)科治療的主要手段，其中順鉑治療效果好，但易引起嚴(yán)重惡心嘔吐(chemotherapy-induced nausea and vomiting, CINV)，使患者對(duì)順鉑望而卻步，影響治療依從性[2]。目前臨床主要應(yīng)用5-羥色胺3受體拮抗劑(5-HT3RA)聯(lián)合地塞米松防治急性CINV，其對(duì)于遲發(fā)性惡心嘔吐的治療效果不佳[3]。阿瑞匹坦是2003年美國(guó)食品藥品監(jiān)督管理局(FDA)批準(zhǔn)上市的第一個(gè)神經(jīng)激肽-1受體拮抗劑，可透過(guò)血腦屏障作用于腦干嘔吐中樞，對(duì)于急性及遲發(fā)性惡心、嘔吐均有一定的治療效果。本文研究阿瑞匹坦對(duì)使用含順鉑化療方案的晚期乳腺癌患者惡心、嘔吐的預(yù)防效果，現(xiàn)將結(jié)果報(bào)告如下。

1 資料與方法

1.1 研究對(duì)象 選擇我院2014年1月—2016年5月使用含順鉑化療方案的晚期乳腺癌56例，均為女性，由細(xì)胞學(xué)或病理學(xué)檢查明確診斷為乳腺癌，TNM分期均為IV期；年齡25～73歲，中位年齡55歲；美國(guó)東部腫瘤協(xié)作組(ECOG)評(píng)分均<2分；預(yù)測(cè)生存期>3個(gè)月。所有患者化療前血常規(guī)、生化全項(xiàng)、心電圖等檢查基本正常，無(wú)化療禁忌證，均予2～8個(gè)周期含順鉑的化療方案化療,且均簽署知情同意書，自愿參與并配合治療。

1.2 一般資料 將56例按照隨機(jī)數(shù)字表法分為觀察組和對(duì)照組，每組各28例?；煼桨赴═P方案(多西紫杉醇+順鉑)、GP方案(吉西他濱+順鉑)及NP方案(長(zhǎng)春瑞濱+順鉑)。兩組一般資料比較差異無(wú)統(tǒng)計(jì)學(xué)意義，具有可比性(P>0.05)，見表1。

表1 采用不同止吐方法的乳腺癌化療兩組一般資料[例(%)]

注：TP方案為多西緊彬醇+順鉑,GP方案為吉西他濱+順鉑,NP方案為長(zhǎng)春瑞濱+順鉑;ECOG評(píng)分為美國(guó)東部腫瘤協(xié)作組評(píng)分

1.3 治療方法 所有患者均應(yīng)用含順鉑的化療方案，順鉑劑量為75 mg/m2。觀察組于化療首日用藥前1 h口服阿瑞匹坦(意美，美國(guó)Merck Sharp&Dohme Corp)125 mg/d，第2、3天晨起口服阿瑞匹坦80 mg/d，同時(shí)予格拉司瓊、地塞米松各5 mg/d靜脈推注。對(duì)照組予安慰劑、格拉司瓊及地塞米松，劑量及用法與觀察組相同。

1.4 惡心、嘔吐評(píng)價(jià)標(biāo)準(zhǔn) 參照《美國(guó)國(guó)家癌癥研究所-通用不良反應(yīng)評(píng)價(jià)標(biāo)準(zhǔn)》(Common Terminology Criteria for Adverse Events， CTCAE)關(guān)于胃腸道不良反應(yīng)的評(píng)價(jià)標(biāo)準(zhǔn)，將應(yīng)用化療藥物24 h內(nèi)發(fā)生的惡心嘔吐為急性惡心并嘔吐，應(yīng)用化療藥物24～96 h內(nèi)出現(xiàn)的惡心嘔吐為遲發(fā)性惡心并嘔吐。記錄患者在化療后96 h內(nèi)出現(xiàn)惡心、嘔吐的情況，統(tǒng)計(jì)CINV的發(fā)生率及不良反應(yīng)發(fā)生情況。

1.5 統(tǒng)計(jì)學(xué)處理 采用SPSS 17.0統(tǒng)計(jì)學(xué)軟件對(duì)數(shù)據(jù)進(jìn)行分析。計(jì)數(shù)資料采用率(%)表示，組間比較采用χ2檢驗(yàn)。以α=0.05為檢驗(yàn)水準(zhǔn)。

2 結(jié)果

2.1 兩組CINV發(fā)生率比較 兩組急性惡心、遲發(fā)性惡心、急性嘔吐、遲發(fā)性嘔吐、急性惡心并嘔吐的發(fā)生率比較差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；與對(duì)照組比較，觀察組遲發(fā)性惡心并嘔吐的發(fā)生率明顯降低，差異有統(tǒng)計(jì)學(xué)意義(P=0.043)；觀察組無(wú)惡心嘔吐17例，對(duì)照組無(wú)惡心嘔吐9例，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)，見表2。

2.2 不良反應(yīng)評(píng)價(jià) 兩組不良反應(yīng)均為輕度，差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)，見表3。阿瑞匹坦未發(fā)生相關(guān)中重度藥物不良反應(yīng)(Ⅲ～Ⅳ度)。

表2 采用不同止吐方法的乳腺癌化療兩組惡心、嘔吐發(fā)生率比較[例(%)]

注：觀察組予阿瑞匹坦、格拉司瓊及地塞米松，對(duì)照組予安慰劑、格拉司瓊及地塞米松

表3 采用不同止吐方法的乳腺癌化療兩組輕度不良反應(yīng)比較[例(%)]

注：觀察組予阿瑞匹坦、格拉司瓊及地塞米松，對(duì)照組予安慰劑、格拉司瓊及地塞米松

3 討論

化療是乳腺癌治療的主要手段之一，易引起惡心、嘔吐、便秘等不良反應(yīng)。按照引起惡心嘔吐的概率分為高、中、低和輕微4個(gè)風(fēng)險(xiǎn)等級(jí)，在無(wú)任何干預(yù)措施時(shí)，風(fēng)險(xiǎn)等級(jí)發(fā)生的概率分別為>90%、30%～90%、10%～29% 和<10%[4]。鉑類、環(huán)磷酰胺及表阿霉素類等乳腺癌化療常用藥物均屬于高致吐藥物，且晚期乳腺癌患者多已進(jìn)行多種治療，一般狀態(tài)較差，對(duì)再次化療的耐受性降低，若不能及時(shí)對(duì)CINV進(jìn)行預(yù)防和處理，將極大影響患者的信心、依從性和治療效果。為盡可能保證患者順利完成化療，在不增加其他相關(guān)不良反應(yīng)的同時(shí)減輕CINV非常重要。

CINV的發(fā)生機(jī)制較復(fù)雜，主要通過(guò)5-羥色胺(5-HT)、P物質(zhì)、組胺等神經(jīng)遞質(zhì)發(fā)揮作用[5]。人體大部分5-HT存在于腸道嗜鉻細(xì)胞中，機(jī)體接受化療藥物刺激后釋放大量5-HT，并與5-HT3受體結(jié)合，興奮迷走神經(jīng)，將信號(hào)傳遞至中樞神經(jīng)系統(tǒng)，從而引起惡心、嘔吐。不同的神經(jīng)遞質(zhì)可能參與不同類型的CINV，其發(fā)揮的作用也不盡相同。P物質(zhì)是一種神經(jīng)調(diào)節(jié)多肽，廣泛分布于外周及中樞神經(jīng)系統(tǒng)，其受體共有3種亞型，分別為神經(jīng)激肽(neurokinin, NK)-1、NK-2和NK-3，其中NK-1與P物質(zhì)的結(jié)合能力最強(qiáng)，且在腦干嘔吐中樞中含量最多，二者結(jié)合后可興奮嘔吐中樞從而誘發(fā)相應(yīng)癥狀[6]。動(dòng)物實(shí)驗(yàn)發(fā)現(xiàn)特異性阻斷NK-1受體可緩解P物質(zhì)引起的惡心嘔吐[7]。

阿瑞匹坦的作用機(jī)制是通過(guò)結(jié)合NK-1受體達(dá)到阻斷P物質(zhì)的作用，且其對(duì)NK-1受體具有高選擇性及高親和力，對(duì)NK-2、NK-3、5-HT3及地塞米松等其他受體的親和力較低，故聯(lián)合其他受體拮抗劑，可明顯改善CINV[8]。阿瑞匹坦與蛋白的結(jié)合率高，可穿透血腦屏障作用于腦干嘔吐中樞的NK-1受體，半衰期長(zhǎng)，對(duì)急性及遲發(fā)性CINV均可發(fā)揮作用，且其為口服制劑，服用方便，不受食物影響，多數(shù)情況下無(wú)需調(diào)整劑量，安全性高，患者耐受性良好[9]。

研究發(fā)現(xiàn)，阿瑞匹坦對(duì)治療遲發(fā)性惡心嘔吐具有顯著優(yōu)勢(shì)，聯(lián)合5-HT3RA與糖皮質(zhì)激素可有效防治CINV[10-12]。然而，在不同的臨床研究中，阿瑞匹坦三聯(lián)方案針對(duì)不同疾病及化療方案的急性惡心嘔吐完全緩解情況尚無(wú)統(tǒng)一結(jié)論，尚需大樣本臨床試驗(yàn)進(jìn)一步證實(shí)[13-14]。隨著對(duì)阿瑞匹坦研究的不斷深入，發(fā)現(xiàn)阿瑞匹坦對(duì)術(shù)后止吐的治療效果良好[15-16]。體外研究發(fā)現(xiàn)，NK-1受體拮抗劑具有促進(jìn)凋亡、抗血管生成從而抑制黑色素瘤的作用[17]。在急性淋巴細(xì)胞白血病的體外研究中亦得出了相似結(jié)論，NK-1受體拮抗劑通過(guò)作用于Akt/ p53軸從而促進(jìn)腫瘤細(xì)胞凋亡[18]。

本研究結(jié)果顯示觀察組未發(fā)生惡心嘔吐的例數(shù)明顯降低，與國(guó)外報(bào)道的研究結(jié)果基本一致[19-21]。本研究應(yīng)用阿瑞匹坦的患者均未發(fā)生其他中重度不良反應(yīng)，且兩組輕度不良反應(yīng)差異比較無(wú)統(tǒng)計(jì)學(xué)意義，患者耐受性及藥物安全性良好。本研究的不足之處在于樣本量偏小，未對(duì)乳腺癌患者進(jìn)行長(zhǎng)期隨訪，無(wú)法評(píng)價(jià)藥物對(duì)乳腺癌無(wú)病生存期及總生存率的影響。

綜上所述，阿瑞匹坦對(duì)應(yīng)用含順鉑化療方案的晚期乳腺癌患者止吐效果好，且不良反應(yīng)輕微，可避免患者因化療導(dǎo)致的生活質(zhì)量大幅下降。然而，阿瑞匹坦費(fèi)用較高，為口服制劑，對(duì)于不便服用口服藥物的患者，靜脈制劑可能是更好的選擇，希望日后隨著NK-1受體拮抗劑的不斷研發(fā)和改進(jìn)，能讓更多腫瘤患者擺脫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 沈陽(yáng)，中國(guó)醫(yī)科大學(xué)附屬盛京醫(yī)院腫瘤科

曾越燦，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 修回時(shí)間：2016-12-26)