張潔霞 蔡 迪 李時(shí)悅 占楊清 周承志 秦茵茵 歐陽銘

(廣州醫(yī)科大學(xué)附屬第一醫(yī)院廣州呼吸疾病研究所 呼吸疾病國家重點(diǎn)實(shí)驗(yàn)室，廣東 廣州 510120)

·論著·

AP與TP方案在EGFR-TKI耐藥的非小細(xì)胞肺癌患者中的療效比較

張潔霞 蔡 迪 李時(shí)悅 占楊清 周承志 秦茵茵 歐陽銘*

(廣州醫(yī)科大學(xué)附屬第一醫(yī)院廣州呼吸疾病研究所 呼吸疾病國家重點(diǎn)實(shí)驗(yàn)室，廣東 廣州 510120)

目的:探討AP(培美曲塞+順鉑)和TP(多西紫杉醇+順鉑)方案對(duì)EGFR-TKIs耐藥的晚期非小細(xì)胞肺癌(NSCLC)患者的療效。方法：回顧性分析2009年2月至2010年3月廣州醫(yī)科大學(xué)附屬第一醫(yī)院收治的232例EGFR-TKIs耐藥的晚期NSCLC患者的臨床資料，根據(jù)化療方案不同分為AP組(培美曲塞+順鉑)和TP組(多西紫杉醇+順鉑)，每組各116例。根據(jù)RECIST標(biāo)準(zhǔn)評(píng)價(jià)近期療效(RR、DCR)、總生存期(OS)，無進(jìn)展生存期(PFS)。結(jié)果：TP組和AP組有效率、自靶向藥物進(jìn)展后總生存期分別為34.5%和24.1%、12.4個(gè)月和12.0個(gè)月，兩組比較，差異無統(tǒng)計(jì)學(xué)意義(P>0.05)。TP組和AP組PFS分別為8.0個(gè)月和6.2個(gè)月，兩組比較，差異有統(tǒng)計(jì)學(xué)差異(P<0.01)。AP組中不吸煙與吸煙患者的總生存期、PFS分別為12.0和9.0個(gè)月、6.5和5.6個(gè)月，兩者比較，差異有統(tǒng)計(jì)學(xué)意義(P<0.01)。兩組吸煙與不吸煙患者疾病控制率比較，差異無統(tǒng)計(jì)學(xué)意義(P>0.05)。TP組中不吸煙與吸煙患者的總生存期分別為14和8.8個(gè)月，兩者比較，差異無統(tǒng)計(jì)學(xué)意義(P=0.725)；TP組中不吸煙與吸煙患者的PFS分別為8.0和6.0個(gè)月，兩者比較，差異有統(tǒng)計(jì)學(xué)意義(P<0.01)。結(jié)論：AP和TP方案對(duì)EGFR-TKI靶向治療耐藥進(jìn)展的晚期NSCLC患者療效相似；吸煙者療效較不吸煙者差。

非小細(xì)胞肺癌；表皮生長因子受體酪氨酸激酶抑制劑；耐藥；培美曲塞；多西紫杉醇

肺癌的治療目前已進(jìn)入個(gè)體化時(shí)代，分子靶向藥物給患者帶來了新的希望。吉非替尼(商品名易瑞沙)對(duì)于非小細(xì)胞肺癌(non-mall-cell carcinoma，NSCLC)EGFR突變陽性患者的療效較為確切，且起效時(shí)間迅速，但患者平均1～2年則會(huì)出現(xiàn)耐藥，需要接受化療。新型化療藥物(如培美曲塞、多西紫杉醇)的合理聯(lián)用能顯著改善患者生活質(zhì)量，且耐受性良好。2009年2月至2010年3月本科對(duì)232例曾經(jīng)口服EGFR-TKI有效的NSCLC患者采用AP(培美曲塞+順鉑)與TP(多西紫杉醇+順鉑)進(jìn)行治療，現(xiàn)報(bào)道如下。

1 資料與方法

1.1 一般資料

本組患者232例，根據(jù)化療方案的不同分為AP組(培美曲塞+順鉑)和TP組(多西紫杉醇+順鉑)，每組各116例?；颊呔?jīng)組織學(xué)或細(xì)胞學(xué)檢查確診為NSCLC；按國際抗癌聯(lián)盟(UICC)標(biāo)準(zhǔn)分期為局部晚期至晚期(ⅢB～Ⅳ期)；經(jīng)EGFR-TKI治療獲緩解3個(gè)月以上又出現(xiàn)進(jìn)展者[1，2]；體力狀況評(píng)分(ECOG

1.2 治療方法

AP組給藥方法:培美曲塞500 mg/m2、順鉑80 mg/m2,靜脈滴注，21 d為1個(gè)周期。TP組給藥方法：多西紫杉醇75 mg/m2、順鉑80 mg/m2,靜脈滴注，21 d為1個(gè)周期。預(yù)防用藥：在使用培美曲塞前1～2周開始給予葉酸和維生素B12預(yù)處理。每2個(gè)周期化療結(jié)束后進(jìn)行評(píng)價(jià)療效，共4～6個(gè)療程。

1.3 療效及毒性評(píng)價(jià)標(biāo)準(zhǔn)

按照世界衛(wèi)生組織(WHO)制定的RECIST療效評(píng)價(jià)標(biāo)準(zhǔn)及抗癌藥物不良反應(yīng)評(píng)價(jià)標(biāo)準(zhǔn)，其中療效分為完全緩解(CR)、部分緩解(PR)、穩(wěn)定(SD)和進(jìn)展(PD)，CR+PR為總有效率(RR)；CR+PR+SD為臨床獲益率(DCR)；不良反應(yīng)分為0～Ⅳ度。無疾病進(jìn)展時(shí)間(PFS)是指化療開始到腫瘤出現(xiàn)進(jìn)展的時(shí)間?？偵嫫?OS)是指口服靶向藥疾病進(jìn)展起至死亡時(shí)間的中位數(shù)。

1.4 統(tǒng)計(jì)學(xué)分析

應(yīng)用SPSS 20.0統(tǒng)計(jì)軟件進(jìn)行分析，計(jì)量資料以中位數(shù)表示，計(jì)量資料的比較使用非參數(shù)檢驗(yàn)，生存期比較使用Log-rank檢驗(yàn)法，并繪制Kaplan-Meier曲線,計(jì)數(shù)資料的比較采用χ2檢驗(yàn),P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié) 果

2.1 近期療效

AP組中PR 35例、SD 68例、PD 13例，有效率為34.5%；TP組中PR 28例、SD 68例、PD 20例，有效率為24.1%，兩組比較，差異無統(tǒng)計(jì)學(xué)意義(P=0.301)，見表1。AP組和TP組自靶向藥物進(jìn)展后總生存期分別為12.4個(gè)月和12.0個(gè)月，兩組比較，差異無統(tǒng)計(jì)學(xué)意義(P=0.133)，見圖1。AP組和TP組PFS分別為8.0個(gè)月和6.2個(gè)月，兩組比較，差異有統(tǒng)計(jì)學(xué)差異(P<0.01)，見圖2。

2.2 療效與吸煙的關(guān)系

TP組中不吸煙與吸煙患者的總生存期、PFS分別為12.0和9.0個(gè)月、6.5和5.6個(gè)月，兩者比較，差異有統(tǒng)計(jì)學(xué)意義(P<0.01)，見表2，圖3，4。TP組吸煙患者疾病控制率為75%，低于不吸煙患者的84%，AP組吸煙患者疾病控制率為85%，低于不吸煙患者的93%，但兩者比較，差異無統(tǒng)計(jì)學(xué)意義(P>0.05)，見表2。AP組中不吸煙與吸煙患者的總生存期分別為14和8.8個(gè)月，兩者比較，差異無統(tǒng)計(jì)學(xué)意義(P=0.725)；TP組中不吸煙與吸煙患者的PFS分別為8.0和6.0個(gè)月，兩者比較，差異有統(tǒng)計(jì)學(xué)意義(P<0.01)，見圖5、6。

表1 AP組與TP組患者的一般資料比較

圖1 多西紫杉醇+順鉑組與培美曲塞+順鉑組總生存期(OS)比較

圖2 多西紫杉醇+順鉑組與培美曲塞+順鉑組無進(jìn)展生存期(PFS)比較

表2 吸煙與不吸煙患者非水細(xì)胞腫癌的臨床特征比較

AP組臨床特征不吸煙(100例)吸煙(16例)P值TP組臨床特征不吸煙(96例)吸煙(20例)P值年齡(歲)58(51～64)71.5(65.5～77.75)0.039性別(男/女)44/648/80.751性別(男/女)32/6415/50.455總生存期(月)12.0(11.7～12.3)9(8.0～9.9)<0.001總生存期(月)14(12.5～15.4)8.8(8.4～9.2)0.725無進(jìn)展生存期(月)6.5(6.0～7.0)5.6(4.7～6.4)<0.001無進(jìn)展生存期(月)8.0(7.4～8.6)6.0(5.7～6.2)<0.001PR(例)2440.931PR(例)3230.104SD(例)6080.451SD(例)57140.375PD(例)1640.376PD(例)730.250RR(%)0.240.250.931RR(%)0.330.180.104DCR(%)0.840.750.376DCR(%)0.930.850.250

圖3 多西紫杉醇+順鉑吸煙組與多西紫杉醇+順鉑不吸煙組總生存期比較

圖4 多西紫杉醇+順鉑吸煙組與多西紫杉醇+順鉑不吸煙組無進(jìn)展生存期比較

圖5 培美曲塞+順鉑吸煙組與培美曲塞+順鉑不吸煙組總生存期比較

圖6 培美曲塞+順鉑吸煙組與培美曲塞+順鉑不吸煙組無進(jìn)展生存期比較

3 討 論

大量研究結(jié)果證實(shí)EGFR-TKI在EGFR突變?nèi)巳阂痪€治療中顯示出較高的腫瘤反應(yīng)率和長PFS[3-8]。2010年ASCO報(bào)道EGFR突變患者接受EGFR-TKI治療的有效率為66%，而接受EGFR-TKI+化療者為69%，由此可見，對(duì)于EGFR突變患者，在TKI基礎(chǔ)上加用化療并不能改善有效率，PFS和OS亦無改善。同步化療和EGFR-TKI尚缺乏充足證據(jù)。一個(gè)Ⅱ期研究顯示聯(lián)合EGFR-TKI和化療能改善PFS，但仍需Ⅲ期研究。

培美曲塞是一個(gè)新的多靶點(diǎn)抗葉酸劑，它通過干擾細(xì)胞復(fù)制過程中葉酸依賴性代謝過程而發(fā)揮作用。2002年，澳大利亞學(xué)者Clarke應(yīng)用培美曲塞治療59例首次采用化療治療NSCLC患者，其中體力狀況評(píng)分為2分的患者占32%(19例)，結(jié)果顯示約16%的患者達(dá)PR，中位緩解期為4.9個(gè)月，中位生存期為7.2個(gè)月[9]。培美曲塞聯(lián)合順鉑是晚期非小細(xì)胞肺癌一線標(biāo)準(zhǔn)治療[10]，且低TS酶者預(yù)測培美曲塞的療效好[11]?！芭嗝狼?lián)合順鉑對(duì)比吉西他濱和順鉑在初治肺癌”和另一個(gè)“對(duì)比培美曲塞對(duì)安慰劑維持治療”兩個(gè)隨機(jī)研究分析了上千例高齡患者，結(jié)果顯示，培美曲塞可使年輕和老年患者同樣獲益，劑量強(qiáng)度和毒性均可接受[12]。Patrick[13]報(bào)道1例患者在接受過厄羅替尼、多西紫杉醇化療后病情進(jìn)展，且ECOG評(píng)分為3分時(shí)接受14個(gè)療程3線單藥培美曲塞化療能夠獲益且療效持續(xù)20個(gè)月。

多西紫杉醇通過使細(xì)胞在有絲分裂過程中不能形成正常的有絲分裂紡錘體，從而抑制了細(xì)胞的分裂和增殖。2000年，Shepherd等[14]通過一個(gè)隨機(jī)Ⅲ期臨床試驗(yàn)比較多西紫杉醇單藥與最佳支持治療，結(jié)果顯示，多西紫杉醇能明顯提高患者生存期(6.8個(gè)月和4.8個(gè)月)和體能狀態(tài)評(píng)分。38.8%TKI繼發(fā)抗藥患者進(jìn)行EGFR突變檢測，其中28.4%為T790M突變；12.3%行c-met拷貝數(shù)；7.1%行c-met擴(kuò)增，3組T790M和c-met擴(kuò)增差異無統(tǒng)計(jì)學(xué)意義。盡管臨床上沒有比通過T790M突變的獲得性抗藥更惰性的過程。EGFR突變患者EGFR-TKI 獲得性耐藥的主要機(jī)制HGF、c-met、IGFR、HER3和50%～60%是T790M[15-19]。針對(duì)這些靶點(diǎn)的藥物有afatinib單獨(dú)或聯(lián)合西妥昔單抗、c-met單抗OAM4558g、ARQ197等。

針對(duì)EGFR靶向治療耐藥問題，現(xiàn)行策略主要有以下幾點(diǎn)：(1)繼續(xù)原分子靶向藥物治療;(2)靶向聯(lián)合單抗或化療，易瑞沙聯(lián)合紫杉醇有一定療效，但很難判定是化療還是聯(lián)合的協(xié)同作用;(3)多靶點(diǎn)藥物連用;多靶點(diǎn)酪氨酸激酶抑制劑能從不同環(huán)節(jié)抑制腫瘤細(xì)胞生長和微環(huán)境的形成。

本研究中AP組和TP組自靶向藥物進(jìn)展后總生存期分別為12.4個(gè)月和12.0個(gè)月，兩組比較，差異無統(tǒng)計(jì)學(xué)意義，但均較既往單純化療的總生存期(8～10個(gè)月)長，可能與對(duì)TKI敏感的腫瘤對(duì)化療也相對(duì)敏感有關(guān)，故生存期和疾病進(jìn)展時(shí)間較長。本研究中TP組中不吸煙與吸煙患者的總生存期、PFS分別為12.0和9.0個(gè)月、6.5和5.6個(gè)月，兩者比較，差異有統(tǒng)計(jì)學(xué)意義。AP組中不吸煙與吸煙患者的總生存期分別為14和8.8個(gè)月，兩者比較，差異無統(tǒng)計(jì)學(xué)意義；TP組中不吸煙與吸煙患者的PFS分別為8.0和6.0個(gè)月，兩者比較，差異有統(tǒng)計(jì)學(xué)意義。何衛(wèi)國等[20]的研究表明P53蛋白和mRNA基因高表達(dá)可以預(yù)測非小細(xì)胞肺癌的耐藥性。吸煙者療效較不吸煙者差，可能與吸煙患者存在TP53突變有關(guān)，且突變與吸煙量有關(guān)[20，21]。總之，培美曲塞及多西紫杉醇含鉑雙藥對(duì)EGFR-TKI耐藥的NSCLC患者有一定療效，可推遲疾病進(jìn)展，延長中位生存期，提高1年生存率。

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(本文編輯:歐陽菁)

Effect of AP protocol versus TP protocol in non-small-cell lung cancer patients with EGFR-TKI resistance

ZhangJiexia,CaiDi,LiShiyue,ZhanYangqing,ZhouChengzhi,QinYinyin,OuyangMing

(GuangzhouInstituteofRespiratoryDiseases,FirstAffiliatedHospitalofGuangzhouMedicalUniversity,StateKeyLaboratoryofRespiratoryDisease,Guangzhou510120,China)

Objective:To investigate the effect of AP (pemetrexed+cisplatin) protocol versus TP (docetaxel+cisplatin) protocol in advanced non-small-cell lung cancer (NSCLC) patients with EGFR-TKI resistance.Methods:The clinical data of 232 advanced NSCLC patients with EGFR-TKI resistance hospitalized in First Affiliated Hospital of Guangzhou Medical University between February 2009 and March 2010 were retrospectively analyzed. Based on different protocols of chemotherapy, all patients were divided into two groups (n=116 each):the AP(premetrex+cisplatin) group and TP (docetaxel+cisplatin) group. The short-term efficacy [response rate (RR) and disease control rate (DCR)], overall survival (OS), progression free survival (PFS) were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results:The RR and OS after the targeted drug developed in TP group and AP group were 34.5% vs. 24.1% and 12.4 months vs. 12.0 months, respectively. And there were no statistically significant differences between the two groups (P>0.05). The PFS in TP group and AP group was 8.0 months vs. 6.2 months, with statistically significant difference (P<0.01). The OS and PFS in non-smokers and smokers of the AP group were 12.0 months vs. 9.0 months and 6.5 months vs. 5.6 months, respectively, with statistically significant differences between the two groups (P<0.01). No statistically significant difference was found in DCR between smokers and non-smokers of the two groups (P>0.05). The OS in non-smokers and smokers of the TP group was 14 months vs. 8.8 months, respectively, with statistically significant difference (P=0.725); while the PFS in non-smokers and smokers of the TP group was 8.0 months vs. 6.0 months, respectively, with statistically significant difference(P<0.01).Conclusion:The effect of AP protocol and TP protocol in advanced NSCLC patients was similar in the development of EGFR-TKI resistance in targeted therapy. And the efficacy in smokers was worse than non-smokers.

non-small-cell lung cancer; epidermal growth factor receptor tyrosine kinase inhibitor; drug resistance; pemetrexed; docetaxel

10.3969/j.issn.2095-9664.2015.01.002

張潔霞(1971-)，女，博士，主任醫(yī)師。

R734.2

A

2095-9664(2015)01-0004-05

2014-04-09)

研究方向：肺癌、乳腺癌等腫瘤的基礎(chǔ)與臨床研究。

*通訊作者：E-mail：Ouyang1135@126.com。