?？颂婺崧?lián)合放療治療EGFR突變型肺腺癌無癥狀腦轉(zhuǎn)移療效觀察

羅鵬輝，王湘萍，莫敦昌，劉艷萍，黃昌杰

(廣西醫(yī)科大學(xué)第三附屬醫(yī)院腫瘤科，廣西南寧530031)

?？颂婺崧?lián)合放療治療EGFR突變型肺腺癌無癥狀腦轉(zhuǎn)移療效觀察

羅鵬輝，王湘萍，莫敦昌，劉艷萍，黃昌杰

(廣西醫(yī)科大學(xué)第三附屬醫(yī)院腫瘤科，廣西南寧530031)

目的評(píng)價(jià)?？颂婺崧?lián)合放療在治療EGFR突變型肺腺癌無癥狀腦轉(zhuǎn)移患者中的作用。方法回顧性分析2012年1月至2015年6月廣西醫(yī)科大學(xué)第三附屬醫(yī)院61例EGFR突變型肺腺癌無癥狀腦轉(zhuǎn)移患者的臨床資料，其中?？颂婺崧?lián)合放療(聯(lián)合組)23例，埃克替尼單藥治療(靶向治療組)38例。靶向治療第1、3、5個(gè)月及之后每3個(gè)月復(fù)查評(píng)價(jià)療效。χ2檢驗(yàn)評(píng)價(jià)兩組客觀緩解率、疾病控制率，Kaplan Meier法和Log-rank法進(jìn)行生存分析。結(jié)果在靶向治療第5個(gè)月，聯(lián)合組的總客觀緩解率和總疾病控制率分別為82.6%和95.7%，均明顯高于靶向治療組的55.3%和76.3%，差異均有統(tǒng)計(jì)學(xué)意義(P＜0.05)；聯(lián)合組的腦轉(zhuǎn)移瘤客觀緩解率和疾病控制率分別為95.7%和100.0%，均明顯高于靶向治療組的55.3%和81.6%，差異均有統(tǒng)計(jì)學(xué)意義(P＜0.05)；中位無進(jìn)展生存時(shí)間聯(lián)合組14個(gè)月，靶向治療組8個(gè)月，差異亦有統(tǒng)計(jì)學(xué)意義(P＜0.05)；Ⅲ～Ⅳ級(jí)毒副反應(yīng)中，聯(lián)合組疲乏、惡心、嘔吐明顯高于靶向治療組，差異均有統(tǒng)計(jì)學(xué)意義(P＜0.05)，但可耐受，皮疹、腹瀉、骨髓抑制差異均無統(tǒng)計(jì)學(xué)意義(P＞0.05)。結(jié)論埃克替尼聯(lián)合放療明顯提高EGFR突變型肺腺癌無癥狀腦轉(zhuǎn)移患者的治療效果，延長(zhǎng)患者中位無進(jìn)展生存時(shí)間，毒副反應(yīng)可以耐受。

肺癌；肺腺癌；腦轉(zhuǎn)移；埃克替尼；放療；靶向治療

肺癌是全世界發(fā)病率和死亡率最高的惡性腫瘤[1]。腦轉(zhuǎn)移瘤的原發(fā)部位最常來源于肺癌，是肺癌患者主要死亡原因[2-3]。肺癌中最容易發(fā)生腦轉(zhuǎn)移(brain metastases，BM)的病理類型是腺癌和小細(xì)胞肺癌，即使采用放療、化療、手術(shù)等積極的治療方法，也難明顯延長(zhǎng)肺癌腦轉(zhuǎn)移患者的生存時(shí)間[4-6]，因此探索肺癌腦轉(zhuǎn)移新的治療方法十分必要。厄洛替尼等表皮生長(zhǎng)因子受體酪氨酸激酶抑制劑能明顯延長(zhǎng)EGFR突變型晚期肺腺癌患者的生存時(shí)間，成為這類患者首選治療方法[7-9]。Weber等[10]研究發(fā)現(xiàn)EGFR-TKIs對(duì)EGFR突變型肺腺癌腦轉(zhuǎn)移病灶有明顯治療效果。Zeng等[11]和Fan等[12]在各自的研究中相繼發(fā)現(xiàn)，EGFR-TKIs聯(lián)合放療治療EGFR突變型肺癌腦轉(zhuǎn)移瘤的療效優(yōu)于單存放療或單存靶向治療。Lee等[13]研究中發(fā)現(xiàn)放療在EGFR突變型非小細(xì)胞肺癌腦轉(zhuǎn)移病灶的效果明顯優(yōu)EGFR野生型患者。但關(guān)于靶向治療、放療在EGFR突變型肺腺癌無癥狀腦轉(zhuǎn)移的療效報(bào)道罕見。因此，筆者回顧三年多在我院接受?？颂婺岚邢蛑委熉?lián)合放療或單純埃克替尼靶向治療的EGFR突變型肺腺癌無癥狀腦轉(zhuǎn)移患者的臨床資料，現(xiàn)將兩組的治療效果及副反應(yīng)情況比較分析如下：

1 資料與方法

1.1 一般資料回顧性分析2012年1月至2015年6月61例在廣西醫(yī)科大學(xué)第三附屬醫(yī)院住院治療的EGFR突變型肺腺癌無癥狀腦轉(zhuǎn)移患者的臨床資料，將其中接受靶向治療聯(lián)合放療的23例患者作為聯(lián)合組，38例單純靶向治療者作為靶向治療組。治療前經(jīng)病理確診為肺腺癌，MRI檢查明確存在腦轉(zhuǎn)移瘤，基因檢測(cè)確診EGFR基因突變，兩組患者的臨床資料比較見表1。

1.2 治療方法靶向治療采用口服鹽酸?？颂婺崞?，每次125 mg，3次/d，至疾病進(jìn)展或出現(xiàn)無法耐受的副反應(yīng)時(shí)停藥；放療采用全腦照射(兩側(cè)野對(duì)穿照射)30 Gy，局部病灶調(diào)強(qiáng)放療加量至60 Gy，1次/d，每周5 d，每次劑量200 cGy。

1.3 療效評(píng)價(jià)方法采用新版實(shí)體瘤療效評(píng)價(jià)標(biāo)準(zhǔn)(RECIST 1.1版)[14]，在靶向治療第1、3、5個(gè)月及之后每3個(gè)月復(fù)查胸部CT、頭顱MRI，及療效評(píng)價(jià)。在靶向治療第5個(gè)月進(jìn)行總體療效評(píng)價(jià)和腦轉(zhuǎn)移病灶的局部療效評(píng)價(jià)?？陀^有效率為(CR+PR)/(CR+PR+SD+ PD)×100%，疾病控制率為(CR+PR+SD)/(CR+PR+SD+ PD)×100%。統(tǒng)計(jì)分析兩組患者無進(jìn)展生存時(shí)間。

表1 兩組患者的臨床資料比較(例)

1.4 不良反應(yīng)評(píng)估方法采用美國(guó)國(guó)家癌癥研究所制定的毒副評(píng)價(jià)標(biāo)準(zhǔn)進(jìn)行不良反應(yīng)評(píng)估[15]。

1.5 統(tǒng)計(jì)學(xué)方法應(yīng)用SPSS19.0統(tǒng)計(jì)軟件進(jìn)行數(shù)據(jù)分析，兩組間計(jì)數(shù)資料比較采用Pearson χ2檢驗(yàn)，采用Kaplan Meier法進(jìn)行生存分析，并行Log-rank法檢驗(yàn)，以P＜0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié)果

2.1 兩組患者的總體客觀有效率和疾病控制率比較兩組患者生存時(shí)間大于5個(gè)月，CR、PR、SD、PD在聯(lián)合組中分別為8例、11例、3例、1例，靶向治療組分別為3例、18例、8例、9例，差異均有統(tǒng)計(jì)學(xué)意義(χ2= 9.522，P=0.023)。聯(lián)合組客觀有效率和疾病控制率分別為82.6%、95.7%，靶向治療組分別為55.3%、76.3%，經(jīng)統(tǒng)計(jì)學(xué)分析，差異均有統(tǒng)計(jì)學(xué)意義(χ2=4.746，P= 0.029；χ2=3.909，P=0.048)。

2.2 兩組患者腦轉(zhuǎn)移病灶的客觀有效率和疾病控制率比較兩組患者腦轉(zhuǎn)移病灶CR、PR、SD、PD在聯(lián)合組中分別為17例、5例、1例、0例，靶向治療組分別為6例、15例、10例、7例，差異均有統(tǒng)計(jì)學(xué)意義(χ2= 22.283，P=0.000)。聯(lián)合組客觀有效率和疾病控制率分別為95.7%、100%，靶向治療組分別為55.3%、81.6%，差異均有統(tǒng)計(jì)學(xué)意義(χ2=11.236，P=0.001；χ2= 4.786，P=0.029)。

2.3 兩組患者嚴(yán)重不良反應(yīng)比較在嚴(yán)重不良反應(yīng)表現(xiàn)中，聯(lián)合組疲乏、惡心、嘔吐發(fā)生率均高于靶向治療組，差異均有統(tǒng)計(jì)學(xué)意義(P＜0.05)，而皮疹、腹瀉、骨髓抑制發(fā)生率比較差異均無統(tǒng)計(jì)學(xué)意義(P＞0.05)，見表2。所有不良反應(yīng)經(jīng)對(duì)癥處理后患者均能耐受。

表2 嚴(yán)重不良反應(yīng)發(fā)生率(例)

2.4 兩組患者無進(jìn)展生存時(shí)間比較隨訪5～29個(gè)月，聯(lián)合組中位無進(jìn)展生存時(shí)間14個(gè)月(95%CI：8.690～19.310)，靶向治療組中位無進(jìn)展生存時(shí)間8個(gè)月(95%CI：5.738～10.262)，差異具有統(tǒng)計(jì)學(xué)意義(χ2= 5.753，P=0.016)。見圖1。

圖1 兩組無進(jìn)展生存曲線

3 討論

EGFR-TKIs是晚期EGFR突變型非小細(xì)胞肺癌一線治療藥物，在疾病控制率和總體生存率方面明顯優(yōu)于化療[14-15]。由于血腦屏障的原因，化學(xué)藥物等大分子、親水性物質(zhì)很難進(jìn)入顱內(nèi)，而EGFR-TKIs等小分子靶向藥物能通過血腦屏障、進(jìn)入顱內(nèi)殺滅腦轉(zhuǎn)移瘤。Miller等[16]用厄洛替尼聯(lián)合放療治療腦膠質(zhì)瘤，進(jìn)行藥代動(dòng)力學(xué)研究發(fā)現(xiàn)7%的厄洛替尼可透過血腦屏障，作用于腦膠質(zhì)瘤，最大穩(wěn)態(tài)腦脊液濃度達(dá)130 ng/mL，證實(shí)EGFR-TKIs可通過血腦屏障、治療顱內(nèi)腫瘤。

目前也有研究證實(shí)EGFR-TKIs對(duì)非小細(xì)胞肺癌腦轉(zhuǎn)移瘤治療有效。Weber等[10]用[11C]標(biāo)記厄洛替尼，治療EGFR基因突變型(19外顯子缺失)非小細(xì)胞肺癌腦轉(zhuǎn)移患者，用PET/CT檢測(cè)顱內(nèi)被[11C]標(biāo)記的厄洛替尼的聚集情況，發(fā)現(xiàn)厄洛替尼能滲透過血腦屏障，在腦轉(zhuǎn)移病灶中濃聚，經(jīng)厄洛替尼治療后腦轉(zhuǎn)移瘤明顯縮小。Fan等[12]對(duì)20例已有腦轉(zhuǎn)移的非小細(xì)胞肺癌患者采用埃克替尼靶向治療聯(lián)合全腦放療(其中EGFR突變型18例，EGFR野生型2例)，同時(shí)檢測(cè)腦脊液和血漿中?？颂婺岬臐舛?，中位隨訪20個(gè)月，結(jié)果總反應(yīng)率為80%，中位無進(jìn)展生存時(shí)間7個(gè)月，中位生存時(shí)間14.6個(gè)月，其中EGFR突變型患者中位生存時(shí)間22個(gè)月，野生型7.5個(gè)月，腦脊液中?？颂婺釢舛葹?11.6±9.1)ng/mL，?？颂婺嵬ㄟ^血腦屏障的滲透率為(1.4±1.1)%。這兩項(xiàng)研究均證實(shí)EGFR-TKIs藥物厄洛替尼、?？颂婺崮芡高^EGFR突變型非小細(xì)胞肺癌患者的血腦屏障，對(duì)肺癌患者的腦轉(zhuǎn)移病灶有治療作用。本組61例EGFR突變型肺腺癌無癥狀腦轉(zhuǎn)移患者接受埃克替尼靶向治療后顱內(nèi)病灶均得到控制，聯(lián)合組腦轉(zhuǎn)移病灶疾病控制率為100%，靶向治療組腦轉(zhuǎn)移病灶疾病控制率為81.6%。

放射治療是腦轉(zhuǎn)移瘤的主要治療模式。腦轉(zhuǎn)移瘤的放療方式包括全腦放療(whole brain radiotherapy，WBRT)和立體定向放療(stereotactic radiosurgery，SRS)，腦轉(zhuǎn)移瘤患者WBRT的中位生存期(median overall survival，mOS)3～6個(gè)月，SRS可延長(zhǎng)至10個(gè)多月，但SRS主要適用于腦轉(zhuǎn)移灶數(shù)目較少、體積較小的患者[4,17]，因此靠單純放療明顯延長(zhǎng)腦轉(zhuǎn)移瘤患者的生存時(shí)間可能性不大。EGFR-TKIs問世以后，研究者們不斷嘗試用EGFR-TKIs聯(lián)合放療治療腦轉(zhuǎn)移瘤，來提高腦轉(zhuǎn)移瘤患者的生存時(shí)間。如Olmez等[18]采用全腦放療聯(lián)合厄洛替尼治療8例非小細(xì)胞肺癌腦轉(zhuǎn)移患者，結(jié)果所有患者顱內(nèi)轉(zhuǎn)移病灶得到有效控制，但出現(xiàn)明顯的Ⅲ～Ⅳ級(jí)毒副反應(yīng)；Welsh等[19]用厄洛替尼聯(lián)合全腦放療治療40例出現(xiàn)腦轉(zhuǎn)移的非小細(xì)胞肺癌患者，結(jié)果發(fā)現(xiàn)總反應(yīng)率為86%，無神經(jīng)毒性及Ⅳ級(jí)毒副反應(yīng)發(fā)生，中位隨訪28.5個(gè)月，中位生存時(shí)間11.8個(gè)月。其中17例進(jìn)行了EGFR基因檢測(cè)，EGFR野生型患者中位生存時(shí)間9.3個(gè)月，EGFR突變患者中位生存時(shí)間19.1個(gè)月。提示EGFR-TKIs聯(lián)合放療可協(xié)同放射線作用，增加放療對(duì)EGFR突變型非小細(xì)胞肺癌患者腦轉(zhuǎn)移病灶治療效果，使非小細(xì)胞肺癌腦轉(zhuǎn)移患者獲得更長(zhǎng)的生存時(shí)間。本研究回顧性分析61例EGFR突變型肺腺癌無癥狀腦轉(zhuǎn)移患者的臨床資料，其中埃克替尼聯(lián)合放療(聯(lián)合組)23例、單純埃克替尼靶向治療(靶向治療組)38例，隨訪時(shí)間大約5個(gè)月，經(jīng)統(tǒng)計(jì)分析發(fā)現(xiàn)聯(lián)合組比靶向治療組有效，聯(lián)合組總客觀緩解率、總疾病控制率、腦轉(zhuǎn)移病灶客觀緩解率、腦轉(zhuǎn)移病灶疾病控制率比靶向治療組均高，聯(lián)合組的中位無進(jìn)展生存時(shí)間比靶向治療組長(zhǎng)，聯(lián)合組Ⅲ～Ⅳ毒副反應(yīng)如疲乏、惡心、嘔吐等發(fā)生率高于靶向治療組，但可耐受。

綜上所述，EGFR突變型肺腺癌無癥狀腦轉(zhuǎn)移患者能從EGFR-TKIs靶向治療聯(lián)合放療的治療方案中獲益，副反應(yīng)能耐受。但是放療后腦轉(zhuǎn)移瘤進(jìn)展時(shí)如何選擇治療方案，是否可以繼續(xù)放療，還是換用新的靶向治療藥物，及治療時(shí)機(jī)如何確定，值得我們進(jìn)一步探討。本研究為回顧性研究，入組病例較少，未能將化療聯(lián)合放療進(jìn)行對(duì)比，未將EGFR基因不同突變類型進(jìn)行分層分析，隨訪時(shí)間較短，且未對(duì)比患者的總生存時(shí)間，值得在今后的研究中不斷深入分析。

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Clinical effect of icotinib combined with radiotherapy for asymptomatic brain metastasis in patients with epidermal growth factor receptor mutant non-small cell lung cancer.

LUO Peng-hui,WANG Xiang-ping,MO Dun-chang,LIU Yan-ping,HUANG Chang-jie.Department of Oncology,the Third Affiliated Hospital of Guangxi Medical University,Nanning 530031,Guangxi,CHINA

ObjectiveTo assess the efficacy of icotinib combined with radiotherapy for asymptomatic brain metastasis(BM)in patients with epidermal growth factor receptor(EGFR)mutant non-small cell lung cancer(NSCLC). MethodsSixty-one patients diagnosed as EGFR mutant NSCLC with asymptomatic BM treated in the Third Affiliated Hospital of Guangxi Medical University from January 2012 to June 2015 were retrospectively reviewed.Twenty-three of them were treated with icotinib and brain radiotherapy(joint therapy group).Thirty-eight of them were treated with Icotinib only(targeting treatment group).The curative effect in target therapy after 1,3,5 months and every 3 months(including cranial MRI examination),and at the end of radiotherapy were evaluated.χ2test between two groups was carried out to evaluate the objective response rate(ORR),disease control rate(DCR),and the Kaplan Meier method and the Log-rank method were used for survival analysis.ResultsIn the fifth month of targeted therapy,the overall ORR and DCR in the joint therapy group were 82.6%and 95.7%,which in the targeting treatment group were 55.3%and 76.3%,showing the differences were statistically significant(P＜0.05).The levels of ORR and DCR about brain metastasis in the joint therapy group were 95.7%and 100.0%,which were significantly higher than those in the targeting treatment group(55.3%and 81.6%),showing the differences were statistically significant(P＜0.05).The median progression-free survival time in the joint therapy group was 14 months,but which in the targeting therapy group was 8 months,showing the differences were statistically significant(P＜0.05).Regarding theⅢ～Ⅳdegree of toxicity,the incidence of fatigue, nausea and vomiting in the joint therapy group were significantly higher than those in the targeting treatment group, which could be tolerated(P＜0.05).But no difference existed in the occurrence of erythra,diarrhea and myelosuppression(P＞0.05).ConclusionIcotinib combined with radiotherapy could obviously improve the outcome and the median progression-free survival time of the asymptomatic BM in patients with EGFR mutant NSCLC,and side effects are tolerable.

Lung carcinoma;Adenocarcinoma of lung;Brain metastasis;Icotinib;Radiotherapy;Targeted therapy

10.3969/j.issn.1003-6350.2017.08.005

R734.2

A

1003—6350（2017）08—1219—04

2016-11-13)

廣西科學(xué)研究與技術(shù)開發(fā)計(jì)劃（編號(hào)：桂科攻14124004-1-21）

黃昌杰。E-mail：youyougu23@sina.com