張余飛康靜波溫居一杜銳張新紅
·臨床研究與應(yīng)用·
RECIST 1.1標(biāo)準(zhǔn)和mRECIST標(biāo)準(zhǔn)在原發(fā)性肝癌SBRT治療后療效評(píng)價(jià)中的對(duì)比研究*
張余飛①②康靜波①②溫居一①②杜銳②張新紅②
目的:回顧性分析對(duì)比研究實(shí)體瘤療效評(píng)價(jià)標(biāo)準(zhǔn)1.1版(Response Evaluation Criteria in Solid Tumors1.1,RECIST 1.1)和修改后實(shí)體瘤療效評(píng)價(jià)標(biāo)準(zhǔn)(modified Response Evaluation Criteria in Solid Tumors,mRECIST)在原發(fā)性肝癌射波刀治療后療效評(píng)價(jià)的差異。方法:回顧性分析2014年1月至2015年8月在安徽醫(yī)科大學(xué)海軍總醫(yī)院治療的原發(fā)性肝癌患者35例,分別按照RECIST 1.1標(biāo)準(zhǔn)和mRECIST標(biāo)準(zhǔn)評(píng)價(jià)立體定向放療射波刀治療后療效。結(jié)果:按照RECIST 1.1標(biāo)準(zhǔn),在射波刀治療后3個(gè)月,全組35例患者完全緩解(complete response,CR)為1例、部分緩解(partial response,PR)為20例、疾病穩(wěn)定(stable disease,SD)為11例、疾病進(jìn)展(progressive disease,PD)為3例,近期有效率(CR+PR)60%,而按照mRECIST標(biāo)準(zhǔn),在射波刀治療后3個(gè)月,CR為10例、PR為16例、SD為6例、PD為3例,近期有效率(CR+PR)74.28%;經(jīng)統(tǒng)計(jì)學(xué)分析Kappa=0.402(χ2=43.3,P<0.001),說明兩個(gè)診斷標(biāo)準(zhǔn)一致性尚未達(dá)到滿意程度。按照mRECIST標(biāo)準(zhǔn),客觀緩解組的患者(CR+PR)與非客觀緩解組患者(SD+PD)在無進(jìn)展生存期(progression free survival,PFS)上顯示優(yōu)勢(shì)(P<0.001)。結(jié)論:對(duì)于不可手術(shù)的原發(fā)性肝癌射波刀治療后的療效評(píng)價(jià),mRECIST標(biāo)準(zhǔn)可能能夠更好地區(qū)分不同患者的療效,預(yù)測(cè)患者預(yù)后。
肝細(xì)胞癌 立體定向放療 放射學(xué)評(píng)估
Correspondence to:Jingbo KANG;E-mail:kjbnet@126.com
1Anhui Medical University,Hefei 230032,China;2Department of Radiation Oncology and Integrative Oncology,Navy General Hospital of PLA,Beijing 100048,China
This work was supported by the International Medical Exchange Foundation(No.CIMF-F-H001-208)
原發(fā)性肝癌是我國最常見的惡性腫瘤之一[1],約80%的原發(fā)性肝癌患者感染乙肝病毒,其他一些致病因素包括:丙肝、黃曲霉、飲用污染水和過量的酒精攝入等。而隨著醫(yī)學(xué)影像學(xué)的快速進(jìn)展,大部分原發(fā)性肝癌患者可得到準(zhǔn)確的臨床診斷。計(jì)算機(jī)斷層掃描(CT)和磁共振成像(MRI)是診斷原發(fā)性肝癌的主要非侵入性技術(shù)手段。此外,正電子發(fā)射計(jì)算機(jī)斷層顯像(PET-CT)也有助于原發(fā)性肝癌的診斷。根據(jù)原發(fā)性肝癌的不同分期,可選的治療方法很多,包括手術(shù)治療和種類繁多的局部治療,而非手術(shù)治療包括肝動(dòng)脈栓塞(hepatic artery embolism,HAE)、肝動(dòng)脈栓塞化療(transcatheter hepatic arterial chemoemboli zation,TACE)、射頻消融和放療。此外,一些研究也證實(shí)分子靶向治療,如口服多激酶抑制劑索拉非尼可改善生存質(zhì)量[2-3]。然而,無論采取何種治療手段,明確的判定治療療效的標(biāo)準(zhǔn)是必須的,目前腫瘤治療后有多種療效評(píng)價(jià)標(biāo)準(zhǔn)可供參考,最初有WHO標(biāo)準(zhǔn)和RECIST標(biāo)準(zhǔn)[4]。然而,當(dāng)病灶邊緣不規(guī)則或不明確時(shí),人為測(cè)量誤差較高。因此,RECIST標(biāo)準(zhǔn)更新到RECIST 1.1版本[5],以解決RECIST標(biāo)準(zhǔn)的局限性,主要的更新涉及病變的數(shù)目,淋巴結(jié)的腫瘤浸潤和非靶病變的評(píng)估,另外PET-CT也被納入RECEIST 1.1標(biāo)準(zhǔn)之中。然而,WHO標(biāo)準(zhǔn)和RECIST標(biāo)準(zhǔn)均忽視治療后的腫瘤壞死,測(cè)量可見病灶的直徑并不能反映腫瘤的活性區(qū)域。為解決RECIST 1.1標(biāo)準(zhǔn)的限制,EASL標(biāo)準(zhǔn)最早被推薦評(píng)估臨床評(píng)估腫瘤療效[6],該標(biāo)準(zhǔn)采用增強(qiáng)CT或增強(qiáng)MRI對(duì)比的影像學(xué)資料估計(jì)有活力的腫瘤區(qū)域變化作為評(píng)估腫瘤療效的依據(jù),而將治療后的腫瘤壞死區(qū)域排除。有活力的腫瘤區(qū)域被定義為在增強(qiáng)CT或MRI檢查中動(dòng)脈期造影劑的攝取強(qiáng)化的區(qū)域。2010年AASLD-JNCIRECIST指南修訂基于RECIST標(biāo)準(zhǔn)修改的療效評(píng)價(jià)標(biāo)準(zhǔn),目的在于將之前研究中有活力腫瘤區(qū)域的概念補(bǔ)充到RECIST標(biāo)準(zhǔn)中,這被稱為mRECIST標(biāo)準(zhǔn)[7]。新的mRECIST標(biāo)準(zhǔn)制定之后,研究普遍發(fā)現(xiàn),mRECIST標(biāo)準(zhǔn)評(píng)價(jià)動(dòng)脈栓塞化療治療原發(fā)性肝癌、索拉非尼靶向藥物治療原發(fā)性肝癌方面更加科學(xué),從遠(yuǎn)期療效的觀察上也提示,mRECIST標(biāo)準(zhǔn)能較好地預(yù)測(cè)預(yù)后[8-9]。而國內(nèi)外關(guān)于mRECIST標(biāo)準(zhǔn)在采用射波刀治療原發(fā)性肝癌后的療效評(píng)價(jià)的報(bào)道較少,本研究旨在探討對(duì)于射波刀治療后原發(fā)性肝癌,mRECIST標(biāo)準(zhǔn)能否更好地區(qū)分出患者的不同療效,并且能夠真實(shí)地反映到無進(jìn)展生存期(progressive free survival,PFS)。
1.1病例特征
回顧性分析2014年1年至2015年8月在安徽醫(yī)科大學(xué)海軍總醫(yī)院行射波刀治療的原發(fā)性肝癌患者35例,入組對(duì)象符合以下條件者納入本研究:KPS評(píng)分>70分;病灶數(shù)目<3個(gè),且3個(gè)病灶直徑之和<6 cm;代償性肝硬化期;Child分級(jí)A或B;全部患者有治療前的可評(píng)估影像資料(增強(qiáng)CT或增強(qiáng)MRI),射波刀治療后36個(gè)月后的影像資料。最終納入本回顧性研究患者共35例,其中男性25例,女性10例,患者中位年齡57(32~71)歲,KPS評(píng)分78(70~90)分,34例患者感染乙肝病毒,僅1例患者感染丙肝病毒,腫瘤最大直徑<5 cm為33例,>5 cm為2例,單發(fā)病灶患者25例,2個(gè)腫瘤病灶患者8例,3個(gè)腫瘤病灶患者3例,Child分級(jí)A級(jí)30例,B級(jí)5例,依照巴塞羅那(Barcelona Clinic Liver Cancer Stage,BCLC)分期為A期5例,B期24例,C期6例,其中合并門脈癌栓患者9例,射波刀處方劑量分割36~48 Gy/3~6 fx。
1.2方法
1.2.1采用G4型射波刀患者取仰臥位,采用體位固定床和真空負(fù)壓袋固定體位,體表標(biāo)記重復(fù)擺位點(diǎn)。經(jīng)腹部CT增強(qiáng)掃描,層厚5 mm,在醫(yī)師結(jié)合CT定位圖像和MRI圖像勾畫靶體積和危及器官,給定處方劑量及劑量限值,將圖像及勾畫好的靶體積和危及器官推至射波刀的SGI(cyberknife rave system,版本C310),在服務(wù)器上將圖像及勾畫好的靶體積和危及器官加載至計(jì)劃數(shù)據(jù)庫遙在計(jì)劃系統(tǒng)(cyberknife data management system)上建立新計(jì)劃,選擇大小恰當(dāng)?shù)臏?zhǔn)直器進(jìn)行優(yōu)化計(jì)算,包繞95%以上靶體積的劑量作為處方劑量,兼顧總跳數(shù)以及射束數(shù)。經(jīng)主管醫(yī)師確認(rèn)后方可形成可執(zhí)行計(jì)劃進(jìn)行三維圖像重建并勾畫靶區(qū)。危及器官限量:脊髓≤40 Gy,胃、十二指腸、結(jié)腸≤45 Gy,50%肝臟體積≤30 Gy,30%雙腎體積≤20 Gy。
1.2.2評(píng)價(jià)標(biāo)準(zhǔn)根據(jù)RECIST 1.1標(biāo)準(zhǔn)[5],腫瘤完全緩解(complete response,CR)定義為腫瘤消失,部分緩解(partial response,PR)和疾病進(jìn)展(progressive disease,PD)定義為腫瘤長徑之和至少分別縮小30%和增加20%,既不符合PR和PD要求屬于疾病穩(wěn)定(stable disease,SD)。mRECIST標(biāo)準(zhǔn)[7]要求測(cè)量增強(qiáng)區(qū)域?yàn)闇?zhǔn),CR動(dòng)脈增強(qiáng)期所有病灶無增強(qiáng);PR和PD分別為動(dòng)脈期對(duì)比增強(qiáng)病灶直徑之和至少縮小30%或增加20%,既不符合PR也不符合PD屬于SD。
1.3隨訪與數(shù)據(jù)收集
35例患者中位隨訪期15(8~26)個(gè)月,治療后每3個(gè)月復(fù)查1次增強(qiáng)CT或增強(qiáng)MRI,隨訪截止到2016年4月30日,隨訪率100%,所有患者治療后均有增強(qiáng)CT或增強(qiáng)MRI,由兩位有經(jīng)驗(yàn)的高年資醫(yī)師核查所有患者治療圖像資料,并參考既往影像報(bào)告單,分別按照RECIST 1.1標(biāo)準(zhǔn)和mRECIST標(biāo)準(zhǔn)評(píng)價(jià)射波刀治療后療效。
1.4統(tǒng)計(jì)學(xué)分析
采用SPSS 22.0軟件進(jìn)行統(tǒng)計(jì)學(xué)分析,RECIST 1.1標(biāo)準(zhǔn)和mRECIST標(biāo)準(zhǔn)一致性研究采用配對(duì)資料的χ2檢驗(yàn)及Kappa檢驗(yàn)。Kaplan-Meier生存曲線分析不同組別間PFS的差異,經(jīng)Log-rank檢驗(yàn),以P<0.05為差異具有統(tǒng)計(jì)學(xué)意義。
2.1療效
按照RECIST 1.1標(biāo)準(zhǔn),在射波刀治療后3個(gè)月,全組35例患者CR為1例、PR為20例、SD為11例、PD為3例,近期有效率(CR+PR)為60.00%,而按照mRECIST標(biāo)準(zhǔn),在射波刀治療后3個(gè)月,CR為10例、PR為16例、SD為6例、PD為3例,近期有效率(CR+PR)為74.28%;mRECIST標(biāo)準(zhǔn)有效率較RECIST 1.1標(biāo)準(zhǔn)高,兩者之間差異具有統(tǒng)計(jì)學(xué)意義(χ2=17.646,P<0.001)。
如圖1所示:50歲的肝癌患者,治療前的肝臟病灶最大直接約4.8 cm(圖1A),射波刀治療后復(fù)查隨訪CT圖,肝臟病灶最大約4.6 cm(圖1B),而增強(qiáng)部分病灶直徑約2 cm,按照RECIST 1.1標(biāo)準(zhǔn)評(píng)價(jià)為SD,而按照mRECIST標(biāo)準(zhǔn)評(píng)價(jià)為PR,圖2所示:合并癌栓的肝細(xì)胞癌患者治療前后對(duì)比。
其中mRECIST療效評(píng)價(jià)為CR患者,治療前AFP值為710.6±390.2,治療后3個(gè)月AFP值為147.2± 72.9,與治療前AFP值對(duì)比,P<0.001。
2.2一致性評(píng)價(jià)
對(duì)每一組不同療效患者內(nèi)部進(jìn)行分析,結(jié)果顯示,在根據(jù)RECIST標(biāo)準(zhǔn)符合PR的20例患者中,根據(jù)mRECIST標(biāo)準(zhǔn)有CR和PR兩種不同療效,其中9例(45%)患者為CR,11例(55%)為PR。同樣,根據(jù)RECIST標(biāo)準(zhǔn)SD的11例患者中,根據(jù)mRECIST標(biāo)準(zhǔn),分別有5例(45.46%)為PR,6例(54.54%)為SD。因此,兩種評(píng)價(jià)方法顯示療效出現(xiàn)不同的患者為14例,占總研究例數(shù)的40%。經(jīng)統(tǒng)計(jì)學(xué)分析Kappa=0.402,說明兩個(gè)診斷標(biāo)準(zhǔn)一致性尚未達(dá)到滿意程度,差異具有統(tǒng)計(jì)學(xué)意義(χ2=43.3,P<0.001)。
2.3PFS觀察
按照mRECIST標(biāo)準(zhǔn)時(shí),客觀緩解組(CR+PR)中位無進(jìn)展生存期(median progression free survival,mPFS)9個(gè)月(95%CI:7.35~10.65),非客觀緩解組(SD+PD)mPFS 5個(gè)月(95%CI:4.08~5.92),按照RECIST 1.1標(biāo)準(zhǔn)時(shí),客觀緩解組mPFS 8個(gè)月(95%CI:6.53~9.48),非客觀緩解組中位無進(jìn)展生存期6個(gè)月(95%CI:1.11~10.89),在mRECIST標(biāo)準(zhǔn)中進(jìn)行PFS的比較(圖3),客觀緩解組的患者(CR+PR)與非客觀緩解組患者(SD+PD)顯示出優(yōu)勢(shì)(均P<0.001)。而按照RECIST 1.1標(biāo)準(zhǔn)時(shí)(圖4),客觀緩解組的患者較非客觀緩解組患者未顯示出明顯優(yōu)勢(shì),差異無統(tǒng)計(jì)學(xué)意義(P=0.291)。
圖1 肝細(xì)胞癌患者治療前后對(duì)比Figure 1Example of follow-up computed tomography images
圖2 合并癌栓的肝細(xì)胞癌患者治療前后對(duì)比Figure 2Example of follow-up computed tomography images
圖3 按照mRECIST標(biāo)準(zhǔn)客觀緩解組與非客觀緩解組的Kaplan-Meier生存曲線Figure 3Kaplan-Meier curves generated to compare PFS between responders and nonresponders assessed through mRECIST
圖4 按照RECIST 1.1標(biāo)準(zhǔn)客觀緩解組與非客觀緩解組的Kaplan-Meier生存曲線Figure 4Kaplan-Meier curves generated to compare PFS between responders and nonresponders assessed through RECIST1.1
放射治療對(duì)于不可切除的原發(fā)性肝癌治療已有近40年的歷史,在早期臨床試驗(yàn)中,對(duì)全肝的放射治療常常聯(lián)合化療,而報(bào)道的2年生存率<10%且不良反應(yīng)難以接受[10],隨著三維適型放療及調(diào)強(qiáng)放療的普及,通過優(yōu)化靶區(qū)的劑量分布,促使放療療效得到很大提升,且不良反應(yīng)顯著降低[11-14],然而三維適型放療以及調(diào)強(qiáng)放療的低劑量照射區(qū)對(duì)正常肝組織的損傷是不可避免的,直到射波刀治療技術(shù)的誕生,這一問題才得以解決,由于射波刀采用的大分割放射治療可降低腫瘤細(xì)胞的再增殖,因此可以獲得比常規(guī)分割放射治療更好的療效[14-15],且不良反應(yīng)輕微,據(jù)相關(guān)文獻(xiàn)綜述報(bào)道,在肝功能尚可的患者射波刀治療后的嚴(yán)重不良反應(yīng)發(fā)生率一般<10%[15],近年來已有研究證實(shí)對(duì)于不可手術(shù)的原發(fā)性肝癌,射波刀可望成為一線治療方案,且療效不劣于射頻消融RFA,而射波刀由于采用單次大劑量放療更易導(dǎo)致靶區(qū)內(nèi)出現(xiàn)放射性壞死,繼續(xù)采用RECIST 1.1標(biāo)準(zhǔn)往往不能反應(yīng)治療后病灶的短期變化,而mRECIST標(biāo)準(zhǔn)近年來被諸多研究證實(shí)在評(píng)價(jià)肝動(dòng)脈化療栓塞以及索拉非尼治療后療效評(píng)價(jià)上,mRECIST標(biāo)準(zhǔn)較RECIST 1.1標(biāo)準(zhǔn)更合理[8-9,16-17],Jung等[17]回顧性研究WHO標(biāo)準(zhǔn)、RECIST標(biāo)準(zhǔn)、mRECIST標(biāo)準(zhǔn)、EASL標(biāo)準(zhǔn)在TACE治療原發(fā)性原發(fā)性肝癌后應(yīng)用對(duì)比,研究表明WHO標(biāo)準(zhǔn)和RECIST標(biāo)準(zhǔn)與mRECIST標(biāo)準(zhǔn)、EASL標(biāo)準(zhǔn)評(píng)價(jià)結(jié)果差異較大,差異具有統(tǒng)計(jì)學(xué)意義,并且對(duì)114例患者進(jìn)行生存時(shí)間的多因素回歸分析,發(fā)現(xiàn)mRECIST標(biāo)準(zhǔn)評(píng)價(jià)的客觀緩解組(CR+PR)組較非客觀緩解組(SD+PD)具有更長的生存獲益,而RECIST標(biāo)準(zhǔn)客觀緩解組(CR+PR)較非客觀緩解組(SD+PD)生存獲益,差異無統(tǒng)計(jì)學(xué)意義,本研究提示對(duì)于放射治療原發(fā)性肝癌尤其是射波刀治療原發(fā)性肝癌后不同評(píng)價(jià)標(biāo)準(zhǔn)的對(duì)比研究,國內(nèi)外報(bào)道較少,Price等[18]研究團(tuán)隊(duì)報(bào)道26例應(yīng)用射波刀治療原發(fā)性肝癌分別按照RECIST標(biāo)準(zhǔn)和EASL標(biāo)準(zhǔn)評(píng)價(jià)治療后療效對(duì)比發(fā)現(xiàn),EASL標(biāo)準(zhǔn)可能較RECIST標(biāo)準(zhǔn)更適用于射波刀治療后6~12個(gè)月的病灶變化。
本研究表明RECIST 1.1標(biāo)準(zhǔn)與mRECIST標(biāo)準(zhǔn)評(píng)價(jià)射波刀治療原發(fā)性肝癌后的短期療效,療效評(píng)價(jià)結(jié)果差異較大,差異具有統(tǒng)計(jì)學(xué)意義,并且mRECIST標(biāo)準(zhǔn)評(píng)價(jià)后的客觀緩解組(CR+PR)患者較非客觀緩解組(SD+PD)有更長的PFS,差異具有統(tǒng)計(jì)學(xué)意義,而RECIST 1.1標(biāo)準(zhǔn)評(píng)價(jià)后的客觀緩解組(CR+PR)患者較非客觀緩解組(SD+PD)PFS未顯示出明顯優(yōu)勢(shì),差異無統(tǒng)計(jì)學(xué)意義,初步表明mRECIST標(biāo)準(zhǔn)可能更能區(qū)分不同患者治療后的療效差異,依據(jù)mRECIST標(biāo)準(zhǔn)評(píng)價(jià)為CR的患者,治療后的甲胎蛋白較治療前的甲胎蛋白有明顯下降,從側(cè)面表明mRECIST標(biāo)準(zhǔn)可能更能區(qū)分不同患者治療后的療效差異。然而由于本臨床研究病例相對(duì)較少,并且隨訪時(shí)間相對(duì)較短,入組的患者并未全部到達(dá)死亡終點(diǎn),僅憑PFS這一指標(biāo)區(qū)別兩種評(píng)價(jià)標(biāo)準(zhǔn)的優(yōu)劣可能不如總生存期(overall survival,OS)更具有說服力,另外由于本研究為回顧性研究,PFS等遠(yuǎn)期療效觀察指標(biāo)可能受年齡,腫瘤分期,是否合并癌栓等多因素影響,這也是本研究不可回避的缺陷之一,mRECIST標(biāo)準(zhǔn)和RECIST 1.1標(biāo)準(zhǔn)評(píng)價(jià)后的客觀緩解組(CR+PR)與非客觀緩解組(SD+PD)是否有OS上的差異以及是否受其他相關(guān)因素影響,尚需本研究中心進(jìn)一步隨訪觀察,并且擴(kuò)大病例數(shù)進(jìn)行多因素回歸生存分析。
本研究回顧性分析發(fā)現(xiàn),對(duì)于不可切除的原發(fā)性肝癌射波刀治療后的療效評(píng)價(jià),mRECIST療效評(píng)價(jià)標(biāo)準(zhǔn)能夠更好地區(qū)分不同患者的療效,預(yù)測(cè)患者預(yù)后。
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(2016-06-12收稿)
(2016-08-16修回)
(編輯:周曉穎校對(duì):孫喜佳)
張余飛專業(yè)方向?yàn)槟[瘤放療學(xué)臨床研究。
E-mail:zyfhjzyy@163.com
Comparison study of efficacy evaluation based on RECIST 1.1 and mRECIST in hepatocellular carcinoma treated with SBRT
Yufei ZHANG1,2,Jingbo KANG1,2,Juyi WEN1,2,Rui DU2,Xinhong ZHANG2
Objective:To compare the difference of Response Evaluation Criteria in Solid Tumors 1.1(RECIST 1.1)and modified Response Evaluation Criteria in Solid Tumors(mRECIST)in the treatment of hepatocellular carcinoma(HCC)after stereotactic body radiotherapy(SBRT).Methods:From Janurary 2014 to August 2015,thirty-five patients with HCC treated with SBRT were included in Department of Radiation Oncology and Integrative Oncology of Navy General Hospital of PLA,and SBRT efficacy was evaluated based on RECIST 1.1 and mRECIST criteria.Results:Under RECIST 1.1,one patient had complete response(CR),20 had partial response(PR),and 11 achieved stable disease(SD)at three months.Three patients had progressive disease(PD).The overall best response rate(CR+PR) was 60%.In comparison,under mRECIST,10 patients had CR,16 had PR,and 6 achieved SD at three months.Three patients had PD. The overall best response rate was 74.28%.The statistical analysis showed that Kappa=0.402(χ2=43.3,P<0.001)was less than 0.75 but greater than 0.4,indicating that it had not reached the two diagnostic criteria of consistency degree of satisfaction.According to the mRECIST criteria,the objective remission group(CR+PR)was superior to the nonobjective remission group(SD+PD)in progression-free survival(P<0.001).Conclusion:For unresectable HCC,mRECIST may be more useful than RECIST 1.1 in evaluating HCC response to SBRT.
hepatocellular carcinoma,stereotactic body radiotherapy,radiographic response
10.3969/j.issn.1000-8179.2016.20.689
①安徽醫(yī)科大學(xué)海軍總醫(yī)院臨床學(xué)院(合肥市230032);②中國人民解放軍海軍總醫(yī)院腫瘤診療中心
*本文課題受中華國際醫(yī)學(xué)交流基金會(huì)先聲抗腫瘤治療專項(xiàng)基金項(xiàng)目(編號(hào):CIMF-F-H001-208)資助
康靜波kjbnet@126.com