孟召偉 宋興華 譚建 張桂芝 何雅靜 賈強(qiáng) 張富海

王任飛 鄭薇 李雪 張建萍

·薈萃分析·

不同放射性活度131I清除分化型甲狀腺癌患者殘留甲狀腺的薈萃分析

孟召偉 宋興華 譚建 張桂芝 何雅靜 賈強(qiáng) 張富海

王任飛 鄭薇 李雪 張建萍

目的使用薈萃分析方法匯總所有的隨機(jī)對(duì)照研究，比較不同放射性活度131I清除術(shù)后殘留甲狀腺(清甲)的成功率，明確最佳的清甲劑量。方法以‘thyroid’ + ‘cancer or carcinoma’ + ‘a(chǎn)blat$’(包括了ablation、ablative和ablate)為關(guān)鍵詞檢索2014年3月前Cochrane Library、MEDLINE、EMBASE和SCOPUS等數(shù)據(jù)庫(kù)評(píng)估不同放射性活度131I清甲成功率的隨機(jī)對(duì)照研究文獻(xiàn)，并用Google學(xué)術(shù)查找相關(guān)文獻(xiàn)。用RevMan 5.2進(jìn)行統(tǒng)計(jì)學(xué)分析，依據(jù)Cochrane質(zhì)量評(píng)價(jià)標(biāo)準(zhǔn)進(jìn)行文獻(xiàn)質(zhì)量評(píng)估。納入標(biāo)準(zhǔn)如下：(1)已發(fā)表的比較不同劑量131I對(duì)分化型甲狀腺癌(DTC)清甲成功率的研究。(2)患者均行甲狀腺切除術(shù)。(3)均為術(shù)后首次131I治療。(4)服131I后3～12個(gè)月行清甲成功率評(píng)估。(5)服131I劑量為888～4 440 MBq(24～120 mCi)。本研究定義低劑量為888～1 443 MBq(24～39 mCi)、中劑量為1 480～2 923 MBq(40～79 mCi)、高劑量為2 960～4 440 MBq(80～120 mCi)。當(dāng)研究間存在異質(zhì)性時(shí)(I2>50%)、采用隨機(jī)效應(yīng)模型進(jìn)行薈萃分析，否則采用固定效應(yīng)模型進(jìn)行薈萃分析。結(jié)果共納入17個(gè)隨機(jī)對(duì)照研究，包括3 737例患者(低劑量1 514例、中劑量811例、高劑量1 412例)。5項(xiàng)研究比較了低劑量與中劑量的成功率，研究間有異質(zhì)性(I2=67%，P=0.02)、采用隨機(jī)效應(yīng)模型，薈萃分析結(jié)果顯示兩組的清甲成功率差異無(wú)統(tǒng)計(jì)學(xué)意義[風(fēng)險(xiǎn)比(RR)=0.89(0.80～1.00)，P=0.06]。7項(xiàng)研究比較了中劑量與高劑量的成功率，研究間無(wú)異質(zhì)性(I2=34%，P=0.17)，采用固定效應(yīng)模型，薈萃分析結(jié)果顯示兩組劑量的清甲成功率差異無(wú)統(tǒng)計(jì)學(xué)意義[RR=0.94(0.89～1.00)，P=0.05]。11項(xiàng)研究比較了低劑量與高劑量的成功率，研究間有異質(zhì)性(I2=70%，P=0.000 2)，采用隨機(jī)效應(yīng)模型，薈萃分析結(jié)果顯示高劑量的清甲成功率顯著高于低劑量[RR=0.89(0.81～0.97)，P=0.008]。結(jié)論對(duì)于術(shù)后DTC患者，低劑量與中劑量131I以及中劑量與高劑量131I的清甲成功率無(wú)明顯差異，但高劑量131I的清甲成功率顯著高于低劑量。

分化型甲狀腺癌；131I；清除殘留甲狀腺；隨機(jī)對(duì)照試驗(yàn)

甲狀腺癌是目前發(fā)病率最高的內(nèi)分泌系統(tǒng)惡性腫瘤，近年來(lái)其發(fā)生率明顯上升。2014年Cancer Statistics預(yù)計(jì)美國(guó)將有62 980例甲狀腺癌新發(fā)病例(男15 190例、女37 790例)[1]。甲狀腺切除術(shù)后131I清除殘留甲狀腺(清甲)及終身甲狀腺激素抑制治療已經(jīng)成為分化型甲狀腺癌(DTC)的規(guī)范治療方法[2-5]。131I清甲破壞殘留甲狀腺細(xì)胞、根除潛在癌灶，并提高術(shù)后131I掃描及血清甲狀腺球蛋白檢測(cè)的敏感性。但是，目前對(duì)于清甲的最佳131I劑量尚存很大爭(zhēng)議[3-5]。

目前已發(fā)表的相關(guān)文獻(xiàn)大多數(shù)是規(guī)模較小的觀察研究，隨機(jī)對(duì)照試驗(yàn)(RCT)不多[6-16]。近兩年，有6篇新發(fā)表的RCT，為進(jìn)一步做薈萃分析提供了更多數(shù)據(jù)資料[17-22]。本文旨在對(duì)所有已發(fā)表的相關(guān)RCT做薈萃分析，進(jìn)而評(píng)估低、中、高劑量131I清甲成功率是否存在差異并明確最佳劑量。

1 資料與方法

1．1 文獻(xiàn)檢索 以‘thyroid’ + ‘cancer or carcinoma’ + ‘a(chǎn)blat$’(包括了ablation、ablative和ablate)為關(guān)鍵詞檢索2014年3月前Cochrane Library、MEDLINE、EMBASE和SCOPUS等數(shù)據(jù)庫(kù)有關(guān)評(píng)估不同劑量131I清甲成功率的RCT文獻(xiàn)，并用Google學(xué)術(shù)搜索引擎查找相關(guān)文獻(xiàn)，無(wú)語(yǔ)言限制。

1.2 文獻(xiàn)篩選和數(shù)據(jù)提取 研究者分別獨(dú)立閱讀所獲文獻(xiàn)題目和摘要，在排除明顯不符合納入標(biāo)準(zhǔn)的文章后，對(duì)可能符合標(biāo)準(zhǔn)的文章閱讀全文，以確定是否真正符合納入標(biāo)準(zhǔn)。研究者交叉核對(duì)納入試驗(yàn)的結(jié)果，對(duì)存在分歧的文章通過(guò)研讀原文數(shù)據(jù)、分析并討論其是否納入。以文章第一作者姓氏及發(fā)表年記錄文獻(xiàn)。當(dāng)納入試驗(yàn)同時(shí)具有多個(gè)記錄結(jié)果時(shí)，納入隨訪時(shí)間最長(zhǎng)的研究，以避免數(shù)據(jù)的重復(fù)。文獻(xiàn)納入標(biāo)準(zhǔn)如下：(1)已發(fā)表的比較DTC術(shù)后131I清甲療效的RCT。(2)患者均已行甲狀腺切除手術(shù)。(3)術(shù)后首次131I治療。(4)131I治療后3～12個(gè)月評(píng)估清甲成功率。(5)服131I劑量為888～4 440 MBq(24～120 mCi)。

匯總的資料包括：(1)一般資料：作者姓氏、所在國(guó)家、文章發(fā)表年份。(2)研究特征：研究對(duì)象的性別比例、組織學(xué)分型、術(shù)式、隨訪時(shí)間、成功清甲的標(biāo)準(zhǔn)及清甲劑量。

1.3 質(zhì)量評(píng)估 所納入研究的方法學(xué)質(zhì)量評(píng)估及偏倚風(fēng)險(xiǎn)評(píng)估使用Cochrane風(fēng)險(xiǎn)評(píng)估工具進(jìn)行，共包括7個(gè)方面：隨機(jī)序列產(chǎn)生(random sequence generation)、分配隱藏(allocation concealment)、對(duì)參與者和實(shí)施者的盲法(blinding of participants and personnel)、對(duì)結(jié)局評(píng)價(jià)實(shí)施盲法(blinding of outcome assessment)、結(jié)局?jǐn)?shù)據(jù)完整性(incomplete outcome data)、選擇性發(fā)表(selective reporting)、其他偏倚(other bias)[23-24]。研究者分別獨(dú)立評(píng)估每篇RCT文獻(xiàn)的偏倚風(fēng)險(xiǎn)，交叉核對(duì)評(píng)價(jià)結(jié)果，并作出偏倚風(fēng)險(xiǎn)圖及偏倚風(fēng)險(xiǎn)概要圖。

1.4 統(tǒng)計(jì)學(xué)處理 采用Cochrane提供的RevMan 5.2進(jìn)行薈萃分析，制作森林圖及偏倚風(fēng)險(xiǎn)圖。所有結(jié)果均采用二分變量，以風(fēng)險(xiǎn)比(RR)及其95%可信區(qū)間(CI)表示結(jié)果。采用χ2檢驗(yàn)和I2檢驗(yàn)對(duì)納入研究結(jié)果進(jìn)行異質(zhì)性檢驗(yàn)；若I2<50%，提示各研究間有同質(zhì)性，采用固定效應(yīng)模型進(jìn)行薈萃分析；若I2>50%，提示各研究間存在異質(zhì)性，采用隨機(jī)效應(yīng)模型進(jìn)行薈萃分析。

2 結(jié)果

初檢共獲得相關(guān)文獻(xiàn)1 454篇，經(jīng)閱讀題目及摘要剔除1 419篇明顯不符合納入標(biāo)準(zhǔn)的文獻(xiàn)，閱讀全文最后納入本薈萃分析的文獻(xiàn)數(shù)為17篇，共3 737例DTC患者。將888～4 440 MBq(24～120 mCi)作為低劑量組、1 480～2 923 MBq(40～79 mCi)作為中劑量組、2 960～4 440 MBq(80～120 mCi)作為高劑量組。其中有1 514例患者接受了低劑量131I治療、811例患者接受中劑量131I治療、1 412例患者接受高劑量131I治療。各研究的資料見(jiàn)表1。

根據(jù)Cochrane推薦的偏倚風(fēng)險(xiǎn)評(píng)價(jià)標(biāo)準(zhǔn)對(duì)所有納入的文獻(xiàn)進(jìn)行偏倚風(fēng)險(xiǎn)評(píng)價(jià)?？偟膩?lái)說(shuō)， 17篇RCT的方法學(xué)整體質(zhì)量很好。所有研究均采用隨機(jī)方法并提供了足夠的分析數(shù)據(jù)。筆者將所有偏倚風(fēng)險(xiǎn)指標(biāo)均低的研究定義為高質(zhì)量，符合高質(zhì)量的RCT研究有5篇[8,10,13,17,21](圖1中⊕)。納入文獻(xiàn)中，有2篇為開(kāi)放性試驗(yàn)[19-20]。另外1篇所有患者均被告知試驗(yàn)操作流程[11]。因此，這3篇研究的偏倚風(fēng)險(xiǎn)高(圖1中?)。另外9個(gè)研究有1～2個(gè)偏倚的風(fēng)險(xiǎn)評(píng)估信息不足[6,7,9,12,14,16,18,20，22](圖1?○)。偏倚高風(fēng)險(xiǎn)和風(fēng)險(xiǎn)未知的情況越多，統(tǒng)計(jì)分析結(jié)果發(fā)生偏倚的可能性越大。

表1 納入隨機(jī)對(duì)照研究的特征和一般情況

注：WBS(-)：全身131I掃描未見(jiàn)異常示蹤劑攝取病灶；USG(-)：頸部超聲檢查陰性；Tg：甲狀腺球蛋白；清甲：清除殘留甲狀腺

注：偏倚風(fēng)險(xiǎn)概要圖：⊕表示偏倚低風(fēng)險(xiǎn)， ?○表示風(fēng)險(xiǎn)未知，?表示偏倚高風(fēng)險(xiǎn)圖1 納入隨機(jī)對(duì)照試驗(yàn)的質(zhì)量評(píng)估

本文中，筆者做了3組薈萃分析：低、中劑量的對(duì)比；中、高劑量的對(duì)比以及低、高劑量的對(duì)比。5個(gè)RCT報(bào)道了低、中劑量的對(duì)比，研究之間有統(tǒng)計(jì)學(xué)異質(zhì)性(I2=67%，P=0.02)、采用隨機(jī)效應(yīng)模型，薈萃分析結(jié)果顯示(圖2)二者的清甲成功率差異無(wú)統(tǒng)計(jì)學(xué)意義[RR=0.89(0.80～1.00)，P=0.06][8-10,16-17]。7個(gè)RCT報(bào)道了中、高劑量的對(duì)比，研究之間無(wú)統(tǒng)計(jì)學(xué)異質(zhì)性(I2=34%，P=0.17)、采用固定效應(yīng)模型，薈萃分析結(jié)果顯示(圖3)二者的清甲成功率差異無(wú)統(tǒng)計(jì)學(xué)意義[RR=0.94(0.89～1.00)，P=0.05][8，11-14，16-17]。11個(gè)RCT報(bào)道了低、高劑量的對(duì)比，研究之間有統(tǒng)計(jì)學(xué)異質(zhì)性(I2=70%，P=0.000 2)、采用隨機(jī)效應(yīng)模型，薈萃分析結(jié)果顯示(圖4)高劑量的清甲成功率顯著高于低劑量[RR=0.89(0.81～0.97)，P=0.008][6-8,15-22]。

3 討論

全甲狀腺切除術(shù)后131I清甲是DTC治療的重要組成部分和常規(guī)手段[3-5]。美國(guó)甲狀腺協(xié)會(huì)指出，除微小甲狀腺癌且無(wú)危險(xiǎn)因素(腺外浸潤(rùn)、淋巴結(jié)轉(zhuǎn)移和遠(yuǎn)處轉(zhuǎn)移)的情況外，均應(yīng)該進(jìn)行131I清甲治療[3]。全甲狀腺切除后用131I治療的意義主要包括：(1)有利于轉(zhuǎn)移病灶的探查及明確分期。(2)有利于通過(guò)血清甲狀腺球蛋白和全身顯像監(jiān)測(cè)疾病進(jìn)展。(3)是131I清除轉(zhuǎn)移灶的基礎(chǔ)。(4)治療潛在的轉(zhuǎn)移病灶和復(fù)發(fā)病灶。(5)減少?gòu)?fù)發(fā)風(fēng)險(xiǎn)、降低死亡率[3-5]。

但是，到目前為止，學(xué)術(shù)界對(duì)清甲最佳的131I劑量仍然存在很大爭(zhēng)議[3-5]。臨床實(shí)踐中，各醫(yī)院也在使用不同劑量的131I做治療；甚至，在各國(guó)的指南上對(duì)該問(wèn)題也沒(méi)有統(tǒng)一的建議。美國(guó)甲狀腺協(xié)會(huì)的建議是“為實(shí)現(xiàn)成功清甲的目的，可以使用從1 100 MBq到3 700 MBq的131I做治療”[3]。歐洲指南也同樣推薦使用低或高劑量131I(即1 100 MBq或3 700 MBq)[5]。在之前的一篇薈萃分析中，Hackshaw等[25]指出，這種現(xiàn)象可能與缺少較多患者數(shù)量的RCT有關(guān)。近2年，共有6篇新的RCT發(fā)表，為薈萃分析提供了新的數(shù)據(jù)資料。其中4篇研究結(jié)果表明低、高劑量的清甲成功率并無(wú)差別[17-20]。而另外2篇結(jié)果顯示高劑量的清甲成功率高于低劑量[21-22]。

本研究的薈萃分析中，劃分了低、中、高劑量組作比較。分析結(jié)果顯示低、中劑量及低、高劑量的比較中，各納入研究之間存在異質(zhì)性(I2分別為67%和70%)、采用隨機(jī)效應(yīng)模型[26]。而中、高劑量的對(duì)比，各納入研究之間無(wú)明顯異質(zhì)性(I2=34%)、采用固定效應(yīng)模型。這種異質(zhì)性或偏倚可能是3種不同劑量組的劃分所致， 也可能與各研究對(duì)清甲成功的不同定義所致。但是，匯總RCT文章顯示整體質(zhì)量好、存在的偏倚風(fēng)險(xiǎn)有限(圖1)。本分析結(jié)果顯示低、中劑量及中、高劑量清甲成功率均無(wú)統(tǒng)計(jì)學(xué)差異；而高劑量的清甲成功率較低劑量高11%，即當(dāng)每組有100例DTC患者接受131I清甲治療后，高劑量組清甲成功人數(shù)要比低劑量組多11例。近期，Cheng等[27]的薈萃分析認(rèn)為低、中、高劑量的使用對(duì)于清甲成功率的影響差異無(wú)統(tǒng)計(jì)學(xué)意義；而筆者納入了最近發(fā)表的2篇RCT文獻(xiàn)[17, 22]。并增加了3篇Cheng等漏掉的既往關(guān)于低、高劑量療效比較的RCT文獻(xiàn)[6-7,16]。

圖2 低、中劑量131I清除殘留甲狀腺成功率的比較

圖3 中、高劑量131I清除殘留甲狀腺成功率的比較

圖4 低、高劑量131I清除殘留甲狀腺成功率的比較

與之前的幾篇薈萃分析相比，本研究的優(yōu)勢(shì)在于包含了2014年3月前所有已發(fā)表的RCT、數(shù)據(jù)資料更加全面，相信這會(huì)使得分析結(jié)果更加可靠[25,27-28]。本研究結(jié)果顯示DTC術(shù)后使用高劑量131I清甲的成功率較低劑量高。理論上講，131I劑量越大，胃腸不適、惡心、味覺(jué)改變、唾液腺損傷、口干等不良反應(yīng)發(fā)生的風(fēng)險(xiǎn)越大，但是這些大多是暫時(shí)性的、且可以忍受，無(wú)需特殊處理，幾天內(nèi)可消失。因此，筆者認(rèn)為較高的清甲成功率應(yīng)該作為131I治療劑量選擇的首要目的，因?yàn)槿舻蛣┝?31I治療清甲不完全，需再次131I治療，而多次131I治療造成的不良反應(yīng)會(huì)更加明顯。

總之，本薈萃分析結(jié)果顯示：對(duì)于DTC患者131I清甲治療，低、中劑量及中、高劑量的131I對(duì)比差異均無(wú)統(tǒng)計(jì)學(xué)意義，但高劑量的清甲成功率顯著高于低劑量。

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Differentactivitiesof131Iforremnantthyroidablationinpatientswithdifferentiatedthyroidcancer:ameta-analysis

MengZhaowei,SongXinghua,TanJian,ZhangGuizhi,HeYajing,JiaQiang,ZhangFuhai,WangRenfei,ZhengWei,LiXue,ZhangJianping.

DepartmentofNuclearMedicine,TheGeneralHospital,TianjinMedicalUniversity,Tianjin300052,China

ObjectiveTo compare the successful rate of different activities of131I for postoperative remnant ablation in randomized controlled trials (RCTs), and determine the optimal dose with a meta-analysis.MethodsSources were retrieved from the Cochrane Library, MEDLINE, EMBASE, SCOPUS and Google Scholar until March 2014. The search strategy included the terms:′thyroid′ +′cancer or carcinoma′ + ′ablat$′ (to cover ablation, ablative and ablate).All RCTs that assessed the efficacy of different doses of131I for ablation were selected. Statistics were performed by Review Manager 5.2 software. The risk of bias and quality in each eligible study was assessed by Cochrane′s risk of bias tool. Studies were included for analysis if they met the following criteria:(1) RCTs were published as articles that compared the efficacy of different dose131I in ablation of differentiated thyroid cancer (DTC).(2) patients had undergone thyroidectomy.(3) patients were treated with131I for the first time after surgery.(4) assessed the successful remnant ablation at 3 to 12 months after131I administration.(5)131I activity was less than 4 440 MBq (120 mCi) and more than 888 MBq (24 mCi). We defined low dose as from 888 to 1 443 MBq(24-39 mCi), moderate dose as from 1 480 to 2 923 MBq (40-79 mCi), and high dose as from 2 960 to 4 440 MBq (80-120 mCi). Statistical heterogeneity between studies was assessed by means ofI2value.A fixed-effect model was used for calculations unless significant heterogeneity existed (I2>50%), in which case a random-effect model was used.ResultsSeventeen RCTs were considered eligible, involving 3 737 patients (1 514 low dose, 811 moderate dose and 1 412 high dose). Five trials compared low versus moderate dose activities. Heterogeneity was found (I2=67%,P=0.02), and the random effect model was used. This analysis showed no significant difference in successful rate of thyroid remnant ablation[risk ratio (RR)=0.89 (0.80 to 1.00),P=0.06]. Seven trials compared moderate versus high dose activities. No heterogeneity was found (I2=34%,P=0.17), and the fixed-effect model was used. This analysis also showed no significant difference [RR=0.94(0.89 to 1.00),P=0.05]. Eleven trials compared low versus high dose activities. Heterogeneity was found (I2=70%,P=0.000 2), and the random-effect model was used. The successful rate of thyroid remnant ablation of high dose was statistically significant higher than that of low dose[RR=0.89(0.81 to 0.97),P=0.008].ConclusionsThere is no significant difference in successful rate of thyroid remnant ablation between low and moderate dose treatment, or moderate and high dose treatment in patients after DTC operation. However, high dose is significantly better than low dose.

Differentiated thyroid cancer;131I;Remnant thyroid ablation;Randomized controlled trial

(IntJEndocrinolMetab，2015，35：16-21)

10.3760/cma.j.issn.1673-4157.2015.01.004

300052 天津醫(yī)科大學(xué)總醫(yī)院核醫(yī)學(xué)科

2014-10-08)