杜承潤應(yīng)紅梅程競儀周珺珺蔣津津王孝深胡超蘇
1.復(fù)旦大學(xué)附屬腫瘤醫(yī)院放療科,復(fù)旦大學(xué)上海醫(yī)學(xué)院腫瘤學(xué)系,上海 200032;
2.復(fù)旦大學(xué)附屬腫瘤醫(yī)院核醫(yī)學(xué)科,復(fù)旦大學(xué)上海醫(yī)學(xué)院腫瘤學(xué)系,上海 200032
雙時相99mTc-MIBI SPECT/CT顯像預(yù)測局部晚期鼻咽癌對含多西他賽新輔助化療敏感性的價值
杜承潤1應(yīng)紅梅1程競儀2周珺珺1蔣津津2王孝深1胡超蘇1
1.復(fù)旦大學(xué)附屬腫瘤醫(yī)院放療科,復(fù)旦大學(xué)上海醫(yī)學(xué)院腫瘤學(xué)系,上海 200032;
2.復(fù)旦大學(xué)附屬腫瘤醫(yī)院核醫(yī)學(xué)科,復(fù)旦大學(xué)上海醫(yī)學(xué)院腫瘤學(xué)系,上海 200032
背景與目的:在局部晚期鼻咽癌的治療中,含多西他賽新輔助化療正得到廣泛的應(yīng)用,其可能進(jìn)一步提高局部晚期鼻咽癌的生存率。如果能在化療前預(yù)測鼻咽癌對含多西他賽新輔助化療的敏感性,將有助于更合理地為鼻咽癌患者制定個體化的治療方案。前期研究發(fā)現(xiàn),99mTc-MIBI顯像能夠預(yù)測鼻咽癌對經(jīng)典的順鉑聯(lián)合5-氟脲嘧啶(5-FU)的化療敏感性,但99mTc-MIBI顯像對含多西他賽方案化療敏感性的預(yù)測價值有待進(jìn)一步探討。本研究的目的是探討雙時相99mTc-MIBI SPECT/CT顯像預(yù)測局部晚期鼻咽癌對含多西他賽新輔助化療敏感性的價值。方法:31例局部晚期鼻咽癌患者,分別于注射99mTc-MIBI后即刻和2 h后進(jìn)行早期和晚期99mTc-MIBI SPECT/CT顯像。所有患者行2個療程TPF方案(多西他賽+順鉑+5-FU)新輔助化療。分析99mTc-MIBI SPECT/CT顯像中早期攝取率、晚期攝取率和清除率與新輔助化療的療效關(guān)系。結(jié)果:根據(jù)磁共振評價新輔助化療療效,化療高反應(yīng)病灶的早期攝取率為2.67±0.83,而化療低反應(yīng)病灶的早期攝取率為1.69±0.46,差異有統(tǒng)計學(xué)意義(P=0.003);晚期攝取率分別為1.46±0.39和1.06±0.62,差異有統(tǒng)計學(xué)意義(P=0.026)。清除率在化療高反應(yīng)病灶(44.9%±13.9%)和化療低反應(yīng)病灶(35.5%±30.5%)之間的差異無統(tǒng)計學(xué)意義(P=0.23)。ROC曲線分析,早期攝取率AUC=0.84,最佳診斷界點為1.97,其靈敏度為74.2%,特異度為87.5%,陽性預(yù)測值為95.8%,陰性預(yù)測值為46.7%,準(zhǔn)確率為76.9%。結(jié)論:99mTc-MIBI SPECT/CT顯像早期攝取率和晚期攝取率能夠預(yù)測局部晚期鼻咽癌對含多西他賽方案新輔助化療的敏感性。
鼻咽癌;99mTc-MIBI SPECT/CT顯像;新輔助化療;多藥耐藥
鼻咽癌(nasopharyngeal carcinoma)是我國南方和東南沿海地區(qū)發(fā)病率較高的腫瘤之一[1];同期放化療加輔助化療是局部晚期鼻咽癌的標(biāo)準(zhǔn)治療模式[2-3]。在這標(biāo)準(zhǔn)治療模式下,主要的治療失敗原因是遠(yuǎn)處轉(zhuǎn)移。未能有效降低遠(yuǎn)處轉(zhuǎn)移率的一個主要原因可能是患者對輔助化療的依從性較差。為了進(jìn)一步提高局部晚期鼻咽癌的治療療效,學(xué)者提出用新輔助化療代替輔助化療。新輔助化療的優(yōu)勢是在于依從性好,使腫瘤體積縮小有利于放療的實施和可能在早期就消除遠(yuǎn)處微轉(zhuǎn)移灶。近幾年,紫杉類藥物被廣泛用于實體瘤的治療。在頭頸部腫瘤中,多西他賽+順鉑+氟尿嘧啶(5-FU)方案相對于順鉑+5-FU取得了更好的生存率[4-5]。在鼻咽癌的新輔助化療中,含紫衫醇類的化療方案也取得了可喜的結(jié)果[6-7]。Hui等[8]發(fā)現(xiàn)在同期放化療之前加用多西他賽聯(lián)合順鉑的新輔助化療,能提高局部晚期鼻咽癌患者3年無進(jìn)展生存率和總生存率。但是,對新輔助化療不敏感的患者來說,新輔助化療使其根治性放療延后和發(fā)生不必要的不良反應(yīng)。如果能在化療前預(yù)測鼻咽癌對含多西他賽新輔助化療的敏感性,將有助于更合理地選擇治療方案,為個體化治療提供依據(jù)。
99m锝-甲氧基異丁基異腈(Technetium-99mmethoxy-isobutyl-isonitrile,99mTc-MIBI)是親脂性帶正電荷的核素示蹤劑,在心肌灌注顯像中廣泛應(yīng)用。它依靠細(xì)胞負(fù)性的跨膜電位通過細(xì)胞膜進(jìn)入細(xì)胞,聚集于線粒體中[9-10]。由于腫瘤細(xì)胞代謝速率高,使細(xì)胞內(nèi)外膜之間的電位差增大和線粒體的數(shù)量增加,99mTc-MIBI進(jìn)入體內(nèi)更易聚集腫瘤細(xì)胞中,因此99mTc-MIBI可用來腫瘤成像。研究發(fā)現(xiàn)對99mTc-MIBI攝取率高的腫瘤對化療敏感性高,而對99mTc-MIBI攝取率低的腫瘤對化療敏感性低。這一現(xiàn)象已經(jīng)在多種惡性腫瘤中得到證實,如肺癌[11-12]、乳腺癌[13]、淋巴瘤[14]和多發(fā)性骨髓瘤[15]??赡軝C(jī)制是腫瘤表達(dá)P糖蛋白(P-glycoprotein,Pgp),它是轉(zhuǎn)運(yùn)蛋白,可將多種細(xì)胞毒藥物和99mTc標(biāo)記的親脂性示蹤劑轉(zhuǎn)運(yùn)至細(xì)胞外[16-18]。另一個機(jī)制是凋亡抑制因子Bcl-2 (B cell lymphoma/leukemia-2)的高表達(dá)降低了線粒體外膜的通透性,使99mTc-MIBI 在細(xì)胞內(nèi)聚集減少[19]。
我們在前期研究中發(fā)現(xiàn),99mTc-MIBI SPECT/CT (single photon emission computer tomography and computer tomography)顯像能夠預(yù)測鼻咽癌對經(jīng)典的順鉑聯(lián)合5-FU新輔助化療的敏感性[20],但對更有應(yīng)用前景的含多西他賽方案化療敏感性的預(yù)測價值有待進(jìn)一步探討。本研究旨在探討雙時相99mTc-MIBI SPECT/CT顯像在預(yù)測局部晚期鼻咽癌對含多西他賽的新輔助化療敏感性的價值。
1.1 入組標(biāo)準(zhǔn)
經(jīng)病理證實為非角化性癌低分化型或未分化型鼻咽癌且分期為AJCC (American Joint Committee on Cancer) 2002 分期Ⅲ期、ⅣA期和ⅣB期的患者。
共有31例鼻咽癌患者入組,所有患者都給予TPF方案化療2個療程,其中男性21例,女性10例,年齡18~68歲,中位年齡47歲。臨床病例特征見表1。
表 1 患者的臨床病理特征Tab. 1 Distribution of clinic data and pathological findings for all patients
1.299mTc-MIBI顯像掃描方法
所有入組患者經(jīng)肘靜脈注射25~30 mCi99mTc-MIBI, 分別于注射后即刻和2 h后在GE公司HAWKEYE SPECT/CT上行早期時相顯像和晚期時相顯像。經(jīng)過重建后對融合圖像進(jìn)行分析。在圖像的橫斷面、矢狀面和冠狀面上,選取病灶放射性計數(shù)最高的層面,勾畫鼻咽部病灶與頸部腫大淋巴結(jié)的感興趣區(qū),并測量相應(yīng)區(qū)域的最大放射性計數(shù)值 , 取這3個研究區(qū)域所取得的最大放射性計數(shù)值的平均值作為該靶病灶的放射性計數(shù)值。選取項部肌肉作為本底進(jìn)行計算。
早期攝取率(early uptake ratio,EUR):早期靶病灶的放射性計數(shù)(T)/早期本底的放射性計數(shù)(N);晚期攝取率(delayed uptake ratio, DUR):晚期靶病灶的放射性計數(shù)(T)/晚期本底的放射性計數(shù)(N);清除率計算公式為:(EUR-DUR)/ EUR×100%。
1.3 新輔助化療方案
患者接受2個療程TPF新輔助化療(多西他賽60 mg/m2,第1天;順鉑25 mg/m2,第1~3天;5-FU 500 mg/m2,第1~5天),每3周為1個療程。
1.4 新輔助化療療效評價
完成2個新輔助化療療程后1周行磁共振成像(magnetic resonance imaging,MRI)檢查評價化療療效。當(dāng)病灶垂直徑乘積<3 cm2時,核素顯像可能存在誤差,因此,本研究只分析鼻咽和頸部淋巴結(jié)病灶的垂直徑乘積>3 cm2的病灶,評價標(biāo)準(zhǔn):①完全緩解(complete response,CR):病灶完全消失;②部分緩解(partial respome,PR):基線腫瘤最大垂直徑之積減少50%以上;③疾病穩(wěn)定(stable disease,SD):既不符合PR,又不符合PD者;④疾病進(jìn)展(progressive disease,PD):基線腫瘤最大垂直徑之積增加25%以上或出現(xiàn)新病灶。 當(dāng)病灶的最大垂直雙徑乘積減小≥50%, 則認(rèn)為此病灶對化療高反應(yīng)(CR+PR);當(dāng)病灶的最大垂直徑乘積減少<50%或增大,則認(rèn)為此病灶對化療低反應(yīng)(SD+PD)。
1.5 統(tǒng)計學(xué)處理
早期時相攝取率和晚期時相攝取率用x±s的方式表示,各組間攝取率和清除率之間的差別用Mann-Whitney U方法檢驗。連續(xù)性變量相關(guān)分析用Pearson相關(guān)分析。繪制受試者工作特征曲線(receiver operating characteristic curve,ROC)并計算曲線下面積(area under curve,AUC)。 ROC曲線上,將Youden指數(shù)最大的切點確定截斷值(cut off值)。統(tǒng)計學(xué)檢驗均為雙側(cè)檢驗,P<O.05為差異有統(tǒng)計學(xué)意義。統(tǒng)計分析由SPSS 13.0軟件包完成。
2.1 新輔助化療療效
在鼻咽原發(fā)灶中,20例病灶>3 cm2,新輔助化療后,2例為CR,14例為PR,4例為SD,無患者出現(xiàn)PD,因此,化療高反應(yīng)者16例,低反應(yīng)者4例;頸部轉(zhuǎn)移灶有19例>3 cm2的病灶,新輔助化療后,2例為CR,13例為PR,4例為SD,無PD的病灶,因此,高反應(yīng)者15例,低反應(yīng)者4例;鼻咽病灶和頸部病灶對新輔助化療的敏感性差異無統(tǒng)計學(xué)意義(P=0.939)。
2.299mTc-MIBI顯像參數(shù)與新輔助化療療效的關(guān)系
對化療高反應(yīng)病灶的EUR為2.67±0.83,而對化療低反應(yīng)病灶為1.69±0.46,差異有統(tǒng)計學(xué)意義(P=0.003)。對化療高反應(yīng)病灶的DUR為1.46±0.39,而對化療低反應(yīng)病灶為1.06±0.62,差異亦有統(tǒng)計學(xué)意義(P=0.026)。對化療高反應(yīng)病灶的清除率為44.9%±13.9%,而對化療低反應(yīng)病灶的清除率為35.5%±30.5%,差異無統(tǒng)計學(xué)意義(P=0.23)。
2.3 ROC曲線分析
ROC曲線分析(圖1),EUR診斷新輔助化療耐藥性AUC=0.84(SE:0.064,95%CI:0.715~0.967,P=0.003),最佳診斷界點為1.97,其靈敏度為74.2%,特異度為87.5%,陽性預(yù)測值為95.8%,陰性預(yù)測值為46.7%。DUR診斷新輔助化療耐藥性AUC=0.752(SE:0.118,95%CI:0.521~0.983,P=0.03,圖2),最佳診斷界點為1.06,其靈敏度為87.1%,特異度為62.5%,陽性預(yù)測值為90%,陰性預(yù)測值為66.6%。
圖 1 早期攝取率預(yù)測化療敏感性的ROC曲線Fig. 1 ROC curve of EUR for predicting chemotherapy sensitivity
圖 2 晚期攝取率預(yù)測化療敏感性的ROC曲線Fig. 2 ROC curve of DUR for predicting chemotherapy sensitivity
含多西他賽的化療方案在鼻咽癌中的療效受多種因素的影響,其中包括多藥耐藥。由多藥耐藥基因1(multidrug resistance gene,MDR1)編碼的Pgp是一個ATP依賴的轉(zhuǎn)運(yùn)蛋白,能夠?qū)⒍喾N細(xì)胞毒藥物(如多西他賽)轉(zhuǎn)運(yùn)至細(xì)胞外,而引起多藥耐藥。99mTc-MIBI也是Pgp的轉(zhuǎn)運(yùn)底物,99mTc-MIBI在細(xì)胞中攝取濃度與Pgp的表達(dá)水平呈負(fù)相關(guān)[16-18]。凋亡抑制因子Bcl-2的表達(dá)可使腫瘤細(xì)胞對多種化療藥物誘導(dǎo)的凋亡信號表現(xiàn)出耐受,進(jìn)而使腫瘤細(xì)胞出現(xiàn)耐藥[21]。Del Vecchio等[22]研究發(fā)現(xiàn),Bcl-2的高表達(dá)會降低99mTc-MIBI在細(xì)胞中的攝取和聚集,證明了細(xì)胞凋亡、化療敏感性和99mTc-MIBI攝取率之間的聯(lián)系。99mTc-MIBI顯像能夠預(yù)測腫瘤的耐藥性與上述兩方面因素密切相關(guān)。近年來,有觀點認(rèn)為99mTc-MIBI攝取和清除分別反映著不同的機(jī)制:99mTc-MIBI的攝取率主要受凋亡抑制因子Bcl-2表達(dá)水平的影響,而清除率更多地受Pgp的影響。
本研究結(jié)果表明,99mTc-MIBI SPECT/CT顯像中EUR和DUR與局部晚期鼻咽癌對TPF新輔助化療的敏感性相關(guān),而清除率與化療敏感性不相關(guān)。EUR與病灶退縮率呈線性相關(guān)(P=0.016),但相關(guān)系數(shù)r=0.382,說明線行相關(guān)關(guān)系程度較弱;ROC曲線分析99mTc-MIBI SPECT/CT顯像EUR和DUR在預(yù)測TPF新輔助化療療效上AUC分別為0.84和0.752,說明其在診斷化療耐藥性上具有中等價值,并且EUR優(yōu)于DUR。
攝取率能夠預(yù)測化療敏感性與我們前期研究所得的結(jié)果一致。在多數(shù)關(guān)于肺癌的研究中,也肯定了攝取率預(yù)測化療敏感性的作用。Yuksel等[23]發(fā)現(xiàn)在37例非小細(xì)胞肺癌患者中,化療敏感者的99mTc-MIBI EUR和DUR顯著高于化療不敏感者(3.09±1.14 vs 2.24±0.88,P<0.03;3.09±1.08 vs 2.37±1.06,P<0.05),而99mTc-MIBI的清除率在兩者中差異無統(tǒng)計學(xué)意義。Kao等[24]發(fā)現(xiàn)在15例對化療敏感的淋巴瘤患者中,99mTc-MIBI SPECT顯像EUR(3.3±0.6)高于對化療不敏感的患者(1.2±0.1)。
但亦有不少研究結(jié)果肯定了清除率或滯留率在預(yù)測化療敏感性中的作用。Song等[14]在治療前為40例淋巴瘤患者行雙時相99mTc-MIBI顯像,分析病灶化療近期療效,發(fā)現(xiàn)達(dá)到CR患者的99mTc-MIBI滯留率(retention rate)高于未達(dá)到CR的患者,而化療近期療效與EUR和DUR無關(guān)。在Pace等[15]的研究中,40例多發(fā)骨髓瘤患者分別于注射99mTc-MIBI后15和60 min進(jìn)行掃描成像,結(jié)果在隨訪中出現(xiàn)疾病進(jìn)展患者的99mTc-MIBI清除率大于病灶消退患者(19.3%±9.8% vs 12.8%±6.9%,P<0.05)。
EUR、DUR和清除率的意義在各研究間的差別可能反映了不同腫瘤之間耐藥機(jī)制的不同。證實EUR、DUR能夠預(yù)測化療敏感性的研究多來自肺癌的研究。在肺癌99mTc-MIBI耐藥顯像中,主要反映Pgp表達(dá)情況的清除率缺乏預(yù)測作用,而與Bcl-2關(guān)系密切的攝取率對肺癌化療敏感性有預(yù)測作用,可能因為肺癌中Pgp的表達(dá)并不常見[25],而Bcl-2在肺癌中表達(dá)更常見[26]。在鼻咽癌中,Wang等[20]進(jìn)行15 min的早期顯像,發(fā)現(xiàn)早期顯像攝取率能夠預(yù)測順鉑聯(lián)合5-FU方案(非Pgp底物)新輔助化療的敏感性。由于多西他賽已被證實是Pgp的轉(zhuǎn)運(yùn)底物[27],所以本研究進(jìn)行了早晚期雙時相顯像來計算清除率,希望能夠更好反映腫瘤Pgp表達(dá)情況,進(jìn)而提高99mTc-MIBI顯像預(yù)測鼻咽癌對含多西他賽化療敏感性的準(zhǔn)確性。但是,結(jié)果發(fā)現(xiàn)清除率與化療敏感性無關(guān),而攝取率具有預(yù)測作用,提示引起鼻咽癌耐藥現(xiàn)象的主要原因可能是Bcl-2的高表達(dá)所致,而Pgp不是引起耐藥的主要原因,這一推論有待今后進(jìn)一步驗證。
Akgun等[12]認(rèn)為,由于以往所采用的成像方法不同,導(dǎo)致各研究結(jié)果存在差異。以往研究多采用99mTc-MIBI平面顯像,平面顯像的空間分辨率較低,對病灶的攝取率測量易受主觀因素的影響。機(jī)器設(shè)備發(fā)展和新技術(shù)的運(yùn)用,有助于減少這方面的差異。本研究采用SPECT/CT進(jìn)行顯像,相對以往的平面顯像具有更高的空間分辨率,與CT配準(zhǔn)后有助于感興趣區(qū)域(region of interest,ROI)的勾畫,減少主觀的誤差,顯像結(jié)果的穩(wěn)定性增強(qiáng)。在鼻咽癌中,病灶體積較小,并且病灶常與99mTc-MIBI高攝取的正常組織相鄰,如唾液腺。因此,相對于平面顯像,SPECT/CT在確定病灶和準(zhǔn)確測量攝取率上有明顯的優(yōu)勢。因此,在SPECT/CT條件下,99mTc-MIBI顯像預(yù)測鼻咽癌化療耐藥性的應(yīng)用值得進(jìn)一步研究。但是SPECT/CT顯像時間較以前平面顯像時間更長,在計算清除率時應(yīng)盡量行快速成像。有學(xué)者提出可以通過改變掃描方法來縮短掃描時間。Moorin等[28]發(fā)現(xiàn),行180°的弧形顯像有助于加快成像速度,減小因成像時間延長所引起的清除率誤差,使清除率預(yù)測Pgp引起的化療耐藥更準(zhǔn)確。本研究采用的是雙探頭掃描,能夠較迅速的完成成像,每一次顯像時間耗時20~30 min。
本研究入組患者經(jīng)過中位隨訪期11(4~16)個月隨訪,化療敏感者中有1例鼻咽局部復(fù)發(fā),2例出現(xiàn)遠(yuǎn)處轉(zhuǎn)移;化療不敏感者中有1例出現(xiàn)遠(yuǎn)處轉(zhuǎn)移,無局部復(fù)發(fā)者。由于本研究旨在探討雙時相99mTc-MIBI SPECT/CT顯像預(yù)測局部晚期鼻咽癌對含多西他賽新輔助化療敏感性的價值,對于99mTc-MIBI SPECT/CT顯像是否可以預(yù)測鼻咽癌治療后最終控制率,還需進(jìn)一步擴(kuò)大樣本量及延長隨訪時間才能確定。
綜上所述,99mTc-MIBI SPECT/CT顯像EUR和DUR能夠預(yù)測局部晚期鼻咽癌對含多西他賽新輔助化療的敏感性,可以作為個體化選擇局部晚期鼻咽癌治療方案的依據(jù)。
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《抗癌》雜志征稿啟事
《抗癌》雜志于1988年創(chuàng)刊,主管單位為上海市科學(xué)技術(shù)協(xié)會,主辦單位為上海市抗癌協(xié)會,雜志刊號:CN31-1664/R ISSN 1008-3065。征稿欄目及內(nèi)容如下。
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The role of 99mTc-MIBI SPECT/CT in predicting response to neoadjuvant chemotherapy with docetaxel-based regimen for locoregionally advanced nasopharyngeal carcinoma
DU Cheng-run1, YING Hong-mei1, CHENG Jing-yi2, ZHOU Jun-jun1, JIANG Jin-jin2, WANG Xiao-shen1, HU Chao-su1(1.Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; 2.Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China)
YING Hong-mei E-mail: yinghongmei2012@sina.com
Background and purpose: Neoadjuvant chemotherapy with docetaxel was gaining more attention in the treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). The prediction of the sensitivity to neoadjuvant chemotherapy with docetaxel could enable clinicians to individualize treatment protocols for NPC. Recently we found that99mTc-MIBI imaging in NPC could predict tumor response to chemotherapy with cisplatin plus 5-FU. However, there was no study to support similar findings in NPC patients receiving chemotherapy containingdocetaxel. This study was to evaluate the value of double-phase99mTc-MIBI SPECT/CT in predicting response to neoadjuvant chemotherapy with docetaxel-based regimen for nasopharyngeal carcinoma. Methods: Thirty-one nasopharyngeal carcinoma patients participated in this prospective study. Before treatment, early and delayed singlephoton emission computed tomography/compute tomography (SPECT/CT) images were obtained instantly and 2 hours after an intravenous injection of 25-30 mCi99mTc-MIBI. All patients
neoadjuvant chemotherapy consisting of docetaxel, cisplatin plus 5-FU for two cycles. The relationships between efficacy of neoadjuvant chemotherapy and the early uptake ratio, late uptake ratio and washout rate of99mTc-MIBI were evaluated.Results: According to the MRI, the early uptake of99mTc-MIBI (2.67±0.83) in the lesions which were sensitive to chemotherapy was significantly higher compared with that (1.69±0.46) in the insensitive lesions(P=0.003). The difference of the late uptake between the sensitive(1.46±0.39) and the insensitive (1.06±0.62) was also statistically significant (P=0.026). However, the washout rate of99mTc-MIBI was not significantly different between the two groups (P=0.23). Through ROC curve analysis, the AUC for early uptake of99mTc-MIBI and late uptake were 0.84. The sensitivity, specificity, positive predictive value and negative predictive value were 74.2%, 87.5%, 95.8% and 46.7% for early uptake when the cut off value of 1.97 was used. Conclusion: The uptake of99mTc-MIBI in both early phase and late phase could predict the efficacy of neoadjuvant chemotherapy with docetaxel-based regimen.
Nasopharyngeal carcinoma;99mTc-MIBI SPECT/CT; Neoadjuvant chemotherapy; Multidrug resistance
10.3969/j.issn.1007-3969.2013.10.009
R739.62
:A
:1007-3639(2013)10-0834-07
2013-04-08
2013-08-25)
上海市科委課題資助(No:10411969700)。
應(yīng)紅梅 E-mail:yinghongmei2012@sina.com