尤文肉瘤腫瘤家族（ESFT）臨床循證診療指南

中國(guó)醫(yī)師協(xié)會(huì)骨科醫(yī)師分會(huì)骨腫瘤專業(yè)委員會(huì)

郭衛(wèi)1*王臻2*郭征2*董揚(yáng)3*

（1.北京大學(xué)人民醫(yī)院骨腫瘤科，北京100044；2.空軍醫(yī)科大學(xué)附屬西京醫(yī)院骨科，西安710032；3.上海市第六人民醫(yī)院骨科，上海200233）

1 方法學(xué)

證據(jù)推薦等級(jí)方法采用GRADE（Grading of Recommendations Assessment,Development and Evaluation）方法，詳見表1。

2 尤文肉瘤腫瘤家族概述

尤文肉瘤腫瘤家族（Ewing sarcoma family tumor,ESFT）是一組小圓細(xì)胞腫瘤的統(tǒng)稱，包括尤文肉瘤、原始神經(jīng)外胚層瘤（primitive neuroectodermal tumor,PNET）、骨PNET和骨外軟組織尤文肉瘤。尤文肉瘤以22q12染色體上EWS基因（EWSR1）與ETS基因家族的幾種基因（FLI1、ERG、ETV1、ETV4、FEV）融合為特征[1,2]。EWS與11號(hào)染色體上的FLI1融合，以及相應(yīng)的t(11;22)(q24;q12)染色體易位導(dǎo)致的EWS-FLI1融合基因轉(zhuǎn)錄，出現(xiàn)在約85%的尤文肉瘤患者中[1]。在5%～10%病例中，EWS與ETS基因家族的其他基因相融合。在極少數(shù)病例中，F(xiàn)US可以替代EWS，導(dǎo)致沒(méi)有EWS的重新排列，即由t(16;21)(p11;q24)易位引起的FUS-ERG融合基因轉(zhuǎn)錄或t(2;16)(q35;p11)易位引起的FUS-FEV融合基因轉(zhuǎn)錄[3,4]。尤文肉瘤還有高表達(dá)細(xì)胞表面糖蛋白MIC2（CD99）的特征[5,6]。雖然MIC2表達(dá)不是特異性的，但可能有助于尤文肉瘤/PNET與其他小圓細(xì)胞腫瘤的鑒別[7]。

表1 GRADE推薦等級(jí)和證據(jù)分級(jí)

ESFT好發(fā)于青少年及年輕人?？梢娪谌砣魏喂趋?，最常見的初始發(fā)病部位為骨盆、股骨以及胸壁[8]。長(zhǎng)骨病變骨干最易受累。影像學(xué)多表現(xiàn)為溶骨性破壞。骨膜反應(yīng)呈典型“洋蔥皮”樣改變。

ESFT患者與大多數(shù)骨組織肉瘤患者一樣常因局部疼痛或腫脹就診。與其他骨起源肉瘤不同的是，全身性癥狀如發(fā)熱、體重下降及疲勞在發(fā)病時(shí)常見。實(shí)驗(yàn)室檢查異常包括血清乳酸脫氫酶（lactate dehydrogenase,LDH）升高及白細(xì)胞增多。

2.1 預(yù)后因素

預(yù)后較好的重要因素包括:原發(fā)腫瘤位于肢體、腫瘤體積＜100 ml、發(fā)病時(shí)LDH水平正常[9-13]。與其他部位的ESFT相比，脊柱及骶骨ESFT預(yù)后更差[14]。

發(fā)病時(shí)即有轉(zhuǎn)移是ESFT最顯著的不良預(yù)后因素，與其他骨起源肉瘤相同，轉(zhuǎn)移最常見于肺、骨和骨髓[13,15,16]。EICESS研究組975例患者的回顧性分析中，診斷時(shí)即有轉(zhuǎn)移的患者5年無(wú)復(fù)發(fā)生存率為22%，而診斷時(shí)無(wú)轉(zhuǎn)移的患者為55%[15]。在有轉(zhuǎn)移灶的患者中，單純肺轉(zhuǎn)移的患者比骨轉(zhuǎn)移或肺骨同時(shí)轉(zhuǎn)移的患者生存時(shí)間更長(zhǎng)[15]。一個(gè)30例患者的回顧性分析表明，腫瘤轉(zhuǎn)移至肺和骨以外的其他位置（如腦、肝、脾）時(shí)預(yù)后更差[17]。無(wú)轉(zhuǎn)移的患者對(duì)化療反應(yīng)不佳，是無(wú)事件生存率的一個(gè)不良預(yù)后因素[12,18,19]。

IESS的303例尤文肉瘤患者的臨床病理學(xué)特征回顧資料顯示，原發(fā)病變位于骨盆的患者較四肢起病患者生存率低[20]。在一個(gè)對(duì)53例尤文肉瘤化療患者預(yù)后的多因素分析中，Gupta等發(fā)現(xiàn)，骨盆是否受累、何時(shí)接受局部治療與無(wú)事件生存率相關(guān)[21]。Lee等將成年人、西班牙裔、有轉(zhuǎn)移灶、腫瘤大、低社會(huì)經(jīng)濟(jì)水平認(rèn)定為總生存率的不良預(yù)后因素[22]。

2.2 檢查

懷疑ESFT的患者，在活檢前應(yīng)進(jìn)行全面的腫瘤分期。應(yīng)包括胸部CT，原發(fā)病變部位MRI、CT、PET掃描和（或）骨掃描以及骨髓活檢，同時(shí)建議行脊柱及骨盆MRI除外骨髓侵犯。在一個(gè)系統(tǒng)性回顧和Meta分析中，Treglia等報(bào)道了將PET/CT與傳統(tǒng)影像學(xué)結(jié)合對(duì)ESFT的分期及再分期很有價(jià)值，敏感性96%，特異性92%[23]?；顧z標(biāo)本應(yīng)進(jìn)行細(xì)胞遺傳學(xué)和（或）分子生物學(xué)分析評(píng)估t(11;22)易位。初步報(bào)道認(rèn)為EWS-FLI1易位較其他變異預(yù)后更好[24-26]。與上述觀點(diǎn)不同，來(lái)自EURO-EWING99及兒童腫瘤組的研究報(bào)道認(rèn)為運(yùn)用當(dāng)前有效的治療后尤文肉瘤患者的療效預(yù)后與融合基因亞型無(wú)關(guān)[27,28]。除了EWS以外，在分子學(xué)診斷上為了確診罕見的帶有FUS-ERG或FUS-FEV融合基因轉(zhuǎn)錄的ESFT病例，F(xiàn)US也應(yīng)該作為融合基因檢測(cè)靶點(diǎn)[3,4]。為完善診斷和分期，應(yīng)常規(guī)進(jìn)行骨髓活檢。血清LDH已被證明是一種具有判斷腫瘤預(yù)后意義的腫瘤標(biāo)志物，指南將該檢驗(yàn)列為尤文肉瘤患者的初步評(píng)估手段。（1B級(jí)）

3 診療規(guī)程

3.1 診斷

所有懷疑ESFT的患者都應(yīng)進(jìn)行詳細(xì)的病史采集及體格檢查，首先對(duì)原發(fā)腫瘤部位行MRI和CT檢查。為評(píng)估疾病的分期，還需行胸部CT、PET掃描和（或）骨掃描檢查以便早期發(fā)現(xiàn)經(jīng)血行轉(zhuǎn)移至肺或骨的病灶。ESFT還容易出現(xiàn)骨髓浸潤(rùn)，所以還需行骨髓活檢、脊柱及盆腔的MRI的篩查。由于ESFT有顯著的遺傳易感性（90%尤文氏瘤家族腫瘤擁有4種特定染色體易位），因此強(qiáng)烈建議患者行細(xì)胞遺傳學(xué)和（或）分子生物學(xué)檢測(cè)（可能因此需要再次活檢）。另外，除常規(guī)血液學(xué)檢查外，ESFT患者還需監(jiān)測(cè)LDH的變化?；颊咴诮邮芊呕熐敖ㄗh至生殖醫(yī)學(xué)科進(jìn)行相關(guān)咨詢。（1B級(jí)）

3.2 治療

由于ESFT多為化療高度敏感的腫瘤，因此建議在局部治療之前至少進(jìn)行12周的化療（1A級(jí)）。并在化療后對(duì)腫瘤進(jìn)行再次分期。對(duì)初診無(wú)轉(zhuǎn)移的局灶病變患者，再次分期評(píng)估包括胸部及原發(fā)部位影像檢查，可考慮行PET掃描或骨掃描檢查。而對(duì)轉(zhuǎn)移性ESFT患者，除行上述檢查外，還需對(duì)初次檢查過(guò)程中所有異常結(jié)果做再次檢查評(píng)估。若腫瘤對(duì)化療有反應(yīng)（病情穩(wěn)定或改善），則對(duì)可切除的局部病灶進(jìn)行廣泛切除，對(duì)不可切除的病灶行根治性放療或繼續(xù)化療（根據(jù)治療的反應(yīng)，對(duì)轉(zhuǎn)移性疾病可考慮延長(zhǎng)初始化療時(shí)間）。

手術(shù)切除后需對(duì)手術(shù)切緣進(jìn)行病理學(xué)評(píng)估，對(duì)切緣陽(yáng)性的病例，術(shù)后繼續(xù)化療后放療，或放療后化療?；煏r(shí)長(zhǎng)28～49周，具體化療周期數(shù)取決于化療方案及劑量的使用，此后進(jìn)行定期隨訪。對(duì)切緣陰性的病例，術(shù)后繼續(xù)輔助化療，此后進(jìn)行定期隨訪。（1A級(jí)）

對(duì)初始化療后再評(píng)估腫瘤進(jìn)展的病例，則考慮先對(duì)原發(fā)病灶行放療和（或）手術(shù)治療，以達(dá)到局部控制或姑息治療的目的。此后繼續(xù)化療或行最佳的支持治療。

3.3 隨訪與監(jiān)測(cè)

患者治療結(jié)束后，需每3個(gè)月進(jìn)行原發(fā)部位的體格檢查、影像學(xué)檢查以及胸部CT檢查，并同時(shí)進(jìn)行血常規(guī)以及其他實(shí)驗(yàn)室檢查，可考慮應(yīng)用PET掃描或骨掃描進(jìn)行監(jiān)測(cè)。24個(gè)月后體格檢查、胸部CT和局部影像檢查的間隔可延長(zhǎng)至6個(gè)月。5年后延長(zhǎng)至每年1次。在隨訪過(guò)程中發(fā)現(xiàn)早期或晚期復(fù)發(fā)的病例，需再次接受化療（對(duì)晚期復(fù)發(fā)的病例，可考慮應(yīng)用前期有效的治療方案再治療）和（或）放療。（1B級(jí)）

4 治療方法說(shuō)明

4.1 局部控制治療

手術(shù)切除及放療是非轉(zhuǎn)移尤文肉瘤患者最常用的局部控制方法。目前沒(méi)有比較此兩種方法的隨機(jī)研究。（1B級(jí)）

多中心研究顯示，治療非轉(zhuǎn)移性尤文肉瘤患者時(shí)，局部控制手段的選擇（手術(shù)、放療或手術(shù)加放療）沒(méi)有對(duì)總體生存率或無(wú)事件生存率產(chǎn)生顯著影響[29,30]。在CESS86臨床試驗(yàn)中，雖然根治性手術(shù)和手術(shù)加放療后的局部控制率（分別為100%和95%）較單純適形放療（86%）更高，但因?yàn)樾g(shù)后存在轉(zhuǎn)移風(fēng)險(xiǎn)，總體生存率方面沒(méi)有提高[29]。在INT-0091研究中，患者單用手術(shù)或放療治療后局部控制失敗的發(fā)生率是相近的（25%），但手術(shù)加放療后的局部控制失敗發(fā)生率更低（10.5%）[30]。5年無(wú)事件生存率同樣在組間沒(méi)有顯著差別（手術(shù)、放療、手術(shù)加放療組分別為42%、52%、47%）。其他回顧性分析的數(shù)據(jù)表明手術(shù)（加或不加術(shù)后放療）對(duì)于局限性病變的局部控制能力優(yōu)于單純放療[31]。1058例CESS81、CESS86及EICESS92臨床試驗(yàn)聯(lián)合分析表明手術(shù)（加或不加術(shù)后放療）后局部控制失敗率，較單純適形放療明顯降低（分別為7.5%和26.3%，P=0.001），而術(shù)前放療組的局部控制率與手術(shù)組（5.3%）相當(dāng)[31]。由兒童腫瘤組開展的回顧性分析（INT-0091、INT-0154或AEWS0031）表明：適形放療與手術(shù)加放療相比有更高的局部控制失敗風(fēng)險(xiǎn)，但對(duì)遠(yuǎn)隔部位治療失敗沒(méi)有影響。

適形放療可以作為對(duì)腫瘤部位難以手術(shù)廣泛切除的一種有效治療方法[32,33]。一個(gè)針對(duì)CESS81/86與EICESS92研究中，治療椎體尤文肉瘤患者的回顧性分析顯示，適形放療的局部控制率為22.6%，與其他部位腫瘤接受適形放療后的水平相當(dāng)；5年無(wú)事件生存率和總生存率分別為47%和58%[33]。對(duì)于接受化療和適形放療的非轉(zhuǎn)移性尤文肉瘤患者，腫瘤大小和放療劑量被證實(shí)可以用于預(yù)測(cè)局部控制率[34,35]。

尤文肉瘤家族腫瘤放療原則如下。

4.1.1 原發(fā)腫瘤治療

4.1.1 .1根治性放療：應(yīng)在VAC/IE化療方案12周或VIDE化療方案18周后開始。

放射治療范圍和劑量：①腫瘤區(qū)（GTV）45 Gy照射劑量，臨床靶區(qū)1（CTV1）擴(kuò)大1～1.5 cm，計(jì)劃靶區(qū)1（PTV1）再擴(kuò)大0.5～1 cm；②錐形下區(qū)（CD）覆蓋病變骨范圍，化療后軟組織區(qū)（GTV2）總量55.8 Gy照射劑量，CTV2擴(kuò)大1～1.5 cm，PTV2再擴(kuò)大0.5～1 cm；③化療反應(yīng)度＜50%腫瘤，考慮增加到總量59.4 Gy的增強(qiáng)劑量。

4.1.1 .2術(shù)前放療：對(duì)擬邊緣切除腫瘤考慮術(shù)前放療，對(duì)鞏固性化療患者同時(shí)進(jìn)行。

放射治療范圍和劑量：36～45 Gy照射劑量對(duì)初始GTV，擴(kuò)大2 cm。

4.1.1 .3術(shù)后放療：術(shù)后60 d內(nèi)開始放療，對(duì)鞏固性化療患者同時(shí)進(jìn)行。

照射范圍和劑量：①R0切除：組織學(xué)反應(yīng)差，即使邊界切除充分，仍考慮放療（GTV2：45 Gy照射劑量，CTV1：擴(kuò)大1～1.5 cm，PTV1：擴(kuò)大0.5～1 cm）；②R1切除：GTV2 45 Gy照射劑量，CTV1擴(kuò)大1～1.5 cm，PTV1再擴(kuò)大0.5～1 cm；③R2切除：GTV2 45 Gy照射劑量，CTV1擴(kuò)大1～1.5 cm，PTV1再擴(kuò)大0.5～1 cm，繼續(xù)對(duì)殘余病灶行CD照射，GTV2總量55.8 Gy照射劑量，CTV2擴(kuò)大1～1.5 cm，PTV2再擴(kuò)大0.5～1 cm。

4.1.1 .4半胸照射：原發(fā)于胸壁合并胸膜受累15～20 Gy（1.5 Gy/fx），繼續(xù)對(duì)原發(fā)病灶行CD照射（最終劑量以切除邊緣為基礎(chǔ)）。

4.1.2 轉(zhuǎn)移病灶治療：全肺照射后行徹底化療/轉(zhuǎn)移灶切除：①14歲以下患者15 Gy（1.5 Gy/fx）；②14歲以上患者行18 Gy。目前COG研究以年齡在6歲上下進(jìn)行分層（12 Gy∶15 Gy）。

4.2 化療（1A級(jí)）

美國(guó)和歐洲的單中心及多中心合作臨床研究表明，包含異環(huán)磷酰胺和（或）環(huán)磷酰胺、依托泊苷、多柔比星和（或）放線菌素D、長(zhǎng)春新堿的多藥聯(lián)合化療對(duì)非轉(zhuǎn)移性尤文肉瘤有效。術(shù)前的新輔助化療可縮減腫瘤體積，增加完整切除并獲得鏡下陰性邊緣的幾率。外科切除術(shù)后輔助化療可提高大部分患者的RFS和OS[32,36-39]。

IESS-Ⅰ和IESS-Ⅱ證明，在病灶局限的、非轉(zhuǎn)移性患者中，放療聯(lián)合VACD方案輔助化療（長(zhǎng)春新堿、放線菌素D、環(huán)磷酰胺和多柔比星）比VAC方案（長(zhǎng)春新堿、環(huán)磷酰胺和多柔比星）療效好[37]。其5年RFS分別為60%和24%（P＜0.001），相應(yīng)的OS分別為65%和28%（P＜0.001）。

對(duì)于初治無(wú)轉(zhuǎn)移的尤文肉瘤患者，在標(biāo)準(zhǔn)方案的基礎(chǔ)上可單獨(dú)加用異環(huán)磷酰胺或同時(shí)聯(lián)合依托泊苷[36,40-44]。在兒童癌癥協(xié)作組（POG-COG）的研究中（INT-0091），共398例非轉(zhuǎn)移性ESFT患者隨機(jī)接受共計(jì)17周期VACD或VACD-IE（VACD-異環(huán)磷酰胺+依托泊苷）方案化療[36]。5年EFS VACD-IE組顯著高于VACD組（分別為69%及54%，P=0.005）。5年OS VACD-IE組也顯著提高（分別為72%及61%，P=0.01）。無(wú)論局部治療方式如何，與VACD組相比，VACD-IE組局部復(fù)發(fā)率更低（分別為30%和11%）；5年累積局部控制失敗率在VACD組為30%，VACD-IE組為11%[30]。

VAC-IE方案中烷化劑劑量的提高不能改善非轉(zhuǎn)移性患者的預(yù)后[45]，但縮短化療間期可改善非轉(zhuǎn)移性患者的預(yù)后[46]。在一項(xiàng)針對(duì)50歲以內(nèi)非轉(zhuǎn)移性尤文肉瘤（n=568）的隨機(jī)臨床試驗(yàn)中，Womer等報(bào)道VAC-IE2周方案比3周方案更有效，且藥物毒性沒(méi)有增加；兩組患者5年EFS分別為73%、65%[46]。

研究發(fā)現(xiàn)，對(duì)于初治即有轉(zhuǎn)移的患者，加用異環(huán)磷酰胺/依托泊苷并不能改善其預(yù)后[36,40,42,47]。在INT0091試驗(yàn)中，共120例轉(zhuǎn)移性患者，VACD-IE組與VACD組在EFS和OS均無(wú)顯著區(qū)別[36]。二者五年EFS均為22%，5年OS在VACD-IE組為34%，在VACD組為35%。在68例患者中（44例非轉(zhuǎn)移性，24遠(yuǎn)處轉(zhuǎn)移），Kolb等報(bào)道4年EFS和OS分別為82%和89%，其中非轉(zhuǎn)移性患者接受密集化療[多柔比星和長(zhǎng)春新堿和（或）大劑量環(huán)磷酰胺]并加用異環(huán)磷酰胺和依托泊苷[40]。在遠(yuǎn)處轉(zhuǎn)移患者中，相應(yīng)的生存率為12%和18%。Miser等也報(bào)道了在轉(zhuǎn)移性尤文肉瘤/PNET患者中的類似情況[47]。

EICESS-92試驗(yàn)旨在探索在標(biāo)準(zhǔn)危險(xiǎn)度尤文肉瘤患者（小的局限性腫瘤）中環(huán)磷酰胺是否與異環(huán)磷酰胺有類似的療效，以及在高?；颊撸[瘤體積大或初治即有轉(zhuǎn)移）已使用異環(huán)磷酰胺的基礎(chǔ)上再加用依托泊苷能否提高生存率[48]。標(biāo)準(zhǔn)危險(xiǎn)度患者被隨機(jī)分配，在VAIA（長(zhǎng)春新堿、放線菌素D、異環(huán)磷酰胺和多柔比星，n=76）后接受VAIA或VACA（長(zhǎng)春新堿、放線菌素D、環(huán)磷酰胺和多柔比星，n=79）[48]。VACA組和VAIA組的3年EFS分別為73%和74%，說(shuō)明在此類型患者中，環(huán)磷酰胺與異環(huán)磷酰胺療效相當(dāng)。高危組患者被隨機(jī)分配至VAIA組以及VAIA加依托泊苷（EVAIA組），3年EFS在兩組患者中無(wú)明顯差異（EVAIA組為52%，VAIA組為47%）。但有證據(jù)表明，加用依托泊苷的非轉(zhuǎn)移性患者（P=0.18）比轉(zhuǎn)移性患者獲益更多（P=0.84）[48]。

作為對(duì)EICESS-92試驗(yàn)的隨訪，Euro-EWING99-R1試驗(yàn)評(píng)估了856例標(biāo)準(zhǔn)危險(xiǎn)度的尤文肉瘤患者使用VIDE（長(zhǎng)春新堿，異環(huán)磷酰胺，多柔比星，依托泊苷）后，聯(lián)用長(zhǎng)春新建和放線菌素D時(shí)以環(huán)磷酰胺代替異環(huán)磷酰胺（VAC vs VAI），VAC方案相對(duì)于VAI方案并無(wú)統(tǒng)計(jì)學(xué)優(yōu)勢(shì)，但時(shí)間發(fā)生率稍低（3年EFS降低2.8%）。發(fā)生嚴(yán)重血液學(xué)毒性的患者比例在VAC組略高，但VAI組患者腎小管功能損傷更為顯著[49]。

4.3 大劑量化療后行干細(xì)胞移植（2B級(jí)）

大劑量化療后行干細(xì)胞移植（HDT/SCT）在非轉(zhuǎn)移性及轉(zhuǎn)移性ESFT患者中均有評(píng)估。HDT/SCT在未轉(zhuǎn)移性患者中可提高生存率[50,51]。但是針對(duì)轉(zhuǎn)移性患者的研究得出相反結(jié)論[51-57]。

EURO-EWING 99是第一個(gè)大型隨機(jī)臨床試驗(yàn)，旨在評(píng)估6周期VIDE的多藥聯(lián)合方案，局部治療（手術(shù)和/或放療），和HDT/SCT在281例初治轉(zhuǎn)移性尤文肉瘤患者中的療效[53]。在中位隨訪3.8年后，全部患者3年的EFS和OS分別為27%和34%[55]。HDT/SCT后獲得完全或部分緩解的患者，其EFS分別為57%和25%?；颊吣挲g、腫瘤體積、疾病進(jìn)展程度都是相關(guān)危險(xiǎn)因素。由于非移植組早期偏倚較大（82%未進(jìn)行HDT/SCT的患者在平均1年內(nèi)死亡），HDT/SCT對(duì)預(yù)后的影響沒(méi)有得出最終結(jié)論。

4.4 治療方法小結(jié)

所有尤文肉瘤患者均采取以下方案治療：初始誘導(dǎo)化療后接受局部控制治療[手術(shù)和（或）放療]和輔助治療。

初始治療包括多藥化療以及粒細(xì)胞集落刺激因子支持，至少12周。已有轉(zhuǎn)移灶的患者根據(jù)化療反應(yīng)可以適當(dāng)延長(zhǎng)初始誘導(dǎo)化療周期。VAC/IE（長(zhǎng)春新堿、阿霉素和環(huán)磷酰胺與異環(huán)磷酰胺和依托泊苷交替）是局部尤文肉瘤的首選方案，而VAC（長(zhǎng)春新堿、阿霉素和環(huán)磷酰胺）是有轉(zhuǎn)移灶患者的首選方案[36,40,47]。

初始治療后應(yīng)根據(jù)病變部位MRI和胸部檢查再分期。根據(jù)初始診斷時(shí)所用的影像學(xué)技術(shù)，PET掃描和（或）骨掃描也可以用于再分期。初始治療后患者維持穩(wěn)定狀態(tài)或腫瘤縮小應(yīng)進(jìn)行局部控制治療。

局部控制治療方法包括局部切除、適形放療，甚至截肢[31,33,34,58]。局部控制方法的選擇應(yīng)個(gè)性化，根據(jù)腫瘤位置、大小、對(duì)化療的反應(yīng)、患者年齡、功能預(yù)期來(lái)制定。

無(wú)論手術(shù)切緣如何，建議對(duì)所有患者進(jìn)行術(shù)后輔助化療。強(qiáng)烈建議廣泛切除后的化療持續(xù)時(shí)間為28～49周，根據(jù)方案和劑量制定具體時(shí)間[36,37,39]。對(duì)于切緣陽(yáng)性或外科邊緣非常鄰近的患者，建議在化療的基礎(chǔ)上增加術(shù)后放療[31]。Denbo等最近報(bào)道在小體積腫瘤（＜8 cm）及切緣陰性的患者中，可以不采用術(shù)后放療而總體生存率無(wú)降低[59]。接受輔助放療患者的15年預(yù)計(jì)總體生存率為80%，未經(jīng)輔助放療的患者為100%。本指南建議對(duì)廣泛病灶切除及切緣陰性患者單用輔助化療。（1B級(jí)）

初始治療后的進(jìn)展性疾病的最好治療方法是對(duì)原發(fā)病灶進(jìn)行放療和（或）手術(shù)，之后采取化療或最好的支持性治療。

4.5 復(fù)查監(jiān)測(cè)

尤文肉瘤患者的復(fù)查包括3個(gè)月進(jìn)行1次體格檢查、血常規(guī)和其他實(shí)驗(yàn)室檢查、胸片和局部病灶影像學(xué)檢查。復(fù)查間隔在2年后應(yīng)延長(zhǎng)至6個(gè)月。5年后的長(zhǎng)期監(jiān)測(cè)應(yīng)每年進(jìn)行1次[60]。（2B級(jí)）

4.6 復(fù)發(fā)或難治性疾病

30%～40%ESFT患者會(huì)復(fù)發(fā)[局部復(fù)發(fā)和（或）遠(yuǎn)處轉(zhuǎn)移]，預(yù)后很差。首次復(fù)發(fā)的間隔時(shí)間越長(zhǎng)，患者的生存機(jī)會(huì)越大。晚期復(fù)發(fā)（首診后≥2年）、只有肺部轉(zhuǎn)移、可以用積極性手術(shù)切除的局部復(fù)發(fā)和密集化療是最有利的預(yù)后因素，而有肺部和（或）其他部位轉(zhuǎn)移的早期復(fù)發(fā)（首診后＜2年）、局部及遠(yuǎn)處都有復(fù)發(fā)、首診LDH升高以及首次即有復(fù)發(fā)被認(rèn)為是不良預(yù)后因素[61-63]。在一個(gè)近期的回顧性分析中，初次復(fù)發(fā)的部位及間隔時(shí)間對(duì)于成人局限性尤文肉瘤患者來(lái)說(shuō)是重要的預(yù)后因素[64]。局部和遠(yuǎn)處復(fù)發(fā)患者的復(fù)發(fā)后5年預(yù)計(jì)生存幾率分別為50%和13%。晚期復(fù)發(fā)患者的復(fù)發(fā)后5年預(yù)計(jì)生存率顯著高于早期復(fù)發(fā)患者[64,65]。

有臨床試驗(yàn)評(píng)估聯(lián)合異環(huán)磷酰胺與依托泊苷（加或不加卡鉑）治療復(fù)發(fā)或難治性肉瘤患者效果[66,67]。在一個(gè)Ⅱ期研究中，對(duì)于兒童及年輕人的復(fù)發(fā)性肉瘤患者采用異環(huán)磷酰胺及依托泊苷聯(lián)合治療在可接受的毒性范圍內(nèi)有明顯效果[66]。由兒童腫瘤組開展的Ⅰ/Ⅱ期研究表明，復(fù)發(fā)性或難治性肉瘤患者的總體反應(yīng)率為51%；1年及2年的總體生存率分別為49%和28%。腫瘤有完全或部分反應(yīng)的患者的總體生存率明顯提高[67]。

不以異環(huán)磷酰胺為基礎(chǔ)的化療方案在復(fù)發(fā)性或難治性骨組織肉瘤患者中也顯示有效。多西他賽與吉西他濱聯(lián)合被證實(shí)有很好的耐受性，治療后患有難治性骨組織肉瘤的兒童及年輕人的總體客觀反應(yīng)率為29%；中位反應(yīng)持續(xù)時(shí)間為4.8個(gè)月[68]。拓?fù)洚悩?gòu)酶Ⅰ抑制劑（拓?fù)涮婵岛鸵亮⑻婵担┡c環(huán)磷酰胺與替莫唑胺聯(lián)合治療復(fù)發(fā)或難治性骨組織肉瘤時(shí)有可觀的反應(yīng)率[69-75]。對(duì)54例復(fù)發(fā)或難治性肉瘤患者，環(huán)磷酰胺和拓?fù)涮婵翟?4%患者中展現(xiàn)了治療反應(yīng)（35%患者完全反應(yīng)，9%部分反應(yīng)）[71]。在中位隨訪時(shí)間23個(gè)月后，26%患者位于持續(xù)性緩解期。對(duì)患有復(fù)發(fā)性或進(jìn)展期尤文肉瘤患者的回顧性分析中，伊立替康和替莫唑胺治療后的總體客觀反應(yīng)率為63%。所有可評(píng)估患者（20例）的腫瘤進(jìn)展中位時(shí)間（TTP）為8.3個(gè)月（復(fù)發(fā)患者為16.2個(gè)月）[70]。與診斷后兩年內(nèi)復(fù)發(fā)和診斷時(shí)即有轉(zhuǎn)移的患者比較，2年初次緩解和原發(fā)局限性腫瘤患者的中位TTP更好。復(fù)發(fā)或難治性尤文肉瘤患者對(duì)長(zhǎng)春新堿、伊立替康與替莫唑胺聯(lián)合用藥的反應(yīng)好且耐受性好，總體反應(yīng)率為68.1%[76]。

總之，復(fù)發(fā)或難治性患者的治療方法包括參加臨床試驗(yàn)和化療（加或不加放療）。ESFT有時(shí)會(huì)出現(xiàn)延遲復(fù)發(fā)，采用以前有效的治療方案可能有作用。所有復(fù)發(fā)和轉(zhuǎn)移的患者均應(yīng)考慮參加研究新型治療方法的臨床試驗(yàn)。

4.7 尤文肉瘤化療方案匯總

4.7.1 一線治療方案（初始/新輔助/輔助治療）：①VAC/IE（長(zhǎng)春新堿、阿霉素聯(lián)合環(huán)磷酰胺或異環(huán)磷酰胺聯(lián)合足葉乙甙）[36]；②VAI（長(zhǎng)春新堿、阿霉素聯(lián)合異環(huán)磷酰胺）[19,48]；③VIDE（長(zhǎng)春新堿、異環(huán)磷酰胺、阿霉素聯(lián)合足葉乙甙）[53]。

4.7.2 就診即存在轉(zhuǎn)移病灶初始治療：①VAdriaC（長(zhǎng)春新堿、阿霉素聯(lián)合環(huán)磷酰胺）[47]；②VAC/IE[36]；③VAI[19,48]；④VIDE[53]。

4.7.3 二線治療方案（復(fù)發(fā)/難治性或轉(zhuǎn)移）：①環(huán)磷酰胺聯(lián)合拓?fù)涮婵礫69,71-73]；②伊立替康±替莫唑胺[70,74,75,77-80]；③異環(huán)磷酰胺聯(lián)合足葉乙甙[66]；④異環(huán)磷酰胺、卡鉑、足葉乙甙[67]；⑤多西紫杉醇聯(lián)合吉西他濱[68]。

5 不同部位的外科治療

5.1 四肢尤文肉瘤的外科治療

5.1.1 外科邊界的選擇與預(yù)后：對(duì)于肢體尤文肉瘤來(lái)說(shuō)，在完成術(shù)前新輔助化療后且可以保肢時(shí)，應(yīng)首選切緣陰性的廣泛切除或根治性手術(shù)[81-88]。

肢體尤文肉瘤患者的5年生存率在50%～75%之間[31,89-92]，高于脊柱及骨盆尤文肉瘤的5年生存率[30,90,93-95]。尤文肉瘤惡性程度高，易發(fā)生遠(yuǎn)處轉(zhuǎn)移，尤其是肺[16,85,86,96]，其遠(yuǎn)處轉(zhuǎn)移率為60%左右[85,86,96]。因此肢體尤文肉瘤必須選擇切緣陰性的廣泛切除或根治性手術(shù)[81-88]。

Sluga等在2001年于Eur J Surg Oncol發(fā)表的數(shù)據(jù)顯示，無(wú)轉(zhuǎn)移的肢體尤文肉瘤做切緣陰性的廣泛切除后與囊內(nèi)切除患者的五年生存率分別為60.2%和40.1%[97]。其他肢體尤文肉瘤的回顧性研究顯示，切緣陰性的廣泛切除或根治性手術(shù)的局部復(fù)發(fā)率為10%左右[98-100],而囊內(nèi)刮除術(shù)后局部復(fù)發(fā)率較高約為30%[98,99]。因此，切緣陰性的廣泛切除或根治性手術(shù)較囊內(nèi)刮除術(shù)可以減少肢體尤文肉瘤的局部復(fù)發(fā)率，并且五年生存率亦有所提高。

由此看來(lái)，外科邊界的滿意程度是肢體尤文肉瘤預(yù)后重要的影響因素之一。（1B級(jí)）

5.1.2 復(fù)發(fā)病例的處理：肢體尤文肉瘤局部復(fù)發(fā)率為10%～30%[65,101-104]，復(fù)發(fā)病例是否接受二次手術(shù)需根據(jù)個(gè)體情況決定，部分患者可能從中受益[64]。

初次手術(shù)外科邊界的滿意程度是肢體尤文肉瘤局部復(fù)發(fā)最重要的影響因素[105]。局部復(fù)發(fā)與預(yù)后不良密切相關(guān)[65,105]。局部復(fù)發(fā)患者要根據(jù)患者實(shí)際情況考慮推薦給予放療、再次手術(shù)或化療[58,105]。（1B級(jí)）5.1.3截肢和保肢的選擇：當(dāng)肢體尤文肉瘤體積巨大且新輔助化療效果不佳，腫瘤累及主要血管神經(jīng)，或復(fù)發(fā)、放療等因素造成局部軟組織條件不良的情況下應(yīng)選擇截肢。（1B級(jí)）

截肢和保肢手術(shù)對(duì)于尤文肉瘤患者的生存率、局部復(fù)發(fā)率無(wú)統(tǒng)計(jì)學(xué)差異[106-108]，Schrager的數(shù)據(jù)顯示，截肢組和保肢組的生存率分別為63.1%和71.8%[108]。保肢與截肢患者的生存質(zhì)量沒(méi)有明顯差異，但截肢患者較保肢患者社會(huì)適應(yīng)性更差[109]；保肢患者術(shù)后功能有好于截肢患者的趨勢(shì)，但研究的統(tǒng)計(jì)學(xué)差異不顯著[110-112]。亦有學(xué)者認(rèn)為保肢患者的功能比截肢患者好[113]。隨著影像學(xué)和計(jì)算機(jī)技術(shù)的發(fā)展，目前對(duì)肢體尤文肉瘤的診斷、外科邊界已經(jīng)更加精確[114-116]。

肢體尤文肉瘤切除方式的選擇需充分考慮新輔助化療后腫瘤累及主要的血管神經(jīng)、周圍軟組織條件等因素，綜合評(píng)判選擇保肢或截肢術(shù)。

5.1.4 肢體尤文肉瘤切除后的功能重建：對(duì)于接受保肢手術(shù)的尤文肉瘤患者，在切除腫瘤后應(yīng)進(jìn)行缺損區(qū)域的功能重建，以恢復(fù)肢體的功能。重建方法的選擇應(yīng)根據(jù)患者年齡、病變部位等因素綜合考慮。重建主要有生物學(xué)重建、機(jī)械性重建以及復(fù)合重建。（1B級(jí)）

對(duì)于腫瘤切除后的缺損區(qū)域可以采用機(jī)械性重建的方法，比如鄰近關(guān)節(jié)的缺損可以采用關(guān)節(jié)假體置換的重建方法[117-121]，全部骨干的缺損則可以采用全骨假體置換的方法重建[122,123]。此外，也可以采取生物學(xué)重建方法，針對(duì)不同部位可以采用腫瘤滅活再植、大段異體骨、游離腓骨移植等方法進(jìn)行重建[124-126]。復(fù)合型重建亦可用于缺損的重建[124,127]。

5.2 脊柱尤文肉瘤的外科治療

5.2.1 新輔助化療有利于提高總的生存率和手術(shù)方式的制定（1A級(jí)）：原發(fā)脊柱尤文肉瘤占所有尤文肉瘤的3.5%～10%[128-132]。平均發(fā)病年齡為13歲，通常源于單一脊椎（61%）的后半部分（65%），胸腰椎占絕大多數(shù)（91%）[133]。脊柱尤文肉瘤單純手術(shù)或放療的5年生存率為5%～20%[134,135]。多藥聯(lián)合化療結(jié)合手術(shù)或放療使得脊柱尤文肉瘤的5年生存率提高至41%～80%[33,136,137]，局部控制率達(dá)到 50%～80%[37,138,139]。Oberlin等報(bào)道一組67例患者，化療對(duì)尤文肉瘤的有效率為61%[129]。

新輔助化療的益處包括三個(gè)方面[140]：①對(duì)化療敏感的脊柱尤文肉瘤的軟組織包塊能夠很快縮小，脊髓受壓能夠很快減輕[141]，并使得部分原先不能切除的腫瘤可以切除。Vogin等報(bào)道了一組脊柱尤文肉瘤病例，實(shí)行新輔助化療組的患者37%獲得了R0切除，而未行新輔助化療直接行椎板減壓組無(wú)一例獲得R0切除[133]。②系統(tǒng)化療可以消滅循環(huán)腫瘤細(xì)胞和微轉(zhuǎn)移灶。③腫瘤對(duì)于化療的敏感性有利于制定術(shù)后化療方案。對(duì)于脊髓神經(jīng)功能穩(wěn)定的患者，活檢確診后即開始新輔助化療，對(duì)于確診時(shí)脊髓功能已經(jīng)受到損害的患者，行椎管減壓后開始化療[136]。

5.2.2 術(shù)前動(dòng)脈栓塞有利于手術(shù)的安全進(jìn)行（1B級(jí)）：動(dòng)脈栓塞逐漸成為原發(fā)和繼發(fā)脊柱腫瘤治療有效和安全的方法。術(shù)前栓塞可以有效減少腫瘤的血供，使瘤體縮小，減少術(shù)中出血，改善總體預(yù)后[142,143]。脊柱尤文肉瘤的出血傾向雖不如腎癌、甲狀腺癌等轉(zhuǎn)移瘤，但仍推薦患者接受術(shù)前栓塞治療[144]。

5.2.3 就診時(shí)有脊髓功能損害需緊急進(jìn)行椎管減壓手術(shù)（1B級(jí)）：雖然脊柱尤文肉瘤體的初始體積不大（平均60 ml），但腫瘤向椎管內(nèi)生長(zhǎng)導(dǎo)致脊髓或馬尾癥狀時(shí)，需行緊急椎管減壓手術(shù)（全椎板切除減壓或前方減壓）[140,141]。Vogin等報(bào)道了75例脊柱尤文肉瘤，57例（79%）就診時(shí)表現(xiàn)為神經(jīng)受壓的癥狀，69%行減壓手術(shù)[133]。Marco等報(bào)道13例脊柱尤文肉瘤患者中10例行椎板切除減壓術(shù)[141]。Indelicato等報(bào)道27例脊柱尤文肉瘤中6例行緊急椎板切除減壓[136]。Sharafuddin等報(bào)道的7例脊柱尤文肉瘤中4例行椎板切除減壓，1例行前方減壓[140]。椎管減壓后超過(guò)三分之二的患者神經(jīng)功能可以恢復(fù)[136,140,145]。

5.2.4 切緣陰性的整塊切除是無(wú)轉(zhuǎn)移脊柱尤文肉瘤局部治療的首選方法（1B級(jí)）：與瘤內(nèi)切除或單純放療相比，整塊切除局部復(fù)發(fā)風(fēng)險(xiǎn)低，并可能提高長(zhǎng)期生存率[141,146]。Boriani等報(bào)道了27例脊柱尤文肉瘤，總生存率為40.7%，而6例行整塊切除且切緣陰性的患者中5例長(zhǎng)期無(wú)瘤生存，總生存率為83.3%[147]。Ulf等報(bào)道了7例行整塊切除的脊柱尤文肉瘤，5例達(dá)到廣泛切除，1例邊緣切除，1例瘤內(nèi)切除，隨訪10～96個(gè)月，5例無(wú)瘤生存，1例由于其他疾病死亡，1例帶瘤生存[98]。李曉等[148]報(bào)道整塊切除可降低局部復(fù)發(fā)率，7例中1例復(fù)發(fā)，2例出現(xiàn)肺轉(zhuǎn)移。分塊切除20例，局部復(fù)發(fā)8例。但脊柱腫瘤整塊切除技術(shù)要求高[141]，容易出現(xiàn)大的并發(fā)癥，死亡率可達(dá)7.7%（0～7.7%），最常見的死亡原因?yàn)楹粑ソ遊149]，術(shù)后并發(fā)癥的發(fā)生率為10%～30%，主要包括血管神經(jīng)損傷、傷口預(yù)后不良、感染和內(nèi)固定失敗等[133,150]，故采取整塊切除應(yīng)根據(jù)腫瘤的分期和患者的狀況在專業(yè)的骨腫瘤中心進(jìn)行。

5.2.5 脊柱尤文肉瘤是否采用瘤內(nèi)切除尚存在爭(zhēng)議（2B級(jí)）：瘤內(nèi)切除相對(duì)于整塊切除技術(shù)要求低，對(duì)脊柱穩(wěn)定性影響小，多數(shù)醫(yī)師可以實(shí)施，手術(shù)后局部癥狀可以很快部分緩解[141]。但由于局部仍有腫瘤殘留，局部復(fù)發(fā)率較整塊切除高[146]，術(shù)后需要進(jìn)行輔助放療。瘤內(nèi)切除或邊緣切除后輔助放療是否比單純根治性放療更使患者獲益尚存在爭(zhēng)議。Vogin等報(bào)道一組病例脊柱尤文肉瘤，56例行手術(shù)切除，其中R0切除11例、R1切除8例、R2切除37例，術(shù)后50例行輔助放療，與19例單純行根治性放療患者相比，前者局部控制率為83%，后者為74%，兩者無(wú)統(tǒng)計(jì)學(xué)差異[133]。Schuck等觀察了111例脊柱尤文肉瘤，單純放療組75例局部控制率為77.4%，手術(shù)結(jié)合放療組32例局部控制率為81.3%，兩組無(wú)統(tǒng)計(jì)學(xué)差異，47例患者出現(xiàn)放療相關(guān)的急性并發(fā)癥[33]。Indelicato等報(bào)道了一組27例脊柱尤文肉瘤，其中5例在確診時(shí)已有轉(zhuǎn)移。單純放療21例，手術(shù)結(jié)合放療6例，單純放療組平均放療劑量為55 Gy。腫瘤局部控制率在單純放療組為84%，手術(shù)結(jié)合放療組為100%，兩組無(wú)統(tǒng)計(jì)學(xué)差異。5年總生存率分別為50%和80%，無(wú)瘤生存率分別為35%和69%，兩組之間均無(wú)統(tǒng)計(jì)學(xué)差異。10例患者（37%）出現(xiàn)嚴(yán)重并發(fā)癥，其中3例與放療相關(guān)，包括食道狹窄、頑固性惡心嘔吐和膀胱肥大導(dǎo)致的雙腎積水[136]。Boriani等報(bào)道27例脊柱尤文肉瘤，其中瘤內(nèi)切除并輔以放療的11例患者均死亡，而單純放療的9例中5例存活[147]。但術(shù)后放療與單純放療相比，由于瘤內(nèi)切除后局部只有少量腫瘤殘留，所需的放療劑量低[141]，低劑量放療也降低了放療相關(guān)的肉瘤變[151-154]和放射性脊髓病的風(fēng)險(xiǎn)[155-157]。

5.2.6 放療在脊柱尤文肉瘤局部治療中具有重要作用，瘤內(nèi)切除或單純椎板減壓術(shù)后需行輔助放療（1B級(jí)）：尤文肉瘤對(duì)放療相對(duì)敏感，長(zhǎng)期以來(lái)放療在尤文肉瘤局部控制中占有重要的地位，單純放療所需劑量為55～60 Gy，超過(guò)了脊髓的耐受劑量，易于引起放射性脊髓病[136]。另外放療可以導(dǎo)致脊柱畸形、軟組織纖維化、攣縮和第二惡性腫瘤的發(fā)生風(fēng)險(xiǎn)[158,159]。多數(shù)學(xué)者對(duì)于腫瘤較大，侵及范圍較廣，無(wú)法手術(shù)的傾向于單純放療[148]。放療的范圍為包括病變脊椎和其上下各一個(gè)脊椎[136]。Marco等報(bào)道13例單純局部放療的治療結(jié)果：放療劑量為30～66 Gy，平均48 Gy，5年無(wú)瘤生存率為49%，局部控制率率為77%[141]。瘤內(nèi)切除或單純椎板減壓術(shù)后由于局部有腫瘤的殘留，需行術(shù)后輔助放療，放療的劑量一般低于45 Gy，以降低放療相關(guān)的脊髓病的發(fā)生[133,155-157]，也可降低放療相關(guān)的肉瘤發(fā)生的風(fēng)險(xiǎn)[151-154]。放療后局部復(fù)發(fā)的原因在于在放療區(qū)域內(nèi)有活的腫瘤細(xì)胞殘存[141]。Tellers等通過(guò)尸解在化療結(jié)合放療的20例患者中13例發(fā)現(xiàn)腫瘤殘留[160]。

5.2.7 椎板切除減壓或整塊切除術(shù)后需進(jìn)行脊柱穩(wěn)定性重建（1B級(jí)）：?jiǎn)渭冏蛋鍦p壓后易于發(fā)生遠(yuǎn)期脊柱的畸形和神經(jīng)系統(tǒng)的并發(fā)癥。Vogin報(bào)道一組脊柱尤文肉瘤病例，在存活超過(guò)5年的患者中神經(jīng)和脊柱畸形的并發(fā)癥發(fā)生率分別為32%和73%[133]，而在兒童患者中，脊柱畸形的發(fā)生率可達(dá)95%～100%[161-163]。最常見的脊柱畸形為椎板減壓后的后凸畸形，其發(fā)生率為40%～75%[141,145]。單純放療可以導(dǎo)致椎體前方或一側(cè)的楔形變，隨后發(fā)生脊柱的側(cè)彎或后凸畸形，其發(fā)生率為10%～100%[164]。脊柱尤文肉瘤行椎板減壓后的患者一般需行輔助放療，已經(jīng)行椎板減壓的患者再行放療可導(dǎo)致嚴(yán)重的脊柱畸形[165,166]。故在行單純椎板切除減壓后需行脊柱穩(wěn)定手術(shù)[136,141]，如椎板成形術(shù)或后外側(cè)融合術(shù)并輔以外固定以預(yù)防脊柱畸形的發(fā)生[164]，行全脊椎整塊切除的患者則應(yīng)進(jìn)行包括前柱在內(nèi)的360°穩(wěn)定性重建。

5.3 骨盆/骶骨尤文肉瘤的外科治療

5.3.1 外科邊緣（1B級(jí)）：建議采用國(guó)際抗癌聯(lián)盟（UICC）手術(shù)切緣（“R”切緣），因?yàn)槎鄶?shù)患者需要考慮術(shù)后放療。對(duì)于骨盆/骶骨的尤文肉瘤病例來(lái)說(shuō)，在放療或（和）化療的基礎(chǔ)上，為使患者獲得更高的局部控制率以及更好的預(yù)后，首選外科初始治療方案均為切緣陰性（R0切除）的廣泛切除，盡量避免囊內(nèi)切除[94,95,167-169]。

國(guó)際抗癌聯(lián)盟手術(shù)切緣定義為：手術(shù)切緣鏡下觀察，R0為無(wú)微小病灶殘留，R1為微小病灶殘留，R2為肉眼可見病灶殘留。經(jīng)多學(xué)科的協(xié)作治療，骨盆/骶骨尤文肉瘤患者的5年生存率在45%～75%[95,167,169,170]，而四肢尤文肉瘤患者的5年無(wú)進(jìn)展生存期、總體生存率以及局部控制率分別為：24.1%，43.5%～64%，以及55%[171,172]。骨盆/骶骨尤文肉瘤患者的預(yù)后差[14,172]，對(duì)于骨盆/骶骨的尤文肉瘤病例來(lái)說(shuō)，無(wú)論病理分級(jí)如何，外科手術(shù)都首選切緣陰性的廣泛切除[94,95,167-169]。滿意的外科邊界可能降低局部復(fù)發(fā)的風(fēng)險(xiǎn)[81]。Hoffmann等報(bào)道的大樣本對(duì)照研究長(zhǎng)達(dá)13年的隨訪結(jié)果顯示，接受外科手術(shù)的骨盆/骶骨尤文肉瘤患者，廣泛切除使得無(wú)轉(zhuǎn)移的入組治療患者無(wú)進(jìn)展生存率達(dá)到60%，而邊緣切除與囊內(nèi)切除為52%；廣泛切除使得無(wú)轉(zhuǎn)移的隨訪患者其無(wú)進(jìn)展生存率達(dá)到37%，而邊緣切除與囊內(nèi)切除為0%[93]。盡量避免囊內(nèi)切除，因?yàn)榇朔N手術(shù)與單純放療相比并無(wú)獲益[15]。非常接近腫瘤的骨盆/骶骨尤文肉瘤R0邊緣，也建議采用術(shù)后放療[31]。由于骨盆/骶骨的尤文肉瘤來(lái)源特性、解剖部位、放化療敏感性等特征，NCCN推薦的廣泛切除的概念即為R0切除。

局部治療中手術(shù)切除是最佳方法；外科手術(shù)邊界不足時(shí)應(yīng)予以術(shù)后放療；術(shù)后組織學(xué)反應(yīng)不良時(shí)應(yīng)考慮放療（與放療醫(yī)師討論）。

如果可能，切緣陰性的廣泛切除是局部的最佳選擇，局部放療也是對(duì)局限性病變的局部控制方法，但是目前沒(méi)有比較此兩種方法的隨機(jī)研究。合作性研究小組的尤文肉瘤局部控制方式的對(duì)比研究發(fā)現(xiàn)，局部控制手段（手術(shù)、放療或手術(shù)加放療）沒(méi)有對(duì)總體生存率以及無(wú)進(jìn)展生存率產(chǎn)生十分顯著的影響[29,30,173]。在CESS86臨床試驗(yàn)中，雖然積極的手術(shù)和切除再加放療后的局部控制率（分別為100%和95%）較適形放療（86%）更高，但因?yàn)橥饪剖中g(shù)后發(fā)生轉(zhuǎn)移的風(fēng)險(xiǎn)更高，在無(wú)復(fù)發(fā)生存率或總體生存率方面沒(méi)有顯著提高[29]。在INT-0091研究中，患者單獨(dú)手術(shù)或放療治療后局部控制失敗的發(fā)生率是相近的（25%），但手術(shù)加放療后的局部控制失敗的發(fā)生率更低（10.5%）[169]。5年無(wú)事件生存率同樣在組間沒(méi)有顯著差別（手術(shù)、放療、手術(shù)加放療組分別為42%、52%、47%）。其他回顧性分析的數(shù)據(jù)表明手術(shù)（加或不加術(shù)后放療）對(duì)于局限性病變的局部控制能力優(yōu)于單純放療[31,168]。1058例CESS81、CESS86及EICESS92臨床試驗(yàn)聯(lián)合分析表明手術(shù)（加或不加術(shù)后放療）后局部控制失敗率，較適形放療明顯降低（分別為7.5%和26.3%，P=0.001），而術(shù)前放療組的局部控制率與手術(shù)組（5.3%）相當(dāng)[31]。由兒童腫瘤組開展的對(duì)于序貫性研究（INT-0091、INT-0154和AEWS0031）的回顧性分析表明：適形放療與手術(shù)加放療相比有更高的局部控制失敗風(fēng)險(xiǎn)，但對(duì)遠(yuǎn)隔部位治療失敗沒(méi)有影響[168]。然而，對(duì)于手術(shù)邊界不足的患者，術(shù)后應(yīng)當(dāng)給予局部放療，以期提高局部控制率。當(dāng)術(shù)后標(biāo)本的組織學(xué)應(yīng)答不良（即腫瘤細(xì)胞存活率＞10%）時(shí)應(yīng)與放療科醫(yī)師討論是否予以術(shù)后放療[15]。

5.3.2 復(fù)發(fā)、轉(zhuǎn)移病例的處理（1B級(jí)）：建議對(duì)骨復(fù)發(fā)或轉(zhuǎn)移病灶進(jìn)行手術(shù)治療或放療。建議對(duì)單純肺轉(zhuǎn)移患者行全肺放療。

尤文肉瘤較易復(fù)發(fā)，單純局部病灶患者的復(fù)發(fā)率為30%～40%，存在原發(fā)轉(zhuǎn)移以及播散的患者的復(fù)發(fā)率為60%～80%[48,62]。對(duì)于復(fù)發(fā)患者，目前發(fā)現(xiàn)唯一的預(yù)后因素是復(fù)發(fā)的時(shí)間：初始診斷2年以后復(fù)發(fā)者預(yù)后較好（P＜0.0001）[15,65]。而且，局部復(fù)發(fā)患者的5年生存率為13%～30%，優(yōu)于全身或者合并復(fù)發(fā)患者[54,65]。對(duì)于復(fù)發(fā)性骨病灶，建議行手術(shù)切除和（或）放療[58]，部分患者可以從中獲益。20%～25%患者在診斷時(shí)已有轉(zhuǎn)移（肺：10%；骨/骨髓：10%；上述兩種部位或其他：5%）[15,16,19,69,174]，單純肺轉(zhuǎn)移患者預(yù)后優(yōu)于骨轉(zhuǎn)移患者以及同時(shí)肺轉(zhuǎn)移、骨轉(zhuǎn)移的患者[15,19,174]，5年無(wú)進(jìn)展生存率分別為29%、19%和8%（P＜0.001）[15]。對(duì)單純骨轉(zhuǎn)移患者建議行外科手術(shù)切除和（或）放療[58]，對(duì)肺轉(zhuǎn)移患者進(jìn)行全肺放射治療可能會(huì)提高生存率[175]。

5.3.3 骨盆重建手術(shù)（1B級(jí)）：在術(shù)中條件允許的情況下應(yīng)進(jìn)行恢復(fù)肢體功能的骨盆重建。

骨盆的功能是傳導(dǎo)軀體的重量和參與構(gòu)成髖關(guān)節(jié)。如果在腫瘤切除后，股骨-骶骨之間的骨連續(xù)性和髖關(guān)節(jié)的結(jié)構(gòu)不完整，則需要進(jìn)行重建。對(duì)于Ⅲ型或骶髂關(guān)節(jié)穩(wěn)定性未受到影響的Ⅰ型切除，通常不需要重建。對(duì)于骶髂關(guān)節(jié)的穩(wěn)定性受到影響的Ⅰ型或Ⅰ+Ⅳ型切除，需要進(jìn)行重建，恢復(fù)骨盆環(huán)的連續(xù)性[176,177]。骨盆惡性腫瘤切除后的功能重建是骨腫瘤醫(yī)師的一大挑戰(zhàn)，重建方法包括人工假體和骨水泥[178-180]、馬 鞍 式假體[181]、病 灶 骨 滅活[182,183]或 者輻照[184,185]再植、近端股骨自體骨移植[186]、同種異體骨移植[187-192]以及帶血管蒂的腓骨瓣移植[193]等，國(guó)內(nèi)王臻教授團(tuán)隊(duì)也提出了兒童及青少年尤文肉瘤“髖臼挽救”的概念[194,195]。同種異體移植骨重建方法的優(yōu)點(diǎn)在于能夠重建復(fù)雜的骨盆骨結(jié)構(gòu)，但是文獻(xiàn)報(bào)道此種方法的并發(fā)癥[187-191]，如：感染、異體骨吸收等發(fā)生率較高[187,189,190,192]。而且可調(diào)式人工半骨盆假體的術(shù)后功能及并發(fā)癥發(fā)生率均優(yōu)于馬鞍式假體[179-181]。

5.3.4 截肢手術(shù)的選擇（1B級(jí)）：當(dāng)體積巨大的骨盆軟骨肉瘤累及主要血管神經(jīng)，或復(fù)發(fā)、放療等因素造成局部軟組織條件不良的情況下應(yīng)選擇截肢。

局部控制可通過(guò)保肢或截肢來(lái)實(shí)現(xiàn)。對(duì)部分病例而言，截肢可能是達(dá)到這一目標(biāo)的最佳選擇。但是，能夠合理保全功能，應(yīng)選擇保肢手術(shù)[31,176,196]。保留髖臼患者M(jìn)STS評(píng)分高于髖臼切除的骨盆尤文肉瘤患者M(jìn)STS評(píng)分[197]。截肢和保肢手術(shù)獲得滿意的外科邊界的比例無(wú)統(tǒng)計(jì)學(xué)差異[198]。

5.3.5 切除技術(shù)與重建技術(shù)（1B級(jí)）：建議采用數(shù)字導(dǎo)航技術(shù)以及數(shù)字化骨科技術(shù)（3D打印模型與假體、3D打印截骨導(dǎo)板）。

骨盆腫瘤導(dǎo)航手術(shù)便于骨盆區(qū)域深部骨性結(jié)構(gòu)和腫瘤的觀察，可以做到內(nèi)植物的精確放置，減少并發(fā)癥，避免因反復(fù)透視增加輻射危害。計(jì)算機(jī)導(dǎo)航側(cè)重于術(shù)中影像學(xué)輔助腫瘤定位，引導(dǎo)切除腫瘤和骨盆截骨[199,200]。計(jì)算機(jī)導(dǎo)航輔助腫瘤切除和個(gè)體化定制髖臼假體重建能夠滿足髖臼腫瘤精確切除和重建的要求，腫瘤切除徹底、髖臼重建滿意、并發(fā)癥發(fā)生率低、近期效果良好，是外科治療惡性髖臼腫瘤的一種有效方法。3D打印手術(shù)導(dǎo)板很好地適應(yīng)了骨腫瘤手術(shù)個(gè)體化要求，可實(shí)現(xiàn)術(shù)前設(shè)計(jì)，不同3D打印技術(shù)制備的手術(shù)導(dǎo)板各有優(yōu)勢(shì)，需根據(jù)具體手術(shù)方式選擇。

5.3.6 腰骶穩(wěn)定（1B級(jí)）：建議對(duì)骶髂關(guān)系不穩(wěn)的進(jìn)行穩(wěn)定性重建。

國(guó)內(nèi)郭衛(wèi)教授團(tuán)隊(duì)報(bào)道了新的骶骨惡性腫瘤的外科分區(qū)系統(tǒng)，對(duì)于低位骶骨（骶2、3間盤以下）的惡性腫瘤來(lái)說(shuō)，外科切除后無(wú)需重建。高位骶骨（骶2、3間盤以上）惡性腫瘤切除后需重建骶髂關(guān)節(jié)連續(xù)性[201]。也有其他研究支持這一結(jié)論[196,202]。

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