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胃肠道间质瘤诊断和治疗进展前言胃肠道间质肿瘤（GastrointestinalStromalTumor，GIST）是一种发生在胃肠道的最常见的间叶性肿瘤。近来，因其作为对于其组织发生、分化、生物学行为、治疗及预后等诸多方面是目前研

究的热点。前言GIST是胃肠道间叶源性肿瘤（GastrointestinalMesenchymalTumorGIMT）最常见的一种约占GIMT的70％；而GIMT是指胃肠道所有非淋巴非上皮的软组织肿瘤。历史回顾1983年以前发生在胃肠道间叶来源的

肿瘤，一般都被认识为是平滑肌肿瘤、平滑肌肉瘤、平滑肌母细胞瘤、上皮样平滑肌瘤。历史回顾1983年Mazur和Clark研究发现这类肿瘤缺乏平滑肌细胞和雪旺细胞的超微结构和免疫表型的特征，可以用更一般的名称“间质瘤”（“stromaltumor”）来命名这些分化方向难以明确的肿瘤，即胃肠道间质瘤（

gastrointestinalstromaltumor，GIST）历史回顾20世纪末Mikhael等（1994）、Miettinen等（1995）证实CD34抗原免疫组化标记可将GIST与真正平滑肌瘤和雪旺瘤分开。Maeda等（1992）和Hulzlnga等（1995）证实肠道C

ajal间质细胞（ICC）和肠道起搏点激活需要c-kit基因的参与.历史回顾20世纪末Hirota等（1998）发现人GIST中存在c-kit基因功能获得性突变和CD117蛋白的特异表达，补充了GIST的概念.R

indlom等（1998）发现GIST显示胃肠道Cajal间质细胞相同的表型，认为GIST可能起源于Cajal间质细胞.肿瘤起源随着对GIST研究和认识进一步深入，大多数学者都趋向于GIST的起源可能

是Cajal间质细胞（ICC）和可能起源于向ICC分化的幼稚间充质干细胞。概念目前认为胃肠道间质瘤（GIST）是指那些具有频发性c-kit基因突变并且表达CD117蛋白，组织学上以富于梭形细胞、上皮样细胞偶或多形性细胞，束状或弥漫性排列为特征的胃肠道间叶源性肿瘤。GIST的一般特征发病率GIST

的发病率约为1-2/10万人–胃恶性肿瘤的2.2%–小肠恶性肿瘤的13.9%–结直肠恶性肿瘤的0.1%（NCI’sSEERdata，1995）美国临床上检测到新病例从原来估计的300-500例/年已上升到5000-6000例/年中国每年的发病人数在2—3万之间，主要发生在中老年人性别、年龄性别

男性略多或男女相等年龄高峰年龄55-65岁，中位年龄为60岁，40岁以下少见，20岁以下罕见发生部位85%位于消化道：–胃50—60%–小肠20—30%–结直肠及食管<10%胃肠道以外：–肠系膜、网膜、后腹膜以及胆囊、膀胱等（约占GIST的4%）。临床表现早期无症状,往往被偶尔发现（约占2

1％）常见症状（69％因症状就医）-腹痛-腹部肿块（有症状6cm，无症状1.5cm）-胃肠道出血-梗阻常见转移部位：肝脏，偶有腹腔播散大体形态肿瘤大小不一，境界清楚，但无包膜肿瘤大多位于肌壁间（66%），少数位于浆膜层（26%），可附于胃肠的

外表面、或位于粘膜下（8%），可向腔内突起呈息肉状胃部小病灶在粘膜下部可有溃疡、胃壁内和浆膜小结节。稍大肿瘤可突入胃腔内，浆膜外的大肿块直接浸润胰腺和肝脏。大体形态良性行为的肿瘤通常≤2cm，结节状，质坚实，切面灰白色，均一。恶性

行为的肿瘤通常＞5cm，可浸润周围组织或粘连，粘膜溃疡形成，质较软，切面灰白，灰红或暗褐色，可见出血、坏死和囊性变电子胃镜观察电子胃镜观察粘膜下切开肌壁间切开肠管浆膜外切开腹腔播散组织学分化按起组织分化途径的差异可向以下四方面分化:1.平滑肌分化为主型的肿瘤.2.神经源分化为主型的肿瘤.3.双

向分化型的肿瘤.4.不向平滑肌分化也不向神经源分化的肿瘤.组织细胞学类型梭形细胞型(70%)上皮样细胞型20%混合细胞型梭形细胞型（占70%）一致的梭形细胞组成，胞浆淡嗜酸性，合体状，胞界不清，呈束状或漩涡状，甚至栅栏状排列。核大小较一致，多呈卵圆形，较平

滑肌细胞核短，染色质呈泡状。约5%的病例梭形细胞可见核旁胞浆小泡（胃中更明显）。胶原数量少，管型血管较多，间质常见出血。上皮样细胞＜10%，多见于结、直肠上皮样细胞型（占20%）上皮样细胞＞50%，少见。多发生于胃由数量不等嗜酸

性或透明胞浆的圆形细胞组成，有时见胞浆中类似嗜酸性包涵体样物，瘤细胞核圆至卵圆形，一致性泡状染色质。瘤细胞更倾向于巢状排列，易误为上皮性肿瘤或黑色素瘤。混合细胞型由梭形细胞区和上皮样细胞区组成，或由一种“中间型”卵圆形细胞组成。上皮样细胞10-50%，少见。见于胃、小肠

GIST的免疫组化表型抗体名称阳性率阳性着色部位CD11796.0（100）胞浆弥漫强CD3477.2（60-70）胞浆弥漫强α-SMA22.3（30-40）胞浆局灶弱desmin2.2（＜5）胞浆局灶弱S-10017.5（10）胞浆局灶弱MSA17.

9（-）PGP9.512.5（-）H-caldesmin-（80）Calponin-（25）GIST中CD117的表达梭形细胞上皮样细胞GIST中CD34的表达梭形细胞上皮样细胞栅栏状排列印戒样细胞核端空泡细胞片巢状排列GIST诊断新共识GIST诊断新标准胃肠道梭形细胞病灶CD1

17阳性和CD34阳性GIST胃肠道梭形细胞肿瘤的鉴别CD117CD34SMAdesminS-100GIST++（60-70%）+（30-40%）很罕见+5%平滑肌肿瘤-+（10-15%）++罕见神经源性肿瘤----+纤维瘤病+罕

见GIST的生物学行为上海朱雄增研究表明；CD34阳性表达与GIST的部位有关，小肠阳性率为42.9%，食管和直肠阳性率分别为100%和96.8%,胃为88.5%。GIST的生物学行为最近有研究报道显示：GIST可恒定表达巢蛋白（nestin)

,敏感性高于CD34,这样可能对GIST鉴别诊断有提供新的依据。GIST的生物学行为最近有研究报道显示：GIST可较特异表达波形蛋（Vimestin),几乎100%表达,但缺乏良恶性的差异,这样可能对GIST鉴别

诊断有提供新的依据。GIST的生物学行为至今尚无可靠的指标预测GIST的生物学行为，许多学者推荐依据肿瘤大小和核分裂数来估计转移的危险性，并认为至少在目前使用“良性”GIST这一术语是不明智的.有些学者认为尽管偶有例外

，依据肿瘤大小、核分裂数和其它一些指标，可以将肿瘤区分为良性、恶性和不确定或低度恶性潜能三类.确定GIST侵袭行为危险性方案危险程度大小核分裂数很低＜2cm＜5/50HPF低2-5cm＜5/50HPF中等

＜5cm5-10cm6-10/50HPF＜5/50HPF高＞5cm＞10cm不计＞5/50HPF不计＞10/50HPFGIST良恶性与肿瘤大小、核分裂数可能良性–肠：最大直径≤2cm和核分裂数≤5/50HPF–胃：最大直径≤5cm和核分裂数≤5/50HPF恶性–肠：最大直径＞5cm

或核分裂数＞5/50HPF–胃：最大直径＞10cm或核分裂数＞5/50HPF不能确定或低度恶性潜能–肠：最大直径2-5cm和核分裂≤5/50HPF–胃：最大直径5-10cm和核分裂数≤5/50HPF恶性指征腹膜播散和肝转移肌层、粘膜和

/或周围组织浸润脉管浸润或瘤栓形成肿瘤性坏死最大直径＞10cm核分裂数＞10/50HPF细胞密集、明显异型瘤细胞围绕血管簇状分布良性指征最大直径＜2cm肿瘤境界清楚细胞欠丰富核分裂不易找见往往其它手术时偶尔

发现潜在恶性指征与周围组织粘连最大直径≥5cm，但＜10cm（胃间质瘤>5.5cm，肠间质瘤>4cm)核分裂数＜10/50HPF其他相关因素年龄、性别、腹部不适、消化道出血、病程、肿瘤生长方式、溃疡出血、囊变等指标在良恶性判断

上无参考价值。也有人建议把PCNA和P53蛋白性表达也作为GIST是否潜在恶性的判断指标。诊断术语比较过去现在食管平滑肌瘤平滑肌肉瘤大多真正平滑肌瘤大多GIST，少数平滑肌肉瘤胃平滑肌（肉）瘤平滑肌母细胞瘤大多GIST，极少数平滑肌瘤上皮样GIST小肠平滑肌肉瘤

大多GIST诊断术语比较过去现在结直肠平滑肌瘤平滑肌肉瘤仅累及粘膜肌层小肿瘤为真正平滑肌瘤女性结直肠外的有些肿瘤为子宫型平滑肌瘤（ER+、PR+）大多数腔内肿瘤为GIST，极少数真正平滑肌瘤大多GIST，少数真正的平滑肌肉瘤诊断术语比较过去现在胃肠道自主神经瘤（GNAT）是具有神经分泌颗

粒的GIST变型网膜和肠系膜平滑肌（肉）瘤大多EGIST，少数真正平滑肌肉瘤腹膜后平滑肌肉瘤约1/3EGIST治疗现状胃肠间质瘤1/3以上表现为恶性胃肠道外间质瘤大多数为交界性和恶性胃肠间质瘤的5年生存率为28~80%预后差的原因为复发或转移治疗外科手术是GIST的主要治疗手段

—5年生存率50％—65%—术后复发或转移率高，可能10年后复发，长期无病生存率<10%(MDAnderson癌症中心191例肿瘤<5cm手术完全切除）—完全切除后治愈率10％—35％治疗不能完全切除----中位生存期10-23月，复发转移者-----中位生存期12-19月。化疗及放疗GIST

对化疗不敏感—缓解率：<10%—对生存期无益处GIST对放疗不敏感—缓解率：<5%EffectiveoraldrugwithlowtoxicityprofileVandenAbbeele.Baueretal.预后差的原因为复发或转移Ob

jectives:Primary:OSonimatinibmesylateinadjuvantsetting18FDG-PETcanbeusedtoassesscontinuingresponsetothera

pydespitepersistentCTabnormalitiesandtodetectrecurrence最近有研究报道显示：GIST可恒定表达巢蛋白（nestin),敏感性高于CD34,这样可能对GIST鉴别诊断有提供新的依据。2001;344:1052.

格列卫推荐用量400mg/d或600mg/d*vanOosterometal.GIST的分子靶向治疗靶点：受体酪氨酸激酶c-Kit(CD117)新药：格列卫（Glevic,Gleevec；甲磺酸伊马替尼，伊马替尼，lmatinib；

ST1517,57148B)美国FDA2002年2月批准用于GIST治疗机理：细胞信号抑制剂伊马替尼化学名：4-[(4-甲基-1-哌嗪基）甲基]-N-[4-甲基-3-[4-(3-吡啶基）-2-嘧啶基]-苯基]苯甲酰胺甲磺酸酯GIST患者c-kit基因突变格列卫®作用机制格列卫®作用于c-Kit,

Bcr-Abl,和PDGF-R酪氨酸激酶区的特定部位格列卫®作用机制—格列卫®结合在c-Kit上正常情况下ATP所在部位—格列卫®阻断c-Kit激活的信号转导通道体外实验：抑制GIST细胞增殖格列卫治疗首例病案肝脏和上腹部多发转移18FDG在转移病灶处浓聚伊马替尼治疗

4周后18FDG的摄取吸收显著减少JoensuuHetal.NEnglJMed.2001;344:1052-1056.II期临床试验两个剂量组疗效无显著差异临床II期研究：确认最佳缓解率GeorgeD.NEJM.2002;7:472-479.CT扫描结果：肿瘤体积缩小2000年6月27日200

0年10月4日伊马替尼治疗前伊马替尼治疗后CT与PET扫描比较2000年7月3日2000年10月5日伊马替尼治疗前伊马替尼治疗后不良反应Drug2003,63(5):513不良反应（任何级别、3～4级）常见：水肿/水钠潴留（74%、21

%)恶心（52%、1.4%)腹泻（45%、2%)乏力（35%、0%)少见：皮炎、皮疹、腹痛特殊：肿瘤相关出血（5%)两个剂量组不良反应无显著差异II期临床试验结论格列卫是第一个有效治疗GIST的药物：—40%部分缓解率（PR)—41%疾病稳定率（SD)格列卫治疗GIST安全性可接受格列卫推荐

用量400mg/d或600mg/d**依照各地使用剂量规定调整进行中的临床试验1、美国外科医生学院肿瘤组（AmercianCollegeofSurgeonsOncologyGroup,ACOSOG)2001年开始对GIST高危险复发的患者完全切除后用Glivec辅助治疗（

II期试验）条件：直径≥10cm、肿瘤破裂、腹腔出血、腹腔多发病灶（<5个）用药：术后400mgqd×12月目的：明确用Glivec辅助治疗能否将5年生存率提高50%以上进行中的临床试验2、美国外科医生学院肿瘤组（ACOSOG)——随机试

验用上述剂量：对直径≥3cm者，随机分试验组：400mgqd×12月对照组：安慰剂目的：能否降低死亡危险率35%以上（降低40%相当79%2年生存率）进行中的临床试验3、放疗肿瘤组能切除的GIST（原发或复发）服用Glivec600mgqd×4周，如

有效则继续服用4周，然后手术切除，术后2～4周再服24个月：术前Glivec600mgqd×4周有效无效600mgqd×4周手术切除手术切除600mgqd×24周2～4周III期临床试验（进行中）两项III期试验：入组1700例初步疗效：RR53.7%

（CR5%)SD27.9%1年生存率80%建议推荐治疗模式GIST能切除者：手术＋伊马替尼GIST不能切除者：伊马替尼治疗＋手术＋伊马替尼治疗GIST广泛转移者：伊马替尼治疗建议推荐治疗剂量400～600mg

/d,治疗时间不少于4个月。GIST诊治进展小结GIST是一种免疫表型上表达c-kit蛋白（CD117）、遗传学上存在频发性c-kit基因突变、组织学上以富于梭型和上皮细胞呈束状或弥漫性排列为特征的胃肠最常见的间叶源性肿瘤.GIST诊治进展小结CD117和CD34是检测确诊G

IST的关键环节.依据肿瘤是否表达c-kit可作为GIST与胃肠道其他间叶肿瘤（平滑肌瘤、平滑肌肉瘤、神经鞘瘤和神经纤维瘤等）的鉴别诊断。GIST诊治进展小结GANT表达c-kit蛋白，存在c-kit基因突变，形态学相识于GIST，故可视为具有神经内分泌颗粒的

GIST变型。GIST诊治进展小结依据肿瘤的大小、生长方式、瘤细胞异型性、核分裂和肿瘤性坏死等大体和镜下表现，可对大多数GIST生物学行为作出正确判断。GIST诊治进展小结GIST治疗模式是以手术＋伊马替

尼为主的综合治疗伊马替尼使GIST治疗进入分子靶向治疗时代GIST诊治进展小结伊马替尼是目前治疗转移性、不能切除胃肠间质瘤的有效手段，推荐剂量400mg/d伊马替尼的耐药性、治疗时机和时间、完全缓解（CR）率低、能否用于术后辅助治疗、联合

用药提高疗效等问题尚待研究GIST诊治进展小结伊马替尼治疗GIS的总的有效率经过大量病例验证在81％左右。手术是胃肠道间质病主要和首选的治疗手段。淋巴结清扫不提倡GIST诊治进展小结间质瘤扩大切除的切缘，具体数值病没有统一的标准，因此建议手术中根据肿瘤大小、性质、部位、年龄及全身状况综合考虑后确

定手术切缘和切除范围。联合脏器切除不提高生存率GIST诊治进展小结胃肠道间质瘤常有内何包膜，具有在一定的张力、易破溃，建议在手术原则上不主张瘤体触摸探查。如认为可以切除，即行非接触性手术切除，避免腹腔内种植转移

。GIST诊治进展小结常见的复发和转移部位使腹腔和肝脏，不在单个可以切除的复发转移病灶，仍推荐再次手术。但文献报道再次手术不提高生存，因此再次手术只限于解除急症和减少肿瘤负荷，价值有限。GIST诊治进展小结对于恶性肿瘤能评价肿瘤高危险度的间质患者

建议术前服用格列卫辅助治疗，对于复发转移或者无法手术切除的间质瘤患者也推荐首选格列卫治疗。尚未解决存在问题药物的最佳剂量和疗程辅助及分析辅助治疗药物的耐药问题手术的地位和价值等等尚须进一步探索和总结ImatinibMe

sylateinGIST:ClinicalEfficacyFirstPatientWithGISTtoReceiveImatinibMesylate:Proof-of-Concept•Exploratorystud

ywithasinglepatientwithoralimatinibmesylateat400mg/d•Dramaticclinicalresponse–Disappearanceofexcessmetabolicactivityat4weeksby1

8FDG-PET–75%reductionintumorsizeat8-monthfollow-up–Tumorbiopsiesshowedhistologicevidenceofmyxoiddegenerationandlackofmitotica

ctivity–SymptomaticreliefJoensuuetal.NEnglJMed.2001;344:1052.Joensuuetal.NEnglJMed.2001;344:1052.Copyright©2001MassachusettsMed

icalSociety.Multipleliverandupperabdominal18FDG-accumulatingmetastasesAmarkeddecreasein18FDGuptake4weeksafterstartingimatinibmesylate(400mg/d)E

ORTCPhaseIStudyofImatinibMesylateinGISTandOtherSarcomas:StudyDesignvanOosterometal.Lancet.2001;358:1421.vanOosterometal.Eu

rJCancer.2002;38(suppl5):S83.Objectives:Primary:EstablishMTDforimatinibmesylateSecondary:SafetyandtolerabilityD

eterminetheactivityofimatinibmesylateinGISTandnon-GISTsarcomasusingradiologic(18FDG-PET),hematologic,andbiochemicalmeasurementsTreatment:Imatinibmesy

lateadministeredat400mg/d,dosesincreasedby200mg/dupto1000mg/dInclusion:Soft-tissuesarcoma(KIT-positivehistologic

stainingforGISTdiagnosis)Evidenceofprogression<6weekspriortotrialstartChemotherapydiscontinued4weekspriortotrialst

art•90%ofpatientshadconfirmedKIT-positiveGIST•75%ofpatientshadmetastasesintheliver•60%ofpatientshadreceivedpriorc

hemotherapyvanOosterometal.Lancet.2001;358:1421.vanOosterometal.EurJCancer.2002;38(suppl5):S83.Timetotumorresponse=1wee

kafterfirstimatinibmesylatetherapyDLT=1000mg/d(in5of40patients);MTD=400mgbidvanOosterometal.Lancet.2001;358:1421.vanOosteromet

al.EurJCancer.2002;38(suppl5):S83.20406080100PartialresponseStablediseaseProgressivedisease51%31%8%0Percent•Atarangeofdosesfrom

400-1000mg/d,800mg/distheMTD•ImatinibmesylatehassignificantactivityinpatientswithadvancedGIST(n=35),butlittleornoactivityinnon-GISTpatientsEORTCPhase

ITrial:ConclusionsvanOosterometal.Lancet.2001;358:1421.Objectives:Primary:ResponseratewithimatinibmesylateinpatientswithGISTSecondary:Pharma

cokineticprofileTimetotreatmentfailureSurvivalSafetyandtolerabilityTreatment:Imatinibmesylateadministeredateither400or600mg/dtocontinueaslongasbe

nefit;crossoverallowedfrom400to600mg/dafterdiseaseprogressionInclusion:HistologiccriteriaofGISTwithKIT-positives

tainingconfirmedbycentralpathologyreviewMetastaticand/orunresectablediseaseNoconcomitanttherapyfordiseaseImatinibMesylateinGIST:PivotalPhaseIIT

rialStudyDesignDemetrietal.NEnglJMed.2002;347:472.ConfirmedObjectiveResponsesImatinibMesylateinGIST:EvolutionofTumorResponsesOverTime010203

04050607049589(Demetrietal)626515(vonMehrenetal)400mg/d(n=73)600mg/d(n=74)%ofpatients33437(ImatinibmesylatePI)676634(Blankeetal)Gleevec®(imati

nibmesylate)PI.Demetrietal.NEnglJMed.2002;347:472.vonMehrenetal.ProcAmSocClinOncol.2002;21:403a.Abstract160

8.Blankeetal.ASCO2004GastrointestinalCancersSymposium.Abstract2.Medianfollow-up(mo)ImatinibMesylateinGIST:Piv

otalTrial—Conclusions•147patientsrandomizedto400or600mg/d•83%ofpatientsshowedaclinicalbenefit–67%PR/CR–16%stabledisease(SD

)•Mediantimetoprogression(TTP)was84weeks•Medianoverallsurvival(OS)hasnotbeenreachedatmedianfollow-upof

34months•ImatinibmesylatehasanacceptablesafetyprofileinpatientswithGISTBlankeetal.ASCO2004GastrointestinalCanc

ersSymposium.Abstract2.Gleevec®(imatinibmesylate)PI.Drukeretal.NEnglJMed.2001;344:1031.ImatinibMesylateIndicatio

n•IndicateddoseforpatientswithKIT-positive,unresectableormetastaticmalignantGISTis400or600mg/d•400mg/d

effectsameanplasmaconcentrationofimatinibmesylateof1.46µM•Imatinibmesylateshouldbetakenwithfoodandalargeglassofwaterto

minimizeGIirritationImatinibMesylateinGIST:EORTCPhaseIITrial•TrialincludedpatientswithGISTorothersofttissuesarcoma

s(STS)•Patientswereadministeredimatinibmesylate400bid(800mg/d)•InGISTpatients–Trialachievedanoverallresponserate(ORR)of71%,with18%SD–Aft

er1year,73%ofGISTpatientswereprogression-free•InSTSpatients–NoORR;medianTTPwas58daysVerweijetal.EurJCancer2003;3

9:2006.PhaseIIITrials(EORTC62005andUSIntergroupS0033):StudyDesignObjectives:Primary:PFS400mgvsPFS800mgSecondary:ORRSafetyandtole

rabilityTreatment:Imatinibmesylateadministeredat400mg/dor400mgbid(800mg/d);crossoverfrom400to800mg/dafterdiseaseprogression(PD)Inclusion:Presentwi

thmetastaticorunresectableKIT-positiveGISTMeasurableornonmeasurablediseasePriorchemotherapyallowedRankinetal.

ProcAmSocClinOncol.2004;23:815.Abstract9005.Verweijetal.ProcAmSocClinOncol.2003;22:814.Abstract3272.PhaseIIIStudy(EORTC62005):1-YearEstimate

dPFS6469020406080100PFS%ofpatientsImatinibmesylate400mg/d(n=461)Imatinibmesylate800mg/d(n=462)Verweijetal.ProcAmSocClinOncol.2003;

22:814.Abstract3272.CurrentestimateofPFSdifferenceHazardratio=0.78ExtrapolatedmediandifferenceatmedianPFS=8%(50%vs58%)PhaseIIISt

udy(EORTC62005):Efficacy(InterimAnalysis)5.644.732.79.83.947.233.36.90102030405060CRPRSDPD%ofpatientsImat

inibmesylate400mg/d(n=461)Imatinibmesylate800mg/d(n=462)Verweijetal.ProcAmSocClinOncol.2003;22:814.Abstract3272.PhaseIIIStudy(EORTC6200

5):EfficacyFollowingCrossoverto800mg/d02.530.366.40.8010203040506070CRPRSDPDNotevaluable%ofpatientsZalc

bergetal.ProcAmSocClinOncol.2004;23:815.Abstract9004.n=119PhaseIIIStudy(USIntergroupS0033):2-YearEstimated

PFSandOS47765272020406080100PFSOS%ofpatientsImatinibmesylate400mg/d(n=350)Imatinibmesylate800mg/d(n=351)P=0.13P=0.87Rankinet

al.ProcAmSocClinOncol.2004;23:815.Abstract9005.PhaseIIIStudy(USIntergroupS0033):Efficacy34527253452626010203

0405060CRPRSDNR%ofpatientsImatinibmesylate400mg/d(n=350)Imatinibmesylate800mg/d(n=351)NR=noresponse.Rankinetal.ProcAmSocClinOnco

l.2004;23:815.Abstract9005.PhaseIIIStudy(USIntergroupS0033):EfficacyFollowingCrossoverto800mg/d063248130102

030405060CRPRSDPDAssessmentinadequate%ofpatients*Evaluablepatients.Rankinetal.ProcAmSocClinOncol.2004;23

:815.Abstract9005.n=77*ImatinibMesylateinGIST:PhaseIIITrials•TrialsincludedpatientswithmetastaticunresectableGIST•Patientsreceiv

edimatinibmesylate400or800mg/d•EORTCtrialresults–NosignificantdifferencebetweendosesinORR(50.3%vs51.1%)–Possiblesig

nificantadvantageinPFSat800mg/d(P=0.0216)•Intergrouptrialresults–DosessimilarinconfirmedORR(both48%)and2-yearPFS(47%vs52%,P=0.13)Rankinetal.ProcA

mSocClinOncol.2004;23:815.Abstract9005.Verweijetal.ProcAmSocClinOncol.2003;22:814.Abstract3272.%ofpatientsMonthsafterrandomization161

4121086420100806040200Stoptherapy(n=25)MedianPFS:6monthsContinuoustherapy(n=23)P=0.0001GIST:Discontinuati

onofImatinibMesylateIncreasestheRiskofProgression(BFR14)•Patientswhoachievedclinicalbenefitafter12monthswer

erandomizedtocontinueortostopimatinibmesylatetherapy•RandomizationhasbeensuspendedBlayetal.ProcAmSocClinOncol.2004;23:815.Abstract9006.Ne

oadjuvantImatinibMesylateTherapyforGIST:Rationale•Fewcompleteresponseswithimatinibmesylatetherapy–Mostre

spondinglesionshaveviablecells•Cytoreductionmayimprovesurgicaloutcomes•PotentialtoincreaseresectabilityorreducetheextentofsurgeryEisenberg

andvonMehren.ExpertOpinPharmacother.2003;4:869.EisenbergandJudson.AnnSurgOncol.2004;11:465.AdjuvantImatinibMesylateT

herapyforGIST:Rationale•Highrecurrenceratesespeciallyforhigh-riskGIST•Effectiveoraldrugwithlowtoxicityprofile•M

ayhaveefficacyinlow-volumemicroscopicdisease•ACOSOGdesigned2adjuvanttrials–Highrisk,nonrandomized(completedaccrual)–Intermediatetohighrisk(op

en)EisenbergandvonMehren.ExpertOpinPharmacother.2003;4:869.EisenbergandJudson.AnnSurgOncol.2004;11:465.GIST:SelectedOngoin

gClinicalTrialsintheAdjuvantandNeoadjuvantSettingsTrialNPhaseRegimenSettingPrimaryEndPointStatus*ACOSOGZ900089III

matinibmesylate400mg/dAdjuvantOSCompletedaccrualACOSOGZ9001380IIIImatinibmesylate400mg/dvsplaceboAdjuvantOSRecruitingRTOGS-013263IIImatinibmesylate6

00mg/dNeoadjuvant/adjuvantPFSRecruiting*AsofJanuary30,2004.EisenbergandvonMehren.ExpertOpinPharmacother.2003;4:869.EisenbergandJudson.AnnSurgOnco

l.2004;11:465.PhaseIITrial(ACOSOGZ9000):StudyDesignObjectives:Primary:OSonimatinibmesylateinadjuvantsettin

gSecondary:2-and5-yearrecurrenceToxicityinadjuvantsettingTreatment:Imatinibmesylate400mg/dInclusion:Hig

h-riskGISTSurgerywithin70dayspriortoregistrationKIT-positiveGISTImatinibmesylate–naiveNoprioradjuvantth

erapyPhaseIIITrial(ACOSOGZ9001):StudyDesignObjectives:Primary:OSwithimatinibmesylateinadjuvantsettingrelativetoplaceboSecondary:Recur

rence-freesurvivalSafety/efficacyinadjuvantsettingTreatment:Imatinibmesylateadministeredat400mg/dInclusion:3

cmGISTSurgerywithin70dayspriortoregistrationKIT-positiveGISTImatinibmesylate–naiveNoprioradjuvanttherapyPhaseIITrial(RTO

GS-0132):StudyDesignObjectives:Primary:PFSwithimatinibmesylateinadjuvantsettingSecondary:ResponserateinneoadjuvantsettingCompareCTandPETresponsesin

neoadjuvantsettingSafetyinadjuvantsettingTreatment:Imatinibmesylate600mg/dInclusion:PresentwithKIT-positivemalignant

GISTImatinibmesylate–naiveNopriortherapy28daysbeforeentryClinicalEfficacy:Summary•Imatinibmesylatehasprovenclinicalefficacyinunresectableormetastati

cGIST–Imatinibmesylateistheonlyapprovedtherapyeffectiveintreatingmetastatic,unresectableGIST–Imatinibmesylateineffectat400and800mg/d–800-mg/ddosewasa

ssociatedwithPFSinoneongoingphaseIIItrial•Discontinuationofimatinibmesylatefollowingresponseincreasesthelikelihoodofprogres

sion•Efficacyofimatinibmesylateisunderinvestigationintheadjuvantandneoadjuvantsettings–PhaseII/IIItrialsareongoingPatientManagementGIST:PatientFlow•M

ultidisciplinaryteamsneededtooptimizecare•Pathologistandradiologistinvolvementensurescorrectdiagnosisandrespo

nseevaluation•Patienteducationaboutmalignantpotentialkeyforadequatefollow-upPCP=primarycarephysician.GI=gastroenterologist.Demetrietal.JNCCN.20

04;21(suppl1):S1.PCPSurgeonGIMedicaloncologistPathologistRadiologistGastrointestinalStromalTumors(GIST)Version1.20

04Version1.2004©2004NationalComprehensiveCancerNetwork,Inc.Allrightsreserved.Theseguidelinesandthisillustra

tionmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.Neoadjuvanttherapynotconsidere

dResectmassVersion1.2004©2004NationalComprehensiveCancerNetwork,Inc.Allrightsreserved.Theseguidelinesandthisillustrationmayno

tbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.Version1.2004©2004NationalComprehensiveC

ancerNetwork,Inc.Allrightsreserved.Theseguidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpe

rmissionofNCCN.Version1.2004©2004NationalComprehensiveCancerNetwork,Inc.Allrightsreserved.Theseguidelinesandthisillustrationmaynotbereproducedinany

formwithouttheexpresswrittenpermissionofNCCN.Version1.2004©2004NationalComprehensiveCancerNetwork,Inc.Allrightsreserved.T

heseguidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.Version1.2004©2004Nationa

lComprehensiveCancerNetwork,Inc.Allrightsreserved.Theseguidelinesandthisillustrationmaynotbereproducedinanyform

withouttheexpresswrittenpermissionofNCCN.Version1.2004©2004NationalComprehensiveCancerNetwork,Inc.Allrightsreserved.Theseguidelinesandthisillustrati

onmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.Version1.2004©2004NationalComprehensiveCancerNetwork

,Inc.Allrightsreserved.Theseguidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermis

sionofNCCN.Version1.2004©2004NationalComprehensiveCancerNetwork,Inc.Allrightsreserved.Theseguidelinesandthisillustrationmaynotbereproducedi

nanyformwithouttheexpresswrittenpermissionofNCCN.Version1.2004©2004NationalComprehensiveCancerNetwork,Inc.Allrightsreserved.Thesegui

delinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.Version1.2004©200

4NationalComprehensiveCancerNetwork,Inc.Allrightsreserved.Theseguidelinesandthisillustrationmaynotbereproducedinany

formwithouttheexpresswrittenpermissionofNCCN.Version1.2004©2004NationalComprehensiveCancerNetwork,Inc.Allrightsreserved.T

heseguidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.Follow-UpImaging:NCCNGuidel

ine•PostsurgicalCTperformedevery3-6monthsfor5years,thenannually–Lessfrequentfollow-upappropriateforpatientsw

ithverylowriskGIST•Tumorresponsetoimatinibmesylatetherapycanbeevaluatedafter–1month(CT)–1-2weeks(18FDG-PET)Demetrietal.JNCCN.2004;21(suppl1)

:S1.GIST:ManagementofHemorrhage•SpontaneoushemorrhageoccursinGIST•Bleedingmaybeassociatedwithorbeaconsequenceofresponse•Patientsneedtob

eevaluatedforbleedingaftersurgeryorimatinibmesylate,especiallyifsevereanemiaorabdominalpainoccurs•Vigilantpatientmanagementisrequired,especiall

yduringimatinibmesylatetherapyGleevec®(imatinibmesylate)PI.Demetrietal.JNCCN.2004;21(suppl1):S1.GIST:DurationofTreatment•Durationoftreatment

withimatinibmesylateisconsideredtobelife-long•Adjuvantimatinibmesylatetherapymayhavearoleinpreventingrecu

rrence•Discontinuationofimatinibmesylatetherapycouldleadtoacceleratedtumorgrowth•Focalresistancetoimatinibmesylatethera

pycandevelopinspecificlesions–Considerresectionofprogressinglesions–Imatinibmesylatediscontinuationisn

otrecommendedoutsideofatrialDemetrietal.JNCCN.2004;21(suppl1):S1.GIST:MechanismsofPotentialResistancetoImatinibMesylate•Resi

stancecanbeprimaryorsecondary(followinginitialresponse)•Mechanisms–Imatinibmesylate–resistantmutationsinKITorP

DGFRAkinasedomain–KITorPDGFRAgeneamplification–Activationofalternativekinase•Resistancemaybeevidencedasprogr

essionofsomelesionsbutnotothers–FocalvsgeneralvsnovelresistanceFletcheretal.ProcAmSocClinOncol.2003;22:81

5.Abstract3275.GIST:ManagementofResistance•Ifthemajorityoftumoriscontrolledbyimatinibmesylate,thencontinu

etherapy•Doseescalationupto800-1000mg/d•Surgicalresectionofprogressingsitesifpossible•OthertrialsDemetrietal.JNCCN.2004;21(

suppl1):S1.ResistancetoImatinibMesylate:RecognitionofClonalEvolutionCourtesyofDr.G.D.Demetri.Pretreatment6months10monthsIm

atinibMesylateinGIST:FocalResistanceFollowingResponseCourtesyofDr.R.DeMatteo.Completedisappearanceofallmeasurableande

valuabledisease,confirmedat4weeksCourtesyofDr.—术后复发或转移率高，可能10年后复发，长期无病生存率<10%(MDAnderson癌症中心191例肿瘤<5cm手术完全切除）Imatinib

MesylateinGIST:RapidResponseinLiverMetastasisExploratorystudywithasinglepatientwithoralimatinibmesylateat

400mg/dGIST:MechanismsofPotentialResistancetoImatinibMesylateDecreaseincontrastenhancementoftumors(vonMehrenetal)

2002;347:472.TheseguidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PhaseIIISt

udy(EORTC62005):Efficacy(InterimAnalysis)ImatinibMesylateforNonresectableandMetastaticGIST:CaseStudy(cont’d)Allrightsreserved.2、美国外科医生学院肿瘤组（AC

OSOG)目的：明确用Glivec辅助治疗能否将5年生存率提高50%以上Joensuuetal.Onlythelargestdiameterismeasured2004;23:815.GIST:Detecting

RecurrentDiseasebyCT•Developmentofanewlesionatthesiteofpriorresectionofaprimarytumor•Detectionofintratumoralnoduleswithintumorsun

dertreatment•Developmentofmetastaticlesions•IncreaseintumorsizeDemetrietal.JNCCN.2004;21(suppl1):S1.On

therapy17daysafterdiscontinuationCourtesyofDr.A.D.VandenAbbeele.GIST:18FDG-PETFlaresAfterImatinibMesylate

Discontinuation•Imatinibmesylatetherapyshouldbecontinuedifthemajorityofthetumorburdenisundercontrol•Rapiddiffusew

orseningofGISTmayoccurifimatinibmesylateisstoppedResponseEvaluationObjectiveResponsesinSolidTumors•Thetraditionalresponsecriteriaarebasedontumorsi

ze–RECIST:UsedinphaseIandIIIclinicaltrialsofimatinibmesylateinGIST–SWOGcriteria:UsedinthepivotaltrialofimatinibmesylateinGIST(B2222)vanOoster

ometal.Lancet.2001;358:1421;Demetrietal.NEnglJMed.2002;347:472;Rankinetal.ProcAmSocClinOncol.2004;23:815.Abstract9005;Verweijetal.ProcAmSocCli

nOncol.2003;22:814.Abstract3272.ResponseEvaluationCriteriainSolidTumors(RECIST)MeasurableDiseaseCRPRSDNeitherPRno

rPDPD20%increaseoversmallestsumobserved,ortheappearanceofnewlesionsLesionsthatcanbemeasuredinatleast1dimension:–Theminimalsizeofthelesionshould

benolessthandoubletheslicethicknessofCT–Onlythelargestdiameterismeasured30%decreasefrombaselineofthesumoftheindividualmeasurement

s,confirmedat4weeksCompletedisappearanceofalltargetlesions,confirmedat4weeksTherasseetal.JNatlCancer

Inst.2000;92:205.MeasurableDiseaseCRPRSDNeitherPRnorPDPD50%increaseofallmeasurablelesions,orworseningfrompreviousassessment,orreappearanc

eoflesionLesionsthatcanbemeasuredin2dimensions,withbothdiameters2cm,byimagingscanorbypalpation50%decreasefrombaselineofth

esumoftheproductsofperpendiculardiameters,confirmedat4weeksCompletedisappearanceofallmeasurableandevaluabledisease,confirmedat4weeksSouthwestOncol

ogyGroup(SWOG)CriteriaGreenandWeiss.InvestNewDrugs.1992;10:239.ImatinibMesylateinGIST:RapidResponseinPrimaryTumorPre-imatinibmes

ylate4weeksofimatinibmesylateCT18FDG-PETCourtesyofDr.G.D.DemetriandDr.A.D.VandenAbbeele.ImatinibMesylateinGIST:RapidResponse

inLiverMetastasisCourtesyofDr.G.D.DemetriandDr.A.D.VandenAbbeele.Pre-imatinibmesylate4weeksofimatinibmesylateCT18FDG-PETGIST:Issue

sWithConventionalResponseEvaluation•IssueswithRECISTinGIST–Tumorshrinkagemayevolveslowly–Mayunderestimateoverallclinicalbenefit–GISTcane

xhibitfocalprogressionsevenifthemajorityofthetumorisresponding•CTusingconventionalsizecriteriamaybecomplementedby18FDG-PET

–18FDG-PETmayclarifyambiguousCTGIST:ObjectiveResponseEvaluationonCT•CTand18FDG-PETearlyintreatment–Asearlyas24hours(PET)or1month(CT)–18FDG-PETcanb

eusedtoassesscontinuingresponsetotherapydespitepersistentCTabnormalitiesandtodetectrecurrence–UseofCTearlyi

ntreatmentresponse(ie,earlierthan1month)isunderinvestigation•Tumorsizeanddensity(Hounsfieldunit[HU])onCTtogethermaybeagoodindica

torinobjectiveresponseevaluation•PromisingnewobjectiveresponseevaluationcriteriausingCTareunderdevelopmentAntochetal.JNuclMed.2004;45:357.Choieta

l.ProcAmSocClinOncol.2003;22:819.Abstract3290.Stroobantsetal.EurJCancer.2003;39:2012.GIST:SubjectiveResponseCriteriabyCT•Decreaseint

umordensity•Decreaseincontrastenhancementoftumors•Tumorsizemayremainstableorinitiallyincreasewithres

ponsetoimatinibmesylateNeedtoreevaluatethetraditionalresponsecriteriabasedsolelyontumorsizeBaselineDiseasecontrolledbyimatinibmesylateGIST:ResponseA

ssessmentbyCTUsingCriteriaOtherThanSizeAlone•DecreaseintumordensityduringimatinibmesylatetreatmentisindicativeofresponseCourtesyofDr.G.D.Demetri.C

ontrastNoncontrast•Ifonlysingle-phaseCTwithcontrastwasusedatbaseline,metastaticlesionwouldhavebeenmissed•Metastasisisclearly

seenonnoncontrastCTCourtesyofDr.H.Choi.GIST:TechnicalIssuesWithCTGIST:TriphasicImaginginCTEarlyarterialL

atearterialPortal-venousphase•Hypervascularlesionsinthelivermayescapedetectionduringportal-venousphaseimaging•Triphasicimagingi

mprovesdetection,buttimingofimagingiscritical•NoncontraststudycanbeanalternativeapproachwhentriphasicimagingisnotfeasibleCourtesyofDr.H.Choi.GIS

T:EffectsofImatinibMesylateby18FDG-PETPretreatment1monthposttreatment18FDG-PETcanproviderapidevaluationoftumorre

sponses,earlierthanCTCourtesyofDr.A.D.VandenAbbeele.GIST:AlternativePredictorsofResponsetoImatinibMesylate*Permutati

ontest.CT-BDM=CTbidirectionalmeasurements.Holdsworthetal.ProcAmSocClinOncol.2004;23:197.Abstract3011.PrognosticMetricsPValueOptimizedPET-SUVof3.4<0.

0005*NoCT-BDMgrowth<0.0005*Optimized%reductionPET-SUV(40%)<0.005EORTC(25%SUVreduction)<0.005PET-SUVof2.5<0.05Exon11mutation<0.05SWOG(50%C

Treduction)>0.5•PvalueswerederivedfromTTFcomparisonsTreatmentEvaluation:Summary•RECISTcriteriaarenotwellsuitedtoeva

luateresponses,especiallyinGIST•18FDG-PETprovidesanindicationoftumorresponseearlyafterinitiationoftherapy•Thereisastrongcorrelationbe

tweenCTand18FDG-PETresponses•NewobjectiveCTand18FDG-PETcriteriaareunderdevelopmentPatientManagement:CaseStudiesImatinibMesylateforNonr

esectableandMetastaticGIST:CaseStudy•Patient/presentation:50-year-oldwomanwithalargeabdominalmass•Treatmenthistory:Ini

tialresectionofprimaryandmultiplemetastaticomentallesionsMultipleresectionsofliver,ovaries,andabdominalcavi

tytoremovemetastases•Postsurgicaltreatment–7cyclesof4-agentchemotherapy(MAID)–ExperimentalregimenconsistingofIFN-andthalidomide–Noclinicalresponses

toanysystemictherapyMAID=mesna,doxorubicin,ifosfamide,anddacarbazine.Joensuuetal.NEnglJMed.2001;344:1052.ImatinibMesyla

teforNonresectableandMetastaticGIST:CaseStudy(cont’d)•Patientwastreatedwithimatinibmesylate400mg/d•Toxicitywasassessedduringfollow-

upvisitsevery2-4weeks•Hematologicanalysiswasperformedevery1-2weeks•ResponsewasevaluatedbyCTand18FDG-PETscanning

aswellasserialneedlebiopsiesofalivermetastasisJoensuuetal.NEnglJMed.2001;344:1052.Joensuuetal.NEnglJMed.2001;344:1052.Copyright©200

1MassachusettsMedicalSociety.ImatinibMesylateforNonresectableandMetastaticGIST:CaseStudy(cont’d)Multipleliverandupperabdominal18

FDG-accumulatingmetastasesAmarkeddecreasein18FDGuptake4weeksafterstartingimatinibmesylate(400mg/d)ImatinibMesylateTherapyforKI

T-NegativeGIST:CaseStudyPresentation:PrimarytumorwithlivermetastasisIHCresults:CD34-positive,KIT-negative,DesminandS-100–negativekitgenotype:Ex

on11deletiontypicalforGISTTreatment:Imatinibmesylate400mg/dOutcome:Decreasedtumorsize(byCT)Decreasedmetabolicactivity

belowthatofsurroundingtissue(18FDG-PET)Conclusion:AbsenceofKITexpressiondoesnotexcludearesponsetoimatinibmesylateB

aueretal.CancerChemotherPharmacol.2003;51:261.Rubinetal.CancerRes.2001;61:8118.DoestheLevelofKITExpressionMatterinGIST?History•60-year-oldwo

man•Abdominalmassbiopsied•GISTbylightmicroscopy•Underwentcompleteresection•Recurredwithliverandintraperitonealdisease•Onexam,largei

ntraabdominalmass,hepatomegaly,andlowerextremityedemaCourtesyofDr.J.C.Trent.