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1、胃肠道间质瘤诊断和治疗进展胃肠道间质瘤诊断和治疗进展GIST前言 胃肠道间质肿瘤(Gastrointestinal Stromal Tumor, 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。GIST前言 胃肠道间质肿瘤(GastrointesGIST前言 GIST是胃肠道间叶源性肿瘤(Gastrointestinal Mesenchymal Tumor GIMT)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。GIST前言 GIST是胃肠道间叶源性肿GIST历史回顾19

2、83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。GIST历史回顾1983年以前发生在胃肠道间叶来源的肿瘤,GIST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”(“stromal tumor”)来命名这些分化方向难以明确的肿瘤,即胃肠道间质瘤(gastrointestinal stromal tumor,GIST)GIST历史回顾1983年Mazur和Clark研究发现这GIST历史回顾20世纪末 Mikhael等(1994)、Miettine

3、n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Cajal间质细胞(ICC)和肠道起搏点激活需要c-kit基因的参与.GIST历史回顾20世纪末GIST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. Rindlom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. GIST历史回顾20世纪末GIST肿瘤起源 随着对GIST研究和认识进一步深

4、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。GIST肿瘤起源 随着对GIST研究和认识进GIST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概念目前认为胃肠道间质瘤(GIST) 是指那些具有频GISTGIST 的一般特征GISTGIST 的一般特征GIST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

5、s SEER data,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23万之间,主要发生在中老年人GIST发病率GIST的发病率约为1-2/10万人GIST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GIST性别、年龄性别男性略多或男女相等GIST发生部位85%位于消化道:胃5060%小肠2030%结直肠及食管5.5cm,肠间质瘤4cm)核分裂数10/50HPFGIST潜在恶性指征与周围组织粘连GIST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

6、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。GIST其他相关因素年龄、性别、腹部不适、消化道出血、病程、GIST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GISTGIST诊断术语比较过去现在食管胃小肠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

7、肌瘤大多GIST,少数真正的平滑肌肉瘤GIST诊断术语比较过去现在结直肠GIST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1/3EGISTGIST诊断术语比较过去现在胃肠道自主神经瘤(GNAT)是具GIST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2880%预后差的原因为复发或转移GIST治疗现状胃肠间质瘤1/3以上表现为恶性GIST 治疗外科手术是GIST的主要治疗手段 5年生存率5065% 术后复发或转移率高,可能10年后

8、复发,长期无 病生存率10%(MD Anderson癌症中心191例肿瘤5cm手术完全切除) 完全切除后治愈率10 35GIST 治疗外科手术是GIST的GIST 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。GIST 治疗不能完全切除 -GIST 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%GIST 化疗及放疗GIST对化疗不敏感Effective oral drug with low toxicity profileVan den Abbeele.Bauer et al.预后差的原因为复发或转移Objec

9、tives:Primary:OS on imatinib mesylate in adjuvant setting18FDG-PET can be used to assess continuing response to therapy despite persistent CT abnormalities and to detect recurrence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*van Oosterom et al.GI

10、ST 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Effective oral drug with low tGIST 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 伊马替尼 化学名:4-(GISTGIST患者c-kit基因突变 GISTGIST患者c-kit基因突变 GIST 格列卫作用机制 格列

11、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GIST 格列卫作用机制 格列卫作用于c-GIST体外实验:抑制GIST细胞增殖 GIST体外实验:抑制GIST细胞增殖 GIST 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Joensuu H et al. N Engl J Med. 2001;344:1052-1056.GIST 格列卫治疗首例病案 肝脏和上腹部多发转移伊GIST II期临床试验 两个

12、剂量组疗效无显著差异GIST II期临床试验 两个剂量组疗效GIST临床II期研究:确认最佳缓解率 George D. NEJM. 2002;7:472-479.GIST临床II期研究:确认最佳缓解率 George GISTCT扫描结果:肿瘤体积缩小 2000年6月27日2000年10月4日伊马替尼治疗前伊马替尼治疗后GISTCT扫描结果:肿瘤体积缩小 2000年6月27GIST 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GIST CT与PET扫描比较 2000年7月GIST 不良反应 Drug 2003,63(5):513GIST 不良反应 Dr

13、ug 2003, GIST不良反应(任何级别、34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 GIST不良反应(任何级别、34级) 常见:水肿/ GISTII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 GISTII期临床试验结论 格列卫是第一个有效治疗G GIST进行中的临床试验 1、美

14、国外科医生学院肿瘤组(Amercian College of Surgeons Oncology Group, 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400mg qd12月目的:明确用Glivec辅助治疗能否将5年生存率提高50%以上 GIST进行中的临床试验 1、美国外科医生学院肿瘤组 GIST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:400mg qd12月对照组:安慰剂目的:能否降低死亡危险

15、率35%以上(降低40%相当 79%2年生存率) GIST进行中的临床试验 2、美国外科医生学院肿瘤组 GIST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Glivec 600mg qd4周,如有效则继续服用4周,然后手术切除,术后24周再服24个月:术前Glivec 600mg qd4周有效无效600mg qd4周手术切除手术切除600mg qd24周24周 GIST进行中的临床试验 3、放疗肿瘤组 GISTIII期临床试验(进行中) 两项III期试验:入组1700例初步疗效:RR 53.7%(CR 5%) SD 27.9% 1年生存率 80% GISTIII期临床试

16、验(进行中) GIST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400600mg/d,治疗时间不少于4个月。 GIST建议推荐治疗模式 GI GISTGIST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. GISTGIST诊治进展小结 GISTGIST诊治进展小结 CD117和CD34是检测确诊GIST的关键环节.依据肿瘤是否表达c-kit可作为G

17、IST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。 GISTGIST诊治进展小结 GISTGIST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。 GISTGIST诊治进展小结 GISTGIST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。 GISTGIST诊治进展小结 GISTGIST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 GI

18、STGIST诊治进展小结 GISTGIST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 GISTGIST诊治进展小结 GISTGIST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 GISTGIST诊治进展小结 GISTGIST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

19、切缘和切除范围。联合脏器切除不提高生存率 GISTGIST诊治进展小结 GISTGIST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。 GISTGIST诊治进展小结 GISTGIST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。 GISTGIST诊治进展小结 GISTGIST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

20、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。 GISTGIST诊治进展小结 GIST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 GIST尚未解决 存在问题 Imatinib Mesylate in GIST: Clinical EfficacyGISTImatinib Mesylate in GIST: ClFirst Patient With GIST to Receive Imatinib Mesylate: Proof-of-ConceptExploratory study with a

21、single patient with oral imatinib mesylate at 400 mg/dDramatic clinical responseDisappearance of excess metabolic activity at 4 weeks by 18FDG-PET75% reduction in tumor size at 8-month follow-upTumor biopsies showed histologic evidence of myxoid degeneration and lack of mitotic activitySymptomatic r

22、eliefJoensuu et al. N Engl J Med. 2001;344:1052.GISTFirst Patient With GIST to RecJoensuu et al. N Engl J Med. 2001;344:1052. Copyright 2001 Massachusetts Medical Society.Multiple liver and upper abdominal 18FDG-accumulating metastases A marked decrease in 18FDG uptake 4 weeks after starting imatini

23、b mesylate (400 mg/d)GISTJoensuu et al. N Engl J Med. 2EORTC Phase I Study of Imatinib Mesylate in GIST and Other Sarcomas: Study Designvan Oosterom et al. Lancet. 2001;358:1421.van Oosterom et al. Eur J Cancer. 2002;38(suppl 5):S83.Objectives:Primary:Establish MTD for imatinib mesylateSecondary:Saf

24、ety and tolerabilityDetermine the activity of imatinib mesylate in GIST and non-GIST sarcomas using radiologic (18FDG-PET), hematologic, and biochemical measurements Treatment:Imatinib mesylate administered at 400 mg/d, doses increased by 200 mg/d up to 1000 mg/dInclusion:Soft-tissue sarcoma (KIT-po

25、sitive histologic staining for GIST diagnosis)Evidence of progression 6 weeks prior to trial startChemotherapy discontinued 4 weeks prior to trial startGISTEORTC Phase I Study of Imatini90% of patients had confirmed KIT-positive GIST75% of patients had metastases in the liver60% of patients had rece

26、ived prior chemotherapyvan Oosterom et al. Lancet. 2001;358:1421.van Oosterom et al. Eur J Cancer. 2002;38(suppl 5):S83.GIST90% of patients had confirmed Time to tumor response = 1 week after first imatinib mesylate therapyDLT = 1000 mg/d (in 5 of 40 patients); MTD = 400 mg bidvan Oosterom et al. La

27、ncet. 2001;358:1421.van Oosterom et al. Eur J Cancer. 2002;38(suppl 5):S83.20406080100PartialresponseStablediseaseProgressivedisease51%31%8%0PercentGISTTime to tumor response = 1 weeAt a range of doses from 400-1000 mg/d, 800 mg/d is the MTD Imatinib mesylate has significant activity in patients wit

28、h advanced GIST (n=35), but little or no activity in non-GIST patientsEORTC Phase I Trial: Conclusionsvan Oosterom et al. Lancet. 2001;358:1421.GISTAt a range of doses from 400-1Objectives:Primary: Response rate with imatinib mesylate in patients with GISTSecondary: Pharmacokinetic profile Time to t

29、reatment failure Survival Safety and tolerabilityTreatment:Imatinib mesylate administered at either 400 or 600 mg/d to continue as long as benefit; crossover allowed from 400 to 600 mg/d after disease progressionInclusion:Histologic criteria of GIST with KIT-positive stainingconfirmed by central pat

30、hology reviewMetastatic and/or unresectable diseaseNo concomitant therapy for diseaseImatinib Mesylate in GIST: Pivotal Phase II Trial Study Design Demetri et al. N Engl J Med. 2002;347:472.Objectives:Primary: ResponseConfirmed Objective ResponsesImatinib Mesylate in GIST:Evolution of Tumor Response

31、s Over Time01020304050607049589(Demetri et al)626515(von Mehren et al)400 mg/d (n=73)600 mg/d (n=74)% of patients33437 (Imatinib mesylate PI)676634(Blanke et al)Gleevec (imatinib mesylate) PI.Demetri et al. N Engl J Med. 2002;347:472.von Mehren et al. Proc Am Soc Clin Oncol. 2002;21:403a. Abstract 1

32、608.Blanke et al. ASCO 2004 Gastrointestinal Cancers Symposium. Abstract 2.Median follow-up (mo)Confirmed Objective ResponsesIImatinib Mesylate in GIST: Pivotal TrialConclusions147 patients randomized to 400 or 600 mg/d83% of patients showed a clinical benefit67% PR/CR16% stable disease (SD)Median t

33、ime to progression (TTP) was 84 weeksMedian overall survival (OS) has not been reached at median follow-up of 34 monthsImatinib mesylate has an acceptable safety profile in patients with GISTBlanke et al. ASCO 2004 Gastrointestinal Cancers Symposium. Abstract 2.Imatinib Mesylate in GIST: PiGleevec (

34、imatinib mesylate) PI.Druker et al. N Engl J Med. 2001;344:1031.Imatinib Mesylate IndicationIndicated dose for patients with KIT-positive, unresectable or metastatic malignant GIST is 400 or 600 mg/d400 mg/d effects a mean plasma concentration of imatinib mesylate of1.46 MImatinib mesylate should be

35、 taken with food and a large glass of water to minimize GI irritationGleevec (imatinib mesylate) PImatinib Mesylate in GIST: EORTC Phase II TrialTrial included patients with GIST or other soft tissue sarcomas (STS)Patients were administered imatinib mesylate 400 bid (800 mg/d) In GIST patientsTrial

36、achieved an overall response rate (ORR) of 71%, with 18% SDAfter 1 year, 73% of GIST patients wereprogression-freeIn STS patientsNo ORR; median TTP was 58 daysVerweij et al. Eur J Cancer 2003;39:2006.Imatinib Mesylate in GIST: EPhase III Trials (EORTC 62005 and US Intergroup S0033): Study DesignObje

37、ctives:Primary:PFS 400 mg vs PFS 800 mgSecondary:ORRSafety and tolerabilityTreatment:Imatinib mesylate administered at 400 mg/d or 400 mg bid (800 mg/d); crossover from 400 to 800 mg/d after disease progression (PD)Inclusion:Present with metastatic or unresectable KIT-positive GISTMeasurable or nonm

38、easurable diseasePrior chemotherapy allowedRankin et al. Proc Am Soc Clin Oncol. 2004;23:815. Abstract 9005.Verweij et al. Proc Am Soc Clin Oncol. 2003;22:814. Abstract 3272.Phase III Trials (EORTC 62005 Phase III Study (EORTC 62005):1-Year Estimated PFSVerweij et al. Proc Am Soc Clin Oncol. 2003;22

39、:814. Abstract 3272.Current estimate of PFS differenceHazard ratio = 0.78Extrapolated median difference at median PFS = 8% (50% vs 58%)Phase III Study (EORTC 62005):Phase III Study (EORTC 62005): Efficacy (Interim Analysis)Verweij et al. Proc Am Soc Clin Oncol. 2003;22:814. Abstract 3272.Phase III S

40、tudy (EORTC 62005):Phase III Study (EORTC 62005): Efficacy Following Crossover to 800 mg/dZalcberg et al. Proc Am Soc Clin Oncol. 2004;23:815. Abstract 9004.n=119Phase III Study (EORTC 62005):Phase III Study (US Intergroup S0033): 2-Year Estimated PFS and OSP=0.13P=0.87Rankin et al. Proc Am Soc Clin

41、 Oncol. 2004;23:815. Abstract 9005.Phase III Study (US IntergroupPhase III Study (US Intergroup S0033): EfficacyNR = no response.Rankin et al. Proc Am Soc Clin Oncol. 2004;23:815. Abstract 9005.Phase III Study (US IntergroupPhase III Study (US Intergroup S0033): Efficacy Following Crossover to 800 m

42、g/d*Evaluable patients.Rankin et al. Proc Am Soc Clin Oncol. 2004;23:815. Abstract 9005.n=77*Phase III Study (US IntergroupImatinib Mesylate in GIST:Phase III TrialsTrials included patients with metastatic unresectable GISTPatients received imatinib mesylate 400 or 800 mg/dEORTC trial results No sig

43、nificant difference between doses in ORR (50.3% vs 51.1%) Possible significant advantage in PFS at 800 mg/d (P=0.0216)Intergroup trial resultsDoses similar in confirmed ORR (both 48%) and 2-year PFS (47% vs 52%, P=0.13)Rankin et al. Proc Am Soc Clin Oncol. 2004;23:815. Abstract 9005.Verweij et al. P

44、roc Am Soc Clin Oncol. 2003;22:814. Abstract 3272.Imatinib Mesylate in GIST:Phas% of patientsMonths after randomization1614121086420100806040200Stop therapy (n=25)Median PFS: 6 monthsContinuous therapy (n=23)P=0.0001GIST: Discontinuation of Imatinib Mesylate Increases the Risk of Progression (BFR14)

45、Patients who achieved clinical benefit after 12 months were randomized to continue or to stop imatinib mesylate therapyRandomization has been suspended Blay et al. Proc Am Soc Clin Oncol. 2004;23:815. Abstract 9006.% of patientsMonths after randNeoadjuvant Imatinib Mesylate Therapy for GIST: Rationa

46、leFew complete responses with imatinib mesylate therapy Most responding lesions have viable cellsCytoreduction may improve surgical outcomesPotential to increase resectability or reduce the extent of surgeryEisenberg and von Mehren. Expert Opin Pharmacother. 2003;4:869. Eisenberg and Judson. Ann Sur

47、g Oncol. 2004;11:465.Neoadjuvant Imatinib Mesylate Adjuvant Imatinib MesylateTherapy for GIST: RationaleHigh recurrence rates especially forhigh-risk GISTEffective oral drug with low toxicity profileMay have efficacy in low-volume microscopic diseaseACOSOG designed 2 adjuvant trialsHigh risk, nonran

48、domized (completed accrual)Intermediate to high risk (open)Eisenberg and von Mehren. Expert Opin Pharmacother. 2003;4:869. Eisenberg and Judson. Ann Surg Oncol. 2004;11:465.Adjuvant Imatinib MesylateTheGIST: Selected Ongoing Clinical Trials in the Adjuvant and Neoadjuvant SettingsTrial NPhaseRegimen

49、SettingPrimary End PointStatus*ACOSOG Z900089IIImatinib mesylate 400 mg/dAdjuvantOSCompleted accrualACOSOG Z9001380IIIImatinib mesylate 400 mg/d vs placeboAdjuvantOSRecruitingRTOGS-013263IIImatinib mesylate 600 mg/dNeoadjuvant/adjuvantPFSRecruiting*As of January 30, 2004.Eisenberg and von Mehren. Ex

50、pert Opin Pharmacother. 2003;4:869. Eisenberg and Judson. Ann Surg Oncol. 2004;11:465.GIST: Selected Ongoing ClinicaPhase II Trial (ACOSOG Z9000): Study DesignObjectives:Primary:OS on imatinib mesylate in adjuvant settingSecondary:2- and 5-year recurrenceToxicity in adjuvant settingTreatment:Imatini

51、b mesylate 400 mg/dInclusion:High-risk GIST Surgery within 70 days prior to registrationKIT-positive GISTImatinib mesylatenaive No prior adjuvant therapyPhase II Trial (ACOSOG Z9000):Phase III Trial (ACOSOG Z9001): Study DesignObjectives:Primary:OS with imatinib mesylate in adjuvant setting relative

52、 to placeboSecondary:Recurrence-free survivalSafety/efficacy in adjuvant settingTreatment:Imatinib mesylate administered at 400 mg/dInclusion:3 cm GIST Surgery within 70 days prior to registrationKIT-positive GISTImatinib mesylatenaive No prior adjuvant therapyPhase III Trial (ACOSOG Z9001)Phase II

53、Trial (RTOG S-0132):Study DesignObjectives:Primary:PFS with imatinib mesylate in adjuvant settingSecondary:Response rate in neoadjuvant setting Compare CT and PET responses in neoadjuvant settingSafety in adjuvant settingTreatment:Imatinib mesylate 600 mg/dInclusion:Present with KIT-positive maligna

54、nt GIST Imatinib mesylatenaive No prior therapy 28 days before entryPhase II Trial (RTOG S-0132):Clinical Efficacy: SummaryImatinib mesylate has proven clinical efficacy in unresectable or metastatic GISTImatinib mesylate is the only approved therapy effective in treating metastatic, unresectable GI

55、STImatinib mesylate in effect at 400 and 800 mg/d 800-mg/d dose was associated with PFS in one ongoing phase III trialDiscontinuation of imatinib mesylate following response increases the likelihood of progressionEfficacy of imatinib mesylate is under investigation in the adjuvant and neoadjuvant se

56、ttingsPhase II/III trials are ongoingClinical Efficacy: SummaryImatPatient ManagementPatient ManagementGIST: Patient FlowMultidisciplinary teams needed to optimize carePathologist and radiologist involvement ensures correct diagnosis and response evaluationPatient education about malignant potential

57、 key for adequate follow-upPCP = primary care physician.GI = gastroenterologist.Demetri et al. JNCCN. 2004;21(suppl 1):S1.PCPSurgeonGIMedical oncologistPathologistRadiologistGIST: Patient FlowMultidisciplGastrointestinalStromal Tumors (GIST)Version 1.2004Version 1.2004 2004 National Comprehensive Ca

58、ncer Network, Inc. All rights reserved.These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.GastrointestinalStromal TumorNeoadjuvant therapy not consideredResect massVersion 1.2004 2004 National Comprehensive Cancer Network, Inc. All

59、 rights reserved.These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.Neoadjuvant therapy not considVersion 1.2004 2004 National Comprehensive Cancer Network, Inc. All rights reserved.These guidelines and this illustration may not be

60、 reproduced in any form without the express written permission of NCCN.Version 1.2004 2004 National Version 1.2004 2004 National Comprehensive Cancer Network, Inc. All rights reserved.These guidelines and this illustration may not be reproduced in any form without the express written permission of N

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