胃肠道间质瘤GIST诊断和治疗进展4

,胃肠道间质肿瘤（GIST) 治疗新模式手术与分子治疗相结合,河南省肿瘤医院普外科花亚伟,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,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,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。,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,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 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,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。,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,GIST 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%（NCIs 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,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,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10/50HPF,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,诊断术语比较,GIST,诊断术语比较,GIST,诊断术语比较,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,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 35,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,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,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,GIST,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,GIST患者c-kit基因突变,GIST,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,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,II期临床试验,两个剂量组疗效无显著差异,GIST,临床II期研究：确认最佳缓解率,George D. NEJM. 2002;7:472-479.,GIST,CT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,GIST,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,不良反应,Drug 2003,63(5):513,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,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,GIST,进行中的临床试验,1、美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,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：能否降低死亡危险率35%以上（降低40%相当 79%2年生存率）,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,III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%,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,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,GIST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,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,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,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,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,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,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,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,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,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。,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,Imatinib Mesylate in GIST: Clinical Efficacy,GIST,First Patient With GIST to Receive Imatinib Mesylate: Proof-of-Concept,Exploratory study with a 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 relief,Joensuu et al. N Engl J Med. 2001;344:1052.,GIST,Joensuu 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 imatinib mesylate (400 mg/d),GIST,EORTC Phase I Study of Imatinib Mesylate in GIST and Other Sarcomas: Study Design,van 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:Safety 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-positive histologic staining for GIST diagnosis)Evidence of progression 6 weeks prior to trial startChemotherapy discontinued 4 weeks prior to trial start,GIST,90% of patients had confirmed KIT-positive GIST75% of patients had metastases in the liver60% of patients had received prior chemotherapy,van Oosterom et al. Lancet. 2001;358:1421.van Oosterom et al. Eur J Cancer. 2002;38(suppl 5):S83.,GIST,Time to tumor response = 1 week after first imatinib mesylate therapyDLT = 1000 mg/d (in 5 of 40 patients); MTD = 400 mg bid,van Oosterom et al. Lancet. 2001;358:1421.van Oosterom et al. Eur J Cancer. 2002;38(suppl 5):S83.,20,40,60,80,100,Partialresponse,Stabledisease,Progressivedisease,51%,31%,8%,0,Percent,GIST,At a range of doses from 400-1000 mg/d, 800 mg/d is the MTD Imatinib mesylate has significant activity in patients with advanced GIST (n=35), but little or no activity in non-GIST patients,EORTC Phase I Trial: Conclusions,van Oosterom et al. Lancet. 2001;358:1421.,GIST,Objectives:Primary: Response rate with imatinib mesylate in patients with GISTSecondary: Pharmacokinetic profile Time to treatment 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 pathology reviewMetastatic and/or unresectable diseaseNo concomitant therapy for disease,Imatinib Mesylate in GIST: Pivotal Phase II Trial Study Design,Demetri et al. N Engl J Med. 2002;347:472.,Imatinib Mesylate in GIST: Pivotal TrialStudy Design (contd),Metastatic or unresectable GIST (N=147),PD,Continue to treat as long as benefit,Imatinib mesylate(400 mg/d),Imatinib mesylate (600 mg/d),Functional imaging was performed with CT scan or MRI.PET scan imaging was performed at the discretion of the investigator.Demetri et al. N Engl J Med. 2002;347:472.,Confirmed Objective Responses,Imatinib Mesylate in GIST:Evolution of Tumor Responses Over Time,0,10,20,30,40,50,60,70,49,58,9(Demetri et al),62,65,15(von Mehren et al),400 mg/d (n=73),600 mg/d (n=74),% of patients,33,43,7 (Imatinib mesylate PI),67,66,34(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 1608.Blanke et al. ASCO 2004 Gastrointestinal Cancers Symposium. Abstract 2.,Median follow-up (mo),Imatinib Mesylate in GIST: Pivotal TrialOverall Survival,With a median follow-up of 34 months, median survival has not been reached,Blanke et al. ASCO 2004 Gastrointestinal Cancers Symposium. Abstract 2.,0,1,2,3,4,5,0,20,40,60,80,100,Years after registration,Survival (%),Imatinib mesylate (pooled 400-mg +600-mg),SWOG S8616/S9627,Imatinib Mesylate in GIST: Pivotal TrialConclusions,147 patients randomized to 400 or 600 mg/d83% of patients showed a clinical benefit67% PR/CR16% stable disease (SD)Median time 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 GIST,Blanke et al. ASCO 2004 Gastrointestinal Cancers Symposium. Abstract 2.,Gleevec (imatinib mesylate) PI.Druker et al. N Engl J Med. 2001;344:1031.,Imatinib Mesylate Indication,Indicated 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 taken with food and a large glass of water to minimize GI irritation,Imatinib Mesylate in GIST: EORTC Phase II Trial,Trial included patients with GIST or other soft tissue sarcomas (STS)Patients were administered imatinib mesylate 400 bid (800 mg/d) In GIST patientsTrial 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 days,Verweij et al. Eur J Cancer 2003;39:2006.,Phase III Trials (EORTC 62005 and US Intergroup S0033): Study Design,Objectives: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 nonmeasurable diseasePrior chemotherapy allowed,Rankin 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: Study Design (contd),Metastatic or unresectable GIST,FollowforPFS,Imatinib mesylate(400 mg/d),Imatinib mesylate (800 mg/d),PD,Benjamin et al. Proc Am Soc Clin Oncol. 2003;22:814. Abstract 3271.Rankin 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 Study (EORTC 62005):1-Year Estimated PFS,Verweij et al. Proc Am Soc Clin Oncol. 2003;22:814. Abstract 3272.Verweij et al. At: /ac/1,1003,_12-002511-00_18-0023-00_19-001690,00.asp. Accessed July 2004.,Current estimate of PFS differenceHazard ratio = 0.78Extrapolated median difference at median PFS = 8% (50% vs 58%),Phase III Study (EORTC 62005): Efficacy (Interim Analysis),Verweij et al. Proc Am Soc Clin Oncol. 2003;22:814. Abstract 3272.Verweij et al. At: /ac/1,1003,_12-002511-00_18-0023-00_19-001690,00.asp. Accessed July 2004.,Phase III Study (EORTC 62005): Efficacy Following Crossover to 800 mg/d,Zalcberg et al. Proc Am Soc Clin Oncol. 2004;23:815. Abstract 9004.Zalcberg et al. At: /ac/1,1003,_12-002511-00_18-0026-00_19-0010107,00.asp. Accessed July 2004.,n=119,Phase III Study (US Intergroup S0033): 2-Year Estimated PFS and OS,P=0.13,P=0.87,Rankin et al. Proc Am Soc Clin Oncol. 2004;23:815. Abstract 9005.Rankin et al. At: /ac/1,1003,_12-002511-00_18-0026-00_19-0010571,00.asp. Accessed July 2004.,Phase III Study (US Intergroup S0033): Efficacy,NR = no response.Rankin et al. Proc Am Soc Clin Oncol. 2004;23:815. Abstract 9005.Rankin et al. At: /ac/1,1003,_12-002511-00_18-0026-00_19-0010571,00.asp. Accessed July 2004.,Phase III Study (US Intergroup S0033): Efficacy Following Crossover to 800 mg/d,*Evaluable patients.Rankin et al. Proc Am Soc Clin Oncol. 2004;23:815. Abstract 9005.Rankin et al. At: /ac/1,1003,_12-002511-00_18-0026-00_19-0010571,00.asp. Accessed July 2004.,n=77*,Imatinib Mesylate in GIST:Phase III Trials,Trials included patients with metastatic unresectable GISTPatients received imatinib mesylate 400 or 800 mg/dEORTC trial results No significant 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. Proc Am Soc Clin Oncol. 2003;22:814. Abstract 3272.,% of patients,Months after randomization,16,14,12,10,8,6,4,2,0,100,80,60,40,20,0,Stop therapy (n=25)Median PFS: 6 months,Continuous therapy (n=23),P=0.0001,GIST: Discontinuation of Imatinib Mesylate Increases the Risk of Progression (BFR14),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.,Neoadjuvant Imatinib Mesylate Therapy for GIST: Rationale,Few complete responses with imatinib mesylate therapy Most responding lesions have viable cellsCytoreduction may improve surgical outcomesPotential to increase resectability or reduce the extent of surgery,Eisenberg and von Mehren. Expert Opin Pharmacother. 2003;4:869. Eisenberg and Judson. Ann Surg Oncol. 2004;11:465.,Adjuvant Imatinib MesylateTherapy for GIST: Rationale,High recurrence rates especially forhigh-risk GISTEffective oral drug with low toxicity profileMay have efficacy in low-volume microscopic diseaseACOSOG designed 2 adjuvant trialsHigh risk, nonrandomized (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.,GIST: Selected Ongoing Clinical Trials in the Adjuvant and Neoadjuvant Settings,*As of January 30, 2004.Eisenberg and von Mehren. Expert Opin Pharmacother. 2003;4:869. Eisenberg and Judson. Ann Surg Oncol. 2004;11:465.,Phase II Trial (ACOSOG Z9000): Study Design,Objectives:Primary:OS on imatinib mesylate in adjuvant settingSecondary:2- and 5-year recurrenceToxicity in adjuvant settingTreatment:Imatinib mesylate 400 mg/dInclusion:High-risk GIST Surgery within 70 days prior to registrationKIT-positive GISTImatinib mesylatenaive No prior adjuvant therapy,At: /studies/synopses/Z9000_Synopsis.pdf.,At: /studies/synopses/Z9000_Synopsis.pdf.,Phase II Trial (ACOSOG Z9000): Study Design (contd),Complete resection of high-risk primary GIST,Imatinib mesylate(400 mg/dfor 1 year),FollowforOS,Phase III Trial (ACOSOG Z9001): Study Design,Objectives:Primary:OS with imatinib mesylate in adjuvant setting relative 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 registrati