胃腸道間質(zhì)瘤診斷和治療進展最全課件

1、胃腸道間質(zhì)瘤診斷和治療進展胃腸道間質(zhì)瘤診斷和治療進展GIST前言 胃腸道間質(zhì)腫瘤（Gastrointestinal Stromal Tumor， GIST）是一種發(fā)生在胃腸道的最常見的間葉性腫瘤。近來，因其作為對于其組織發(fā)生、分化、生物學(xué)行為、治療及預(yù)后等諸多方面是目前研究的熱點。GIST前言 胃腸道間質(zhì)腫瘤（GastrointesGIST前言 GIST是胃腸道間葉源性腫瘤（Gastrointestinal Mesenchymal Tumor GIMT）最常見的一種約占GIMT的70；而GIMT是指胃腸道所有非淋巴非上皮的軟組織腫瘤。GIST前言 GIST是胃腸道間葉源性腫GIST歷史回顧19

2、83年以前發(fā)生在胃腸道間葉來源的腫瘤，一般都被認識為是平滑肌腫瘤、平滑肌肉瘤、平滑肌母細胞瘤、上皮樣平滑肌瘤。GIST歷史回顧1983年以前發(fā)生在胃腸道間葉來源的腫瘤，GIST歷史回顧1983年Mazur和Clark研究發(fā)現(xiàn)這類腫瘤缺乏平滑肌細胞和雪旺細胞的超微結(jié)構(gòu)和免疫表型的特征，可以用更一般的名稱“間質(zhì)瘤”（“stromal tumor”）來命名這些分化方向難以明確的腫瘤，即胃腸道間質(zhì)瘤（gastrointestinal stromal tumor，GIST）GIST歷史回顧1983年Mazur和Clark研究發(fā)現(xiàn)這GIST歷史回顧20世紀末 Mikhael等（1994）、Miettine

3、n等（1995）證實CD34抗原免疫組化標(biāo)記可將GIST與真正平滑肌瘤和雪旺瘤分開。 Maeda等（1992）和Hulzlnga等（1995）證實腸道Cajal間質(zhì)細胞（ICC）和腸道起搏點激活需要c-kit基因的參與.GIST歷史回顧20世紀末GIST歷史回顧20世紀末 Hirota等（1998）發(fā)現(xiàn)人GIST中存在c-kit基因功能獲得性突變和CD117蛋白的特異表達，補充了GIST的概念. Rindlom等（1998）發(fā)現(xiàn)GIST顯示胃腸道Cajal間質(zhì)細胞相同的表型，認為GIST可能起源于Cajal間質(zhì)細胞. GIST歷史回顧20世紀末GIST腫瘤起源 隨著對GIST研究和認識進一步深

4、入，大多數(shù)學(xué)者都趨向于GIST的起源可能是Cajal間質(zhì)細胞（ICC）和可能起源于向ICC分化的幼稚間充質(zhì)干細胞。GIST腫瘤起源 隨著對GIST研究和認識進GIST概念目前認為胃腸道間質(zhì)瘤（GIST） 是指那些具有頻發(fā)性c-kit基因突變并且表達CD117蛋白，組織學(xué)上以富于梭形細胞、上皮樣細胞偶或多形性細胞，束狀或彌漫性排列為特征的胃腸道間葉源性腫瘤。GIST概念目前認為胃腸道間質(zhì)瘤（GIST） 是指那些具有頻GISTGIST 的一般特征GISTGIST 的一般特征GIST發(fā)病率GIST的發(fā)病率約為1-2/10萬人胃惡性腫瘤的2.2%小腸惡性腫瘤的13.9%結(jié)直腸惡性腫瘤的0.1%（NCI

5、s SEER data，1995）美國臨床上檢測到新病例從原來估計的300-500例/年已上升到5000-6000例/年中國每年的發(fā)病人數(shù)在23萬之間，主要發(fā)生在中老年人GIST發(fā)病率GIST的發(fā)病率約為1-2/10萬人GIST性別、年齡性別男性略多或男女相等年齡高峰年齡55-65歲，中位年齡為60歲，40歲以下少見，20歲以下罕見GIST性別、年齡性別男性略多或男女相等GIST發(fā)生部位85%位于消化道：胃5060%小腸2030%結(jié)直腸及食管5.5cm，腸間質(zhì)瘤4cm)核分裂數(shù)10/50HPFGIST潛在惡性指征與周圍組織粘連GIST其他相關(guān)因素年齡、性別、腹部不適、消化道出血、病程、腫瘤生長

6、方式、潰瘍出血、囊變等指標(biāo)在良惡性判斷上無參考價值。也有人建議把PCNA和P53蛋白性表達也作為GIST是否潛在惡性的判斷指標(biāo)。GIST其他相關(guān)因素年齡、性別、腹部不適、消化道出血、病程、GIST診斷術(shù)語比較過去現(xiàn)在食管平滑肌瘤平滑肌肉瘤大多真正平滑肌瘤大多GIST，少數(shù)平滑肌肉瘤胃平滑?。ㄈ猓┝銎交∧讣毎龃蠖郍IST，極少數(shù)平滑肌瘤上皮樣GIST小腸平滑肌肉瘤大多GISTGIST診斷術(shù)語比較過去現(xiàn)在食管胃小腸GIST診斷術(shù)語比較過去現(xiàn)在結(jié)直腸平滑肌瘤平滑肌肉瘤僅累及粘膜肌層小腫瘤為真正平滑肌瘤女性結(jié)直腸外的有些腫瘤為子宮型平滑肌瘤（ER+、PR+）大多數(shù)腔內(nèi)腫瘤為GIST，極少數(shù)真正平滑

7、肌瘤大多GIST，少數(shù)真正的平滑肌肉瘤GIST診斷術(shù)語比較過去現(xiàn)在結(jié)直腸GIST診斷術(shù)語比較過去現(xiàn)在胃腸道自主神經(jīng)瘤（GNAT）是具有神經(jīng)分泌顆粒的GIST變型網(wǎng)膜和腸系膜平滑?。ㄈ猓┝龃蠖郋GIST，少數(shù)真正平滑肌肉瘤腹膜后平滑肌肉瘤約1/3EGISTGIST診斷術(shù)語比較過去現(xiàn)在胃腸道自主神經(jīng)瘤（GNAT）是具GIST治療現(xiàn)狀胃腸間質(zhì)瘤1/3以上表現(xiàn)為惡性胃腸道外間質(zhì)瘤大多數(shù)為交界性和惡性胃腸間質(zhì)瘤的5年生存率為2880%預(yù)后差的原因為復(fù)發(fā)或轉(zhuǎn)移GIST治療現(xiàn)狀胃腸間質(zhì)瘤1/3以上表現(xiàn)為惡性GIST 治療外科手術(shù)是GIST的主要治療手段 5年生存率5065% 術(shù)后復(fù)發(fā)或轉(zhuǎn)移率高，可能10年后

8、復(fù)發(fā)，長期無 病生存率10%(MD Anderson癌癥中心191例腫瘤5cm手術(shù)完全切除） 完全切除后治愈率10 35GIST 治療外科手術(shù)是GIST的GIST 治療不能完全切除 -中位生存期10-23月，復(fù)發(fā)轉(zhuǎn)移者-中位生存期12-19月。GIST 治療不能完全切除 -GIST 化療及放療GIST對化療不敏感 緩解率：10% 對生存期無益處GIST對放療不敏感 緩解率：5%GIST 化療及放療GIST對化療不敏感Effective oral drug with low toxicity profileVan den Abbeele.Bauer et al.預(yù)后差的原因為復(fù)發(fā)或轉(zhuǎn)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最近有研究報道顯示：GIST可恒定表達巢蛋白（nestin),敏感性高于CD34,這樣可能對GIST鑒別診斷有提供新的依據(jù)。2001;344:1052.格列衛(wèi)推薦用量400mg/d或600mg/d*van Oosterom et al.GI

10、ST GIST的分子靶向治療 靶點：受體酪氨酸激酶c-Kit(CD117)新藥：格列衛(wèi) （Glevic,Gleevec；甲磺酸伊馬替尼，伊馬替尼，lmatinib ； ST1517,57148B) 美國FDA2002年2月批準用于GIST治療機理：細胞信號抑制劑Effective oral drug with low tGIST 伊馬替尼 化學(xué)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 伊馬替尼 化學(xué)名：4-(GISTGIST患者c-kit基因突變 GISTGIST患者c-kit基因突變 GIST 格列衛(wèi)作用機制 格列

11、衛(wèi)作用于c-Kit, Bcr-Abl,和PDGF-R酪氨酸激酶區(qū)的特定部位格列衛(wèi)作用機制格列衛(wèi)結(jié)合在c-Kit上正常情況下ATP所在部位格列衛(wèi)阻斷c-Kit激活的信號轉(zhuǎn)導(dǎo)通道GIST 格列衛(wèi)作用機制 格列衛(wèi)作用于c-GIST體外實驗：抑制GIST細胞增殖 GIST體外實驗：抑制GIST細胞增殖 GIST 格列衛(wèi)治療首例病案 肝臟和上腹部多發(fā)轉(zhuǎn)移18FDG在轉(zhuǎn)移病灶處濃聚伊馬替尼治療4周后18FDG的攝取吸收顯著減少Joensuu H et al. N Engl J Med. 2001;344:1052-1056.GIST 格列衛(wèi)治療首例病案 肝臟和上腹部多發(fā)轉(zhuǎn)移伊GIST II期臨床試驗 兩個

12、劑量組療效無顯著差異GIST II期臨床試驗 兩個劑量組療效GIST臨床II期研究：確認最佳緩解率 George D. NEJM. 2002;7:472-479.GIST臨床II期研究：確認最佳緩解率 George GISTCT掃描結(jié)果：腫瘤體積縮小 2000年6月27日2000年10月4日伊馬替尼治療前伊馬替尼治療后GISTCT掃描結(jié)果：腫瘤體積縮小 2000年6月27GIST CT與PET掃描比較 2000年7月3日2000年10月5日伊馬替尼治療前伊馬替尼治療后GIST CT與PET掃描比較 2000年7月GIST 不良反應(yīng) Drug 2003,63(5):513GIST 不良反應(yīng) Dr

13、ug 2003, GIST不良反應(yīng)（任何級別、34級） 常見：水腫/水鈉潴留（74%、21%) 惡心（52%、1.4%) 腹瀉（45%、2%) 乏力（35%、0%)少見：皮炎、皮疹、腹痛特殊：腫瘤相關(guān)出血（5%)兩個劑量組不良反應(yīng)無顯著差異 GIST不良反應(yīng)（任何級別、34級） 常見：水腫/ GISTII期臨床試驗結(jié)論 格列衛(wèi)是第一個有效治療GIST的藥物： 40%部分緩解率（PR) 41%疾病穩(wěn)定率（SD)格列衛(wèi)治療GIST安全性可接受格列衛(wèi)推薦用量400mg/d或600mg/d*依照各地使用劑量規(guī)定調(diào)整 GISTII期臨床試驗結(jié)論 格列衛(wèi)是第一個有效治療G GIST進行中的臨床試驗 1、美

14、國外科醫(yī)生學(xué)院腫瘤組（Amercian College of Surgeons Oncology Group, ACOSOG)2001年開始對GIST高危險復(fù)發(fā)的患者完全切除后用Glivec輔助治療（II期試驗）條件：直徑10cm、腫瘤破裂、腹腔出血、腹腔多發(fā)病灶（5個）用藥：術(shù)后400mg qd12月目的：明確用Glivec輔助治療能否將5年生存率提高50%以上 GIST進行中的臨床試驗 1、美國外科醫(yī)生學(xué)院腫瘤組 GIST進行中的臨床試驗 2、美國外科醫(yī)生學(xué)院腫瘤組（ACOSOG) 隨機試驗用上述劑量：對直徑3cm者，隨機分試驗組：400mg qd12月對照組：安慰劑目的：能否降低死亡危險

15、率35%以上（降低40%相當(dāng) 79%2年生存率） GIST進行中的臨床試驗 2、美國外科醫(yī)生學(xué)院腫瘤組 GIST進行中的臨床試驗 3、放療腫瘤組 能切除的GIST（原發(fā)或復(fù)發(fā)）服用Glivec 600mg qd4周，如有效則繼續(xù)服用4周，然后手術(shù)切除，術(shù)后24周再服24個月：術(shù)前Glivec 600mg qd4周有效無效600mg qd4周手術(shù)切除手術(shù)切除600mg qd24周24周 GIST進行中的臨床試驗 3、放療腫瘤組 GISTIII期臨床試驗（進行中） 兩項III期試驗：入組1700例初步療效：RR 53.7%（CR 5%) SD 27.9% 1年生存率 80% GISTIII期臨床試

16、驗（進行中） GIST建議推薦治療模式 GIST能切除者：手術(shù)伊馬替尼GIST不能切除者：伊馬替尼治療手術(shù) 伊馬替尼治療GIST廣泛轉(zhuǎn)移者：伊馬替尼治療 建議推薦治療劑量400600mg/d,治療時間不少于4個月。 GIST建議推薦治療模式 GI GISTGIST診治進展小結(jié) GIST是一種免疫表型上表達c-kit蛋白（CD117）、遺傳學(xué)上存在頻發(fā)性c-kit基因突變、組織學(xué)上以富于梭型和上皮細胞呈束狀或彌漫性排列為特征的胃腸最常見的間葉源性腫瘤. GISTGIST診治進展小結(jié) GISTGIST診治進展小結(jié) CD117和CD34是檢測確診GIST的關(guān)鍵環(huán)節(jié).依據(jù)腫瘤是否表達c-kit可作為G

17、IST與胃腸道其他間葉腫瘤（平滑肌瘤、平滑肌肉瘤、神經(jīng)鞘瘤和神經(jīng)纖維瘤等）的鑒別診斷。 GISTGIST診治進展小結(jié) GISTGIST診治進展小結(jié) GANT表達c-kit蛋白，存在c-kit基因突變，形態(tài)學(xué)相識于GIST，故可視為具有神經(jīng)內(nèi)分泌顆粒的GIST變型。 GISTGIST診治進展小結(jié) GISTGIST診治進展小結(jié) 依據(jù)腫瘤的大小、生長方式、瘤細胞異型性、核分裂和腫瘤性壞死等大體和鏡下表現(xiàn)，可對大多數(shù)GIST生物學(xué)行為作出正確判斷。 GISTGIST診治進展小結(jié) GISTGIST診治進展小結(jié) GIST治療模式是以手術(shù)伊馬替尼為主的綜合治療伊馬替尼使GIST治療進入分子靶向治療時代 GI

18、STGIST診治進展小結(jié) GISTGIST診治進展小結(jié) 伊馬替尼是目前治療轉(zhuǎn)移性、不能切除胃腸間質(zhì)瘤的有效手段，推薦劑量400mg/d伊馬替尼的耐藥性、治療時機和時間、完全緩解（CR）率低、能否用于術(shù)后輔助治療、聯(lián)合用藥提高療效等問題尚待研究 GISTGIST診治進展小結(jié) GISTGIST診治進展小結(jié) 伊馬替尼治療GIS的總的有效率經(jīng)過大量病例驗證在81左右。手術(shù)是胃腸道間質(zhì)病主要和首選的治療手段。淋巴結(jié)清掃不提倡 GISTGIST診治進展小結(jié) GISTGIST診治進展小結(jié) 間質(zhì)瘤擴大切除的切緣，具體數(shù)值病沒有統(tǒng)一的標(biāo)準，因此建議手術(shù)中根據(jù)腫瘤大小、性質(zhì)、部位、年齡及全身狀況綜合考慮后確定手術(shù)

19、切緣和切除范圍。聯(lián)合臟器切除不提高生存率 GISTGIST診治進展小結(jié) GISTGIST診治進展小結(jié) 胃腸道間質(zhì)瘤常有 內(nèi) 何包膜，具有在一定的張力、易破潰，建議在手術(shù)原則上不主張瘤體觸摸探查。如認為可以切除，即行非接觸性手術(shù)切除，避免腹腔內(nèi)種植轉(zhuǎn)移。 GISTGIST診治進展小結(jié) GISTGIST診治進展小結(jié) 常見的復(fù)發(fā)和轉(zhuǎn)移部位使腹腔和肝臟，不在單個可以切除的復(fù)發(fā)轉(zhuǎn)移病灶，仍推薦再次手術(shù)。 但文獻報道再次手術(shù)不提高生存，因此再次手術(shù)只限于解除急癥和減少腫瘤負荷，價值有限。 GISTGIST診治進展小結(jié) GISTGIST診治進展小結(jié) 對于惡性腫瘤能評價腫瘤高危險度的間質(zhì)患者建議術(shù)前服用格列衛(wèi)

20、輔助治療，對于復(fù)發(fā)轉(zhuǎn)移或者無法手術(shù)切除的間質(zhì)瘤患者也推薦首選格列衛(wèi)治療。 GISTGIST診治進展小結(jié) GIST尚未解決 存在問題 藥物的最佳劑量和療程輔助及分析輔 助治療藥物的耐藥問題手術(shù)的地位和價值等等尚須進一步探索和總結(jié) GIST尚未解決 存在問題 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