2010 ASCO年会胃肠道间质瘤研究进展对临床实践的启示

基因分型实现伊马替尼个体化辅助治疗胃肠道间质瘤 2007年ASCO年会首次报告了伊马替尼辅助治疗胃肠道间质瘤（GIST）的随机对照ACOSOGZ9001研究结果,即伊马替尼辅助治疗1年可改善肿瘤直径〉3cm的GIST患者的术后无复发生存（RFS）率。c—kit（一种原癌基因）／血小板衍生生长因子受体A（PDGFRA）基因突变状态可以预测伊马替尼治疗晚期GIST的疗效,     

肿瘤治疗药物Mastinib的Ⅱ期临床试验结束

2012年2月1日。法国AB Science制药公司宣布其在研的肿瘤治疗药物Masitinib用于对伊马替尼耐药的胃肠道间质瘤（GIST）患者的Ⅱ期临床试验取得积极结果。这项试验的受试者为不可手术的局部晚期或转移性GIST患者．且之前在接受伊马替尼治疗期间出现疾病恶化。试验显示．Masitinib治疗组患者在接受治疗18个月后和2年后的生存率均显著高于舒尼替尼对照组。     

中国胃肠间质瘤患者服用伊马替尼稳态谷浓度的初步分析

目的：研究中国胃肠间质瘤（gastrointestinal stromal tumor,GIST）患者服用伊马替尼稳态浓度的分布情况,为开展伊马替尼治疗药物浓度监测和个体化治疗提供依据。方法：收集服用甲磺酸伊马替尼达稳态（29 d）的GIST患者血浆,HPLC-MS/MS法检测血浆伊马替尼浓度。分析不同剂量伊马替尼血药浓度的差异以及个体间和个体内变异。结果：共收集88例GIST患者的154份血浆样本。服用伊马替尼600 mg·d^-1（n=4）、400 mg·d^-1（n=81）、300 mg·d^-1（n=1）、200 mg·d^-1（n=2）的患者血药浓度分别为（3 032.50±679.94）ng·mL^-1,（1 525.14±599.87）ng·mL^-1,1 155 ng·mL^-1,（655.57±21.92）ng·mL^-1。伊马替尼个体间变异39.57%,个体内变异为22.32%。单变量分析显示,伊马替尼血药浓度与性别、年龄、肿瘤切除部位以及是否转移无关。结论：中国GIST患者服用伊马替尼血药浓度个体差异较大,十分有必要进行血药浓度监测。     

伊马替尼停药后复发胃肠道间质瘤的临床特征与KIT/PDGFR基因突变分析

目的 探讨转移性胃肠道间质肿瘤(GIST)患者术后伊马替尼辅助治疗过程中,停药与复发的关系,以及KIT第11外显子突变的患者复发后,对伊马替尼的敏感性研究和预后监测. 方法 对GIST患者复发前后临床特征进行分析比较;利用免疫组织化学的方法 辅助诊断和分析复发前后CD117,CD34等GIST细胞标志物的表达情况;采用基因测序的方法 进行KIT/PDGFR基因突变检测. 结果GIST患者术后,规范伊马替尼治疗3年,停药后1年余腹部包块证实为GIST复发;患者KIT 基因第11外显子检测出有缺失突变：c.1667_1672delAGTGGA,提示该患者仍然对伊马替尼敏感;对于诊断GIST,DOG1比CD34更敏感. 结论 伊马替尼的连续用药延长无进展生存时间及延缓GIST复发,DOG1具有比CD34更好的敏感性,更加适合作为GIST的诊断标记物.     

不同剂量伊马替尼治疗进展期胃肠间质瘤的疗效分析

目的:探讨伊马替尼治疗进展期胃肠间质瘤(gastrointestinal stromal tumor,GIST)和外显子11及9突变病人对高剂量伊马替尼的疗效.方法:计算机检索PubMed、ISC Proceedings、ScienceDirect数据库、OVID数据库等,应用RevMan 5.0.18软件进行Meta分析.结果:共纳入5篇文献,合计2729例病人,各试验间具有基线可比性.Meta分析结果示:高剂量组800mg/d与标准剂量组400 mg/d相比,并不能明显提高患者总生存率;高剂量组800 mg/d对外显子9突变病人与外显子11突变病人相比可显著提高其总生存率(P＜0.0001).结论:对于进展期GIST病人,伊马替尼标准治疗剂量为400mg/d,但对于外显子9突变病人推荐使用高剂量伊马替尼800mg/d.     

FDA批准扩大伊马替尼在罕见胃肠癌患者中的应用

资料来源:FDA网站发布时间:2012.1.31验证性实验表明伊马替尼具有显著的有效延长患者的生存期,药品应给予定期审批。美国食品药品管理局(FDA)今天允许定期审批伊马替尼在成人患者CD117阳性的胃肠道间质瘤(GIST)手术切除后的使用。今天的行为也凸显了,当药物服用为36个月而不是标准的12个月治疗时,患者整体的生存期延长了。     

增加伊马替尼剂量可延长胃肠道间质瘤患者的生存期

诺华公司日前宣布，新的临床研究结果显示，用2倍标准剂量的伊马替尼(imatinib mesylate，格列卫，Gleevec)治疗胃肠道间质瘤(GIST)，可延长患者无疾病发展生存期。     

胃肠道间质瘤术后复发因素分析及药物治疗

目的探讨胃肠道间质瘤的术后复发因素和药物治疗。方法选取2012年12月至2016年9月我院收治并手术的52例胃肠道间质瘤患者。术后均予以伊马替尼400 mg/d治疗,其中先后有21例出现病灶复发,对比分析复发因素,10例给予增加伊马替尼剂量(伊马替尼组),达600 mg/d,11例改为口服舒尼替尼50 mg/d(舒尼替尼组),比较两组病灶范围、不良反应以及总生存率。结果肿瘤直径超过10 cm,未能达到R0根治,核分裂像大于10/50HRF以及高危患者,术后复发率明显增高。治疗上增加伊马替尼剂量(伊马替尼组),病灶范围未见明显缩小,且大部分患者出现药物毒性,而舒尼替尼组病灶范围部分缩小或消失,且总生存率高于伊马替尼组(P<0.05)。结论肿瘤的大小、根治程度、核分裂像以及危险度等级均是胃肠间质瘤术后复发的独立危险因素,而术后常规剂量应用伊马替尼仍有复发时,应及时更换二线药物舒尼替尼。     

胃肠道间质瘤的治疗现状

胃肠道间质瘤是一类起源于胃肠道间叶组织的肿瘤。目前治疗方法主要包括手术治疗和药物治疗。在药物治疗中,伊马替尼治疗不可切除/转移/复发GIST疗效显著,使得伊马替尼辅助治疗的应用日益受到重视。     

舒尼替尼对胃肠道间质瘤患者二线治疗的临床观察

目的 探讨二线药物舒尼替尼治疗胃肠道间质瘤(GIST)的疗效及安全性.方法 回顾性分析经病理组织和免疫组化确诊的GIST患者32例,所有的患者均用二线药物舒尼替尼治疗,37.5 mg·d-1口服,连续给药服用.观察评估舒尼替尼的不良反应及患者的生存时间.结果 舒尼替尼治疗GIST的不良反应轻微,且均可控制.32例患者接受舒尼替尼治疗的时间为3~72个月,中位治疗时间为24个月.获得完全缓解(CR)1例,部分缓解(PR)7例,稳定期(SD)16例,进展(PD)8例,有效率25.0%,疾病控制率75.0%.32例患者中,中位随访时间为96周,中位无进展生存期(PFS)为55周,中位总生存时间(OS)为96周.结论 舒尼替尼治疗伊马替尼耐药进展的GIST疗效可靠,不良反应轻微,安全可控.     

Decrease of CD117 expression as possible prognostic marker for recurrence in the resected specimen after imatinib treatment in patients with initially unresectable gastrointestinal stromal tumors: a clinicopathological analysis

Gastrointestinal stromal tumors (GIST) are the most common malignant mesenchymal tumors of the gastrointestinal tract. The principal treatment modality for primary GIST is surgery whereas for metastatic GIST, imatinib has an established role. In patients with locally advanced and metastatic GIST, the role of surgery in the imatinib era is still unclear. Fifteen patients with locally advanced (n=9) and/or metastatic GIST (n=6) were treated with imatinib followed by resection. Detailed histopathological examination was performed before and after treatment with imatinib, which was given for a median of 11 months before surgery. Ten patients showed a radiographic partial response, four patients had stable disease, and one patient progressed. At the time of surgery, the median tumor diameter was 6.5 cm. In all the nine patients with locally advanced GIST, a R0 resection could be performed. Histopathological examination showed imatinib effects in all tumors, including the case with progressive disease. All patients with locally advanced disease (n=9) were alive after a median follow-up of 40 months (range: 18-59), of which seven patients were free of disease. Four of the six patients treated for metastatic GIST died of disease after 30, 45, 50, and 74 months of follow-up. Remarkably, in five of six patients in whom CD117 expression was diminished or lost in the resection specimen, disease recurrence was observed. In patients with retained CD117 expression, one of the nine patients had recurrent disease. In conclusion, preoperative imatinib treatment in patients with locally advanced GIST resulted in a decrease of tumor load in most patients, enabling complete surgical resection. For patients with metastatic GIST, the role of surgery remains less clear. Loss or decrease of CD117 expression in the resected specimen after imatinib treatment may be associated with disease recurrence.     

胃肠间质瘤的诊断与治疗分析

目的探讨胃肠道间质瘤(GIST)的诊断及治疗方法。方法回顾性分析经手术后病理证实的GIST 16例临床资料。结果肿瘤位于胃部10例,小肠5例,直肠1例。其中12例达到外科根治性切除。2例因肿瘤广泛转移行姑息切除。2例伴肝转移者中1例行原发灶及转移灶切除,1例不能切除的肝转移灶,术后辅以药物治疗。术后平均随访22个月,12例中术后复发转移3例,复发间期平均14个月,其中2例再次手术治疗,其他1例带瘤生存12个月。结论外科手术切除原发灶及肝转移灶是治疗GIST的首选有效方法,不易切除的肝转移灶,术后应辅以药物治疗。GIST远期仍存在较高的复发转移率。对复发转移病例,仍应争取再手术治疗。     

胃肠道间质瘤90例诊治分析

目的 探讨胃肠道问质瘤(gastrointestinal stromal tumor,GIST)的临床及病理特点、治疗方法和预后.方法 对2003年1月至2010年12月90例经病理确诊为GIST患者的临床资料进行回顾性分析并复习文献.结果 患者最常见的临床表现为消化道出血34例(37.8%),腹痛32例(35.6...     

Imatinib: a review of its use in the management of gastrointestinal stromal tumours

Imatinib (Gleevec, Glivec is a small molecule inhibitor of tyrosine kinase that has been evaluated for efficacy in patients with gastrointestinal stromal tumours (GIST). The drug is approved for the treatment of unresectable and/or metastatic, KIT-positive GIST in the US, Europe and many other countries. Imatinib has had a significant impact on the management of advanced GIST, which has traditionally had a poor prognosis, and has quickly become the first choice of treatment in the medical therapy of unresectable and/or metastatic, KIT-positive GIST. In randomised, nonblind trials, imatinib 400-800 mg/day produced complete or partial responses in up to two-thirds of patients, with long-term efficacy, and substantially prolonged progression-free and overall survival. The drug was generally well tolerated in GIST patients, including during long-term treatment. Imatinib dosages higher than 400 mg/day (up to 800 mg/day) may improve progression-free survival, with an increase in dosage benefiting some patients who show disease progression at the lower dosage, particularly in those with exon 9 mutation; however, there is also a dose-related increase in imatinib toxicity. Mutational genotype and other, non-biomolecular factors may aid in guiding imatinib therapy and predicting prognosis in GIST patients. Further data are required to evaluate the use of imatinib in adjuvant and neoadjuvant settings. Nevertheless, imatinib currently provides the most effective treatment option in the management of advanced GIST.     

Is there something other than imatinib mesilate in therapeutic options for GIST?

INTRODUCTION: In the last decade, the introduction of imatinib mesilate into the clinical practice has resulted in a dramatic improvement in the treatment of gastrointestinal stromal tumor (GIST). Nowadays, the median overall survival in patients with advanced disease has increased to 5 years, while recent Phase III trials demonstrated that imatinib mesilate can be successfully employed as adjuvant therapy in patients at significant risk of recurrence. Despite these good results, the emergence of secondary resistance represents the main cause of treatment failure. In recent years, many efforts have been made in search of drugs to overcome imatinib mesilate resistance; some of these have been employed as second-line treatment or salvage therapy. AREAS COVERED: Summarized and investigated in this paper are the results obtained by imatinib mesilate in advanced and adjuvant setting, the role of sunitinib malate as second-line therapy in imatinib mesilate-resistant patients and the clinical results concerning new drugs, mainly tyrosine-kinase inhibitors. EXPERT OPINION: Current research on novel therapeutic agents, as third-line treatments in GIST, is ongoing. However, despite the promising results obtained with the new molecules, imatinib mesilate remains the cornerstone in the medical treatment of GIST and to date no other drugs can replace it.     

Imatinib: as adjuvant therapy for gastrointestinal stromal tumour

Imatinib is a protein-tyrosine kinase inhibitor with antitumour effects in patients with gastrointestinal stromal tumour (GIST) that is indicated for the treatment of unresectable and/or metastatic GIST and as adjuvant therapy in patients with KIT-positive GIST. Imatinib binds to and inhibits KIT and platelet-derived growth factor receptor (PDGFR)-α tyrosine kinases, interfering with their downstream tumourogenic processes. Cell lines with KIT mutations that are common in patients with GIST were sensitive to imatinib at low in vitro concentrations. Patients with exon 11 KIT mutations were significantly more likely to have partial tumour responses and longer overall survival (OS) and were significantly less likely to have progression of disease than patients with exon 9 KIT mutations or no detectable KIT or PDGFR mutations. In a large (n?>?700) randomized, double-blind, placebo-controlled, multinational trial (ACOSOG [American College of Surgeons Oncology Group] Z9001), patients who received 1 year of adjuvant treatment with oral imatinib 400?mg/day after surgical resection of GIST had significantly longer recurrence-free survival than placebo recipients, with an overall hazard ratio of 0.35 (95% CI 0.22, 0.53) [primary endpoint]. At the time of reporting, there was no significant between-group difference in OS. In patients with GIST who received adjuvant imatinib in this trial, adverse events were mostly of mild or moderate severity; the imatinib treatment group had an almost 2-fold higher rate of US National Cancer Institute Common Toxicity Criteria grade 3 or 4 adverse events than the placebo group.     

Impressive long-term disease stabilization by nilotinib in two pretreated patients with KIT/PDGFRA wild-type metastatic gastrointestinal stromal tumours

KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumours (GISTs) showed a response rate to imatinib ranging from 0 to 25%. Nilotinib is a new-generation tyrosine kinase inhibitor that has demonstrated clinical activity in pretreated GIST patients. At present, no correlation between nilotinib activity and clinical/pathological/molecular features is available. We report on two WT GIST patients resistant to imatinib and sunitinib, and enrolled in the CAMN107A2201 study who achieved an impressive disease control by nilotinib. Both patients have germ-line mutations in the SDHA gene. In April 2004, a 39-year-old woman presented gastric GIST with multiple liver metastases and was treated with imatinib 400 mg/day, followed by imatinib 800 mg/day and then sunitinib. In August 2007, because of disease progression, she was enrolled in the CAMN107A2201 study and assigned to the nilotinib 800 mg/day arm. In March 2005, a 27-year-old woman started imatinib 600 mg/day and then sunitinib for gastric GIST with multiple liver and lung metastases. In October 2007, because of disease progression, she was enrolled in the CAMN107A2201 study and assigned to the nilotinib 800 mg/day arm. One patient still showed stable disease after 46 months of treatment according to the Response Evaluation Criteria In Solid Tumors, and a partial response after 9 months according to Choi's criteria. The other patient still showed stable disease after 42 months according to Response Evaluation Criteria In Solid Tumors. At present, they continue to receive nilotinib. We report very long-term disease stabilization under nilotinib treatment in two pretreated WT GIST patients. In-vitro studies and clinical analyses are warranted to evaluate a potential correlation between nilotinib activity and WT genotype or other clinical/pathological features.     

胃肠道间质瘤的治疗效果分析

目的探讨胃肠道间质瘤(GIST)的治疗方式及预后。方法回顾性分析2003年1月至2012年12月手术后经病理证实的43例GIST病例资料。结果肿瘤发生于胃部25例,十二指肠1例,小肠12例,结肠4例,直肠1例。行腹腔镜下胃肿瘤切除术5例、直肠肿瘤切除1例;37例行开腹手术,29例完整切除,其中6例发现肝脏、大网膜转移,行联合脏器切除,2例广泛转移行姑息性手术。无手术死亡病例。30例获随访,9例术后复发,其中7例出现肝脏转移。结论手术切除是GIST治疗的首选,术前转移、Fletcher分级和是否口服甲磺酸伊马替尼与疾病的预后密切相关     

胃肠间质瘤46例临床分析

目的探讨胃的胃肠间质瘤(GIST)临床特点和影响预后的因素。方法回顾性分析手术治疗的46例胃GIST患者的临床、病理资料。结果病变部位:胃底贲门17例(37.0%),胃体22例(47.8%),胃窦部5例(10.9%),占据胃壁两个部位2例(4.3%)。肿瘤直径1.0-15.0cm。全组患者均行肿瘤完整切除;淋巴结清扫11例,未发现转移淋巴结。免疫组织化学染色,CD117阳性率91.3%(42/46),CD34阳性率80.4%(37/46)。40例患者获随访,1、3和5年生存率分别为94.7%、80.2%和56.6%。单因素分析显示,Fletcher分级、肿瘤大小、肿瘤侵犯其他脏器、转移和口服甲磺酸伊马替尼对生存率有影响(P<0.05或P<0.01)。结论手术是治疗胃GIST的主要方法。转移是影响胃GIST预后的独立危险因素。Fletcher分级是判断胃GIST生物学行为及预后简单有效的方法。