伊马替尼耐药胃肠间质瘤治疗药物的研究进展

胃肠间质瘤是胃肠道发生频率最高的间质来源的恶性肿瘤,彻底手术切除是其获得根治的唯一方法,但术后复发和转移的频率较高。伊马替尼在2002年被美国食品药品管理局(FDA)批准用于胃肠间质瘤的治疗,但治疗失败的病例依然不可避免。原发耐药和继发耐药是伊马替尼治疗胃肠间质瘤失败的主要耐药机制。相关指南推荐已获批准的用于伊马替尼治疗失败后的酪氨酸激酶抑制剂舒尼替尼和瑞戈非尼作为二、三线药物治疗,同时ATP类似物索拉非尼、尼洛替尼、帕唑帕尼、帕纳替尼和马赛替尼,其他TKI药物,如达沙替尼、瓦塔拉尼、莫特塞尼,以及其他靶向治疗药物依维莫司和ganetespib在临床试验中显示出对伊马替尼耐药胃肠间质瘤有效。综述伊马替尼治疗失败后用于临床治疗胃肠间质瘤的治疗药物的作用机制、临床应用、作用特点和主要副作用,为临床胃肠间质瘤的治疗药物选择提供参考。     

舒尼替尼治疗伊马替尼耐药晚期胃肠间质瘤的药物经济学评价

目的:比较舒尼替尼和大剂量伊马替尼用于既往伊马替尼治疗耐药的晚期胃肠间质瘤患者的二线治疗的成本-效果。方法:基于Ⅲ期临床试验的研究数据,结合我国相关药物和不良反应治疗成本,利用TreeAge软件建立Markov模型,对两种用药方案进行成本-效果分析。结果:进口药组大剂量伊马替尼和舒尼替尼方案的成本-效果比分别为45 806.19元/质量调整生存月(QALM)和20 330.79元/QALM,计算得到增量成本-效果比超出意愿支付阈值,舒尼替尼为优势药物。国产药组大剂量伊马替尼和舒尼替尼方案的成本-效果比分别为5 855.50元/QALM和15 101.70元/QALM,伊马替尼为优势药物。敏感性分析的结果与成本-效果分析一致。结论:对于伊马替尼耐药的晚期胃肠间质瘤患者,进口药组舒尼替尼治疗比大剂量伊马替尼治疗具有更好的经济性,但在国产药组中大剂量伊马替尼比舒尼替尼治疗具有经济学优势。     

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。     

胃肠间质瘤术后复发临床药物治疗研究

目的探讨胃肠间质瘤术后复发临床应用甲磺酸伊马替尼药物治疗效果。方法选择我院2007年3月至2008年9月收治胃肠间质瘤术后复发患者6例,经CT或MRI检查证实为术后复发,首次服用给予甲磺酸伊马替尼剂量400 mg,1次/d。服药1个月后,观察患者病症改善情况,病症有改善患者,减量至300 mg,1次/d。患者服药1~24个月。结果患者1年生存率为83.33%,2年生存率为66.67%。服药1个月后疗效评价,无完全缓解病例,部分缓解(PR)患者3例(50.0%),稳定(CD)患者2例(33.33%),进展(PD)患者1例(16.67%),总有效率为50.00%,总获益(CR+PR+SD)率83.33%。结论甲磺酸伊马替尼治疗胃肠间质瘤术后复发,起效时间短,患者耐受性好,安全性高,值得临床推广。     

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。     

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.     

多靶点抗肿瘤药物舒尼替尼研究进展

舒尼替尼是目前已知的作用靶点最多的靶向抗肿瘤药物之一,具有广谱的抗肿瘤活性。2006年1月美国食品药品管理局（FDA）批准舒尼替尼用于治疗转移性肾细胞癌和不能耐受或伊马替尼治疗失败的转移性胃肠道间质瘤,2008年5月在我国上市。本文就舒尼替尼的作用机理和临床研究进展作一综述。     

67例胃肠道间质瘤患者伊马替尼辅助治疗的临床观察

目的探讨胃肠道间质瘤(GIST)伊马替尼辅助治疗的临床疗效。方法收集青岛市市立医院及川北医学院附属医院2007年1月至2012年12月间共67例手术切除的胃肠道间质瘤患者临床及随访资料进行回顾性分析。结果 39例局限性患者在随访期间未发生确切转移性病灶;28例转移患者中,伊马替尼治疗2³个月后临床及影像学评价:部分缓解6例,稳定14例,病情进展8例,其中3例患者对伊马替尼耐药,治疗期间病情持续进展,追加剂量后病情仍未控制,后患者放弃治疗,33个月后临床及影像学评价:部分缓解6例,稳定14例,病情进展8例,其中3例患者对伊马替尼耐药,治疗期间病情持续进展,追加剂量后病情仍未控制,后患者放弃治疗,3⁶个月后患者死亡。另5例患者在开始治疗66个月后患者死亡。另5例患者在开始治疗6¹2个月内病情稳定,后出现病情进展,在追加剂量后未能控制病情,患者行姑息性手术部分切除进展病灶后继续行伊马替尼治疗,患者病情稳定。结论胃肠道间质瘤伊马替尼辅助治疗能改善患者的愈后,长期使用伊马替尼的患者肿瘤复发率较低,且多数不良反应患者可以耐受。对于高风险的GIST患者推荐手术结合伊马替尼长期维持治疗。     

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,     

胃肠道间质瘤术后肝转移的临床分析

目的探讨胃肠间质瘤术后肝转移的治疗策略。方法回顾性分析2010年4月至2014年4月收治的16例GIST术后肝转移患者的临床资料、消融治疗及生存情况。结果 9例患者(56.3%)依然存活,其中5例(31.3%)无瘤生存,4例(25.0%)带瘤生存;1年、2年生存率分别为81.3%和56.3%。7例患者进行了微波消融,所有患者均接受伊马替尼400~600 mg/d治疗,耐药改用舒尼替尼治疗。随访期内微波消融组、未消融组中位生存时间分别为25.4、15.7个月。结论对于GIST术后肝转移病例应该首选靶向治疗,靶向治疗联合消融治疗可能是GIST术后肝转移的较佳治疗模式。     

胃肠道间质瘤诊断与治疗的临床研究

目的：分析胃肠道间质瘤临床常用的诊断与治疗方法,并对其方法的有效性、安全性进行研究。方法：选择2005年1月～2010年1月在本院进行了手术治疗的胃肠道间质瘤患者共65例作为治疗组,随机选择同一时段86例胃、结直肠癌患者做为对照组,比较分析治疗组与对照组的CT、消化道造影、内镜＋活检资料的临床价值。将该组胃肠道间质瘤患者按照手术后是否服用甲磺酸伊马替尼分为两组,治疗组：手术＋甲磺酸伊马替尼,对照组：手术。分析二者在疗效上的差异。结果：CT、消化道造影、内镜＋活检等临床资料显示出能够帮助诊断的显著性的差异。是否服用甲磺酸伊马替尼在复发、转移、生存时间等方面具有显著性差异。结论：临床资料不能确诊胃肠道间质瘤,但能够提供相当准确的临床诊断;GIST术后复发率很高,甲磺酸伊马替尼对防止转移、复发、延长生存时间有良好的疗效。     

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.     

Sunitinib: a newly approved small-molecule inhibitor of angiogenesis

The advent of targeted therapies has allowed treatment to be directed at signaling pathways integral to tumor growth and survival. Sunitinib (SU11248, sunitinib malate; Pfizer Inc., New York, NY, USA) is a novel oral small-molecule multitargeted receptor tyrosine kinase inhibitor that has demonstrated direct antitumor activity and antiangiogenic action. It targets the vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), stem-cell factor receptor and Fms-like tyrosine kinase receptor 3 receptor tyrosine-kinases. In January 2006, sunitinib malate was granted approval by the U.S. Food and Drug Administration for the treatment of gastrointestinal stromal tumor after disease progression on, or intolerance to, imatinib mesylate, as well as for the treatment of metastatic renal cell cancer. This review will discuss the development of sunitinib, particularly in acute myeloid leukemia, imatinib-resistant gastrointestinal stromal tumors and renal cell cancer. The review will also discuss ongoing trials with sunitinib in other malignancies such as neuroendocrine tumors and breast cancer, as well as its potential future development in combination therapy with other agents and in other malignancies.     

Neoadjuvant imatinib for unresectable gastrointestinal stromal tumor

We have evaluated the feasibility of the use of neoadjuvant imatinib mesylate in the management of unresectable localized gastrointestinal stromal tumors. In a pilot experience, two patients with unresectable gastrointestinal tumors were treated with neoadjuvant imatinib. Their treatment course and surgical outcomes are described. In both cases, the patient attained sufficient tumor regression to enable complete resection of tumor. We conclude that in the management of unresectable gastrointestinal stromal tumors, neoadjuvant administration of imatinib may facilitate sufficient tumor regression to facilitate subsequent tumor resection with curative intent.     

Emphysematous cholecystitis in a patient with gastrointestinal stromal tumor treated with sunitinib

A 50-year-old man had a metastatic gastrointestinal stromal tumor that was refractory to imatinib. He was prescribed a 6-week course of treatment with oral sunitinib 50 mg/day. During the fourth week of his first cycle of treatment with the drug, the patient developed acute-onset, right upper quadrant pain associated with nausea, vomiting, and fever; laboratory tests revealed leukocytosis and mild hyperbilirubinemia. He was diagnosed with acute emphysematous cholecystitis, which was treated with broad-spectrum antibiotics and percutaneous cholecystostomy. His symptoms resolved, and he successfully completed his course of therapy with sunitinib. Using the Naranjo adverse drug reaction probability scale, a score of 5 was derived, which indicates that the likelihood was probable that this adverse event was caused by sunitinib.     

Gastrointestinal stromal tumor of the rectum: report of three cases

Gastrointestinal stromal tumors (GISTs) account for about 0.2% of all malignancy of gastrointestinal tumors and rarely arise in the rectum. We experienced three patients with large GISTs in the rectum. Case 1 (66-year-old man) underwent abdominoperineal resection (APR) for intrapelvic mass. The tumor was 90 mm and diagnosed to be a Kit-positive GIST. Case 2 (81-year-old woman) underwent right hemicolectomy for concurrent ascending colon cancer by a local physician. In our Hospital, APR was performed for intrapelvic mass. The tumor was 90 mm and diagnosed to be a Kit-positive GIST. Ten months after surgery, multiple liver tumors developed. She received oral imatinib for metastases. Case 3 (83-year-old woman) was yielded a diagnosis of Kit-positive GIST by a percutaneous biopsy. Imatinib was given preoperatively. However, adverse reactions occurred and the drug was withdrawn. APR was performed. The tumor was 70 mm. At present, Case 1 and 3 patients are alive without recurrence.     

胃肠间质瘤122例的预后因素分析

目的 探讨胃肠间质瘤（GISTs）的预后影响因素,为预后评估提供参考.方法 回顾性分析我院122例手术切除且病理确诊的GIST患者的临床特征、病理和免疫组化检查结果、治疗、随访情况,用Log-rank检验/COX模型进行单因素及多因素预后分析.结果 GISTs好发于中年人,胃为好发部位;肿瘤部位、肿瘤大小、核分裂数、肿瘤性坏死、肿瘤细胞显著异型、P53突变、Ki67表达、手术方式是GISTs的预后相关因素.COX多因素分析显示：肿瘤大小、肿瘤细胞显著异型、手术方式3个因素是GISTs预后的独立影响因素.结论 GISTs是具有恶性潜能的消化道间叶肿瘤,肿瘤大小、肿瘤细胞显著异型、手术方式是影响GISTs预后的重要因素,采用R0切除的患者预后较好.