State-of-the art therapy for gastrointestinal stromal tumors

Until recently, there were few effective therapeutic options for patients with gastrointestinal stromal tumors (GISTs). Most patients undergoing even potentially curative resection for early-stage disease recurred if followed for a sufficiently long period, and treatment of advanced tumors with systemic chemotherapy was ineffective. Imatinib mesylate, a molecularly targeted agent that inhibits the KIT receptor tyrosine kinase, has now been demonstrated to be highly effective at inducing objective responses in GIST patients, and it improves overall survival. In locoregional disease, ongoing studies are assessing the use of imatinib pre-or postsurgery. In addition, other agents possessing activity against a variety of molecular targets are being tested in advanced disease. Questions remain about the optimal dose of imatinib, whether to continue drug in the setting of progressive disease, and how best to prevent or overcome resistance.     

甲磺酸伊马替尼治疗胃肠间质瘤毒副作用的深化研究*

目的　进一步观察甲磺酸伊马替尼治疗胃肠间质瘤（ＧＩＳＴ）患者的毒副反应。方法　入组１２８例患者,均口服甲磺酸伊马替尼剂量４００ｍｇ／天,病情进展患者部分加量至６００ｍｇ／天。自服药起观察毒副反应,直至患者死亡或随访结束。结果　甲磺酸伊马替尼毒副反应多发生于治疗的最初１年内,大多数长期服药患者的毒副反应发生率及严重程度增加不显著。常见毒副反应多为１～２级,高剂量组毒副反应未见明显增加。新观察到的毒副反应包括记忆力下降、语言迟缓、阴囊水肿、指甲凸凹不平、皮下瘀斑、肾病综合征样表现,未出现消化道大出血及肿瘤溶解综合征。原发部位、剂量水平、有无肝转移对毒副反应的发生率无显著影响（Ｐ＞０.０５）;性别和年龄对毒副反应的发生率有显著影响（Ｐ＜０.０５）。结论　甲磺酸伊马替尼毒副反应轻微,患者耐受性较好,但药物说明书和文献未提及的毒副反应尤其值得关注。     

Preoperative imatinib mesylate for unresectable or locally advanced primary gastrointestinal stromal tumors (GIST)

Aim

To explore the effect of preoperative imatinib mesylate (IM) in patients with unresectable or locally advanced primary gastrointestinal stromal tumor (GIST).

Methods

From January 2003 to January 2008, all patients affected by bulky localized GIST who presented at our institution were considered for preoperative IM with cytoreductive intent. Clinical, pathological and molecular characteristics were assessed and the rate of response recorded. Progression-free survival (PFS) was calculated according to Kaplan–Meier analysis.

Results

Fifteen patients (1 esophageal, 7 gastric, 3 duodenal, 4 rectal GISTs) received preoperative IM for a median of 9 months. All patients had tumor shrinkage, with a median size reduction of 34%. One patient had radiological complete response. In all cases an improvement of the originally planned surgical procedure was obtained: 3 patients initially considered unresectable underwent complete surgery; 7 patients with initial indication for extensive surgery were more conservatively operated on; 4 patients initially deemed at high perioperative risk underwent safe surgery. Due to the small sample size, no association between tumor shrinkage and tumor site, size, IM duration, mutational status and pathological response could be formally explored. PFS at 3 years from IM onset was 77%.

Conclusions

In unresectable or locally advanced GISTs, preoperative IM is a useful tool both to improve resectability and reduce surgical morbidity. It should be therefore always be considered before embarking on a major surgical procedure. The long-term impact of IM on PFS and survival is presently under investigation in multicenter prospective randomized trials.     

甲磺酸伊马替尼治疗晚期胃肠间质瘤的疗效及预后因素

目的:探讨口服甲磺酸伊马替尼治疗晚期胃肠间质瘤患者的疗效及预后相关因素。方法:102例复发和(或)转移性胃肠间质瘤患者接受甲磺酸伊马替尼口服治疗(起始剂量为400mg/d,病情进展者加量至600mg/d)。结果:99例患者可评价疗效,其中8例(8.1%)完全缓解,68例(68.7%)部分缓解,20例(20.2%)疾病稳定,3例(3.0%)疾病进展;客观缓解率(完全缓解+部分缓解)为76.8%。中位无进展生存期(progression-free survival,PFS)为32.0个月,1、2和3年生存率分别为96.1%、81.2%和70.8%。居住在城市、美国东部肿瘤协作组(Eastern Cooperative Oncology Group,ECOG)体能状况(performance status,PS)<2分或客观缓解的患者有更长的PFS(P<0.05),而年龄<65岁、居住在城市、ECOG PS<2分、单纯肝转移或治疗后病灶密度降低的患者有更长的总生存期(P<0.05)。结论:口服甲磺酸伊马替尼治疗晚期胃肠间质瘤患者安全而有效。年龄、基线PS、近期疗效和治疗后病灶密度的变化是晚期胃肠间质瘤预后的重要相关因素。     

Adherence to imatinib therapy in patients with gastrointestinal stromal tumors

Imatinib mesylate, an oral tyrosine kinase inhibitor, is indicated for first-line treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumors (GIST). Imatinib also is approved as adjuvant therapy for patients following resection of primary GIST. Despite the efficacy of imatinib for the treatment of patients with GIST, adherence to treatment can prove difficult.     

Optimal thresholds of risk parameters for gastrointestinal stromal tumors

BackgroundGastrointestinal stromal tumors (GIST) are the most frequent mesenchymal neoplasms of the gastrointestinal tract with highly variable potential for relapse. Tumor size and mitotic index (MI) are major risk factors that predict the outcome of GIST patients. Recent risk stratification schemes include some or all of the empirical size thresholds of 2 cm, 5 cm, and 10 cm and MI thresholds of 5 per 50 high-power fields (hpf) and 10 per 50 hpf. However, data that verify these numbers are sparse.MethodsBy exhaustive regression tree analysis, maximally selected rank statistics and survival difference analysis with bootstrap sampling on a naive GIST population of 161 patients with a mean follow-up of 44 months, current stratification schemes using tumor size and MI were analyzed herein.Results/Conclusions: Thresholds that optimally stratify the risk of recurrence are observed at tumor sizes of 4–5 cm and 10–11 cm and at mitotic indices of about 5 per 50 hpf and 10 per 50 hpf, respectively. While these data validate the canonical thresholds for size and MI used in risk stratification of GIST, transition regions as well as differences in the implementation of these thresholds between the different classification schemes proposed in the recent years should be considered when classifying GIST.     

胃间质瘤术前辅助伊马替尼治疗的临床意义

目的 胃肠间质瘤(Gastrointestinal stromal tumor,GIST)是胃肠道最常见的间叶来源性肿瘤,根治性手术是GIST获得治愈的唯一希望。为了提高手术根治性切除率,降低手术风险,提高生活质量,伊马替尼(IM)开始被尝试应用于GIST的术前治疗。方法 本研究回顾8例GIST术前辅助治疗后手术的诊疗经过。IM每日一次400mg口服,严密随访,评价疗效,并通过多学科讨论确定手术时机。用药时间12周~40周。对IM术前辅助治疗的临床疗效和安全性予以评价。结果 术前治疗部分缓解率62.5%。本组病例未出现不可耐受的不良反应。全部病例均获R₀切除,未出现术中肿瘤破裂。术后恢复顺利。结论 针对进展期胃部巨大GIST及近贲门区GIST,在多学科诊疗团队的监护下,术前辅助IM治疗安全有效,值得临床推广应用。     

Surgical treatment of locally advanced,non-metastatic,gastrointestinal stromal tumours after treatment with imatinib

Aims

Patients with locally advanced gastrointestinal stromal tumours (GISTs) have a high risk of tumour perforation, incomplete tumour resections and often require multivisceral resections. Long-term disease-free and overall survival is usually impaired in this group of patients. Induction therapy with imatinib followed by surgery seems to be beneficial in terms of improved surgical results and long-term outcome. We report on a large cohort of locally advanced GIST patients who have been treated in four centres in the Netherlands specialized in the treatment of sarcomas.

Methods

Between August 2001 and June 2011, 57 patients underwent surgery for locally advanced GISTs after imatinib treatment. Data of all patients were retrospectively collected. Endpoints were progression-free and overall survival.

Results

The patients underwent surgery after a median of 8 (range 1–55) months of imatinib treatment. Median tumour size before treatment was 12.2 (range 5.2–30) cm and reduced to 6.2 (range 1–20) cm before surgery. No tumour perforation occurred and a surgical complete (R0) resection was achieved in 48 (84%) patients. Five-year PFS and OS were 77% and 88%. Eight patients had recurrent/metastatic disease.

Conclusions

Imatinib in locally advanced GIST is feasible and enables a high complete resection rate without tumour rupture. The combination of imatinib and surgery in patients with locally advanced GIST seems to improve PFS and OS.     

甲磺酸伊马替尼治疗手术无法切除的晚期胃肠间质瘤

目的：探讨甲磺酸伊马替尼用于治疗晚期胃肠间质瘤的疗效及生存获益。方法：收集2004年9 月至2015年6 月天津医科大学肿瘤医院收治的无法手术切除的61例晚期胃肠间质瘤患者的临床资料,接受初始剂量400 mg/d 的口服甲磺酸伊马替尼治疗,定期随访,评价生存获益及药物不良反应。结果：61例患者开始接受治疗1 年后,治疗有效率为57.4%（35/ 61）,疾病控制率为88.5%（54/ 61）,Logic二元回归分析显示性别、年龄和腹盆腔多发病灶是影响治疗有效率的因素（P < 0.05）。 本组患者5 年累积生存率为53% ,Cox 回归模型分析提示腹盆腔的多发病灶是影响患者生存获益的重要因素（P < 0.05）。 除2 例患者出现出血,其余患者不良反应轻微。结论：甲磺酸伊马替尼显著改善晚期胃肠间质瘤的生存获益,可作为无法手术切除的晚期胃肠间质瘤的首选治疗。     

甲磺酸伊马替尼一线治疗复发／转移胃肠间质瘤患者的临床分析

目的 回顾性分析国人复发／转移的胃肠间质瘤（GISTs）患者一线应用甲磺酸伊马替尼的有效性、安全性以及预后的影响因素。方法 对2003年4月至2012年3月接受伊马替尼400mg／d一线治疗的患者进行随访,按RECIST 1.0版进行疗效评价,根据NCI CTC 3.0版标准进行毒副反应评价。应用SPSS 13.0统计学软件进行数据处理,分层分析影响国人肿瘤进展时间（TTP）和总生存时间（OS）的相关因素。结果 接受一线治疗的复发／转移GISTs 患者共105例,中位随访时间126个月（范围：44～348个月）,至随访截止日期死亡36例。获CR 8例（7.6％）,PR 62例（59.0％）,SD 14例（13.3％）,PD 21例（20.0%）;有效率为66.6％,疾病控制率为79.9％。全组患者的中位TTP为61.5个月,中位OS为600个月（95％CI：52.1～67.8个月）。接受辅助治疗与未接受辅助治疗、接受二线治疗与未接受二线治疗的患者比较,中位TTP和OS差异均无统计学意义;停药3～12个月组与停药3个月内组、未停药组的中位TTP差异均有统计学意义（P＜0.05）,而停药3个月内组与未停药组的差异无统计学意义;停药3～12个月组与停药3个月内组、未停药组的中位OS差异均有统计学意义（P＜0.05）,而停药3个月内组与未停药组的差异无统计学意义。主要毒副反应为乏力、皮肤黏膜水肿、白细胞减少、腹泻等,多为1～2级,未发生治疗相关性死亡。结论 对于复发／转移的GISTs患者,一线应用伊马替尼400mg／d治疗安全有效。结合中国患者的依从性和经济等因素,是否接受辅助治疗以及是否接受二线治疗对TTP和OS的影响可能不大,而中断治疗超过3个月可能会导致疾病进展,并最终转化为OS的劣势。     

胃肠间质瘤的外科治疗问题

 靶向治疗的问世使得胃肠间质瘤（GIST）的治疗发生了革命性的变化，但依然应强调外科原则和技巧在治疗GIST中的重要性。对位于食管、胃肠道、结直肠的GIST病例的治疗经验进行了总结。术中外科医师应尽可能完整切除肿瘤，如果术中无法完整切除，可予伊马替尼治疗。由于GIST甚少经淋巴途径转移，故不必常规行淋巴结清扫术。     

甲磺酸伊马替尼治疗胃肠道间质瘤的研究进展

胃肠道间质瘤（GIST）是胃肠道及腹腔最常见的间叶源性肿瘤,对常规的放疗、化疗均不敏感。外科手术是局限性GIST患者的主要治疗方式,但术后复发率较高。对于术前、术后辅助、复发、转移及不能手术切除的患者,酪氨酸激酶抑制剂甲磺酸伊马替尼对其有较好的治疗效果。本文对甲磺酸伊马替尼治疗胃肠道间质瘤的研究进展作一综述。     

非编码RNA在胃肠间质瘤中的研究进展

胃肠间质瘤(gastrointestinal stromal tumor,GIST)是消化道最常见的间叶源性肿瘤,发病原因主要是由于原癌基因受体酪氨酸激酶或血小板衍生生长因子受体基因活化突变。分子靶向治疗药物甲磺酸伊马替尼是抑制KIT、血小板衍生生长因子受体α多肽(platelet-derived growth factor receptor alpha,PDGFRA)基因酪氨酸激酶活性的药物,其能有效治疗进展期GIST。但是,越来越多的研究发现,甲磺酸伊马替尼在治疗GIST过程中存在原发性耐药和继发性耐药。随着近年来对非编码RNA的生理功能和作用机制的深入研究,使人们逐步认识到非编码RNA对基因表达的广泛调控作用,其在肿瘤发生、发展、侵袭、转移和耐药等过程中扮演着重要角色。研究非编码RNA有可能为探讨GIST发病及耐药机制提供新的思路和方向。     

１８例胃肠道间质瘤伊马替尼辅助治疗的临床观察

目的　探讨伊马替尼在胃肠道间质瘤（ＧＩＳＴ）辅助治疗中的地位。方法　收集２００３年至２００９年在苏州大学附属第一医院治疗的３５例ＧＩＳＴ患者的随访资料,１８例术后接受伊马替尼４００ｍｇ／ｄ辅助治疗,１７例仅术后观察,主要的观察指标为２年无复发生存率（ＲＦＳ）。结果　３５例ＧＩＳＴ患者的中位随访时间为２８.３个月;伊马替尼治疗时间１２～３６个月,平均治疗时间为２４个月;治疗组和观察组２年ＲＦＳ分别为７２.２％和４１.２％（Ｐ＜０.０１）;治疗组患者均可评价不良反应,其中１～２级白细胞减少７例,轻度腹泻２例,恶心呕吐６例,眼眶周围水肿１例,轻度皮疹８例,轻度乏力２例。结论　ＧＩＳＴ患者术后给予伊马替尼辅助治疗能提高患者２年ＲＦＳ,且不良反应轻,患者耐受性良好。     

不可切除或转移性胃肠道间质瘤患者甲磺酸伊马替尼治疗前后血清成纤维细胞生长因子2的变化

 目的　探讨不可切除或转移性胃肠道间质瘤患者甲磺酸伊马替尼治疗前后血清成纤维细胞生长因子2（FGF2）水平变化。方法　应用酶联免疫吸附法（ELISA）检测27例不可切除或转移性胃肠道间质瘤患者甲磺酸伊马替尼治疗前后血清FGF2,并进行比较。结果　治疗前血清FGF2阳性率为63.0 %（17／27）,经甲磺酸伊马替尼治疗3个月后降为33.3 %（9／27）,二者间差异有统计学意义（χ2＝4.08,P＝0.039）。伊马替尼治疗3个月后复查CT,无完全缓解 ,部分缓解率51.9 %（14／27）,稳定率48.1 %（13／27）,无进展病例。结论　不可切除或转移性胃肠道间质瘤患者血清FGF2阳性率升高,甲磺酸伊马替尼治疗可以降低不可切除或转移性胃肠道间质瘤患者血清FGF2水平。     

胃肠道间质瘤治疗新进展

胃肠道间质瘤（gastrointestinal stromal tumor,GIST）是胃肠道最常见的间叶源性肿瘤.外科手术是局限性GIST患者的主要治疗手段,对于不能手术切除或复发转移的患者来说,对于传统的全身化疗和放疗不敏感性,使这部分患者的治疗相当棘手.约90%的GIST存在c-kit原癌基因获得性变异,使得酪氨酸激酶持续激活（无需配体即可使酪氨酸残基自体磷酸化）,导致细胞分裂异常、肿瘤增殖.伊马替尼选择性地抑制KIT相关的酪氨酸激酶的活性,使得伊马替尼治疗GIST.引起了广泛的关注.这里我们回顾了GIST治疗的最新进展和对于这些患者的最佳治疗.     

A gist of gastrointestinal stromal tumors: A review

Gastrointestinal stromal tumors (GISTs) have been recognized as a biologically distinctive tumor type, different from smooth muscle and neural tumors of the gastrointestinal tract (GIT). They constitute the majority of gastrointestinal mesenchymal tumors of the GIT and are known to be refractory to conventional chemotherapy or radiation. They are defined and diagnosed by the expression of a proto-oncogene protein detected by immunohistochemistry which serves as a crucial diagnostic and therapeutic target. The identification of these mutations has resulted in a better understanding of their oncogenic mechanisms. The remarkable antitumor effects of the molecular inhibitor imatinib have necessitated accurate diagnosis of GIST and their distinction from other gastrointestinal mes-enchymal tumors. Both traditional and minimally invasive surgery are used to remove these tumors with minimal morbidity and excellent perioperative outcomes. The revolutionary use of specific, molecularlytargeted therapies, such as imatinib mesylate, reduces the frequency of disease recurrence when used as an adjuvant following complete resection. Neoadjuvant treatment with these agents appears to stabilize disease in the majority of patients and may reduce the extent of surgical resection required for subsequent complete tumor removal. The important interplay between the molecular genetics of GIST and responses to targeted therapeutics serves as a model for the study of targeted therapies in other solid tumors. This review summarizes our current knowledge and recent advances regarding the histogenesis, pathology, molecular biology, the basis for the novel targeted cancer therapy and current evidence based management of these unique tumors.     

Efficacy and safety profile of imatinib mesylate (ST1571) in Japanese patients with advanced gastrointestinal stromal tumors: a phase II study (STI571B1202)

BACKGROUND: Imatinib mesylate, an inhibitor of KIT, ABL protein, and platelet-derived growth factor receptor alpha (PDGFRalpha) tyrosine kinase, has recently been found to have a dramatic antitumor effect on gastrointestinal stromal tumor (GIST). The aim of this study was to assess the efficacy and safety of imatinib mesylate in Japanese patients with advanced GIST. METHODS: Patients with measurable lesions were enrolled between April 1, 2002, and September 20, 2002, using a design based on previous phase II studies in the United States and the European Union. The diagnosis of GIST was proven histologically with positive immunostaining for KIT (CD117). Imatinib mesylate was administered at a dose of either 400 mg or 600 mg once a day. Pharmacokinetic parameters and mutation analysis of c-kit were also assessed in a subgroup of patients. RESULTS: A total of 74 patients (28 receiving imatinib mesylate at 400 mg/day; 46 receiving 600 mg/day); median age, 56.0 years, were enrolled. No patient had a complete response, 51 patients (69%) had a partial response, and 19 patients (26%) had stable disease. The median progression-free survival time was 96 weeks. The estimated 3-year overall survival (Kaplan-Meier) rate for all patients was 73.6%. The most frequent adverse effects related to the drug were nausea (78%), diarrhea (70%), dermatitis (62%), facial edema (61%), edema of the lower limbs (58%), vomiting (54%), and eyelid edema (51%). Most of the adverse effects were mild and manageable. CONCLUSION: Imatinib mesylate is generally safe and has significant activity in the treatment of advanced GIST in Japanese patients.     

A successful case of oral molecularly targeted therapy with imatinib for peritoneal metastasis of a gastrointestinal stromal tumor

Gastrointestinal stromal tumors (GISTs) are a group of neoplasms arising from mesenchymal stem cells of the gastrointestinal tract. The prognosis of metastatic or recurrent GISTs is poor, because these tumors resist chemotherapy and radiotherapy. We report a patient with recurrent GIST who underwent molecularly targeted therapy with imatinib, a novel oral tyrosine kinase inhibitor. A 50-year-old woman presented with a huge intra-abdominal mass. The patient had a history of gastrectomy for GIST and hepatectomy for its metastases. She also underwent surgery for resection of peritoneal metastases 9 months before. The abdominal mass was 26 × 17 × 12cm in size, as determined by magnetic resonance imaging, and was diagnosed as a peritoneal relapse of GIST. Treatment with 400mg of imatinib daily was started. After 1 week of treatment with imatinib, reduction of the abdominal tumor began to be recognized on palpation. Computed tomographic scanning on day 28 revealed that the tumor had liquefactively regressed and had reduced in size by 66%. The major side effect was leg edema, which was easily manageable with furosemide. The patient has been receiving imatinib treatment in our outpatient clinic, and the tumor regression has continued for 9 months. Imatinib shows promise as a safe and effective drug for the treatment of patients with recurrent GISTs.     

Is there a role of surgery in patients with recurrent or metastatic gastrointestinal stromal tumours responding to imatinib: A prospective randomised trial in China

ObjectivesFor advanced gastrointestinal stromal tumour (GIST) patients who are responding to imatinib mesylate, the role of surgery has not been formally demonstrated. This multicenter randomised controlled trial was designed to assess whether surgery to treat residual disease for patients with recurrent/metastatic GISTs responding to imatinib mesylate (IM) improved progression free survival (PFS) compared with IM treatment alone.MethodsBetween 3 and 12 months after starting IM for recurrent/metastatic GISTs, eligible patients were randomised to two arms: Arm A (surgery for residual disease) and Arm B (IM treatment alone). In Arm A (19 pts), surgery was performed to remove residual macroscopic lesions as completely as possible, and IM treatment continued after surgery. In Arm B (22 pts), IM was given alone at a dose of 400 mg per day until disease progression. The primary end-point was PFS measured from the date IM started. This study was registered in the ChiCTR registry with the ID number ChiCTR-TRC-00000244.ResultsThis randomised trial was closed early due to poor accrual. Only 41 patients were enrolled as opposed to 210 patients planned. 2-year PFS was 88.4% in the surgery arm and 57.7% in the IM-alone arm (P = 0.089). Median overall survival (mOS) was not reached in the surgery arm and 49 months in patients with IM-alone arm (P = 0.024).ConclusionsWhile no significant differences were observed in the two arms, this study suggests that surgical removal of the metastatic lesion may improve the outcome of advanced GIST patients and should stimulate additional research on this topic.