对伊马替尼继发耐药的晚期胃肠道间质瘤治疗策略探讨

目的 探讨对伊马替尼继发耐药的复发和转移的晚期胃肠道间质瘤（gastrointestinal stromal tumors, GIST）的治疗策略。方法 回顾性分析复旦大学附属中山医院2000—2009年对伊马替尼继发耐药的复发和转移的晚期8例GIST病人的临床资料。结果 所有病人均行手术治疗,完整切除原发肿瘤后,肿瘤复发和（或）转移,口服伊马替尼治疗产生继发耐药,采取手术切除复发和转移灶（特别是耐药病灶）联合伊马替尼等靶向治疗为主的综合治疗模式,均获得较好的治疗效果。1例死亡,存活96个月;其余7例仍存活,目前存活时间65~145个月,平均98.6个月。结论 伊马替尼继发耐药的复发和转移的晚期GIST,选择手术联合酪氨酸激酶抑制剂靶向治疗为主的多学科综合治疗模式,参考肿瘤的基因状态,采取个体化治疗,可取得较好的疗效。     

复发转移胃肠间质瘤的治疗策略

影像学检查是复发转移GIST最常用的诊断方法.Chio标准更能客观反映靶向治疗后肿瘤的有效率.PET和MRI的扩散加权成像可以用于早期评估靶向治疗的疗效.靶向药物是复发转移GIST的首选,伊马替尼耐药后,特别是外显子9突变者接受舒尼替尼治疗可以获得满意的疾病控制率.荟萃分析显示晚期GIST靶向治疗进展者接受手术治疗仍可延长生存,手术切除可能是可以手术的GIST肝转移病例最佳选择,射频治疗的效果次之.在严格掌握适应证的前提下酪氨酸激酶抑制剂联合手术可能是目前治疗转移复发GIST的最佳模式.     

对复发转移性胃肠间质瘤手术还是不手术

复发转移性胃肠间质瘤（GIST）的处理是目前临床治疗的一大难题。国际上一些大型临床试验显示．伊马替尼治疗可显著改善复发转移GIST患者的生存期。而手术联合伊马替尼已成为转移GIST的理想治疗方法。然而．两者如何联合应用尚存在争议。伊马替尼可能影响凝血机制．因此,建议术前1周停药。细胞减灭术在复发转移性GIST中有一定的临床疗效,可与靶向药物联合应用。而复发转移GIST的临床试验尚需进一步评价。     

胃肠间质瘤的诊疗进展

胃肠间质瘤（GISTs）是最常见的间叶来源的恶性肿瘤,起源于胃肠道Cajal间质细胞。GISTs的三种主要分子亚型为KIT突变型、血小板衍生生长因子受体α(PDGFRA)突变型及野生型。大多数GISTs存在KIT或PDGFRA的功能获得性突变。特定的GIST突变限制了明确定义的分子亚型,这些亚型必须在诊断时明确进而指导临床管理和治疗决策。手术是治疗局部GIST的有效方法。目前酪氨酸激酶抑制剂（TKI）伊马替尼已用于转移性GIST的标准一线治疗,虽然其临床获益率为80%,但多数患者接受治疗2～3年后出现疾病进展。二线和三线药物选择分别包括舒尼替尼和瑞戈非尼。近年美国联邦和药物管理局批准了两种新的TKI用于治疗重度预处理的晚期/不可切除的GIST,包括阿伐替尼（PDGFRA外显子18突变的选择性抑制剂,如D842V突变）和瑞派替尼（c-Kit和PDGFRA的广谱激酶抑制剂）。靶向药物和外科手术的联合应用可改善GISTs患者的预后。     

胃肠间质瘤肝转移的规范化治疗

胃肠间质瘤（GIST）肝转移可发生在各个风险级别和各个时期,并且严重影响病人的生存期。GIST中肝转移发生率约为15.9%,其治疗一直以来是外科领域亟待解决的问题。GIST仍以外科治疗为主,手术完整切除肿瘤和术后服用伊马替尼可改善病人预后,提高存活率。其手术方式的选择更多取决于肿瘤的部位和大小。外科治疗联合酪氨酸激酶抑制剂（TKI）治疗是GIST肝转移病人的有效方法,明显延长GIST肝转移病人的生存时间、提高生存质量。TKI联合外科治疗是GIST肝转移的最优策略。     

复发性胃肠间质瘤再次手术

外科手术目前仍是胃肠间质瘤（GIST）病人获得根治的最佳手段,但术后复发转移是GIST病人治疗失败及死亡的主要原因。对于复发性GIST,外科治疗并不是最佳选择,应联合酪氨酸激酶抑制剂甲磺酸伊马替尼,结合病人的不同情况,个体化制定综合治疗方案,以提高病人总生存期。     

酪氨酸激酶抑制剂联合手术治疗转移性胃肠间质瘤

目的 探讨酪氨酸激酶抑制剂（TKI）甲磺酸伊马替尼或舒尼替尼联合手术治疗晚期转移性胃肠间质瘤（GIST）的临床疗效.方法 回顾分析中山大学附属第一医院2007年6月至2009年12月接受TKI治疗后进行手术治疗的转移性GIST患者临床病理资料.结果 共计15例转移性GIST患者在TKI治疗后接受肿瘤切除手术.术前TKI治疗反应分别为疾病控制6例（40.0%）,局限性进展4例（26.7%）,全面性进展5例（33.3%）.手术相关并发症发生率20.0%.全组患者中位无进展生存期18.7个月.其中疾病控制和局限性进展组患者术后无进展中位生存期25.0个月,全面性进展组则仅为3.0个月（P＜0.01）;疾病控制和局限性进展组患者至今仍全部存活,而全面性进展组患者中位总生存期为10.5个月（P＜0.01）.结论 靶向治疗后,疾病控制或局限性进展的晚期转移性GIST患者行手术治疗安全有效,而全面性进展患者手术治疗不能改善其预后,应谨慎选择.     

����������̷���ҩ������θ�������������Ʋ���̽��

目的探讨对伊马替尼继发耐药的复发和转移的晚期胃肠道间质瘤(gastrointestinal stromal tumors,GIST)的治疗策略。方法回顾性分析复旦大学附属中山医院2000—2009年对伊马替尼继发耐药的复发和转移的晚期8例GIST病人的临床资料。结果所有病人均行手术治疗,完整切除原发肿瘤后,肿瘤复发和(或)转移,口服伊马替尼治疗产生继发耐药,采取手术切除复发和转移灶(特别是耐药病灶)联合伊马替尼等靶向治疗为主的综合治疗模式,均获得较好的治疗效果。1例死亡,存活96个月;其余7例仍存活,目前存活时间65～145个月,平均98.6个月。结论伊马替尼继发耐药的复发和转移的晚期GIST,选择手术联合酪氨酸激酶抑制剂靶向治疗为主的多学科综合治疗模式,参考肿瘤的基因状态,采取个体化治疗,可取得较好的疗效。     

甲磺酸伊马替尼血药浓度监测对指导胃肠间质瘤治疗及评估预后临床意义

甲磺酸伊马替尼是一种酪氨酸激酶抑制剂,用于不可切除、转移、复发、原发可切除并有中-高危复发风险胃肠间质瘤（GIST）的治疗。甲磺酸伊马替尼的血药浓度（谷浓度）>1100μg/L时,GIST病人的临床获益明显增加。甲磺酸伊马替尼血药浓度监测有可能成为辅助治疗GIST的重要方面之一。     

靶向治疗时代手术在胃肠间质瘤肝转移治疗中的地位

正肝脏是胃肠间质瘤(gastrointestinal stromal tumor,GIST)最常见的转移部位,约占55%~72%~[1]。在酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)出现之前,手术是GIST主要的治疗手段。TKI的出现,使GIST的治疗进入了一个新时代并成为复发转移GIST治疗的首选方式。在靶向治疗时代,手术是否能使GIST肝转移的患者获益,目     

Role of operative therapy in treatment of metastatic gastrointestinal stromal tumors

BackgroundOperative resection of metastatic gastrointestinal stromal tumors (GIST) is controversial. Current treatment strategies rely on the response to tyrosine kinase inhibitors (TKIs), with resultant individualization of operative intervention. We investigated the role of operative therapy in patients with metastatic GIST.MethodsThis retrospective cohort study included all consecutive patients treated for metastatic and/or recurrent GIST from January 2002 to June 2011. The patients were stratified by the use of operative therapy and disease response to TKI therapy. Kaplan-Meier survival analyses with log-rank comparisons tested the effects of operative therapy and the response to TKIs on survival.ResultsOf the 438 patients treated for GIST during the study period, 87 (median age 61 y, interquartile range 50–71; 55% male) had metastatic GIST (84% metastatic, 3% recurrent, and 13% metastatic and recurrent). Of these patients, 54 (62%) underwent operative exploration. Subtotal resection for palliative debulking (R2 resection) were performed in 19 patients; 32 patients underwent R0 resection. Operative intervention was associated with improved overall survival (OS) compared with systemic therapy alone (1 y OS, 98% versus 80% and 5-y OS, 65% versus 11%, respectively; P < 0.001). A TKI was used before resection in 32 patients. The disease response was partial in 13 patients, stable in 10, and progressive in 9. The 1- and 5-y OS and progression-free survival were strongly associated with the preoperative response to TKI and an R0 resection (all P ≤ 0.002).ConclusionsAmong patients with metastatic GIST, preoperative response to TKI therapy and margin-negative resection were strongly associated with improved progression-free and OS.     

����ת����θ����������������ٴ���ֵ

??Status of surgical treatment in recurrent and metastatic gastrointestinal stromal tumors SHI Ying-qiang, Department of Abdominal Surgery, Cancer Hospital, Fudan University, Shanghai 200032, China
Abstract Surgical treatment is still first choice in primary and local gastrointestinal stromal tumors (GIST). Imatinib was applied in the treatment of GIST patients. How to choose surgical treatment or targeted drug and how to select the combination of the two treatment options in patients with a huge or multiple mass and recurrent and metastatic GIST patients are still controversial, which need further investigation. Amount of bleeding during operation may be much more in GIST patients who choose targeted drug treatment in advance because the blood coagulation function of GIST patients might be affected by imatinib. Therefore, it is necessary to halt the drug and improve the blood coagulation function of GIST patients before operation.     

复发转移性胃肠间质瘤外科治疗临床价值

对于原发的且病灶局限的胃肠间质瘤（GIST）,手术治疗依然是首选的治疗方案。自伊马替尼被用于治疗GIST以来,对于广泛或巨大原发灶,以及复发转移的GIST病人,如何选择手术治疗或靶向药物治疗以及如何把握两者联合治疗,至今仍有争论,尚须进一步探讨。由于伊马替尼对病人的凝血功能可能有影响,对于服药后的GIST病人进行手术治疗时,术中出血量可能较大,所以术前应先停药且纠正凝血功能。     

Analysis of Prognostic Factors Impacting Oncologic Outcomes After Neoadjuvant Tyrosine Kinase Inhibitor Therapy for Gastrointestinal Stromal Tumors

Background

Management of gastrointestinal stromal tumors (GISTs) has been transformed with tyrosine kinase inhibitors (TKIs). While data on optimal duration of adjuvant imatinib remains elusive, guidelines for administration of neoadjuvant TKIs remain unknown.

Methods

Under an institutional review board-approved protocol, patients at our institution with a diagnosis of GIST treated with neoadjuvant TKIs and surgical resection were identified. Clinical and pathologic characteristics were obtained from medical records.

Results

Ninety-three patients underwent surgical resection after neoadjuvant TKI therapy; 41 had primary and 52 had recurrent/metastatic GIST. Median follow-up was 2.4 years. Median duration of neoadjuvant therapy was 315 (range 3–1,611) days for primary and 537 (range 4–3,257) days for recurrent/metastatic GIST (p = 0.001). Two-year, recurrence-free survival (RFS) was 85 and 44 % for primary and recurrent/metastatic disease, respectively, whereas 2-year overall survival (OS) was 97 % for primary and 73 % for recurrent/metastatic GIST. For primary GIST, duration of neoadjuvant therapy >365 days (p = 0.02) was associated with higher risk of recurrence on univariate analysis, whereas none of the clinicopathologic factors impacted OS. For recurrent/metastatic disease, disease progression was associated with a shorter OS (p = 0.001), but no factors were found to impact RFS. Lastly, when examining all patients, KIT mutations (p = 0.03) and multivisceral resection (p = 0.011) predicted shorter RFS.

Conclusions

Neoadjuvant TKIs can be effectively used for the treatment of primary and recurrent/metastatic GIST. While duration of neoadjuvant therapy, KIT mutation status, and the need for multivisceral resection can help to predict higher risk for recurrence, progression on neoadjuvant TKIs can aid in selection of patients with recurrent/metastatic disease for surgical resection.     

Outcome of Metastatic GIST in the Era before Tyrosine Kinase Inhibitors

Background Treatment of metastatic GIST with imatinib mesylate results in a 2-year survival of approximately 72%. The outcome of patients with metastatic GIST not treated with tyrosine kinase inhibitors is not well defined. Methods One hundred nineteen patients with metastatic GIST diagnosed prior to July 1, 1998 (approximately 2 years prior to the use of imatinib for GIST) were identified from an institutional database of patients with pathologically confirmed GIST. Mutational analysis was performed in cases with available tissue. The log rank test and Cox regression models were used to assess prognostic factors. Results Median survival was 19 months with a 41% 2-year survival and a 25% 5-year survival. Resection of metastatic GIST was performed in 81 patients (68%), while 50 (42%) received conventional chemotherapy. Twelve patients (10%) were eventually started on imatinib. Primary tumor size <10 cm, <5 mitoses/50 HPF in the primary tumor, epithelioid morphology, longer disease-free interval, and surgical resection were independent predictors of improved survival on multivariate analysis. Mutational status did not predict outcome. In patients who underwent resection, the 2 year survival was 53%, and negative microscopic margins also independently predicted improved survival. Conclusions Treatment with imatinib appears to improve 2-year survival of metastatic GIST by approximately 20% when compared to surgery alone. The combination of imatinib and surgery for the treatment of metastatic GIST therefore warrants investigation. An erratum to this article can be found at     

������θ�����������ζԲ߼�����

??Strategy and evaluation of diagnosis and treatment on recurrent gastrointestinal stromal tumor LIU Tong, ZHAO Zhi-cheng. Department of General Surgery, Tianjin Medical University General Hospital and Tianjin Institute of General Surgery??Tianjin 300052, China
Corresponding author: LIU Tong, E-mail: liutonga@126.com
Abstract The recurrence following complete resection of primary gastrointestinal stromal tumor (GIST) is a common clinical problem, including three types which are local recurrence in situ, peritoneal dissemination and distant organ metastases. As targeted therapy, the availability of imatinib has altered the treatment approach and improved the outcome of recurrent GIST. Accurate assessment of recurrent lesions using imaging modalities, careful understanding of patient’s medication administrating and general physical condition could be helpful for the choice of therapeutic strategy scientifically. Imatinib is the first line treatment for recurrent GIST and should be administrated continually until patient intolerant or disease progresses because of rare pathologic complete respond. Combined with targeted therapy, appropriate surgical intervention to resection of recurrent or metastatic focus can bring a survival benefit to the patients.     

晚期胃肠道间质瘤靶向治疗后的外科治疗

目的探讨手术对于伊马替尼治疗后晚期胃肠道间质瘤（GIST）患者的临床疗效。方法回顾性分析13例术前予以伊马替尼治疗,然后接受手术切除的晚期GIST患者的临床资料。结果13例伊马替尼治疗后手术切除的患者中,有3例为局部晚期原发肿瘤,10例为复发或转移患者。治疗有效（RD组）的5例中有4例、疾病进展（PD组）的8例中有1例共计5例（38．5％）患者肿瘤获得完全切除。RD组无疾病进展生存（PFS）为24．8个月,PD组的PFS为2．8个月,两组比较,差异有统计学意义（P〈0．01）。RD组和PD组患者的总生存率比较,差异无统计学意义（P〉0．05）。结论在对伊马替尼治疗有效的晚期GIST患者中,伊马替尼治疗后再行外科手术切除是可行的。     

Surgical Resection of Gastrointestinal Stromal Tumors After Treatment with Imatinib

Background Surgical resection of gastrointestinal stromal tumors (GISTs) has been the most effective therapy for these rare tumors. Imatinib has been introduced as systemic therapy for locally advanced and metastatic GIST. In this study, the surgical resection rates and long-term outcomes of patients treated with preoperative imatinib for locally advanced primary, recurrent, or metastatic GISTs were evaluated. Methods Patients were retrospectively assessed for completeness of surgical resection and for disease-free and overall survival after resection. Results Forty-six patients underwent surgery after treatment with imatinib. Eleven were treated for locally advanced primary GISTs for a median of 11.9 months, followed by complete surgical resection. All eleven were alive at a median of 19.5 months, and ten were free of disease. Thirty-five patients were treated for recurrent or metastatic GIST. Of these, eleven underwent complete resection. Six of the eleven patients had recurrent disease at a median of 15.1 months. All eleven patients were alive at a median of 30.7 months. Patients with a partial radiographic tumor response to imatinib had significantly higher complete resection rates than patients with progressive disease (91% vs. 4%; P < .001). Of the 24 patients with incomplete resection, 18 initially responded to imatinib but were unable to undergo complete resection after they progressed before surgery. Conclusions Preoperative imatinib can decrease tumor volume and is associated with complete surgical resection in locally advanced primary GISTs. Early surgical intervention should be considered for imatinib-responsive recurrent or metastatic GIST, since complete resection is rarely achieved once tumor progression occurs. Presented in part at the Annual Meeting of the Society of Surgical Oncology, Atlanta, GA, March 2005.