GIST诊治现状要点.ppt

首次完整切除肿瘤是提高疗效的关键, 完整与否直接与预后相关。 完整的概念中, 一般认为至少应距肿瘤边缘2cm以上, 单纯剜出或局部切除是不够的, 如有周围组织及脏器受累应一并切除, 5 年生存率可达65.2%。 * * * 对于发生在软组织的肿瘤, 寻找其细胞起源是诊断和治疗的关键, GIST治疗的进步也在于此。由于c-K IT 原癌基因产物、表达CD 117的KIT蛋白酪氨酸激酶见于95%以上的GIST患者并在其致病过程中KIT(或PDGFRA)突变起着关键作用, 引发学者们以K IT 蛋白酪氨酸激酶受体作为分子靶寻找特异性抑制药物。 格列卫是第一个，也是唯一一个治疗GIST有效的药物格列卫)酪氨酸激酶受体抑制剂, 原是针对慢性粒细胞白血病的分子起因设计的, 是第一个用于临床治疗恶性肿瘤的细胞信号传导抑制剂。 * 在分子水平，伊马替尼靶向KIT、Bcr-Abl和PDGFRA/B酪氨酸激酶区的特定部位。 基于伊马替尼对Bcr-Abl的作用，其在GIST治疗中可能的作用机理如下： 伊马替尼是一种ATP类似物，但其与KIT亲和力更强，可以竞争性结合在KIT的ATP结合位点上；而KIT酪氨酸激酶的活性依赖其ATP酶的活性；伊马替尼与KIT的结合阻止了其与ATP的结合和水解反应，从而抑制了KIT酪氨酸激酶的作用：阻断了通过磷酸化才能被激活的KIT下游底物； 最终中断了由KIT激活的下游信号转导的通路。 Savage DG, Antman KH. Imatinib mesylate–a new oral targeted therapy. N Engl J Med. 2002;346:683-693. Scheijen B, Griffin JD. Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease. Oncogene. 2002;21:3314-3333. NCCN建议术前IM停药时间为手术当天。而我们的经验是术前3天~7天，视患者服药水肿和有无白细胞减少的副反应而定（IM主要肝代谢，药物清除大约为24h，停药2天患者水肿基本消退） * Rates of recurrence after resection in GIST are high. Imatinib in the adjuvant setting may provide benefits for some patients. Given the favorable efficacy and safety profile of imatinib, adjuvant therapy has a role in preventing recurrence and metastasis1–3 To this end, the American College of Surgeons Oncology Group (ACOSOG) initiated 2 adjuvant trials2 Z9000 included patients with high-risk primary GIST who received adjuvant imatinib therapy Z9001 was a placebo-controlled trial in patients with resected primary GIST who received adjuvant imatinib therapy4 SSGXVIII/AIO trial is a Phase III adjuvant study conducted by the Scandinavian Sarcoma Group (SSG) and Sarcoma Group of the Arbeitsgemeinschaft Internistische Onkologie (AIO) (or Working Group of Medical Oncologists [Germany])2 SSGXVIII/AIO included patients with KIT-positive GIST at high risk (50%) for recurrence following surgery Currently there are 2 ongoing randomized trials with imatinib in an adjuvant setting EORTC 62024 (recently completed) CSTI571BUS282 Eisenberg BL, von Mehren M. Ph