晚期胰腺癌的分子靶向治疗

Novel therapeutic strategies for advanced pancreatic cancer: targeting the epidermal growth factor and vascular endothelial growth factor pathways

胰腺癌的药物治疗目前仍以吉西他滨为主,但是晚期胰腺癌患者的总体预后极差,故其有效治疗亟待新型药物的研发。表皮生长因子受体(EGFR)及其配体的过度表达对肿瘤包括胰腺癌的细胞生存、增殖、血管生成、细胞迁移、细胞的入侵及转移等起到重要作用;此外,胰腺癌的进展、局部浸润及转移均有赖于新生血管的生成。因此,针对EGFR与血管内皮生长因子受体(VEGFR)或其配体的分子靶向治疗药物目前已成为晚期胰腺癌药物治疗的临床研究重点。加拿大国立癌症研究所完成的1项Ⅲ期随机双盲临床研究(NCICPA.3)结果显示,接受酪氨酸激酶抑制剂厄洛替尼与吉西他滨联合方案治疗的晚期胰腺癌患者的1年总生存率与中位生存期均优于仅接受吉西他滨单药治疗者,分别为24%vs17%与6.4个月vs5.9个月,且差异有显著性。目前美国FDA已经批准了厄洛替尼联合吉西他滨治疗晚期胰腺癌的适应证。然而,厄洛替尼作为二线药物用于经吉西他滨治疗失败的胰腺癌,尚未获临床研究结果的支持。目前已完成的其他多项临床研究结果,尚未能证实其他酪氨酸激酶抑制剂或针对EGFR及其配体的单克隆抗体对晚期胰腺癌的疗效。虽然Ⅱ期临床研究结果提示了抗新生血管药物贝伐单抗对晚期胰腺癌的治疗作用,但其疗效未获Ⅲ期随机临床研究结果的支持。旨在研究吉西他滨与厄洛替尼基础上加用贝伐单抗对晚期胰腺癌疗效的AVITA研究,也未能证实该组合可进一步延长患者的中位生存期。其他分子靶向治疗药物如索拉非尼、axitinib与舒尼替尼等药物在晚期胰腺癌的应用目前亦仍有待临床研究结果的证实。本文基于目前已发表的最佳临床证据,就目前在晚期胰腺癌治疗中已获初步进展的抗表皮生长因子及抗新生血管治疗的相关研究及临床应用予以介绍。

The introduction of novel agents targeted to specific molecular targets of cancer cells offers more treatment options and improvement in outcome for exocrine pancreatic adenocarcinoma. Due to the limitations in the scope and scale of researches, this review of clinical studies presents the effects of administering the agents targeting the receptors or ligands of epidermal growth factor （EGF） or vascular endothelial growth factor （VEGF） to treat advanced pancreatic carcinoma. In addition, the basic knowledge on the mechanisms of therapy targeting EGFR and VEGFR were described. Among all agents, erlotinib has been approved by the U.S. Food and Drug Administration and incorporated in a number of treatment guidelines. It has been shown, in a randomized phase III clinical trial reported by the National Cancer Institute of Canada, to extend survival when used in combination with gemcitabine; however, its use as monotherapy has not produced significant efficacy. Furthermore, results from a multicenter randomized clinical trial has demonstrated that the combined utilization of erlotinib and bevacizumab, in current with gemcitabine significantly improved the progression-free survival, but has no significant effect on overall survival of patients with advanced pancreatic cancer. Other agents including cetuximab, bevacizumab, sorafenib, sunitinib, etc. used along or in combination with chemotherapy are under active investigation.