Langer Corey J
Department of Thoracic Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):991-1002. doi: 10.1016/j.ijrobp.2003.09.099.
Combination chemotherapy regimens have emerged as the standard approach in advanced non-small-cell lung cancer. Meta-analyses have demonstrated a 2-month increase in median survival after platinum-based therapy vs. best supportive care, and an absolute 10% improvement in the 1-year survival rate. Just as importantly, cytotoxic therapy has produced benefits in symptom control and quality of life. Newer agents, including the taxanes, vinorelbine, gemcitabine, and irinotecan, have expanded our therapeutic options in the treatment of advanced non-small-cell lung cancer. Despite their contributions, we have reached a therapeutic plateau, with response rates seldom exceeding 30-40% in cooperative group studies and 1-year survival rates stable between 30% and 40%. It is doubtful that substituting one agent for another in various combinations will lead to any further improvement in these rates. The thrust of current research has focused on targeted therapy, and epidermal growth factor receptor inhibition is one of the most promising clinical strategies. Epidermal growth factor receptor inhibitors currently under investigation include the small molecules gefitinib (Iressa, ZD1839) and erlotinib (Tarceva, OSI-774), as well as monoclonal antibodies such as cetuximab (IMC-225, Erbitux). Agents that have only begun to undergo clinical evaluation include CI-1033, an irreversible pan-erbB tyrosine kinase inhibitor, and PKI166 and GW572016, both examples of dual kinase inhibitors (inhibiting epidermal growth factor receptor and Her2). Preclinical models have demonstrated synergy for all these agents in combination with either chemotherapy or radiotherapy, leading to great enthusiasm regarding their ultimate contribution to lung cancer therapy. However, serious clinical challenges persist. These include the identification of the optimal dose(s); the proper integration of these agents into popular, established cytotoxic regimens; and the selection of the optimal setting(s) in which to test these compounds. Both gefitinib and erlotinib have shown clinical activity in pretreated, advanced non-small-cell lung cancer, but placebo-controlled randomized Phase III studies evaluating gefitinib in combination with standard cytotoxic therapy, to our chagrin, have failed to demonstrate a survival advantage compared with chemotherapy alone.
联合化疗方案已成为晚期非小细胞肺癌的标准治疗方法。荟萃分析表明，与最佳支持治疗相比，铂类治疗后中位生存期延长了2个月，1年生存率绝对提高了10%。同样重要的是，细胞毒性疗法在症状控制和生活质量方面也产生了益处。包括紫杉烷类、长春瑞滨、吉西他滨和伊立替康在内的新型药物，扩大了我们在晚期非小细胞肺癌治疗中的治疗选择。尽管它们做出了贡献，但我们已经达到了治疗平台期，在协作组研究中缓解率很少超过30%-40%，1年生存率稳定在30%至40%之间。怀疑在各种联合方案中用一种药物替代另一种药物是否会使这些比率进一步提高。当前研究的重点集中在靶向治疗上，表皮生长因子受体抑制是最有前景的临床策略之一。目前正在研究的表皮生长因子受体抑制剂包括小分子吉非替尼（易瑞沙，ZD1839）和厄洛替尼（特罗凯，OSI-774），以及单克隆抗体如西妥昔单抗（IMC-225，爱必妥）。才刚刚开始进行临床评估的药物包括不可逆的泛erbB酪氨酸激酶抑制剂CI-1033，以及双激酶抑制剂（抑制表皮生长因子受体和Her2）PKI166和GW572016。临床前模型已证明所有这些药物与化疗或放疗联合具有协同作用，这使得人们对它们最终对肺癌治疗的贡献充满热情。然而，严重的临床挑战依然存在。这些挑战包括确定最佳剂量；将这些药物合理地整合到常用的、既定的细胞毒性方案中；以及选择测试这些化合物的最佳环境。吉非替尼和厄洛替尼在预处理的晚期非小细胞肺癌中均显示出临床活性，但令我们懊恼的是，评估吉非替尼与标准细胞毒性疗法联合使用的安慰剂对照随机III期研究未能证明与单纯化疗相比具有生存优势。
