Department of Medical Oncology, Princess Margaret Hospital, 5-708, 610 University Avenue, Toronto, ON M5G 2M9, Canada.
Expert Rev Anticancer Ther. 2010 Apr;10(4):529-40. doi: 10.1586/era.10.21.
The prognosis for advanced pancreatic cancer remains poor and successful drug development in this disease continues to be a major challenge. In the last decade the approach to drug development in pancreatic cancer has included a focus on combinations of cytotoxic agents. While some promising results were seen in Phase II studies, none of the Phase III trials of cytotoxic combinations were able to demonstrate an improvement in overall survival over that seen with the single-agent gemcitabine. Newer studies have assessed the efficacy of 'targeted' agents that inhibit pathways thought to be important in the development, growth, invasion and metastasis of pancreatic cancer. Although some agents had promising activity in preclinical studies, none has made a major impact in the clinic. There has been some success with the addition of the EGF receptor tyrosine kinase inhibitor erlotinib to gemcitabine, which was the first combination to achieve an overall survival benefit compared with gemcitabine alone in a Phase III trial. Future directions for drug development in pancreatic cancer will mainly involve testing new targeted agents, although some cytotoxic combinations are currently in Phase III testing. There is a need to better understand the biology of the disease and incorporate this into trials in an attempt to search for predictive and prognostic markers that will aid in drug development. Control of pancreatic cancer will require combinations of targeted agents, probably individualized based on tumor genetics. We are just beginning to explore the efficacy of combining targeted agents in the clinic.
晚期胰腺癌的预后仍然较差，成功开发治疗这种疾病的药物仍然是一个主要挑战。在过去的十年中，胰腺癌药物开发的方法包括专注于细胞毒性药物的联合应用。虽然在 II 期研究中看到了一些有希望的结果，但细胞毒性联合治疗的 III 期试验均未能证明与单药吉西他滨相比在总生存期方面有所改善。新的研究评估了“靶向”药物的疗效，这些药物抑制了被认为对胰腺癌的发展、生长、侵袭和转移很重要的途径。尽管一些药物在临床前研究中表现出有希望的活性，但没有一种药物在临床上产生重大影响。在吉西他滨中加入表皮生长因子受体酪氨酸激酶抑制剂厄洛替尼取得了一些成功，这是第一个在 III 期试验中与吉西他滨单独治疗相比总生存期获益的联合治疗。未来胰腺癌药物开发的主要方向将涉及测试新的靶向药物，尽管一些细胞毒性联合治疗目前正在进行 III 期测试。需要更好地了解疾病的生物学特性，并将其纳入试验中，以试图寻找有助于药物开发的预测和预后标志物。控制胰腺癌需要联合靶向药物，可能根据肿瘤遗传学进行个体化治疗。我们才刚刚开始探索联合靶向药物在临床上的疗效。
