Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Podium B, 3800 Reservoir Road, NW, Washington, DC 20007, USA.
J Gastrointest Oncol. 2013 Sep;4(3):299-307. doi: 10.3978/j.issn.2078-6891.2013.030.
Inhibition of tumor angiogenesis has emerged as an important therapeutic component in the management of metastatic colorectal cancer. Three anti-angiogenic agents are currently approved in this clinical setting: bevacizumab, ziv-aflibercept, and regorafenib. Bevacizumab, a monoclonal antibody that targets the angiogenesis-driving ligand vascular endothelial growth factor A (VEGF-A), is the only anti-angiogenic agent approved in first-line therapy for metastatic colorectal cancer, where it can be used in combination with intravenous 5-fluorouracil-containing chemotherapy regimens. In conjunction with second-line chemotherapies, bevacizumab also has anti-cancer activity, both for the management of metastatic colorectal cancer in patients who received it as a part of their first line therapy and for those who are naïve to it. Ziv-aflibercept also has demonstrated clinical activity in conjunction with the chemotherapeutic regimen FOLFIRI in the second line management of patients with metastatic colorectal cancer; it functions by binding VEGF-A to the vascular endothelial growth factor proteins VEGF-B and PIGF (placental growth factor). Regorafenib, which inhibits multiple tyrosine kinases, including the VEGF receptors, has proven clinical benefit in the management of patients with metastatic colorectal cancer refractory to all other therapies. For patients' whose cancers are refractory to all other therapies, there is also evidence for the use of bevacizumab with fluoropyrimidine monotherapy, but only in the bevacizumab-naïve patient subset. Presently, it is not clear if any one agent as more activity in a particular line of therapy than another, has greater efficacy when paired with a particular chemotherapy backbone, or if a particular patient subset is more likely to benefit from these agents. Given the present benefit and tolerance data, an anti-angiogenic agent should be considered in all lines of therapy in the management of metastatic colorectal cancer, with the evidence for the use of these agents in each specific line of therapy and in specific chemotherapeutic combinations driving agent selection.
肿瘤血管生成抑制已成为转移性结直肠癌治疗的重要组成部分。目前有三种抗血管生成药物在这种临床情况下被批准使用：贝伐珠单抗、阿柏西普和瑞戈非尼。贝伐珠单抗是一种针对血管生成驱动配体血管内皮生长因子 A（VEGF-A）的单克隆抗体，是转移性结直肠癌一线治疗中唯一被批准的抗血管生成药物，可与静脉注射含氟嘧啶的化疗方案联合使用。与二线化疗联合使用时，贝伐珠单抗也具有抗癌活性，既可以用于接受一线治疗的转移性结直肠癌患者的管理，也可以用于对其治疗方案不敏感的患者。阿柏西普也已被证明在二线治疗中与 FOLFIRI 化疗方案联合使用时对转移性结直肠癌患者具有临床疗效；它通过与血管内皮生长因子蛋白 VEGF-B 和 PIGF（胎盘生长因子）结合来发挥作用。瑞戈非尼抑制多种酪氨酸激酶，包括 VEGF 受体，已被证明在治疗转移性结直肠癌患者中具有临床获益，这些患者对所有其他治疗方法均耐药。对于所有其他治疗方法耐药的患者，也有证据表明在贝伐珠单抗单药治疗中联合氟嘧啶，但仅在贝伐珠单抗初治患者亚组中。目前尚不清楚在特定治疗线中哪种药物的活性更高，与特定化疗方案联合使用时哪种药物的疗效更高，或者哪种特定患者亚组更有可能从这些药物中获益。鉴于目前的获益和耐受数据，在转移性结直肠癌的所有治疗线中都应考虑使用抗血管生成药物，这些药物在每种特定治疗线和特定化疗联合中的使用证据推动了药物的选择。
