Venook Alan P
Department of Clinical Medicine, University of California, San Francisco, San Francisco, California 94115, USA.
J Natl Compr Canc Netw. 2004 Sep;2 Suppl 2:S74-84.
Despite recent advances in chemotherapy, including the development of irinotecan and oxaliplatin, survival of patients with advanced colorectal cancer remains suboptimal. Thanks to an increased understanding of the biologic basis of cancer, investigators are turning to molecularly targeted therapy to further improve outcome. Current research in colorectal cancer focuses on inhibiting the epidermal growth factor receptor and vascular endothelial growth factor. Both are essential to tumor growth and frequently over-expressed in colorectal cancer cells. Epidermal growth factor receptor pathways promote survival of tumor cells through cell proliferation, differentiation, migration, adhesion, and transformation and inhibition of apoptosis, whereas the vascular endothelial growth factor is a key mediator of angiogenesis and may have other biologic roles. Recent phase II and III results show the feasibility and activity of inhibiting both by using monoclonal antibodies in combination with chemotherapy in patients with advanced colorectal cancer. Cetuximab (an epidermal growth factor receptor antibody) plus irinotecan yields an increased overall response in patients with irinotecan-refractory colorectal disease. In previously untreated patients, irinotecan/5-fluoruoracil/leucovorin plus cetuximab also generates an increased overall response rate. Randomized trials of the humanized anti-vascular endothelial growth factor antibody (rhuMAb vascular endothelial growth factor) plus chemotherapy yielded increased overall response rates and median survival times compared with chemotherapy alone. The primary toxicity of cetuximab is an acneform skin rash; rhuMAb vascular endothelial growth factor causes mild hypertension and may cause perturbations in coagulation. Treatment with either does not appear to exacerbate chemotherapy-related toxicity.
尽管近期化疗取得了进展，包括伊立替康和奥沙利铂的研发，但晚期结直肠癌患者的生存率仍不尽人意。由于对癌症生物学基础的认识不断加深，研究人员正转向分子靶向治疗以进一步改善治疗效果。目前结直肠癌的研究重点是抑制表皮生长因子受体和血管内皮生长因子。这两者对肿瘤生长都至关重要，且在结直肠癌细胞中经常过度表达。表皮生长因子受体途径通过细胞增殖、分化、迁移、黏附和转化以及抑制细胞凋亡来促进肿瘤细胞的存活，而血管内皮生长因子是血管生成的关键介质，可能还具有其他生物学作用。最近的II期和III期研究结果显示，在晚期结直肠癌患者中，使用单克隆抗体联合化疗抑制这两者具有可行性和有效性。西妥昔单抗（一种表皮生长因子受体抗体）加伊立替康可使伊立替康难治性结直肠疾病患者的总体缓解率提高。在先前未接受治疗的患者中，伊立替康/5-氟尿嘧啶/亚叶酸加西妥昔单抗也能提高总体缓解率。人源化抗血管内皮生长因子抗体（rhuMAb血管内皮生长因子）联合化疗的随机试验与单纯化疗相比，总体缓解率和中位生存期均有所提高。西妥昔单抗的主要毒性是痤疮样皮疹；rhuMAb血管内皮生长因子会引起轻度高血压，可能还会导致凝血异常。使用这两种药物治疗似乎都不会加重化疗相关毒性。
