Schmoll H J
Departments of Internal Medicine and Hematology/Oncology, Martin Luther University, Halle-Wittenberg, Germany.
Semin Oncol. 2002 Oct;29(5 Suppl 15):34-9. doi: 10.1053/sonc.2002.35531.
In the last 50 years, 5-fluorouracil-based therapy has been the mainstay of adjuvant and palliative treatment for colorectal cancer but response rates and median survival have been dismal despite the introduction of thymidylate synthase modulators such as leucovorin. Recently, new therapeutic approaches have been introduced. These include oral 5-fluorouracil analogues, pure thymidylate synthase inhibitors, dihydropyrimidine dehydrogenase inhibitors, and agents with mechanism of action unrelated to thymidylate synthase such as irinotecan, a topoisomerase I inhibitor, and oxaliplatin, the only platinum derivative with significant activity in colorectal cancer. Current treatment strategies involve combination therapies because this approach is the most effective. For instance, responses observed with oxaliplatin and 5-fluorouracil indicate synergy between the two agents and the combination of capecitabine plus oxaliplatin or irinotecan has shown high activity both in chemotherapy-naive and in pretreated patients with advanced colorectal cancer. Additionally, it is likely that future therapeutic management of advanced colorectal cancer may include combination therapy of one of the new oral 5-fluorouracil analogues, because of the convenient oral regimens. The identification of colorectal cancer-specific prognostic factors will undoubtedly influence treatment decisions. For instance, patients overexpressing epidermal growth factor receptor and p53 with thymidylate synthase have a worse prognosis. To target these biomarkers, antibodies such as cetuximab, an anti-EGFR antibody, and angiogenesis inhibitors and tyrosine kinase inhibitors have been introduced and are undergoing clinical evaluation. Over the last 5 years the armamentarium to fight colorectal cancer has increased significantly, giving more hope for effective disease management.
在过去50年中，基于5-氟尿嘧啶的疗法一直是结直肠癌辅助治疗和姑息治疗的主要手段，但尽管引入了诸如亚叶酸钙等胸苷酸合成酶调节剂，缓解率和中位生存期仍不尽人意。最近，新的治疗方法已经出现。这些方法包括口服5-氟尿嘧啶类似物、纯胸苷酸合成酶抑制剂、二氢嘧啶脱氢酶抑制剂，以及作用机制与胸苷酸合成酶无关的药物，如拓扑异构酶I抑制剂伊立替康和在结直肠癌中具有显著活性的唯一铂类衍生物奥沙利铂。目前的治疗策略涉及联合治疗，因为这种方法是最有效的。例如，奥沙利铂和5-氟尿嘧啶联合使用显示出协同作用，卡培他滨联合奥沙利铂或伊立替康在初治和经治的晚期结直肠癌患者中均显示出高活性。此外，由于口服给药方案方便，未来晚期结直肠癌的治疗管理可能包括使用一种新型口服5-氟尿嘧啶类似物进行联合治疗。结直肠癌特异性预后因素的确定无疑将影响治疗决策。例如，过表达表皮生长因子受体、p53和胸苷酸合成酶的患者预后较差。为了针对这些生物标志物，已经引入了诸如西妥昔单抗（一种抗表皮生长因子受体抗体）、血管生成抑制剂和酪氨酸激酶抑制剂等抗体，并正在进行临床评估。在过去5年中，抗击结直肠癌的武器库显著增加，为有效管理疾病带来了更多希望。
