Jansman F G, Sleijfer D T, Coenen J L, De Graaf J C, Brouwers J R
Department of Clinical Pharmacy, Isala Klinieken, Zwolle, The Netherlands.
Drug Saf. 2000 Oct;23(4):255-78. doi: 10.2165/00002018-200023040-00001.
Antitumour therapy in advanced colorectal cancer has limited efficacy. For decades, fluorouracil has been the main anticancer drug for the treatment of colorectal cancer. Recently, however, new agents have been introduced: raltitrexed, irinotecan and oxaliplatin. Currently, the dosage for an individual patient is calculated from the estimated body surface area of the patient. Toxicity, however, frequently necessitates decreasing the dosage, extending the dose interval or even discontinuing treatment. Risk factors with predictive value for toxicity have been identified in several studies. These risk factors are often determined by the pharmacokinetic and pharmacodynamic properties of the drug. In this review, the risk factors for toxicity of the cytotoxic agents used in the treatment of advanced colorectal cancer are considered. For fluorouracil, age, gender, performance status, genetic polymorphism of dihydropyridine dehydrogenase, drug administration schedule, circadian rhythm of plasma concentrations, history of previous chemotherapy-related diarrhoea, xerostomia, low neutrophil levels, and drug-drug interactions have been identified as affecting chemotherapeutic toxicity. For raltitrexed, gender and renal and hepatic impairment, and for oxaliplatin, renal impairment and circadian rhythm of plasma concentrations, respectively, can be considered as risk factors for toxicity. In addition, age, performance status, bilirubinaemia, genetic polymorphism of uridine 5'-diphosphate-glucuronyltransferase-1A1 and drug administration schedule have been shown to be related to irinotecan toxicity. The available literature suggests that dose adjustment based on these risk factors can be used to individualise the dose in order to decrease toxicity and to improve the therapeutic index. This also applies to therapeutic drug monitoring, which has been shown to be effective controlling the toxicity of fluorouracil in some studies. Future research is warranted to assess the potential advantage of dose individualisation of chemotherapy founded on risk factors, over direct dose calculation from the estimated body surface area, with regard to toxicity, therapeutic index, and quality of life, in patients with advanced colorectal cancer.
晚期结直肠癌的抗肿瘤治疗疗效有限。几十年来，氟尿嘧啶一直是治疗结直肠癌的主要抗癌药物。然而，最近引入了新的药物：雷替曲塞、伊立替康和奥沙利铂。目前，个体患者的剂量是根据患者估计的体表面积计算的。然而，毒性常常需要降低剂量、延长给药间隔甚至停止治疗。在几项研究中已经确定了对毒性具有预测价值的危险因素。这些危险因素通常由药物的药代动力学和药效学特性决定。在本综述中，考虑了用于治疗晚期结直肠癌的细胞毒性药物的毒性危险因素。对于氟尿嘧啶，年龄、性别、体能状态、二氢嘧啶脱氢酶的基因多态性、给药方案、血浆浓度的昼夜节律、既往化疗相关腹泻史、口干、低中性粒细胞水平以及药物相互作用已被确定为影响化疗毒性的因素。对于雷替曲塞，性别以及肾和肝功能损害，对于奥沙利铂，肾功能损害和血浆浓度的昼夜节律，分别可被视为毒性危险因素。此外，年龄、体能状态、胆红素血症、尿苷5'-二磷酸葡萄糖醛酸基转移酶-1A1的基因多态性和给药方案已被证明与伊立替康毒性有关。现有文献表明，基于这些危险因素进行剂量调整可用于个体化给药，以降低毒性并提高治疗指数。这也适用于治疗药物监测，在一些研究中已证明其对控制氟尿嘧啶的毒性有效。有必要进行未来研究，以评估在晚期结直肠癌患者中，基于危险因素的化疗剂量个体化相对于根据估计体表面积直接计算剂量，在毒性、治疗指数和生活质量方面的潜在优势。
