title: Risk factors determining chemotherapeutic toxicity in patients with advanced colorectal cancer.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacy, Isala Klinieken, Zwolle, The Netherlands. f.g.a.jansman@isala.nl
authors.forename: F G
authors.initials: FG
authors.lastname: Jansman
authors.forename: D T
authors.initials: DT
authors.lastname: Sleijfer
authors.forename: J L
authors.initials: JL
authors.lastname: Coenen
authors.forename: J C
authors.initials: JC
authors.lastname: De Graaf
authors.forename: J R
authors.initials: JR
authors.lastname: Brouwers
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000150:complications* / Q000188:drug therapy; D006801:Humans; D012307:Risk Factors
chemical_list: D000970:Antineoplastic Agents