Risk factors determining chemotherapeutic toxicity in patients with advanced colorectal cancer

Antitumour therapy in advanced colorectal cancer has limited efficacy. For decades, fluorouracil has been the main anticancer drug for the treatment o f colorectal cancer. Recently, however, new agents have been introduced: ra ltitrexed, irinotecan and oxaliplatin. Currently, the dosage for an individual patient is calculated from the esti mated body surface area of the patient. Toxicity, however, frequently neces sitates decreasing the dosage, extending the dose interval or even disconti nuing treatment. Risk factors with predictive value for toxicity have been identified in several studies, These risk factors are often determined by t he pharmacokinetic and pharmacodynamic properties of the drug. In this revi ew, the risk factors for toxicity of the cytotoxic agents used in the treat ment of advanced colorectal cancer are con; sidered. For fluorouracil, age, gender, performance status, genetic polymorphism of dihydropyridine dehydr ogenase, drug administration schedule, circadian rhythm of plasma concentra tions, history of previous chemotherapy-related diarrhoea, xerostomia, low neutrophil levels, and drug-drug interactions have been identified as affec ting chemotherapeutic toxicity. For raltitrexed, gender and renal and hepat ic impairment, and for oxaliplatin, renal impairment and circadian rhythm o f plasma concentrations, respectively, can be considered as risk factors fo r toxicity. In addition, age, performance status, bilirubinaemia, genetic p olymorphism of uridine 5'-diphosphate-glucuronyltransferase-1A1 and drug ad ministration 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 dru g 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 indi vidualisation of chemotherapy founded on risk factors, over direct dose cal culation from the estimated body surface area, with regard to toxicity, the rapeutic index, and quality of life, in patients with advanced colorectal c ancer.