A successful approach for preventing severe and life-threatening toxicities in gastrointestinal cancer patients who are candidates for standard 5-FU treatment

The avoidance of severe and life-threatening 5-FU toxicities in patients with impaired 5-FU metabolism is a major problem in oncology. Many attempts have been made to identify patients before the beginning of the chemotherapeutic treatment. Dihydropyrimidine dehydrogenase plays a pivotal role in the metabolism of 5FU and as such, a deficiency of DPD has been recognized as an important risk factor, predisposing patients to the development of severe 5FU-associated toxicity. To date, screening of patients for the presence of a DPD deficiency prior to the treatment is not yet routinely performed. Patients should be informed about the risks of the therapy and should be offered the possibility of testing for the presence of a DPD deficiency in advance of receiving such treatment. Our pro-active contribution to the field is regarding the possibility to safely inject a reduced 5-FU test dose in patients candidate to 5-FU chemotherapy and calculate the pharmacokinetic parameters that could be profoundly altered in the presence of an impaired systemic metabolism such as 5-FU clearance and t_1/2β or 5-FDHU C_max, T_max and t_1/2β. Indeed, our study showed that 3 out of 188 enrolled patients (1.6%) after completing the test dose revealed a marked impaired 5-FU and 5-FDHU kinetics, as previously showed for patients with severe toxicities also in other published studies, highly suggesting a possible profound alteration of the normal 5-FU metabolism. Moreover, we found that the mean half-life of 5-FDHU was longer in patients who experienced grade 2–4 toxicity from 5-FU treatment than in patients with toxicity of grade 0–1, and t_max >30 min was associated with gastrointestinal and hematologic toxicity.

The 5-FU test dose could be performed preferably in a hospital setting. However, we would like to state that this method could be easily followed in a clinical pharmacology unit as the one usually present in medium- or large-size university hospitals of Western countries. In particular, our division has organized a network among the three major General Hospitals of Pisa , Lucca and Livorno involving all the Clinical Oncology units. At the beginning of the week (usually on Monday) the blood samples are taken in a day-hospital regimen and sent to our unit in order to process them in two-three days. The final results (including the pharmacokinetic analysis) are available in one week (usually on Thursday) and sent back to the oncologists. Thus, the patients are ready to start safely in the following week the 5-FU standard therapy after checking the 5-FU and 5-FDHU kinetic parameters.

Bibliographic reference:

Bocci G et al.: "A pharmacokinetic-based test to prevent severe 5-fluorouracil toxicity", Clin Pharmacol Ther. 2006 Oct;80(4):384-95

Guido Bocci

Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Pisa, Italy