Background Appropriate dosing of chemotherapeutic drugs is critical to reducing mortality and increasing progression-free survival. 5-fluorouracil (5-FU) is a widely used chemotherapeutic drug in gastrointestinal cancer. The standard approach to dosing 5-FU is based on body surface area (BSA). However, BSA does not account for many of the factors that are responsible for 5-FU clearance such as age, gender, genotype, disease state, drug-drug interactions, organ dysfunction and co-morbidities. Clinical evidence indicates a strong correlation between both toxicity and therapeutic efficacy and total 5-FU exposure expressed as area under the curve (AUC) concentration. This evidence make 5-FU a good candidate for pharmacokinetic (PK)-guided dosing.
Purpose To evaluate the role of therapeutic drug monitoring (TDM) of 5-FU in daily clinical oncology practise.
Materials and Methods Prospective study of adult patients diagnosed with gastrointestinal cancer treated with infusion schedule regimes based on high doses of 5-FU (2.5–3.2 g/m² in 24–46 h infusion) in a university hospital. All patients were included regardless of disease state or general clinical status. Individual pharmacokinetic parameters were calculated based on anthropometrics and history of 5-FU administration using the Bayesian software programme (USC*Pack). In the first cycle the dose was calculated using the BSA, and subsequent doses were adjusted to an optimal target AUC of 30–35 mg·h/L.
Results Fifty-four patients were included in the study. Male/female ratio was 31/23, and average age and weight were 60.9 ± 12.8 years and 72.2 ± 16.9 Kg. Mean estimated pharmacokinetic parameters for volume of distribution and 5-FU clearance were 0.49 ± 0.08 L/Kg and 203 ± 68.6 L/h, respectively. To achieve the target AUC of 30–35 mg·h/L, the dose had to be increased in 33 (86.8%) patients and adjusted downward in 5 (13%). No adjustment was needed in 16 patients (29.6%).When the estimate was based on BSA, 30 patients (55.6%) had AUC < 25 mg·h/L.
Conclusions BSA-based 5-FU dosing approaches are limited when it comes to achieving optimal plasma levels in most patients. Pharmacokinetically guided dosing represents a better strategy to improve the efficacy and safety of 5-FU.
No conflict of interest.
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