BSA dosing and suboptimal 5-FU exposure among colorectal cancer patients of varying gender and age.

579 Background: 5-Fluorouracil (5-FU) remains the cornerstone of colorectal cancer (CRC) therapy and its dosing is based on body surface area (BSA). Although convenient, BSA dosing disregards factors that impact 5-FU PK such as genotype, age, gender, etc. Thus, patients receiving the same BSA based dose show a wide range of 5-FU plasma levels (measured as AUC in mg·h/L), resulting in ineffective or toxic doses affecting therapy outcome. An optimal therapeutic AUC target range of 20-30 mg·h/L has been proposed. METHODS Plasma samples from the initial treatment cycle of 927 CRC patients who received 2400 mg/m2 continuous infusion of 5-FU over 44-48 hours, with or without bevacizumab, were tested for 5-FU exposure using an immune-based assay (OnDose). AUC results were analyzed to evaluate gender and age effects. RESULTS There are 391 (42.2%) female and 536 (57.8%) male patients with age ranging from 17-93 years (mean/SD: 58.5/11.8). These analyses indicate that in comparison to the proposed optimal AUC target range of 20-30 mg·h/L, females receive supra-optimal doses compared to males (p=0.0083). Age also affects the 5-FU AUC (p=0.0002), with younger patients more likely to receive sub-optimal doses than older patients. CONCLUSIONS BSA dosing is an unreliable indicator of exposure and may lead to under dosing in males and younger patients, and overdosing in females and older patients, potentially resulting in corresponding diminished efficacy or increased toxicity. Data suggest that therapy could be optimized by 5-FU dose adjustment in subsequent cycles based on PK monitoring so that AUC values will converge towards the target range irrespective of gender or age. A large clinical trial is in progress to validate these findings.