Pharmacokinetically Guided Dose Adjustment of 5-FU—A Critical Element Toward Personalized Medicine

Abstract

Colorectal cancer (CRC) is one of the leading causes of cancer mortality in the United States and worldwide. Systemic chemotherapy has been the mainstay treatment approach for patients with metastatic disease and in the adjuvant setting after curative resection of early-stage CRC. Since the 1950s, 5-fluorouracil (5-FU) has been the backbone of systemic combination chemotherapy for the treatment of CRC. The dosing of 5-FU, as is the case for nearly all cytotoxic agents, has traditionally been based on body surface area (BSA). There is now growing evidence that BSA-based 5-FU dosing has several limitations, perhaps the most important being significant interpatient and intrapatient variability in 5-FU drug levels when dosing is based on BSA. 1,2 The situation is further complicated by a narrow therapeutic window leading to dose-limiting toxicity of 5-FU. Several studies have shown that BSA-based dosing results in, at most, 20% to 30% of patients being in the appropriate dose range of 5-FU. 3 Approximately 40% to 60% patients are underdosed, whereas a smaller fraction of patients in the range of 10% to 20% are overdosed. 3 It is now widely accepted that BSA dosing is not accurate for extremes of body size and does not account for important sources of variability such as age, sex, a decrease in 5-FU clearance during the course of chemotherapy, drug interactions, and pharmacogenomic differences. 4 There is a clearly defined relationship between 5-FU plasma concentration and biological effects, including toxicity and efficacy. 5,6 Several studies, including a large multicenter randomized trial in France, have shown that pharmacokinetically guided dose adjustment of 5-FU in patients with metastatic CRC allows individualized dose adjustment and results in improved clinical efficacy and reduced risk of toxicity. 7,8 Pharmokinetically guided dose adjustment of 5-FU in the United States has only been facilitated during the past few years with the recent development of a fast, simple, and relatively inexpensive immunoassay that is now available for clinical use. This test is highly specific for 5-FU, and studies by Beumer et al have shown that this test has a high correlation with validated liquid chromatographyemass spectrometry and high-performance liquid chromatography. 9 In this issue of Clinical Colorectal Cancer, Kline et al have evaluated the impact of pharmacokinetically guided dose adjustment of 5-FU in both patients with early-stage and those with advanced-stage CRC who received infusional 5-FU as part of FOLFOX (5-fluorouracil, leucovorin [folinic acid], oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin [folinic acid], irinotecan) chemotherapy. This study was conducted at a single institution between 2010 and 2013. 10 A total of 84 patients were evaluated, and of this group, 35 patients had stage II/III disease, whereas 49 patients had stage IV disease. Among the 84 patients, 46 patients received 5-FU based on BSA and 38 patients received 5-FU dose adjustment based on pharmacokinetic (PK) monitoring using the 5-FU immunoassay. For patients in the PK dosing arm, the first 5-FU dose was determined using the traditional BSA method, and subsequent dosing was based on 5-FU PK test results targeting the