Special Report: Laboratory Testing to Allow Area Under the Curve (AUC) ???Targeted 5-Fluorouracil Dosing for Patients Administered Chemotherapy for Cancer
Executive Summary
Background
5-Fluorouracil (5???FU) is a widely used antineoplastic chemotherapy drug with a narrow therapeutic index; doses recommended for effectiveness are often limited by hematologic and gastrointestinal toxicity. Moreover, patients administered the same fixed dose, continuous infusion regimen of 5???FU have wide intra- and inter-patient variability in systemic drug exposure as measured by plasma concentration or, more accurately, by area under the curve (AUC) techniques. AUC is a measure of the systemic drug exposure in an individual over a defined period of time.
In general, the incidence of grade 3 to 4 toxicity (mainly neutropenia, diarrhea, mucositis, and handfoot syndrome) increases with higher systemic exposure to 5???FU. Several studies have also reported statistically significant positive associations between 5???FU exposure and tumor response. In current practice, however, 5???FU dose is reduced when symptoms of severe toxicity appear, but seldom increased to promote efficacy.
Based on known 5???FU pharmacology, it is possible to determine a sampling scheme for AUC determination and to optimize an AUC target and dose adjustment algorithm for a particular 5???FU chemotherapy regimen and patient population. For each AUC value or range, the algorithm defines the dose adjustment during the next chemotherapy cycle most likely to achieve the target AUC without overshooting and causing severe toxicity.
Accurate AUC determination relies on sampling at a pharmacokinetically appropriate time, as well as on an accurate method of 5???FU laboratory measurement. In clinical research studies, 5???FU blood plasma levels have most recently been determined by high-performance liquid chromatography or liquid chromatography coupled with tandem mass spectrometry. Without commercially available reagents and protocols, however, both methods require the expertise to develop an in-house assay and may be less amenable to routine clinical laboratory settings. One commercially available alternative is Myriad Genetics' OnDose™, a diagnostic test that is designed to measure colorectal cancer patients' exposure to 5???FU, to help oncologists adjust and optimize 5???FU dosing.
Objective
The purpose of this Special Report is to first review 5???FU pharmacology and early clinical data leading to the hypothesis that 5???FU chemotherapy dosing can be improved by modulating dose to an AUC target value as treatment is delivered, and that this will achieve maximum treatment response but minimal severe toxicity outcomes. Second, this Report will examine available, relevant evidence to support this hypothesis.
Search Strategy
MEDLINE® was searched (via PubMed) using the following strategy: ("Drug Dosage Calculations"[MeSH®] OR "Area Under Curve"[MeSH®] OR plasma concentration*[tw] OR plasma level*[tw]) AND ("Neoplasms"[MeSH®] OR "Neoplasm Metastasis"[MeSH®]) AND "Fluorouracil"[MeSH®]. This search was limited to English-language articles on human subjects. In addition, bibliographies from recent review articles and clinical studies were hand-searched for any relevant studies missed by the electronic search.
Selection Criteria
The following types of studies were included:
* single-arm clinical studies that evaluated 5???FU systemic exposure variability with fixed-dose administration;
* single-arm clinical studies that evaluated the association between fixed-dose systemic 5???FU exposure/AUC and 5???FU treatment response and/or toxicity;
* single-arm or comparative clinical studies that evaluated chronomodulated 5???FU dose delivery and treatment response and/or toxicity;
* single-arm or comparative studies of patients treated with standard fixed-dose 5???FU regimens versus AUC-targeted dosing regimens.
Main Results
The first part of this Report examined the pharmacologic plausibility and early evidence supporting the concept of 5???FU AUC dose targeting to improve treatment response and reduce toxicity.
Several studies document that 5???FU systemic exposure (as measured by AUC or by maximum or stable plasma concentration) shows considerable within- and between-patient variability on fixed-dose treatment regimens. Such large fluctuations could account for the variability in incidence and severity of toxicity experienced by different patients administered 5???FU treatment. Five of 6 studies reported a statistically significant positive association between 5???FU exposure and at least one type of or several types of toxicity, or total toxicity. Five of 7 studies reported statistically significant positive associations between 5???FU exposure and tumor response.
Three published single-arm trials developed 5???FU plasma sampling and AUC determination methods, an AUC target range to maximize treatment response with minimal toxicity, and algorithms for 5???FU dose adjustment to the target AUC range during chemotherapy treatment of patients with advanced colorectal cancer. In general, all 3 single-arm trials used similar AUC targets. Their results suggest consistency of improved tumor response using AUC-targeted 5???FU dose adjustment (overall response range, 24–43%). Historically, trial arms of 5???FU/leucovorin treatment in patients with metastatic colorectal cancer have response rates in the range of 15–25%. The results do not clearly show improved survival or reduced toxicity without fixed-dose treatment arms for comparison. The results of one trial additionally indicated that adding oxaliplatin to a 5???FU/LV regimen increased 5???FU exposure and potential for toxicity unless the treatment regimen was further adjusted. It is consistent with what is known about the pharmacokinetics of 5???FU, that different 5???FU chemotherapy regimens would likely require different dose-adjustment algorithms.
Although less compelling, the results of 2 early studies of AUC-targeted 5???FU dosing in head and neck cancer do not contradict those in colorectal cancer.
These studies used high-pressure liquid chromatography to measure 5???FU plasma concentration in several samples collected during 5???FU infusion during each treatment cycle for calculating AUC. No published studies have used the commercially available 5???FU assay service provided by Myriad Genetics. However, technical performance information provided on the Myriad website includes a favorable comparison to high-pressure liquid chromatography; total error estimate of the assay was estimated at 1.4%.
The second part of this Report asks the question: Does 5???FU dosing to an AUC target range, using laboratory testing to measure exposure during 5???FU administration and an associated algorithm to determine dose modification, result in improved health outcomes compared to fixed, standard dosing in patients with colorectal cancer undergoing 5???FU-based chemotherapy?
The available evidence consists of 2 randomized, controlled trials, one enrolling patients with colorectal cancer and the other patients with head and neck cancer. Treatment regimens are different for each of these cancers, and, because the pharmacokinetics of 5???FU are strongly influenced by the dose and schedule of administration, the use of laboratory testing for AUC dosing must be addressed separately for each regimen and application.
The first trial reported significantly improved tumor response and a trend toward improved survival using AUC-targeted dosing in their randomized, controlled trial in patients with colorectal cancer. The authors also reported 18% grade 3 to 4 diarrhea in the fixed-dose arm. As already noted, this is higher than reported historically, where the rates of grade 3 to 4 diarrhea in 5???FU/ leucovorin treatment arms have ranged from approximately 5–7%. These latter results have been obtained with a 2-hour infusion of leucovorin (200 mg/m2 per day) followed by a 5???FU bolus (400 mg/m2 per day) and a 5???FU 22-hour infusion (600 mg/m2 per day) for 2 consecutive days every 2 weeks (one of several standard regimens identified in current guidelines). Delivery over a longer time period for both 5???FU (22 hours vs. 8 hours) and leucovorin (2 hours vs. bolus) likely minimized toxicity.
The administration schedule used in the AUC dose-modulated trial is "rarely used in current practice in most countries" as described in an accompanying editorial and is absent from current guidelines. In order to apply 5???FU exposure monitoring and AUC-targeted dose adjustment to a different single-agent 5???FU treatment regimen, the following studies would be needed:
* re-optimize 5???FU plasma concentration sampling scheme,
* re-optimize the 5???FU AUC target range,
* re-optimize the 5???FU AUC dose adjustment method, and
* validate the new dose adjustment scheme versus fixed dose in a comparative trial to ensure that tumor response is at least as good as or better than a fixed-dose regimen and toxicity is reduced. If the intent is to show that dose-modulated single-agent 5???FU is comparable to combination regimens such as fixed-dose FOLFOX, then FOLFOX should be added as a third treatment arm.
In contrast to the AUC dose modulation trial in colorectal cancer patients, a second trial in head and neck cancer patients reported overall 5???FU exposures that were significantly reduced after dose adjustment compared to the fixed-dose arm. This resulted in reduced toxicity, but no improvement in clinical response. The dose adjustment method in this trial may have been too complex, as the 12 protocol violations in this treatment arm (of 61 enrolled) were all related to 5???FU dose adjustment miscalculations. Because patients with protocol violations were not evaluated in an intention-to-treat analysis, the results do not reflect the "real world" experience of this study. Multiple disciplines and several, timely steps are required to effect the correct sampling, assay performance, interpretation of drug concentrations, dose adjustments, and drug administration necessary to achieve improved results. The protocol violations in this trial suggest that putting this method into clinical operation may be no small matter.
The AUC dose modulation trial in head and neck cancer patients also used a 2-drug induction therapy regimen, which has now been replaced by a 3-drug regimen with the addition of docetaxel. Re-optimization studies would also be needed to adapt the dose adjustment protocol to the currently accepted induction therapy regimen.
In summary, and given the limitations of the existing evidence, the evidence is insufficient to draw conclusions about the impact of 5???FU exposure measurement and AUC-targeted dose adjustment on outcomes of patients administered contemporary chemotherapy regimens for colorectal or head and neck cancer.
Full Study
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