Modeling the 5-Fluorouracil Area Under the Curve Versus Dose Relationship to Develop a Pharmacokinetic Dosing Algorithm for Colorectal Cancer Patients Receiving FOLFOX6

Kaldate, Rajesh; Haregewoin, Abebe; Grier, Charles E.; Hamilton, Stephanie; McLeod, Howard L.

doi:10.1634/theoncologist.2011-0357

Cited by 77 publications

(88 citation statements)

References 23 publications

(40 reference statements)

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“…Kaldate and colleagues conducted a retrospective analysis of the PK data from 589 CRC patients receiving FOLFOX6 chemotherapy, by utilizing an immunoassay [27]. Patients received infusional 5-FU at a dose of 1,600–3,600 mg/m 2 in cycle 1, and had at least two PK samples drawn on consecutive cycles.…”

Section: Retrospective Studies On Pk-based Dose Adaptationmentioning

confidence: 99%

Therapeutic drug monitoring of 5-fluorouracil

Lee

Beumer

Chu

2016

Cancer Chemother Pharmacol

173

147

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Purpose For over 50 years, 5-FU has played a critical role in the systemic chemotherapy of cancer patients. 5-FU serves as the main backbone of combination chemotherapy for patients with colorectal cancer (CRC) in both the adjuvant and metastatic disease settings. Herein, we review the current status of 5-FU therapeutic drug monitoring (TDM) and discuss its potential role in the clinical practice setting. Method PubMed and abstracts from the American Society of Clinical Oncology (ASCO) were searched up through September 2015 for clinical data relating to 5-FU TDM. Results 5-FU dosing has been typically determined by using body surface area (BSA). However, it is now well-established that BSA-based 5-FU dosing is correlated with a wide variation of 5-FU systemic exposure. Pharmacokinetic (PK) studies of 5-FU systemic exposure have shown a wide range of interpatient variation of 5-FU plasma drug levels. Over the past 30 years, increasing efforts have been placed on optimizing 5-FU dosing with the main goals of increasing antitumor efficacy while reducing drug-associated toxicity. There is growing evidence to show that 5-FU dosing based on plasma 5-FU drug level is feasible and that 5-FU TDM can improve clinical outcomes by improving efficacy of 5-FU-based combination regimens and reducing toxicities. Conclusion Dose adjustment of 5-FU is feasible and PK-based dosing can significantly improve clinical outcomes by reducing toxicities and improving efficacy.

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Section: Retrospective Studies On Pk-based Dose Adaptationmentioning

confidence: 99%

Therapeutic drug monitoring of 5-fluorouracil

Lee

Beumer

Chu

2016

Cancer Chemother Pharmacol

173

147

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“…For an infusion > 40 hours sampling is recommended at least 18 hours after starting infusion. 96 The sample should also be taken during a steady state period of the infusion which is usually about 4 hours before the end of the infusion using a non-battery operated device (which is commonly used in the UK). Depending on practice, it may require an additional visit by a district nurse or an additional outpatient attendance.…”

Section: My5-fu Assaymentioning

confidence: 99%

“…An example of a dose adjustment algorithm for patients with mCRC recommends an optimal therapeutic range of 20-30 mg × hour/l with adjustments of no more than 30% of the dose for each infusion. 96 Patients typically require three or four PK-directed dose adjustments to reach an optimal therapeutic range.…”

Section: My5-fu Assaymentioning

confidence: 99%

“…Dose adjustment during 5-FU treatment requires knowledge of the plasma concentration of 5-FU following the first cycle of treatment to calculate the AUC value, which is known to correlate better with outcomes than initial 5-FU dose. 96 Due to the non-linear PKs of 5-FU, an algorithm is then needed to calculated the new dose for the second 5-FU treatment cycle if the exposure is not within the desired range. Several algorithms have been reported in the literature for different treatment regimens which are described below.…”

Section: Objective A(2)mentioning

confidence: 99%

“…This was adapted and used in subsequent studies by the French group (see Table 18). Kaldate et al 96 carried out a retrospective database analysis of PK data from a commercial laboratory setting to define a dose adjustment algorithm for the FOLFOX6 regimen (5-FU + FA + oxaliplatin) with or without bevacizumab. They used a simple regression analysis to model the change in AUC versus the change in dose in 187 CRC patients.…”

Section: Objective A(2)mentioning

confidence: 99%

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Fluorouracil plasma monitoring: systematic review and economic evaluation of the My5-FU assay for guiding dose adjustment in patients receiving fluorouracil chemotherapy by continuous infusion

Freeman

Connock

Cummins³

et al. 2015

Health Technol Assess

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Background5-Fluorouracil (5-FU) is a chemotherapy used in colorectal, head and neck (H&N) and other cancers. Dose adjustment is based on body surface area (BSA) but wide variations occur. Pharmacokinetic (PK) dosing is suggested to bring plasma levels into the therapeutic range to promote fewer side effects and better patient outcomes. We investigated the clinical effectiveness and cost-effectiveness of the My5-FU assay for PK dose adjustment to 5-FU therapy.ObjectivesTo systematically review the evidence on the accuracy of the My5-FU assay compared with gold standard methods [high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS)]; the effectiveness of My5-FU PK dosing compared with BSA; the effectiveness of HPLC and/or LC-MS compared with BSA; the generalisability of published My5-FU and PK studies; costs of using My5-FU; to develop a cost-effectiveness model.Data sourcesWe searched MEDLINE, EMBASE, Science Citation Index and other databases between January and April 2014.MethodsTwo reviewers independently screened titles and abstracts with arbitration and consensus agreement. We undertook quality assessment. We reconstructed Kaplan–Meier plots for progression-free survival (PFS) and overall survival (OS) for comparison of BSA and PK dosing. We developed a Markov model to compare My5-FU with BSA dosing which modelled PFS, OS and adverse events, using a 2-week cycle over a 20 year time horizon with a 3.5% discount rate. Health impacts were evaluated from the patient perspective, while costs were evaluated from the NHS and Personal Social Services perspective.ResultsA total of 8341 records were identified through electronic searches and 35 and 54 studies were included in the clinical effectiveness and cost-effectiveness reviews respectively. There was a high apparent correlation between My5-FU, HPLC and LC-MS/mass spectrometer but upper and lower limits of agreement were –18% to 30%. Median OS were estimated as 19.6 [95% confidence interval (CI) 17.0 to 21.0] months for PK versus 14.6 (95% CI 14.1 to 15.3) months for BSA for 5-FU + folinic acid (FA); and 27.4 (95% CI 23.2 to 38.8) months for PK versus 20.6 (95% CI 18.4 to 22.9) months for BSA for FOLFOX6 in metastatic colorectal cancer (mCRC). PK versus BSA studies were generalisable to the relevant populations. We developed cost-effectiveness models for mCRC and H&N cancer. The base case assumed a cost per My5-FU assay of £61.03. For mCRC for 12 cycles of a oxaliplatin in combination with 5-fluorouracil and FA (FOLFOX) regimen, there was a quality-adjusted life-year (QALY) gain of 0.599 with an incremental cost-effectiveness ratio of £4148 per QALY. Probabilistic and scenario analyses gave similar results. The cost-effectiveness acceptability curve showed My5-FU to be 100% cost-effective at a threshold of £20,000 per QALY. For H&N cancer, again, given caveats about the poor evidence base, we also estimated that My5-FU is likely to be cost-effective at a threshold of £20,000 per QALY.LimitationsQuality and quantity of evidence were very weak for PK versus BSA dosing for all cancers with no randomised controlled trials (RCTs) using current regimens. For H&N cancer, two studies of regimens no longer in use were identified.ConclusionsUsing a linked evidence approach, My5-FU appears to be cost-effective at a willingness to pay of £20,000 per QALY for both mCRC and H&N cancer. Considerable uncertainties remain about evidence quality and practical implementation. RCTs are needed of PK versus BSA dosing in relevant cancers.FundingThe National Institute for Health Research Health Technology Assessment programme.

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Therapeutic Drug Monitoring in Oncology: International Association of Therapeutic Drug Monitoring and Clinical Toxicology Recommendations for 5‐Fluorouracil Therapy

Beumer

Chu

Allegra

et al. 2018

Clin Pharma and Therapeutics

102

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5-Fluorouracil (5-FU) is dosed by body surface area, a practice unable to reduce the interindividual variability in exposure. Endorsed by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT), we evaluated clinical evidence and strongly recommend TDM for the management of 5-FU therapy in patients with colorectal or head-and-neck cancer receiving common 5-FU regimens. Our systematic methodology provides a framework to evaluate published evidence in support of TDM recommendations in oncology.

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Modeling the 5-Fluorouracil Area Under the Curve Versus Dose Relationship to Develop a Pharmacokinetic Dosing Algorithm for Colorectal Cancer Patients Receiving FOLFOX6

Abstract: ABSTRACT

Cited by 77 publications

References 23 publications

Therapeutic drug monitoring of 5-fluorouracil

Therapeutic drug monitoring of 5-fluorouracil

Fluorouracil plasma monitoring: systematic review and economic evaluation of the My5-FU assay for guiding dose adjustment in patients receiving fluorouracil chemotherapy by continuous infusion

Therapeutic Drug Monitoring in Oncology: International Association of Therapeutic Drug Monitoring and Clinical Toxicology Recommendations for 5‐Fluorouracil Therapy

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