Clinical response and plasma levels of 5-fluorouracil in patients with colonic cancer treated by drug infusion

Hillcoat, B L; McCulloch, P B; Figueredo, A; Ehsan, M H; Rosenfeld, J

doi:10.1038/bjc.1978.278

Cited by 93 publications

(29 citation statements)

References 6 publications

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“…When available, data showed values up to 15 times higher than the normal concentrations expected at our institute and, in most cases, above the plasma concentrations associated with toxicities. 31 Interestingly, patient P18 had an apparent normal DPD function but presented with cutaneous eruption and sepsis after 5-FU-CDDP infusion; 5-FU assay results on that patient showed a 5-FU Css far below the toxic threshold, suggesting that the side effects observed in that patient were not related to the 5-FU intake. More surprisingly, patient P5, also displaying a normal U/UH2 ratio, was found to have elevated 5-FU plasma concentrations.…”

Section: Discussionmentioning

confidence: 90%

A Rapid and Inexpensive Method for Anticipating Severe Toxicity to Fluorouracil and Fluorouracil-based Chemotherapy

Ciccolini¹,

Mercier²,

Evrard³

et al. 2006

Therapeutic Drug Monitoring

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Dihydropyrimidine dehydrogenase (DPD) deficiency leads to dramatic overexposure to fluorouracil (5-FU), resulting in a potentially lethal outcome in patients treated with standard doses. The aim of this study was to validate, in a routine clinical setting, a simple and rapid method to determine the DPD status in a subset of cancer patients, all presenting with life-threatening toxicities following 5-FU or capecitabine intake. In this study, 80 out of 615 patients (13%) suffered severe toxicities, including 5 lethal ones (0.8%), during or after chemotherapy with a fluoropyrimidine drug. Patients with severe toxicities were treated with 5-FU (76 patients) or capecitabine-containing protocols (4 patients). Simplified uracil to di-hydrouracil (U/UH2) ratio determination in plasma was retrospectively performed in these 80 patients, as a surrogate marker of DPD activity. When possible, 5-FU Css determination was performed, and screenings for the canonical IVS14+1G>A mutation were systematically carried out. Comparison of the U/UH2 ratios with a reference, non-toxic population, showed abnormal values suggesting impaired DPD activity in 57 out of the 80 toxic patients (71%) included in this study, and in 4 out of 5 patients (80%) with a fatal outcome. Similarly, drug exposures up to 15 times higher than the range observed in the non-toxic population were also observed. Importantly, no IVS14+1G>A mutation was found in these patients, including those displaying the most severe or lethal toxicities. These data warrant systematic detection of DPD-deficient patients prior to fluoropyrimidine administration, including when oral capecitabine (Xeloda) is scheduled. Finally, the simplified methodology presented here proved to be a low cost and rapid way to identify routinely patients at risk of toxicity with 5-FU or capecitabine.

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Section: Discussionmentioning

confidence: 90%

A Rapid and Inexpensive Method for Anticipating Severe Toxicity to Fluorouracil and Fluorouracil-based Chemotherapy

Ciccolini¹,

Mercier²,

Evrard³

et al. 2006

Therapeutic Drug Monitoring

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“…There are also studies suggesting a relationship between the plasma clearance or AUC offluorouracil and antitumour response. These studies, however, contain only a small number of patients and the results have not been confirmed in larger series (Hillcoat et al 1978;Seitz et al 1983). It has also been shown that there is no relationship between the plasma pharmacokinetics of fluorouracil and the cellular concentration of its metabolites (Finan et al 1987).…”

Section: Fluorouracilmentioning

confidence: 95%

Pharmacokinetic Optimisation of Anticancer Therapy

Liliemark

Peterson

1991

Clinical Pharmacokinetics

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It is obvious that there are great problems with pharmacokinetic individualization of anticancer therapy. The strong relationship between dose intensity (total dose/unit time) and response revealed in clinical trials with some tumours provides a strong support for studies seeking relationships between the individual plasma pharmacokinetic profile and response to treatment. Unfortunately, studies that define a therapeutic window are sparse, and trials that prospectively test such models are even rarer. Thus, for most cancer drugs, it is not possible to give any definite advice on how to use pharmacokinetic determinations to establish individualised therapy, and there is therefore a definite need for such studies. It is important, however, that attempts to establish relationships between drug concentrations and therapeutic effects be founded on a sound theoretical base. When drugs, mainly antimetabolites, are extensively metabolised intracellularly and interact with intracellular processes about which there are data showing a strong interindividual heterogeneity, such data must be considered when designing pharmacokinetic investigations. Cytarabine and fluorouracil are good examples of this. The monitoring of intracellular drug/metabolite concentrations or of the direct biochemical events in the tumour cells seems to be a promising approach with such drugs. It also needs to be emphasised that pharmacokinetically guided individualization cannot be achieved before a therapeutic window is established, i.e. a knowledge of the relationship between drug concentration and clinical effects. The investigators in this field accept a great responsibility when clinical studies are undertaken: a poorly designed study showing no benefit from pharmacokinetically guided individualization can impair the possibilities of performing more adequate studies in the future.

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“…In the 1970s, Hillcoat et al reported on the close correlation between 5-FU plasma drug concentrations and tumor response in patients with gastrointestinal tract (GI) cancers [18]. In this study, patients received 5-day continuous infusion of 5-FU at a dose of 1200 mg/m 2 /day on days 1–5 in combination with the nitrosourea CCNU 150 mg/m 2 on day 1, and this combination regimen was administered every 6 weeks.…”

Section: Existence Of Pk-pd Relationshipsmentioning

confidence: 99%

Therapeutic drug monitoring of 5-fluorouracil

Lee

Beumer

Chu

2016

Cancer Chemother Pharmacol

179

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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Clinical response and plasma levels of 5-fluorouracil in patients with colonic cancer treated by drug infusion

Cited by 93 publications

References 6 publications

A Rapid and Inexpensive Method for Anticipating Severe Toxicity to Fluorouracil and Fluorouracil-based Chemotherapy

A Rapid and Inexpensive Method for Anticipating Severe Toxicity to Fluorouracil and Fluorouracil-based Chemotherapy

Pharmacokinetic Optimisation of Anticancer Therapy

Therapeutic drug monitoring of 5-fluorouracil

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