Dose monitoring of 5-fluorouracil in patients with colorectal or head and neck cancer—status of the art

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Introduction

After nearly 40 years usage, 5-fluorouracil (5-FU) is still widely used against a variety of solid tumors, especially head and neck and colorectal cancers [1], [2]. Recent advances in basic and clinical research have improved its therapeutic efficacy in first line therapy through biochemical modulation [1], [2]. Thus, leucovorin (LV), used as 5-FU biomodulator, has improved its results in colorectal cancer, in terms of response as well as survival [3], [4]. However, in head and neck cancers, though pilot and randomised studies have shown consistent beneficial impact on response, no gain has been obtained on survival [5], [6], [7], [8]. Moreover, LV increases 5-FU toxicity and leads to a reduction of the maximum tolerated dose. In some studies, it does not improve the results [8], [9].

The data concerning pharmacokinetics and metabolism of 5-FU are recent. Fluorouracil has a narrow therapeutic index, i.e. very little difference between the theoretical minimum effective dose and the maximum tolerated dose. It also presents a marked individual pharmacokinetic variability. For a given standard dose, whatever the schedule, 5-FU systemic clearance exhibits a wide range of values among patients [10], [11], [12], [13], [14]. This characteristic contributes to a great variability in the pharmacodynamic effects of a given dose of 5-FU and some inter-patient differences, in terms of toxicity and efficacy. Therefore, an identical dose of 5-FU may result in a therapeutic response with acceptable toxicity in some patients, whereas unacceptable and possibly life threatening toxicity may occur in others, or no response and no toxicity in another category of patients. Yet, certain retrospective analyses in advanced colorectal cancer have strongly suggested a relationship between 5-FU dose and response. They have emphasised the impact of 5-FU dose-intensity on the response rate [9], [15], [16] but a dose limiting haematological and mucosal toxicity has hindered the development of intensive dose strategies [6], [17], [18]. In total, there remains much confusion regarding the optimal 5-FU dose scheduling [2], [4].

The concept of dose-intensity, the increasing risk of both haematological and extra-haematological side effects and the wide inter-patient variability of systemic clearance are strong arguments for individual 5-FU dose monitoring. However, dose adjustment with pharmacokinetic follow-up requires some conditions. At least, the therapeutic index must be determined and the drug kinetics in plasma must be simple enough to permit the dose adjustment [19].

5-FU systemic exposure has been significantly correlated to the risk of developing 5-FU-related toxicities [20], [21]. Individual adjustment of 5-FU dose based on pharmacokinetics has already significantly proven its clinical usefulness for reducing toxicity [22]. A complementary approach is to analyse the link between 5-FU systemic exposure and treatment efficacy. However, the demonstration of such a pharmacodynamic relationship can be hard because the correlation between extra-tumoral and intra-tumoral drug concentrations is weak and 5-FU is just a pro-drug which needs to be activated within the cell [12]. Despite those limits, this relationship has already been studied and some conclusive results are available in head and neck tumours and advanced colon cancer [20], [21], [23].

Finally, the determination of the relationship between pharmacokinetic parameters and the two pharmacodynamic endpoints, toxicity and tumour response, may allow to reach the optimum dosage of 5-FU. The goal is to maximise the likelihood of response and minimise the likelihood of toxicity. For some drugs, e.g. carboplatin, the optimum dosage can be defined individually from measurable physiological variables, such as renal function. The problem is more complicated with 5-FU, because its clearance is not easily predictable for a given patient. Thus, the individual determination of the 5-FU dosage requires pharmacokinetic data from an initial test-dose, and often, more data is needed from subsequent cycles.

In the present review, we will develop the concept of 5-FU pharmacokinetic–pharmacodynamic relationship in head and neck and colorectal cancer, the analysis of the link between 5-FU exposure and both toxicity and efficacy. Then, we will describe the pharmacokinetics of 5-FU in plasma and the approaches for individual dosage adjustment.

Section snippets

Concept of dose-intensity

A relationship between 5-FU dose and response has been strongly suggested in metastatic colorectal cancer by retrospective analyses [9], [15], [16], [17]. Hryniuk et al. in 1987 [16], and then Arbuck in 1989 [9], in metaanalysis, showed a clear relationship between 5-FU dose, in mg m−2 week−1, and response. More recently, Brohee [15], in a multivariate analysis of the response rates in studies with patients treated with 5-FU±LV, found that the most important variables delineated were 5-FU

Relationship between toxicity and 5-fluorouracil pharmacokinetic parameters

The major pharmacokinetic parameter for quantifying the systemic exposure in a pharmacodynamic study is the ‘area under the curve’ (AUC). It simultaneously takes into account both the mean plasma concentration of the drug and the time of exposure. It is better correlated to the intensity of pharmacodynamic effects than the absolute dose, which is subjected to a combination of physiological variables and genetic characteristics that influences the outcome of the drug [19].

A strong correlation

Relationship between tumor response and 5-fluorouracil plasma levels

The next step for defining a therapeutic index is the determination of the therapeutic threshold. The correlation between 5-FU-pharmacokinetics and the response to the treatment has been less extensively explored than that with toxicity (Table 3). Other mechanisms, such as intrinsic cellular resistance and tumor kinetics can be involved in the treatment failure. Consequently, the pharmacokinetic and pharmacodynamic studies are more complicated.

In advanced colorectal cancer, in 1978 Hillcoat et

Fluorouracil metabolism

Fluorouracil is metabolised into dihydrofluorouracil by dihydropyrimidine dehydrogenase (DPD). DPD is the rate-controlling enzyme of pyrimidine catabolism. It is largely widespread in the organism, mainly in liver, lung, kidney and lymphocytes [12]. Its activity can be measured by radioenzymatic assay in lymphocytes. It has recently been the focus of considerable attention. DPD activity presents a great variability within the population, which is due to a genetic polymorphism [34], [35].

Detection of dihydropyrimidine dehydrogenase deficiency

The method of the test-dose is not easy in practice, because plasma kinetics of 5-FU are not linear, especially with IV bolus. Moreover, the administration of a test-dose can be dangerous in case of a marked DPD deficiency. A radioenzymatic technique, using a radiolabelled substrate, has been developed for the determination of DPD activity in lymphocytes, before treatment [41], [42]. Fleming et al. [41] found a significant linear correlation between DPD activity in peripheral blood mononuclear

Individual 5-fluorouracil dose adjustment

The purpose of the individual dose adjustment in practice is to deliver an optimal dose of 5-FU to a given patient so as to target the optimal AUC. Fluorouracil seems to be more interesting in pharmacodynamic studies, even though it is only a pro-drug, than its first catabolite, dihydrogenofluorouracil, which has no activity, and its cell anabolites, 5-fluorodeoxyuridine monophosphate and 5-fluorouridine triphosphate.

The pretreatment study of its outcome would be useful. The individual

Results of 5-fluorouracil dose adjustment

Individual dose adjustment has been poorly investigated in clinical practice and it has been mainly focused on controlling 5-FU-related toxicity. With this purpose, certain authors attempted to adjust individually the dose in neo-adjuvant chemotherapy for head and neck tumours [23]. They controlled AUC at the middle of a 5 day infusion and then adjusted the dose of 5-FU with a nomogram to maintain the total AUC under the toxic value. The possible progressive increase of 5-FU concentrations over

Conclusion

Until recently, 5-FU pharmacokinetic and metabolic characteristics were not taken into account in chemotherapy regimens and results remained mediocre in spite of some progress through biomodulation. New intensive schedules have been attempted. They have provided better results in head and neck and colorectal cancers but 5-FU appeared to have a narrow therapeutic index and to be potentially dangerous. There is increasing evidence that pharmacologic parameters should be included as end points of

Reviewers

This paper was reviewed by Pierre Canal, Pharmacology Laboratory and Pharmacy, Institut Claudis Regaud, 20–24, rue du Pont Saint Pierre, 30152 Toulouse cedex, France; Jacques Robert, Institut Bergonié, 180, rue de Saint-Genès/229, cours de l’Argonne, 33076 Bordeaux cedex, France; and Gerard Milano, Laboratoire D’oncopharmacologie, 33, avenue de Vambrose, 06189 Nice cedex 2, France.



Erick Gamelin MD specialised in Medical Oncology and has a PhD in Pharmacology. He is head of both the Medical Oncology and Oncopharmacology Departments at the Anticancer Centre, Angers, France. He is a member of the American Association for Cancer Research and vice-president of the French Group of Clinical and Oncological Pharmacology. His main topics of study are fluoropyrimidines, platinim derivatives—pharmacokinetics, metabolism, mechanism of action, toxicity, and cellular mechanisms of

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    Erick Gamelin MD specialised in Medical Oncology and has a PhD in Pharmacology. He is head of both the Medical Oncology and Oncopharmacology Departments at the Anticancer Centre, Angers, France. He is a member of the American Association for Cancer Research and vice-president of the French Group of Clinical and Oncological Pharmacology. His main topics of study are fluoropyrimidines, platinim derivatives—pharmacokinetics, metabolism, mechanism of action, toxicity, and cellular mechanisms of resistance—and digestive tract cancers.

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