1 Department of Medicine, University of Chicago Medical Center; 2 University of Chicago Cancer Research Center; 3 University of Chicago Pritzker School of Medicine; 4 University of Chicago Committee on Clinical Pharmacology, Chicago, IL, USA
Received 24 September 2002; revised 28 February 2003; accepted 26 March 2003
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Abstract |
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Patients with hepatic or renal dysfunction are often treated with 5-fluorouracil (5-FU), but there are few data to confirm the safety of this practice.
Patients and methods:
Patients with solid tumors were eligible if they were able to fit into one of three organ dysfunction cohorts: I, creatinine >1.5 but 3.0 mg/dl and normal bilirubin; II, bilirubin >1.5 but <5.0 mg/dl with normal creatinine; or III, bilirubin
5.0 mg/dl with normal creatinine. 5-FU doses were escalated separately within each of the three cohorts. Leucovorin (LV) dosage was fixed at 500 mg/m2. 5-FU was given as a 24-h infusion at 1000, 1800 or 2600 mg/m2, and plasma concentrations were measured every 3 h during the first two infusions for each patient.
Results:
Sixty-four patients were treated. Toxicities did not appear to be related to organ dysfunction cohort. A weekly dose of of 5-FU 2600 mg/m2 produced dose-limiting toxicity (DLT) in six of 20 evaluable patients.These DLTs included grade 3 fatigue (n = 3), grade 2 neutropenia precluding weekly dosing (n = 1), grade 3 thrombocytopenia (n = 1) and grade 3 mental status changes (n = 1). There was no relationship between serum bilirubin or serum creatinine and 5-FU clearance.
Conclusions:
Patients with elevated bilirubin may be safely started on a weekly regimen of 5-FU 2600 mg/m2 with leucovorin 500 mg/m2 as a 24-h continuous infusion.
Key words: 5-fluorouracil, hepatic dysfunction, leucovorin, pharmacokinetics, 24-h infusion
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Introduction |
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The toxicities of 5-FU have been reported to increase with increased 5-FU plasma levels and area under the concentration versus time curve (AUC) [35]. Approximately 90% of a dose of 5-FU is eliminated by metabolism, and only a small percentage undergoes renal excretion. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in 5-FU catabolism [6]. DPD is found in the liver, gastrointestinal tract and tissues throughout the body. It could therefore be hypothesized that no reduction in 5-FU dose needs to be made for patients with hepatic or renal dysfunction. However, a significant portion of 5-FU degradation does take place in the liver [7]. Moreover, it has been reported that patients with clinically evident hepatic metastases have significantly higher plasma levels of 5-FU than patients without liver metastases [8] and that patients with liver metastases associated with jaundice encounter severe toxicity when treated with full doses of 5-FU [9].
We therefore undertook a phase I and pharmacokinetic trial of a 24-h continuous i.v. infusion of 5-FU with leucovorin in patients with elevated bilirubin or mild renal dysfunction to determine the tolerability of this treatment, and to determine whether elevated bilirubin or creatinine affect 5-FU pharmacokinetics in the dose ranges studied. Since it has been reported that drug levels of 5-FU given by continuous i.v. infusion vary significantly over time [1012], we measured 5-FU plasma levels every 3 h.
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Patients and methods |
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Treatment
For inpatients 5-FU was mixed together with LV 500 mg/m2 in 5% dextrose 1000 ml in water and administered i.v. over 24 h. Portable infusion pumps were used for outpatients, and 5-FU and LV were run through separate lines to avoid solubility problems when the drugs were administered in small volumes. Antiemetic therapy was not specified; this trial was initiated prior to the commercial availability of 5HT3 antagonists. Treatments were repeated weekly. Four weekly treatments constituted one cycle.
Doses or dose levels were not changed based on subsequent changes in bilirubin or creatinine. Patients with external biliary drainage catheters were eligible, and continued on study at the same dose even if their bilirubin levels normalized subsequently. Otherwise, each weekly treatment required the same laboratory parameters as the initial treatment, and all treatment-related toxicities except alopecia and anemia must have resolved or be grade 1 or the subsequent treatment was delayed and the 5-FU dose permanently reduced by 400 mg/m2 (200 mg/m2 if at dose level 1). Patients with grade 4 myelosuppression or mucositis, or grade 3 non-hematological toxicity were also treated with a 5-FU 400 mg/m2 dose reduction. Patients with grade 4 toxicities other than myelosuppression or mucositis were removed from the study. Patients who required more than one dose reduction were removed from the study. Changes in bilirubin or creatinine were not treated as toxicity unless regarded by the treating physician as being probably or definitely caused by therapy.
The first two infusions were administered in the Clinical Research Center at the University of Chicago. To eliminate potential confounding by any circadian variation in 5-FU toxicity or plasma levels, the starting time for the first infusion was randomly assigned to be either 6 a.m. or 6 p.m. The starting time for the second infusion was the alternate time point. Blood was obtained every 3 h for measurement of 5-FU plasma concentrations. Subsequent doses could be administered in either the inpatient or outpatient setting at the discretion of the treating physician. A complete blood count with differential count was required weekly while the patient was on study. Electrolytes, creatinine, bilirubin and liver function tests were repeated weekly just prior to each treatment during the first 4 weeks of therapy and monthly thereafter. In this analysis, assignment to a treatment cohort is based on the creatinine and bilirubin values obtained just prior to (same day of) the first 5-FU dose.
Response was not a primary end point of the study, and measurable disease was not an eligibility requirement. However, disease status was reassessed after every eight 5-FU infusions (two cycles). Complete response was defined as disappearance of all clinical and laboratory signs and symptoms of disease for a minimum of 1 month. Partial response was defined as a 50% reduction in the sum of the products of the longest perpendicular diameters of all measured lesions lasting for a minimum of 1 month. Minor response was defined as a 2549% decrease in the sum of the products of the longest perpendicular diameters of all measured lesions lasting for at least 1 month, or objective but incomplete response in patients with nonmeasurable disease and with no lesion growth or new lesions. Progressive disease was a >25% increase in sum of the products of the longest perpendicular diameters of all measured indicator lesions compared with the smallest previous measurement or appearance of new lesions. Stable disease was disease not meeting criteria for response or progression.
Dose escalation
Initial 5-FU doses were the same for all organ dysfunction groups. Dose escalation proceeded as follows: level 1, 1000 mg/m2; level 2, 1800 mg/m2 and level 3, 2600 mg/m2. Doses did not exceed 2600 mg/m2, as this is the recommended 5-FU dose for this regimen in patients with normal hepatic and renal function [2]. For the most part, each organ dysfunction group was to be separately dose escalated. However, if patients in the high bilirubin group were safely escalated to a higher dose level than those in the intermediate bilirubin group, subsequent intermediate bilirubin patients were to be treated at the dose level to which the high bilirubin group was accruing. Doses could be escalated in a given patient if the next higher dose level had been shown to be tolerable in at least three patients of the same cohort, but no patients were actually dose escalated.
At least three patients were treated at each 5-FU dose level. All three were to have completed at least four treatments plus 1 week of observation before patients could be entered at the next higher dose level. The Cancer and Leukemia Group B common toxicity criteria were used, and dose-limiting toxicity (DLT) was defined as any grade 3 or 4 toxicity (excluding anemia) in cycle one or inability to receive one of the first four doses on schedule. If one of the first three patients at a dose level had a DLT, then three more patients were treated at that dose level; at least six patients were to be treated at the recommended phase II dose in each organ dysfunction cohort. The recommended phase II dose was the highest dose level tested at which 1 patients had grade 4 toxicity and
2 patients had grade 3 or higher toxicity.
5-FU plasma concentrations
Seven to ten ml of blood were drawn into a heparinized tube at baseline and then every 3 h during the first two 24-h infusions. Samples were centrifuged promptly, and the plasma was removed and stored at 80°C until high-performance liquid chromotography assay. A modification of a standard assay was used [13]. In brief, proteins (plasma 1 ml) were precipitated with trichloroacetic acid 100 µl and the supernatant was extracted with ethyl acetate 8 ml. The sample was then dried with nitrogen and reconstituted with 0.1 N sodium hydroxide 220 µl. Samples (30 µl) were injected on two Beckman Ultrasphere ODS columns (inside diameter 4.6 ml and length 25 cm) that were connected in series. The mobile phase was sodium perchlorate 3 mM, pH 3, at 1.2 ml/min. The internal standard was 0.1 M bromouracil 100 µl with a detection wavelength of 254 nm. The lower limit of quantitation was 55.4 ng/ml.
Statistical and pharmacokinetic analysis
Patient characteristics, number of doses received and the incidence of DLT were summarized separately by organ dysfunction cohort, as defined by serum bilirubin and creatinine measured on the first day of 5-FU infusion. For the first two doses, the area under the 5-FU concentrationtime curve (AUC) was computed using the linear trapezoidal rule. Since some of the 24-h samples were taken following the end of the infusion (and are therefore lower than they would have been during the infusion), all 24-h values were replaced with the average of the prior values for that dose, and the AUC following 24 h was ignored. 5-FU clearance was computed as (total dose)/AUC, and is reported in ml/min. Clearance was then regressed on serum bilirubin and creatinine, 5-FU dose, body surface area (BSA), gender, age, serum albumin and performance status [14]. Creatinine clearance (as estimated using the CockcroftGault formula) [15] was also tried in place of serum creatinine. These models were initially fit to the data from the first dose only, but were then fit to the data from both doses using bilirubin and creatinine measured prior to the second infusion for the corresponding observations. The latter models were specified as marginal regression models, and were fit using the generalized estimating equations approach with the robust (i.e. sandwich) variance estimator due to the correlation between clearances from the same patient [16].
All computations were performed using the Stata statistical software package, release 7.0 [17]. All reported P values are two-sided.
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Results |
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Table 1 shows patient characteristics summarized by cohort, and Table 2 shows the diagnoses of all patients enrolled in the study. Patients in cohort III (bilirubin 5.0 mg/dl) tended to have a poorer performance status and less prior therapy than patients in the other two cohorts. Forty-three of the 59 patients who fit into cohort I, II or III were considered evaluable for toxicity, meaning that they either completed at least four consecutive doses of treatment or experienced a DLT (Table 3). The remaining 16 patients were removed from study therapy for reasons unrelated to toxicity prior to having completed four weekly treatments. Most had progressive disease or died of disease. No deaths among any of the 64 patients were attributed to therapy.
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Pharmacokinetics
Maximum 5-FU concentration, AUC and clearance for the first two doses are summarized in Table 6, and are comparable to published data for a 24-h 5-FU infusion at these doses [6]. In a multivariate regression model including dose level, gender, age, BSA, performance status and serum albumin, only BSA was correlated with clearance at the 0.05 level; an increase in BSA of 0.1 m2 was associated with an increase in clearance of 201 ml/min (P = 0.028).
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Discussion |
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We have shown that patients with mildly elevated creatinine or elevated bilirubin tolerate usual doses (2600 mg/m2) of 5-FU administered concurrently with LV 500 mg/m2 as a 24-h continuous infusion. We found no evidence of a correlation between either bilirubin level or creatinine level and 5-FU clearance. While we did not study patients with both normal liver and normal renal function, the fact that bilirubin level over a very wide range of values had no discernible effect on 5-FU concentrations suggests that levels in patients with elevated bilirubin will be similar to those seen in patients with normal organ function. Although it is possible for a group of patients to suffer more toxicity for reasons other than increased plasma drug concentrations, we saw no evidence that patients with a higher bilirubin or creatinine level were more likely to suffer toxicity.
The increase in 5-FU clearance with increasing BSA is consistent with that observed by other investigators. Gusella et al. [20] and Port et al. [21] both examined the relationship between body surface area and 5-FU pharmacokinetics using a bolus dosing schedule, and found significant correlations between BSA and clearance [20, 21]. This is compatible with the hypothesis that 5-FU undergoes extensive extra-hepatic drug metabolism that may be increased in larger individuals, and is consistent with our findings that liver dysfunction does not appear to impact significantly on 5-FU pharmacokinetics. For this drug, unlike agents for which there is no association between body weight or BSA and clearance, an increase in dose for patients of increasing size (as is usual clinical practice) remains appropriate.
Creatinine clearance was not used for determining eligibility and the degree of renal dysfunction in the high creatinine group could vary. For example, using the CockroftGault formula, a hypothetical 70-year-old woman, 60 kg (weight), 160 cm (height) with a creatinine of 3 mg/dl (the upper limits of eligibility), would have an estimated creatinine clearance of 16.5 ml/min (or 10 ml/min/m2). The actual range of creatinine values for patients entered on the renal dysfunction cohort of this trial was 1.62.6 mg/dl, with a median of 2.1 mg/dl. Renal clearance is not of major importance in the metabolism of 5-FU, but our data do not allow us to comment on the safety of this regimen in patients with severe renal dysfunction.
Our trial also did not examine tolerance of patients to standard 5-FU doses on a bolus schedule. It is well known that the pharmacokinetics of bolus 5-FU are dose-dependent, with lower clearance at higher doses and with shorter infusion times. Much higher peak plasma levels are achieved with a bolus dose of 5-FU, and the effects of organ dysfunction might be more detectable.
It is already fairly common to treat patients who have an elevated bilirubin level with standard doses of continuous-infusion 5-FU. Our large sample confirms the appropriateness of and provides pharmacokinetic rationale for this practice.
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Acknowledgements |
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Footnotes |
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References |
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