1 Centre Antoine Lacassagne, Nice; 2 Institut Claudius-Regaud, Toulouse, France
Received 16 May 2002; revised 12 November 2002; accepted 3 December 2002
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Abstract |
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Carboplatin is the only cancer drug for which conventional doses are individually adjusted according to estimated clearance and target area under the curve (AUC). The aim of this prospective study was (i) to evaluate intra- and interpatient variability of ultrafilterable (UF) carboplatin AUC0 and (ii) to test whether the prediction of carboplatin clearance according to the Chatelut formula established for conventional carboplatin doses was accurate for low carboplatin doses.
Materials and methods:
Thirty-one head and neck cancer patients (29 men, two women, mean age 55.9 years) received concomitant radiotherapy (R 2 Gy/day) and chemotherapy (carboplatin 50 mg/m2/day i.v.) for 7 weeks: R
was administered 5 days/week (days 15) and carboplatin 2 days/week (days 1 and 4). Pharmacokinetics was performed once per week. A limited sample strategy based on Bayesian analysis was first validated and blood was subsequently taken 1 and 4 h after the end of carboplatin administration.
Results:
A total of 143 cycles was analyzed. Ultrafilterable carboplatin AUC0 ranged from 0.360 to 4.200 mg·min/ml (mean 0.830, median 0.670). As a corollary, UF carboplatin clearance ranged from 19.1 to 244.7 ml/min. Ultrafilterable carboplatin concentrations were very stable over time: AUC0
variability due to treatment duration contributed to <1% of the total variance, while interpatient variability contributed to 68.6%. Accordingly, intrasubject effect was not significant (P = 0.38) whereas intersubject effect was highly significant (P <0.001). These results suggest that optimal dosage for targeting a given AUC may vary within a 13-fold range between patients. The Chatelut formula, based on creatininemia, body weight, age and sex, over estimates carboplatin clearance by 40% on average (bias 95% CI 29.6% to 51.1%). No significant relationship was observed between either bone marrow toxicity or creatinine clearance decrease and carboplatin pharmacokinetics.
Conclusions:
The Chatelut carboplatin clearance model established for conventional carboplatin dosages (>100 mg/m2) is not applicable for targeting low AUC (<1 mg·min/ml).
Key words: carboplatin disposition, Chatelut formula, head and neck cancer, low-dose carboplatin, pharmacokinetic, radiotherapy
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Introduction |
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Other studies indicate that these methods of calculation for estimating carboplatin AUC are also applicable to high carboplatin exposures [7], although this view is not unanimously shared [8]. In head and neck cancer, given the limited results of radiotherapy alone, the association of conventional once-a-day radiotherapy with platinum analogs, including carboplatin, has been extensively explored [913], as well as combinations with other cytotoxic drugs. Our institute is strongly involved in this multidisciplinary therapeutic strategy [14]. A meta-analysis published in 1996 [15] clearly showed a benefit, in terms of locoregional control in head and neck cancer, for combined treatment as compared with radiotherapy alone. Another more recent meta-analysis [16] has confirmed these conclusions with an absolute benefit of 4% in 5-year survival for patients receiving chemoradiotherapy, this benefit being 2-fold higher (8%) when concomitant chemoradiotherapy was administered. Thus, chemoradiotherapy is currently becoming a standard in induction therapy for advanced head and neck cancer patients. This treatment approach is also promising for the management of advanced cervix cancer [17]. One means of limiting the unavoidable side-effects linked to this treatment is to reduce the interpatient variability in drug exposure. A valuable approach to reach this objective would be to apply an AUC-targeted strategy when carboplatin is the platinum analog associated with radiotherapy. The purpose of this prospective study was thus to examine the distribution of carboplatin AUC values in a group of 31 head and neck cancer patients treated by low-dose carboplatin (143 cycles analyzed) in concomitant association with radiotherapy, and to evaluate whether the Chateluts formula is applicable to this specific situation of low-dose carboplatin combined with radiotherapy.
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Materials and methods |
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Radio- and chemotherapy-related toxicities were recorded at each cycle, according to the International Union Against Cancer (UICC) criteria. Renal function was evaluated before each cycle, by estimating creatinine clearance (CC) according to the Cockcroft formula [18]: CC (ml/min) = (140 age) x body weight (kg)/[0.8 x serum creatinine (µM)]. For women, a factor of 0.85 was applied. The relative decrease of CC at cycle i as compared with CC measured before starting carboplatin was then defined as 100 x (CC cycle 1 CC cycle i)/(CC cycle 1).
Sampling strategy and pharmacokinetics analyses
A limited sampling strategy based on Bayesian analysis using the NONMEM program (previously developed with data obtained after carboplatin administration at conventional doses [19]) was first validated on the first six patients (20 cycles) treated at low doses. For that purpose, extended blood sampling was performed on completion of the carboplatin 15-min infusion, and 1, 4, 6 and 8 h after the end of carboplatin administration. Ultrafilterable (UF) carboplatin plasma concentrations from these six patients (20 cycles) were combined with a database composed from 103 patients; no covariate was taken into account in order to obtain individual carboplatin AUC (by first-order conditional estimation). This validated limited sampling strategy led to the adoption, for subsequent patients, of a limited blood sampling 1 and 4 h following carboplatin administration.
Ultrafilterable carboplatin systemic clearance (CL) was defined as carboplatin total dose divided by UF carboplatin AUC0.
Carboplatin analysis
Blood samples (5 ml in EDTA tubes) were immediately placed in a water bath containing ice for transportation (within 15 min) to the laboratory and centrifuged for 10 min at 4°C. 500 µl of the resulting plasma was then centrifuged for 30 min (2000 g at 4°C) in a Centrifree micropartition unit (Amicon, Denvers, MA, USA) in order to obtain UF carboplatin. Ultrafiltrate samples were stored at 20°C until analysis.
UF carboplatin was measured by means of atomic absorption spectrophotometry using a PerkinElmer 3030 with background correction by the Zeeman effect. UF samples taken at 1 and 4 h were diluted 1:10 and 1:2, respectively, in 0.9% NaCl. The injected volume was 20 µl. Measured platinum concentrations were recalculated as carboplatin levels. Concentrations and AUC were thus expressed as the carboplatin levels. The standard curve was automatically performed (0, 308, 618 and 1236 ng/ml). The limit of sensitivity was 20 ng/ml. Interassay variability was evaluated by analysis of spiked samples containing 100 and 400 ng/ml carboplatin, respectively; coefficients of variation were 9.8% and 6.9%, respectively, from 11 consecutive analyses.
Statistics
Statistics were performed on SPSS software (Chicago, IL, USA). AUC0 did not fit the normal distribution and was thus analyzed as logarithm 10, which fitted the Gaussian law. Two types of analyses of variance were performed for AUC0
on the group of 23 patients with pharmacokinetics available from cycle 1 to cycle 5: (i) a component variance analysis to assess respective variance contributions; and (ii) a repeated measures analysis to test intra- and intersubjects effects.
An analysis of variance of the relative decrease of CC was performed with log AUC0 as covariate, subject as random effect and cycle number as fixed factor, in order to analyze the possible influence of carboplatin cycle and pharmacokinetics on the renal function.
The applicability of the Chatelut formula [5] for predicting CL was assessed by computing the bias defined as 100 x (predicted CL observed CL)/(observed CL). The link between the above-defined bias and the observed CL was subsequently analyzed by means of Spearman rank correlation.
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Results |
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Analysis of carboplatin AUC during the treatment course
A total of 143 cycles was analyzed (Table 1). Carboplatin doses actually administered closely fitted those initially planned (mean 49.5 mg/m2, range 4353). UF carboplatin AUC0 exhibited wide variability, with values ranging from 0.360 to 4.200 mg·min/ml (mean 0.830, median 0.670, firstthird quartile 0.5350.890). As a corollary, CL ranged from 19.1 to 244.7 ml/min (mean 130, median 132, firstthird quartile 97.5164.3). Figure 1 illustrates the marked interpatient variability in AUC0
values.
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Application of the Chatelut formula
For each cycle, we estimated the CL using the Chatelut model established for conventional carboplatin dosages. The mean predicted CL arising from this model was 160.7 ml/min (median 163, range 44.6279.2, 143 cycles analyzed). Intra-individual analysis of the bias showed that the Chatelut formula overestimates CL by 40% on average (n = 143, mean bias 40.4%, median 24%, 95% CI 30% to 51%, extremes 43% to 336%). Similar bias was observed when considering only the first chemotherapy cycle (n = 31, mean bias 44.3%). The poor applicability of the Chatelut formula in the present situation of low-dose administration is illustrated in Figure 2. Of note, a strong correlation was demonstrated between bias and observed CL: the lower the observed CL, the greater the bias (Spearman rank correlation, n = 143, r2 = 0.47, P <0.001; Figure 3).
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No clinical nephrotoxicity was observed. Renal function was evaluated before each cycle, by estimating CC according to the Cockcroft formula [18]. The relative decrease of CC was quite stable during the treatment course (mean 0.2%, median 0%, range 80% to 62%). Analysis of variance demonstrated that the relative decrease of CC during treatment was not related to carboplatin cycle (P = 0.69), nor to carboplatin AUC0 (P = 0.97). However, it is interesting to note that for patient 18, with the highest AUC0
, CC was 62.1 and 23.8 ml/min at cycles 1 and 2, respectively.
Limiting toxicity was related to radiotherapy, with dermatitis observed in 57.3% of cycles (55 grade 1, 22 grade 2, five grade 3) and mucositis in 54.5% of cycles (38 grade 1, 30 grade 2, 10 grade 3); none of these toxicities was related to carboplatin pharmacokinetics.
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Discussion |
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Footnotes |
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References |
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