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Journal of Clinical Oncology, Vol 24, No 10 (April 1), 2006: pp. 1499-1506 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.0056 Evaluation of an Alternate Dosing Strategy for Cisplatin in Patients With Extreme Body Surface Area Values
From the Department of Medical Oncology, Erasmus MC, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands Address reprint requests to Walter J. Loos, PhD, Department of Medical Oncology, Erasmus MC, Daniel den Hoed Cancer Center, PO Box 5201, 3008 AE Rotterdam, the Netherlands; e-mail: w.loos{at}erasmusmc.nl
PURPOSE: The majority of cytotoxic drugs for adults are dosed based on body surface area (BSA), aiming to reduce interpatient variability in drug exposure. We prospectively studied the usefulness of BSA-based dosing of cisplatin in patients at extremes of BSA values. PATIENTS AND METHODS: Patients were randomly assigned to receive a fixed dose of cisplatin in course 1, and a BSA-adjusted dose in course 2, or vice versa. The fixed dose was based on the average BSA for males and females, while extremes were set at BSA values exceeding the average ± 1 standard deviation. Subsequently, we retrospectively analyzed data from a normal population.
RESULTS: In 25 patients assessable for both courses, the use of a fixed dose of cisplatin resulted in reduced exposure to unbound platinum in patients at the upper extremes of BSA (P = .003) and higher exposures in patients at the lower extremes (P = .009), as compared with exposures following the BSA-adjusted dose. Although clearance was related to BSA (R2 = 0.44; P < .001), only a small reduction in interpatient variability in clearance after correction for BSA was achieved (20.8% v 17.1%). In the retrospective analysis, compared with the average patient, the clearance of unbound platinum in patients with a BSA value
CONCLUSION: Unless better predictors for platinum clearance are identified, fixed-dose regimens per BSA cluster (
Cancer patients have a highly variable capacity to metabolize and eliminate commonly administered drugs.1 This variability originates from a combination of physiologic variables and intrinsic characteristics, such as genetic components, as well as environmental factors, which together determine a patient's phenotype.2 To eliminate pharmacokinetic and subsequent pharmacodynamic variability between patients, the dose of most anticancer drugs has traditionally been adjusted on the basis of an individual's body surface area (BSA).3 During the last few decades, various investigators have questioned the routine use of BSA in dosing strategies for anticancer agents.4-11 Indeed, based on a retrospective analysis involving 33 different drugs, it has been estimated that BSA-based dosing is statistically significantly associated with a reduction in interindividual pharmacokinetic variability in only approximately 15% of anticancer drugs.12 In the absence of a better alternative, we and others have propagated that for the vast majority of currently used agents, flat-fixed doses should be used regardless of body size. Drug dosing recommendations are usually based on results from clinical trials that included patients who are considered typical of those likely to receive the drug in clinical practice. In many cases however, the large and/or obese, or small and/or thin patient may not be well represented, and therefore, extrapolation of dosing recommendations to these groups must be performed arbitrarily when the dose is required to be standardized to a particular patient demographic like BSA.13 It is also clear that the effectiveness of formulas used to calculate BSA has not been appropriately evaluated in patients who are severely obese or frail. Furthermore, the original formulas for calculating BSA-based drug dosages were developed in a population with an average BSA.14,15 Most importantly, prior studies evaluating alternative dosing strategies for anticancer drugs have not taken into account patients at the upper or lower ends of BSA. To address this issue, we prospectively investigated the role of BSA-based dosing in adult cancer patients, selected at the upper and lower extremes of BSA, using cisplatin as a model drug. Since both the population average BSA and also possibly the clearance (CL) of cisplatin differ between males and females,8 patient sex was also taken into account.
Patient Selection Criteria Patients with malignant solid tumors for which cisplatin-based therapy was a viable treatment option were eligible for the study. Based on an average male BSA of 1.90 ± 0.16 m2, males with a BSA less than 1.75 or greater than 2.05 m2 could be included. Based on the average female BSA of 1.76 ± 0.16 m2, included female patients had a BSA less than 1.60 or greater than 1.90 m2 (derived from an unpublished data set of our Dutch population). Other inclusion criteria included the following: no previous radiotherapy or chemotherapy for at least 4 weeks before study entry; WHO performance status  2; absolute neutrophil count  1.5 x 109/L; absolute platelet count 100 x 109/L; serum bilirubin less than 1.5x the upper limit of normal; and creatinine CL 60 mL/min. The study was approved by the ethical committee of the Erasmus Medical Center (Rotterdam, the Netherlands), and all patients gave written informed consent.
Administration of Cisplatin
Cisplatin (Platosin) was purchased as a powder from Pharmachemie (Haarlem, the Netherlands) and was administered in a solution with 250 mL of 3% (wt/vol) saline as a 3-hour continuous infusion. Patients received a prehydration infusion of at least 1 L and a posthydration infusion of at least 3 L of 0.9% (wt/vol) saline, or a mixture of dextrose 5% (wt/vol) and 0.9% (wt/vol) saline, supplemented with 20 mmol/L potassium chloride and 2 g/L magnesium sulfate. Standard antiemetic prophylaxis was administered and consisted of the combination of dexamethasone and granisetron.
Pharmacokinetic Sampling Procedure and Analysis Plasma concentrations of unbound platinum were determined according to a slightly optimized method as described earlier.16 In brief, immediately after collection, plasma was separated by centrifugation at 3,000 x g for 10 minutes, after which 500-µL aliquots of the plasma supernatant were mixed with 1.0 mL of ice-cold (–20°C) ethanol. The ethanolic samples were stored at or below –20°C for a maximum of 24 hours, after which the ethanolic supernatant was collected by centrifugation of the samples at maximum speed (23,000 x g) in an Eppendorf centrifuge (Eppendorf AG, Hamburg, Germany) for 5 minutes. The clear supernatant was subsequently stored at –70°C until analysis for unbound platinum. Aliquots of 1,000 µL of the ethanolic supernatant were evaporated to dryness under nitrogen at 80°C, and the residue was reconstituted in 200 µL water containing 0.2% (vol/vol) Triton X-100 and 0.06% (wt/vol) cesium chloride. A volume of 20 µL, in duplicate, was injected onto the graphite furnace of a PerkinElmer model 4110 ZL atomic absorption spectrophotometer (Uberlingen, Germany). Platinum peak areas were measured at 265.9 nm. The lower limit of quantitation was established at 0.0300 µg/mL unbound platinum in plasma. Pharmacokinetic parameter estimates of unbound platinum were derived from weighted (1/y) noncompartmental analysis using WINNonlin (Scientific Consultant, Apex, NC) version 4.0 (Pharsight Corp, Mountain View, CA).
Statistical Evaluation
Patient Population Fourty-two patients were included in the study between August 2002 and February 2005, and 39 patients were assessable for pharmacokinetic analysis during the first course. One patient never started the therapy, while in two patients, some samples were processed inadequately. Of the 41 patients starting therapy, 11 received only a single administration of cisplatin: one because of a change in chemotherapy regimen, four because of rapid disease progression and/or clinical deterioration, three because of toxicity (two renal function deterioration, one sepsis), two because of disease-related thromboembolic events, and one refusal of further pharmacokinetic sampling. Eventually, 30 patients received both the BSA-based dose and the fixed dose of cisplatin. Of these patients, five were not assessable for pharmacokinetic analysis during course 2 due to sample processing errors. Hence, 25 patients were included in the paired pharmacokinetic analysis. A summary of demographic characteristics of these patients is presented in Table 2.
Paired Pharmacokinetic Analysis Since different dosing schedules were applied, depending on an individual's BSA, the observed area under the concentration-time curve (AUC) values of unbound platinum were all normalized as though the patients were treated with 75 mg/m2 in the BSA-based dosing course and with 140 mg in the fixed-dose course. The AUC of unbound platinum in the 12 studied patients with a high BSA value (six of whom were randomly assigned to start with the BSA-based dose) was significantly higher after BSA-based dosing compared with fixed dosing (difference, 18.4%; P = .003, Wilcoxon signed rank test; Fig 1 and Table 3). In line with this, the AUC of unbound platinum in the 13 studied patients with lower BSA values (nine of whom were randomized to start with the BSA-based dose) was significantly lower after BSA-based dosing compared with fixed dosing (difference, 22.9%; P = .009). The CL and volume of distribution (V) of unbound platinum were not significantly different between the two dosing regimens (P > .24).
Pharmacokinetic Analysis Course 1 A summary of the pharmacokinetics of unbound platinum during course 1 in the 39 pharmacokinetically assessable patients is given in Table 4. The mean CL of unbound platinum in the entire population was 27.6 ± 5.72 L/h (coefficient of variance [CV] = 20.8%) and 14.6 ± 2.49 L/h/m2 (CV = 17.1%) when corrected for BSA. The mean V of unbound platinum was 42.2 ± 13.2 L (CV = 31.3%) and 22.0 ± 5.34 L/m2 (CV = 24.2%) after BSA correction. Correction of unbound platinum CL and V for BSA resulted in relative reductions in interpatient variability of only 17.8% and 22.7%, respectively. The absolute unbound platinum CL and V were respectively significantly faster and larger in large patients compared with small patients (P < .016, Mann-Whitney rank sum test; Table 5). Furthermore, we observed no significant differences in unbound platinum CL and V between male and female patients (P > .16). Despite the extensive variability, unbound platinum CL and V were both significantly correlated with BSA in the entire population (R2 > 0.42; P < .001; Fig 2).
Adaptation of Dosing Regimens Since the number of studied patients in this prospective study is relatively small, and, more importantly, no population was studied with BSA values within the normal range, we subsequently clustered data from 268 previously treated patients8 in three BSA clusters. Extremes were set at BSA values exceeding the mean ± 1 SD of the normal population (1.86 ± 0.19 m2), and values were rounded to the nearest 0.05 m2. The population has a normal distribution: 183 (68%) of the patients fall in the cluster of the average patient with a BSA value of 1.66 to 2.04 m2; 43 (16%) patients, in the cluster with a BSA value 1.65 m2; and 42 (16%) patients, in the cluster with a BSA value 2.05 m2 (Table 6) . Compared with the unbound platinum CL in an average patient (ie, BSA cluster 1.66 to 2.04 m2), the CL in patients with a BSA value 1.65 m2 was 16% slower (P < .001, t test), while an 18% faster (P < .001, t test) unbound platinum CL was observed in patients with a BSA value 2.05 m2 (Table 6). The same holds true for V, which was 15% less (P = .027) in patients with a BSA value 1.65 m2 and 15% greater (P = .031) in patients with a BSA value 2.05 m2 compared with V in an average patient.
Although the interindividual variability in BSA in the three clusters was reduced by approximately 50% compared with the variability in the whole population, the interindividual variability in unbound platinum CL and V in the clusters still remained in the same order, and was also not reduced after correction of the unbound platinum CL and V for BSA (Table 6). The underlying cause for the slightly faster unbound platinum CL in the retrospective study compared with that of the prospective study is unclear.
In this study, we explored fixed dosing of cisplatin for patients with BSA values at the upper and lower extremes of BSA, as a simple therapeutic alternative dosing strategy for cisplatin in routine clinical practice.
There is no doubt that BSA contributes to CL and V of the pharmacologically active unbound fraction of platinum in adult cancer patients, as shown recently in several population pharmacokinetic studies of cisplatin in adult cancer patients.17-19 However, the effect is only marginal considering the minor decrease in the variability in dose-corrected AUCs after BSA-based dosing compared with fixed dosing. Moreover, the contribution of BSA to cisplatin CL seems to be insignificant for patients with an average BSA value. In view of the relatively high interindividual variability in CL (ie, > 25%) and the relatively small variability in BSA (ie, Because the interpatient variability in unbound platinum CL and V in the three BSA-clusters (as analyzed retrospectively) is still larger than the variability in the BSA in those clusters and correction of unbound platinum CL and V for BSA in the clusters does not reduce the interpatient variability, BSA-based dosing for the entire population does not seem better than simple fixed-dosing strategies. Nevertheless, a fixed-dosing regimen, with a cisplatin dose based on the average BSA-value of 1.86 m2 in the current population, will result in a significantly higher exposure to unbound platinum in patients at the lower extremes of BSA, and a significantly lower exposure to unbound platinum in patients at the upper extremes of BSA compared with the commonly applied BSA-based dosing strategy. It is important to point out that our study has a few limitations. Specifically, as this was merely an exploratory study to prospectively evaluate the usefulness of BSA-based dosing of cisplatin in adult cancer patients at extremes of BSA value, no a priori sample size calculation was done. The intent of the study was to support that dose individualization of cisplatin solely based the BSA of the individual patient does not decrease the interpatient variability in unbound platinum exposure, and thus CL. As shown, the variability in CL does not even decrease by retrospective clustering of the patients into three BSA cohorts. Nevertheless, significant differences in cisplatin CL were observed. This suggests that equal fixed dosing for all patients based on the BSA of the average patients might potentially lead to exacerbated toxicities in small patients and underdosing in large patients. As all patients with malignant solid tumors for which cisplatin-based therapy was a viable treatment option were eligible for the present study, a comparison of observed toxicities or efficacies was not feasible, and this aspect requires further investigation. Another potential limitation might be placed by the number of patients prospectively studied. Because only 25 of the 42 patients randomized were eligible for the primary analysis, we might have lost the comparability between the groups. Specifically, of 12 studied patients with a high BSA, six started with a BSA-based course, and of 13 studied patients with a low BSA, nine started with the BSA-based course. Nevertheless, as no alteration in CL of unbound platinum was observed after multiple courses of cisplatin,8 the lack of complete balance between BSA and fixed-dosing random assignment in the latter mentioned group will likely have no effect on the results and conclusions. Finally, it is important to point out that the unbound platinum concentration was measured, instead of the intact molecule. Cisplatin degrades rapidly in aqueous solutions into several hydrated complexes.20 Since atomic absorption spectrometry, as applied in this study, is not able to distinguish the different platinum compounds, unbound platinum does not entirely reflect unbound cisplatin. However, due to the instability of cisplatin in aqueous solutions and the complex measurement of unbound cisplatin concentrations, use of unbound platinum concentrations for pharmacokinetic purposes is widely accepted, correlating to adverse effects and response.21 In addition, it has recently been shown that 90% of the quantified unbound platinum is derived from intact unbound cisplatin.22 An alternative approach to reduce the interpatient variability in exposure to cisplatin could be therapeutic drug monitoring, in which doses for individual patients are adapted based on pharmacokinetic information obtained in prior cycles of treatment. Such adaptive intrapatient dose modification has been pursued for cisplatin in patients with head and neck cancer23 and non–small-cell lung cancer.24 While this approach was unsuccessful in the former study,23 in the latter, it seems potentially promising.24 Further prospective randomized clinical trials will be needed to reveal whether the response rate, and more importantly, the time to progression and survival, can be increased by intrapatient pharmacokinetically guided dose adaptation of cisplatin. Although it is attractive from a scientific point of view, therapeutic drug monitoring for cisplatin is technically and logistically infeasible in current daily practice since specialized equipment and personnel are required. In conclusion, we propose that fixed dosing of cisplatin per BSA cluster and administration regimen could serve as a simple alternative to BSA-based dosing that would be more convenient for the treating physicians and pharmacists, would reduce dosing errors, and would likely be more cost-effective. Table 7 presents recommended fixed doses of cisplatin per BSA cluster for the different administration schedules as currently applied in our institution, with proposed fixed doses based on the average BSA value of the cluster (Table 6), rounded to the nearest 5 mg. The slightly different recommended fixed doses, corresponding to 50 and 100 mg/m2, compared with the doses applied in this study, are obtained by rounding the fixed dose to 10 mg cisplatin in the study regimen and to 5 mg cisplatin for the recommended doses. A prospective validation of the proposed dosing strategy is desirable to demonstrate that this strategy does not increase toxicities nor hamper antitumor activity compared with the conventionally used BSA-based dosing strategies.
The authors indicated no potential conflicts of interest.
Presented in part at the Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, Orlando, FL, March 2-6, 2005. F.E.J. is currently with the Department of Internal Medicine, Ikazia Hospital, Rotterdam, the Netherlands, and A.S. is currently with the National Cancer Institute, Bethesda, MD. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10%) in our normal Dutch (white) population, BSA-based dosing apparently does not increase the accuracy of predicting the exposure to the biologically active unbound fraction of cisplatin compared with a fixed-dose scheme.
