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© 2000 American Society for Clinical Oncology Prospective Validation of Renal Function–Based Carboplatin Dosing in Children With Cancer: A United Kingdom Children’s Cancer Study Group TrialFrom the Departments of Oncology and Child Health, University of Newcastle, Newcastle; Royal Marsden Hospital, Sutton, Surrey; Birmingham Hospital for Sick Children, Birmingham; St James’ Hospital, Leeds, Yorkshire; United Kingdom Children’s Cancer Study Group, University of Leicester, Leicester; and on behalf of the New Agents Group of the United Kingdom, Children’s Cancer Study Group. Address reprint requests to David R. Newell, PhD, Cancer Research Unit, Medical School, University of Newcastle, Framlington Place, Newcastle, NE2 4HH, England, United Kingdom.
PURPOSE: Carboplatin dosing in adults with cancer is based on renal function. The purpose of the current study was to validate a previously developed pediatric carboplatin-dosing formula. PATIENTS AND METHODS: Thirty-eight pediatric patients were randomized to receive a carboplatin dose calculated according to surface area or a renal function–based dosing formula. On the next course of therapy, the alternative dosing method was used for each patient. Carboplatin pharmacokinetics (based on free plasma platinum concentrations) were measured after both courses. RESULTS: The mean observed areas under the carboplatin concentration–versus-time curve (AUCs) after renal function– and surface area–based dosing were 98% and 95% of the target AUCs, respectively. The variation in the observed AUC was significantly less after renal function–based dosing (F test, P = .02), such that 74% of courses had an observed AUC within ± 20% of the target value, versus 49% for courses after dosing according to surface area. Only one of 22 courses at the center with the most experience with renal function–based dosing was associated with an AUC outside ± 20% of the target value, versus nine of 22 courses after surface area–based dosing in the same center. There was a relationship (r2 = .71) between carboplatin AUC and thrombocytopenia in 10 neuroblastoma patients treated with a combination of carboplatin, vincristine, etoposide, and cyclophosphamide. CONCLUSION: Renal function–based carboplatin dosing in children results in more consistent drug exposure than surface area–based drug administration.
THE PLATINUM COMPLEX carboplatin is often used in place of cisplatin for the treatment of solid pediatric malignancies, largely because carboplatin displays reduced nonhematologic toxicities.1 In adult studies, carboplatin has been shown to have activity equal to that of cisplatin in terms of response, disease-free survival, and overall survival rates in the majority of tumor types, with the exceptions being testicular cancer and, possibly, head and neck cancer.2-4 For the treatment of solid tumors in adults, it is recommended that carboplatin dosing be based on renal function, with the intention of achieving a specific, protocol-dependent area under the carboplatin plasma concentration–versus-time curve (AUC).2-5 Renal function–based dosing is derived from the observation that the clearance of carboplatin is almost exclusively (up to 80%) via the renal route,5 with the remainder being due to irreversible binding to plasma/cellular macromolecules. Furthermore, the mechanism of carboplatin renal clearance is glomerular filtration,5 and a simple formula that predicts the absolute dose of carboplatin required to achieve a target AUC in adults has been developed6 and is now in widespread clinical use: 
Pharmacokinetic studies in children have also shown a large degree of interpatient variability in the AUC achieved in children for a given surface area–based dose.13-17 Furthermore, there was a sigmoidal relationship between the carboplatin AUC and thrombocytopenia in one study in which patients were treated with carboplatin alone or carboplatin in combination with vincristine.15 Given the relationships between carboplatin AUC and both toxicity and, possibly, response in adults, carboplatin pharmacokinetic variability in children could lead to life-threatening toxicity (overdosing) or inadequate treatment and tumor recurrence (underdosing). Therefore, in line with studies in adults, pharmacologically guided carboplatin dosing has been explored in children.15,18-22 Although renal function–based dosing is now widely recommended for the carboplatin treatment of adult patients, and a number of derivatives of equation 1 have been used for dosing children,18-22 the use of renal function–based dosing in pediatric patients in comparison to surface area–based dosing has not been prospectively validated. The aim of the current study was to determine prospectively whether renal function–based dosing more accurately and/or precisely achieves target carboplatin AUC values than surface area–based dosing.
The development of the equation used (equation 2) for renal function–based dosing in children has been previously described.15 This equation estimates the renal elimination of carboplatin using 51Cr-EDTA clearance and nonrenal clearance using body weight.
The characteristics of the patients studied are summarized in Table 1. To be eligible, patients had to be between 0 and 18 years old and scheduled to receive carboplatin on at least two occasions according to the protocols listed in Table 2. Patients were randomized by the United Kingdom Children’s Cancer Study Group (UKCCSG) data center, on their first study course of treatment, to receive carboplatin dosed on the basis of renal function so as to achieve a target AUC (see below) or conventional surface area–based dosing according to the relevant protocol. Patients were then crossed over to the alternative method of dosing for the next course. Before each course of carboplatin treatment, the half-life of 51Cr-EDTA was determined using blood samples taken at 1, 2, and 4 hours, and the plasma clearance of 51Cr-EDTA (ie, GFR) was determined from these data as previously described using whole plasma and not plasma ultrafiltrate.15 Blood counts were repeated weekly after each treatment, and any hematologic or nonhematologic toxicities were recorded. For renal function–based dosing, the target AUC was 1.325 mg/mL·min per 100 mg/m2 of the protocol dose of carboplatin that each patient was scheduled to receive (Table 2). The value of 1.325 mg/mL·min per 100 mg/m2 was determined from the median carboplatin plasma clearance in 22 pediatric patients previously studied.15
Carboplatin was administered as a 60-minute intravenous infusion in 5% (w/v) dextrose. Blood samples were obtained from either a central or peripheral venous catheter before and during the administration of carboplatin (at 30 and 60 minutes) and then at 15, 30, 60, 90, 120, 240, 360, 480, and 1,440 minutes after the end of the infusion. Blood samples were then placed into tubes containing heparin. The tubes were immediately centrifuged at 1,000 x g for 10 minutes at room temperature, and the plasma was decanted. One milliliter of the resultant plasma was removed, placed in the upper reservoir of a Centrifree micropartition unit (Amicon, Beverly, MA), and centrifuged at 3,000 x g for 10 minutes at room temperature. The platinum concentration in the ultrafiltrate sample was analyzed by atomic absorption spectrophotometry, as previously described.15 The pharmacokinetics of free plasma platinum were assumed to represent those of intact carboplatin for the first 8 hours of sampling. The AUC of carboplatin was calculated using a combination of trapezoidal and log-trapezoidal methods. Extrapolation beyond the 8-hour sample was achieved using the slope of the terminal elimination phase. The latter parameter was determined using the maximum a posteriori estimator in the ADAPT II program (Biomedical Simulations Resource, University of Southern California, Los Angeles, CA), with weighting as described previously.16 The use of the maximum a posteriori estimator was necessary due to variability in the timing of the last sample taken. For the analysis of carboplatin AUC values in relation to dosing method, the distribution of observed values (% target) was checked for normality and the variability for the two dosing methods was compared by the variance ratio or F test. Potential period effects, ie, the effect of randomization to either dosing method on the first course of therapy, were analyzed using t tests. The binary outcome, carboplatin exposure within 20% of the target AUC, was tested using the Mainland-Gart test to allow for any effect of occasion, and differences in precision in the two dosing methods were confirmed by analyzing the differences from target using t tests. Multiple log-linear regression analysis was used to study the potential impact of covariates (treatment center, sex, age, protocol, order of dosing method, time between courses, target AUC, and dose), separately, on the precision of the two dosing methods. The toxicities observed after the two dosing methods were compared using nonparametric methods (Wilcoxon rank sum tests). The study was approved by the UKCCSG and by the institutional review board of each participating hospital, and patients and/or their parents or guardians gave informed consent before participating.
Fifty patients were randomized into the study from four UKCCSG treatment centers. Eleven of these patients were withdrawn either before therapy (n = 4, centers 1 and 4) or after only one course of treatment (n = 7, centers 1, 2, and 4) due to either progressive disease (n = 7, centers 1 and 4), toxicity (n = 2, centers 1 and 2), a hypersensitivity reaction to the carboplatin (center 4), or needle phobia (center 1). Failure to complete the intended two courses of carboplatin therapy was not clearly related to the treatment center. The remaining 39 patients received carboplatin by both surface area– and renal function–based dosing. However, one patient (center 3) was excluded from the final analysis because the blood samples taken for pharmacokinetic analysis were contaminated with the carboplatin infusate. The characteristics of the remaining 38 patients are summarized in Table 1. The half-life of 51Cr-EDTA was measured for 73 of the 76 courses of carboplatin administered. Carboplatin was administered according to surface area–based dosing on the three courses for which 51Cr-EDTA measurements were not taken. The absolute and surface area–normalized GFR values are also listed in Table 1. For courses for which carboplatin dosing was based on surface area, doses were as indicated in Table 2 (median, 500 mg/m2; range, 500 to 750 mg/m2). For renal function–based dosing, the median dose given was 581 mg/m2 (range, 344 to 843 mg/m2). The absolute observed carboplatin AUC values versus the absolute target values for all courses of therapy are shown in Fig 1. The mean AUC as a percentage of the target AUC was 98% for renal function–based dosing (median, 100%; range, 62% to 138%) and 95% for surface area–based dosing (median, 88%; range, 63% to 171%) (Fig 2). The variation of individual observed AUC values around the target AUC was significantly greater (P = .02, F test) when patients were dosed according to surface area as compared with renal function (Fig 2). The SD of the mean percentage of target AUC was 25% for surface area but only 17% when the same patients were dosed using renal function. As a result of the greater dosing precision, significantly (P = .03, Mainland-Gart test) more patients received a carboplatin exposure within 20% of the target AUC when dosed by renal function (74%) as compared with surface area (49%) (Fig 2).
In all, eight patients received an AUC outside 80% to 120% of the target value after renal function–based dosing. Of these, four were treated at either center 3 or 4 (AUCs of 128%, 66%, 138%, and 77% of target). Of the other four patients, one was treated at center 1 (AUC, 126% of target) and three were treated at center 2 (AUCs of 62%, 74%, and 75% of target). As listed in Table 3, the numbers of patients studied in centers 1, 2, 3, and 4 were 22, 11, four, and one, respectively. These results strongly suggest that experience with renal function–based dosing improves the precision of this method of carboplatin administration. In contrast, as would be predicted, the precision of surface area–based dosing seemed to be independent of the center in which the study was performed (Table 3). Factors other than center of treatment that could have contributed to the accuracy of renal function– or surface area–based dosing were sex, age, protocol, order of dosing method, time between courses, target AUC, and dose; however, none of these variables influenced the accuracy of dosing.
The pharmacokinetics of carboplatin in the 38 patients studied are summarized in Table 4. Intrapatient variation, ie, course 1 to course 2 variation, in carboplatin and 51Cr-EDTA clearances are also shown. In line with the basic premise of renal function–based carboplatin dosing, for all courses for which carboplatin pharmacokinetics and renal function had been determined (n = 73), there was a highly significant linear relationship between carboplatin and 51Cr-EDTA clearances (r = .61, P < .0001) (Fig 3).
Toxicities observed after treatment with carboplatin-containing regimens were thrombocytopenia, leukopenia, mucositis, diarrhea, alopecia, and infection. The nadirs for thrombocytopenia and leukopenia, expressed as the percent fall in the cell count, are shown in Fig 4. For the patient population as a whole, there was no relationship between the percentage fall in the thrombocyte or leukocyte count and either carboplatin dose or AUC (data not shown). However, the majority of patients were treated with combinations of myelosuppressive drugs (Table 2); hence, relationships between carboplatin AUC values and hematologic toxicity were not anticipated. Concomitant myelosuppressive cytotoxic therapy varied between patients in terms of both the drugs and the doses used (Table 2), further reducing the likelihood of identifying any independent effect of carboplatin. The single largest group of patients receiving the same therapy were those treated with the vincristine/carboplatin/etoposide/cyclophosphamide protocol for stage 3 or 4 neuroblastoma over the age of 1 (Table 2). In this group of 10 patients, there was a sigmoidal (r2 = .71) relationship between carboplatin AUC and the magnitude of thrombocytopenia, whereas there was no relationship between surface area–normalized dose and the percent fall in the platelet count (Fig 5). It should be noted, however, that the frequency of blood sampling (weekly) may have resulted in an inaccurate estimation of nadir hematologic cell counts, such that not all relationships between carboplatin exposure and toxicity were detected. The incidences of other toxicities (mucositis, diarrhea, alopecia, and infection) were not influenced by the method of carboplatin dosing (data not shown; P  .22, Wilcoxon rank sum test).
The aim of our study was to compare the accuracy and precision of carboplatin dosing according to surface area and renal function in pediatric patients. The development of a pediatric carboplatin-dosing formula based on renal function has previously been described,15 and the present investigation sought to validate the formula in a randomized cross-over study. Renal function– and surface area–based carboplatin dosing were both accurate (unbiased), with observed mean AUC values of 98% and 95% of target values, respectively, for the two methods of administration. This result is not unexpected due to the fact that the target AUC was based on the median clearance of a prior similar population of pediatric patients.15 Thus, the median GFR and carboplatin clearance rate in the current study were not significantly different from those in the patient population used to develop the dosing formula validated here (GFR current study, 44 mL/min [range, 15 to 184 mL/min]; GFR previous study, 58 mL/min [range, 14 to 138 mL/min]; carboplatin clearance current study, 83 mL/min [range, 45 to 119 mL/min]; carboplatin clearance previous study, 75 mL/min [range, 42 to 130 mL/min]). Renal function–based dosing was, however, significantly more precise than surface area–based dosing (P = .02), with 30 of 38 courses of renal function–based dosing producing AUC values within ± 20% of the target value. Furthermore, at the center with the greatest experience with renal function–based dosing (center 1), only one of 22 courses of renal function–based carboplatin therapy was associated with a carboplatin AUC outside ± 20% of the target, and even this single course was only 26% greater than target. In contrast, after surface area–based dosing, nine of 22 courses at center 1 were associated with observed AUC values outside ± 20% of the target value. Thus, with frequent use, renal function–based dosing with carboplatin according to the method described here can be anticipated to result in highly consistent carboplatin AUC values.
A number of pediatric carboplatin-dosing formulas have been described and used to treat children with cancer. These formulas are based on the adult dosing formula described by Calvert et al,6 with varying degrees of modification. For example:
The accuracy and precision of the first two formulas have not been reported; however, the latter formula, when used in a dose-escalation trial of carboplatin in combination with ifosfamide and etoposide, produced AUC values within ± 20% of target in seven of 14 patients.20 The same formula, when used to dose carboplatin in combination with cyclophosphamide and etoposide, resulted in 15 of 21 patients receiving AUC values within ± 20% of the target value.18 The precision and accuracy of renal function–based carboplatin dosing observed in the current study most likely reflects the simple yet robust method used to calculate GFR. Thus, a measured 51Cr-EDTA half-life and a calculated 51Cr-EDTA volume of distribution provided an estimate of the GFR that could in turn be used to define the dose of carboplatin needed to achieve a target AUC. Although 51Cr-EDTA is not available in all countries or centers, alternative measures of GFR can be used, provided they too are accurate. For example, the studies performed by Rodman et al successfully used 99mTc-diethylenetriaminepenta-acetic acid to measure GFR.18-20 However, GFR values estimated from plasma creatinine values should be avoided as these can be extremely inaccurate, particularly in children. The difficulty in obtaining complete urine collections from children, particularly infants, further strengthens the case for restricting GFR estimations to those based on plasma tracer pharmacokinetics in the context of pediatric carboplatin dosing.23 A potentially important difference between the renal function–based dosing equation used in the current study and those previously reported concerns the estimation of nonrenal clearance. In the adult dosing equation, a fixed value of 25 mL/min is used; however, given the wide range of body sizes encountered in pediatric oncology, a fixed value would be inappropriate in children. Although previous pediatric dosing equations have scaled the nonrenal clearance of carboplatin according to surface area, the measurement of surface area in infants can again be difficult. As measuring body weight is simple, regardless of patient age, the equation used in the current study scaled the nonrenal clearance of carboplatin according to weight, ie, 0.36 x body weight (kg) mL/min. It is important to note that the patients who took part in this study had a wide range of ages and weights (Table 1). As a consequence, the renal function–based dosing equation has been shown to be applicable to the full range of patients who are likely to be encountered by pediatric oncologists. In some protocols for the treatment of infants with carboplatin, dosing is currently based on body weight. This nonvalidated method should now be replaced by renal function–based dosing.
A second factor to note with regard to the characteristics of the patients studied is the range of their renal functions (27 to 114 mL/min/m2, Table 1), and caution should be exercised in applying the pediatric dosing formula to patients whose GFR falls outside this range. However, there is no theoretical reason to anticipate any problem in doing so because of the physiologic basis of the dosing equation. In anephric patients (ie, GFR = 0 mL/min), the formula has been successfully applied by omitting the GFR term completely,24 ie, dosing according to the equation:
Conversely, for patients with well-above-average renal function, ie, GFR values greater than 200 mL/min, the equation should also be applicable given the extensive experience with renal function–based dosing in adults. However, in such cases, the accuracy of the renal function estimate should always be confirmed by performing a repeat GFR test before dosing. Furthermore, it is helpful to confirm the accuracy of pharmacologically guided carboplatin dosing in patients with extremes of renal function. Pediatric limited-sampling strategies for carboplatin have been developed and validated, allowing confirmation to be done with minimum patient inconvenience.16,25 The use of therapeutic drug monitoring may also be a sensible precaution in high-dose protocols, where exceeding the target AUC by even a small amount can result in life-threatening toxicity.26 An alternative to the physiologically based approach to carboplatin dosing described in this article is the implementation of a population pharmacokinetic analysis to determine covariates that influence carboplatin clearance. Such an analysis has been reported for children by Chatelut et al,27 who showed that serum creatinine, body weight, and nephrectomy status accounted for the majority of the interindividual variation in carboplatin pharmacokinetics that was observed in 57 children. The advantage of the final formula described by these authors is the use of simple measures of renal function, ie, serum creatinine and nephrectomy status, as opposed to the isotopic tracer technique used in the current study. However, the prospective validation of the population analysis–based formula for calculating carboplatin clearances, and its application for determining carboplatin doses in children, has yet to be reported. In light of the superior precision of renal function–based carboplatin dosing, this method of drug administration should now replace dosing according to surface area or body weight. For the majority of the protocols investigated in the current article (Table 1), a target AUC of 7 mg/mL·min represents a dose level that produces significant but not unacceptable toxicity. For other existing protocols, the conversion factor of 1.325 mg/mL·min per 100 mg/m2 protocol dose can be used, as in the current study. In the development of novel combinations, escalation of the carboplatin AUC values is needed to identify the optimal value for each drug combination and for each target patient population, as described by Rodman et al for combinations with etoposide and cyclophosphamide or ifosfamide.18-20 However, the maximum-tolerated AUC may not be the one that produces the highest response rates, despite early retrospective analyses,7 as shown by the recent randomized study of the Danish Ovarian Cancer Group in which AUC 8 was not more active than AUC 4.28 Furthermore, the greater toxicity of higher AUC values may result in a lower-than-expected overall increase in AUC intensity.29 Notwithstanding the importance of the clinical outcomes of such studies, the use of pharmacologically guided dosing to remove pharmacokinetic variability as a potential source of variation in response and/or toxicity is critical because it allows the true impact of the effect of dose, or dose-intensity, to be determined. For example, the effect of doubling the carboplatin dose-intensity has been studied as part of the European Neuroblastoma Study Group protocol 5 (Table 2); however, interpatient pharmacokinetic variation may prevent differences being detected due to overlap in the received AUC values between the high-dose and standard-dose groups. In conclusion, this study has shown for the first time in a prospective, randomized, cross-over trial that renal function–based carboplatin dosing in children is more precise than surface area–based drug administration. The simple carboplatin-dosing equation developed was used in more than one treatment center. With experience with its use, the vast majority of patients can be expected to receive carboplatin AUC values within ± 20% of the target value. The use of renal function–based carboplatin dosing avoids both underdosing, and hence inadequate treatment, and overdosing and the risk of unacceptable life-threatening toxicity.
Supported by grants from the Cancer Research Campaign, London, and the North of England Children’s Cancer Research Fund, Newcastle, United Kingdom. The authors are indebted to the patients who took part in these studies and their parents and guardians. Likewise, the assistance of the nursing and medical staff at all of the contributing institutions is greatly appreciated. The standard carboplatin used for the analysis of carboplatin plasma concentrations was a generous gift from Johnson Matthey plc, Sonning Common, Reading, United Kingdom.
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Bertelsen JK, Anderson JE, Havsteen H, et al: Dose-effect study of carboplatin in ovarian cancer: A Danish Ovarian Cancer Group study. J Clin Oncol 15: 193-198, 1997 29. Gore M, Mainwaring P, A’Hern R, et al: Randomised trial of dose-intensity with single-agent carboplatin in patients with epithelial ovarian cancer. J Clin Oncol 16: 2426-2434, 1998[Abstract] Submitted March 13, 2000; accepted June 16, 2000.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) or surface area–based (
) dosing. Solid line is the line of identity.
