European Journal of Cancer (2014) 50, 944– 952

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Performance of formulae based estimates of glomerularfiltration rate for carboplatin dosing in stage 1 seminoma

0959-8049/$ - see front matter � 2014 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.ejca.2013.12.021

⇑ Corresponding author: Address: The Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow G12 8TA, United KiTel.: +44 7791253556; fax: +44 141330271.

E-mail address: scott.shepherd@glasgow.ac.uk (S.T.C. Shepherd).

Scott T.C. Shepherd a,⇑, Gerry Gillen b, Paula Morrison a, Carla Forte a,Iain R. Macpherson a, Jeff D. White a, Patrick B. Mark c

a Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, United Kingdomb Department of Nuclear Medicine, Gartnavel Hospital, Glasgow G12 0YN, United Kingdomc Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom

Available online 17 January 2014

KEYWORDS

CarboplatinGlomerular filtration rateFormulaSeminomaDosing

Abstract Background: Single cycle carboplatin, dosed by glomerular filtration rate (GFR), isstandard adjuvant therapy for stage 1 seminoma. Accurate measurement of GFR is essentialfor correct dosing. Isotopic methods remain the gold standard for the determination of GFR.Formulae to estimate GFR have improved the assessment of renal function in non-oncolog-ical settings. We assessed the utility of these formulae for carboplatin dosing.Methods: We studied consecutive subjects receiving adjuvant carboplatin for stage 1 semi-noma at our institution between 2007 and 2012. Subjects underwent 51Cr-ethylene diaminetetra-acetic acid (EDTA) measurement of GFR with carboplatin dose calculated using theCalvert formula. Theoretical carboplatin doses were calculated from estimated GFR usingChronic Kidney Disease-Epidemiology (CKD-EPI), Management of Diet in Renal Disease(MDRD) and Cockcroft–Gault (CG) formulae with additional correction for actual body sur-face area (BSA). Carboplatin doses calculated by formulae were compared with dose calcu-lated by isotopic GFR; a difference <10% was considered acceptable.Results: 115 patients were identified. Mean isotopic GFR was 96.9 ml/min/1.73 m2. CG andCKD-EPI tended to overestimate GFR whereas MDRD tended to underestimate GFR. TheCKD-EPI formula had greatest accuracy. The CKD-EPI formula, corrected for actual BSA,performed best; 45.9% of patients received within 10% of correct carboplatin dose. Patientspredicted as underdosed (13.5%) by CKD-EPI were more likely to be obese (p = 0.013); therewere no predictors of the 40.5% receiving an excess dose.

ngdom.

S.T.C. Shepherd et al. / European Journal of Cancer 50 (2014) 944–952 945

Conclusions: Our data support further evaluation of the CKD-EPI formula in this patientpopulation but clinically significant variances in carboplatin dosing occur using non-isotopicmethods of GFR estimation. Isotopic determination of GFR should remain the recommendedstandard for carboplatin dosing when accuracy is essential.

� 2014 Elsevier Ltd. All rights reserved.

1. Introduction

Stage 1 seminoma is the most common presentationof testicular germ cell tumour (GCT) and accounts forapproximately 40% of all occurrences [1]. The manage-ment of stage 1 seminoma historically included adjuvantradiotherapy, however following orchidectomy, casescan be managed by surveillance alone or single agentcarboplatin adjuvant therapy [2,3]. Carboplatin is aplatinum based alkylating agent that interferes withDNA processes and is used in the treatment of severalmalignancies [4]. The main therapeutic and toxic effectsof carboplatin are related to its cytotoxicity. The mostimportant dose-limiting toxicity of carboplatin exposureis myelosuppression, particularly thrombocytopaenia.Carboplatin exposure, defined as the area under theplasma concentration versus time curve (AUC), is asso-ciated with both severity of toxicity and anti-tumoureffect [5]. Carboplatin is mainly eliminated by the kid-neys. In patients with normal renal function, approxi-mately 60–70% of an administered carboplatin dose isexcreted by the kidneys within 24 h of administration.Carboplatin clearance is poorly associated with bodysurface area (BSA) but has a linear relationship withglomerular filtration rate (GFR) [5,6].

The Calvert formula is widely used for dosing carbo-platin and incorporates GFR as its key variable [6]. It istherefore essential to establish an accurate GFR. Clini-cal data are suggestive of a dose–response curve acrosstherapeutically deliverable doses of carboplatin [4]. Con-sistent with these data, an exploratory analysis of theMRC TE19/EORTC 30982 study, a randomised trialcomparing carboplatin with radiotherapy (RT) as adju-vant treatment for stage 1 seminoma, found a higherrisk of relapse in patients where carboplatin dose wascalculated based on creatinine clearance with an arbi-trary 10% dose reduction applied, in comparison tothose patients dosed according to isotopic GFR [3]. Thishighlights the importance of accurate assessment ofGFR and hence carboplatin dose in this setting. In theUK current oncological practice commonly employs iso-topic methods to calculate measured GFR such as thechromium-51 ethylene diamine tetra-acetic acid (EDTA)clearance method (51Cr-EDTA) [7,8]. 51Cr-EDTA isaccurate, reproducible, is validated for prescription ofchemotherapy, and is considered ‘gold-standard’ in thissetting. However, it is relatively time consuming,requires access to specialised equipment (a gamma

counter), nuclear medicine expertise and involves thehandling and disposal of radioactive materials. Centreswithout access to a nuclear medicine department mayexperience logistical difficulties in obtaining the estima-tion of renal function for accurate prescription ofchemotherapy.

A number of methods of deriving GFR based on esti-mating equations have been developed. The most wide-spread in routine clinical practice in the generalpopulation is the 4-point MDRD (Management of Dietin Renal Disease (MDRD)) formula, which calculatesestimated glomerular filtration rate (eGFR) [9]. This for-mula is widely used for the diagnosis and classificationof chronic kidney disease [10]. This takes into accountage, gender, race (white or Afro-Caribbean) and serumcreatinine. A calculated MDRD eGFR is issued withall biochemistry reports measuring the biochemicalpanel of urea, creatinine and electrolytes in the UnitedKingdom. Whilst well validated as a measure of kidneyfunction, this formula was derived from patients withknown kidney disease and has not been robustly vali-dated in patients without renal impairment, and is gen-erally considered inadequate for use in calculating drugdosing. In addition to kidney function, serum creatinineis influenced by other factors including diet, muscle mass(low in the elderly, cachexia and amputees) and drugs(e.g. trimethoprim impairs tubular secretion of creati-nine). Whilst eGFR reporting has improved detectionand management of chronic kidney disease, the MDRDformula tends to underestimate eGFR at higher levels ofkidney function [11]. To address the limitations of theMDRD formula the Chronic Kidney Disease-Epidemi-ology (CKD-EPI) formula has emerged to derive aneGFR, demonstrating less bias, greater accuracy andimproved precision [12] and it is likely that this will bewidely adopted as the standard measure of kidney func-tion in all adult patients, following its endorsement inthe most recent Kidney Disease Improving Global Out-comes (KDIGO) guidelines [10].

The Cockcroft–Gault (CG) formula is still widelyused for the calculation of renal function to guide dosingfor many drugs (e.g. gentamicin). Cockcroft–Gault cal-culates creatinine clearance (CrCl) rather than GFR[13]. In general CrCl tends to overestimate GFR dueto tubular secretion of creatinine, particularly at lowerlevels of kidney function. Moreover, with obese patients,who have a relatively lower muscle mass, if actual bodyweight is used, CG will overestimate GFR, whilst if ideal

946 S.T.C. Shepherd et al. / European Journal of Cancer 50 (2014) 944–952

body weight is used (as recommended by CG), GFRmay be underestimated. In the absence of access to iso-topic measurement of GFR, many centres employ Cock-croft–Gault derived CrCl to calculate carboplatindosing.

We determined to investigate the accuracy of theCockcroft–Gault, MDRD and CKD-EPI formulae inestimating GFR compared with the gold standard mea-surement of GFR using the 51Cr-EDTA method in arelatively homogenous population comprising men withstage 1 seminoma. We also report the impact of usingthese formulae on carboplatin dosing in this cohort.

2. Methods

2.1. Patients

We retrospectively identified all men who hadreceived adjuvant carboplatin AUC7 for stage 1 semi-noma at our institution between January 2007 andAugust 2012 using chemotherapy prescribing software(Chemocare vers 5.2, CIS Healthcare, Belfast, UnitedKingdom (UK)). Patient demographics and co-morbid-ities were recorded from initial visit. Body Mass Index(BMI) [14], Body Surface Area (BSA using the DuBoisformula) [15] and Ideal Body Weight (IBW) were calcu-lated [16]. The West of Scotland Research Ethics Com-mittee granted a waiver as approval of this study on thebasis that it represented analysis of routinely collecteddata to improve clinical care.

2.2. 51Cr-EDTA glomerular filtration rate

51Cr-EDTA clearance was performed in accordancewith the method described by the British Nuclear Med-icine Society [17]. Briefly, following injection of 3 MBqchromium 51 EDTA, four accurately timed blood sam-ples are taken between two and four hours post-admin-istration. Cr-51 EDTA clearance is used to calculatemeasured GFR using the slope-intercept method with

Table 1Calculations used. Key: Wt: weight in kg, Ht: height in cms, AUC: area undrate in ml/min; Modified Cockcroft and Gault (C&G) equation for estima(MDRD) formulae; Chronic Kidney Disease Epidemiology (CKD-EPI). A

Formula

Body Surface Area (BSA) (m2) [DuBois] 0.007184Body Mass Index (kg/m2) Wt/HeigIdeal Body Weight [Devine] Male: 50Calvert (mg) AUC �Cockcroft-Gault for males (ml/min) (140-ageCockcroft-Gault (ml/min/1.73 m2) CrCl � (MDRD (ml/min/1.73 m2) 32,788 �

by 1.212CKD-EPI for males (ml/min/1.73 m2) If sCr 6

If sCr >8if patien

Correction of estimated glomerular filtration rate (eGFR)formulae for actual BSA (ml/min/x m2)

eGFR �

correction for the systematic error introduced asdescribed by Brochner-Mortensen [18]. GFR valueswere reported as GFR corrected for body surface area(using Haycock formula) [19] and uncorrected GFR.

2.3. Biochemistry

Routine biochemistry was performed in a standardNational Health Service laboratory using a standardJaffe method for the measurement of serum creatinine(measured on Abbott Architect) The adjustment factorsproduced by the UK National External Quality Assess-ment Service were used for the creatinine assay toproduce isotope dilution mass spectrometry (IDMS) –traceable serum creatinine values (as is routine clinicalpractice). Only laboratory values obtained within lessthan one week of the 51Cr-EDTA GFR measurementwere used.

2.4. Estimated creatinine clearance and glomerularfiltration rate

Estimated Creatinine Clearance was calculated usingthe CG formula using actual body weight (ABW) andideal body weight (IBW). Further correction was per-formed to correct CrCl to standardise measurementsto 1.73 m2 of BSA (Table 1). The Estimated glomerularfiltration rate (eGFR) was, calculated using the Man-agement of Diet in Renal Disease (MDRD) [9] andthe Chronic Kidney Disease Epidemiology (CKD-EPI)[12] formulae (Table 1).

2.5. Correction for body surface area

51Cr-EDTA assays are reported as their measuredvalue in ml/min usually accompanied by a standardisedcorrection for a BSA of 1.73 m2. eGFR formulae arecalculated to report for a BSA of 1.73 m2. The Calvertformula [6] incorporates the measured (ml/min) GFRin calculation of carboplatin doses.

er the concentration curve in mg/ml/min; GFR is glomerular filtrationted creatinine clearance (CrCl); Modification of Diet in Renal Diseasell formulae are listed for males.

e

�Wt0.725 � Ht0.425

ht (m)2

+ (0.906 � (Ht–152.4))(GFR + 25)) � weight � 1.23/sCr1.73/BSA)(sCr)–1.154 � (Age)–0.203 (Multiply by 0.742 if female and additionallyif patient is Afro-Caribbean)

80 lmol/L = 141 � (sCr/0.9)–0.411 � (0.993)age

0 lmol/L = 141 � (sCr/0.9)–1.209 � (0.993)age (multiply answer by 0.87t is Afro-Caribbean)(xBSA/1.73)

S.T.C. Shepherd et al. / European Journal of Cancer 50 (2014) 944–952 947

In this study, we compared 51Cr-EDTA ml/min/1.73 m2 with eGFR (ml/min/1.73 m2) when evaluatingthe performance of formulae and similarly 51Cr-EDTAml/min with eGFR ml/min (with correction for actualBSA).

As a separate analysis, we also incorporated addi-tional correction for patient’s actual BSA to the eGFRformulae (ml/min) (Table 1) to investigate whether thiswould improve accuracy of dosing. We refer to this asCKD-EPI uncorrected (CKD-EPIUNCORR).

2.6. Carboplatin dosing

Using the Calvert equation (Table 1), an AUC 7 mg/ml/min carboplatin dose was calculated for each patientusing the GFR obtained from the 51Cr-EDTA method[6]. Carboplatin dose was calculated using GFR in ml/min in accordance with clinical practice [6]. Theoreticalcarboplatin doses were also calculated for each patientusing each of the GFR estimating formulae as well asthe CG formula for CrCl based on both actual and idealbody weight. For each formula, theoretical carboplatindoses were calculated for GFR ml/min and GFR cor-rected for 1.73 m2 BSA.

2.7. Statistical methods

Measured and estimated GFR were compared graph-ically using the Bland Altman method to illustrate limitsof agreement between the different estimating methodsand the measured GFR [20]. Bias was assessed as themean difference, with positive values indicating anunder-estimation of measured GFR. Precision wasassessed as standard deviation for the differences. Accu-racy was assessed using the standard error of the esti-mate in a linear regression analysis (root mean squareerror) relative to measured GFR. Accuracy was alsoassessed as the percent of estimates within 30% of themeasured GFR (P30), which takes into account highererrors at higher values and absolute values of the differ-ence between measured and estimated GFR. Meanswere compared using the paired t-test. Theoretical car-boplatin doses were compared with doses obtained usingmeasured GFR in terms of percentage error (PE) and

Table 2Baseline characteristics (n = 115).

n = 115

Age at glomerular filtration rate (GFR) (years)WeightHeight (cm)Body Surface Area (BSA) (m2)Body Mass Index (BMI) (kg/m2)Serum creatinine (lmol/L)Chromium 51 ethylene diamine tetra-acetic acid (EDTA) GFR (ml/min)Chromium 51 EDTA GFR (ml/min/1.73 m2)Carboplatin dose (mg)

absolute percentage error (APE). An APE of >10%was considered clinically significant variation in carbo-platin dosing. All analyses were performed using theSPSS 19.0 software package (IBM, Armonk, NY, Uni-ted States of America (USA)). Figures were preparedusing Minitab 15.0 (Minitab, State College, PA, USA).

3. Results

3.1. Patient characteristics

We identified 115 male subjects who had receivedadjuvant carboplatin AUC7 for with stage 1 seminoma.The baseline patient characteristics are shown in Table 2.The median age was 39.4 (range 20.8–68.9). All patientswere Caucasian. The majority of patients had no comor-bidity (90.4%). Eight patients (7%) had hypertension,two patients (1.7%) had diabetes mellitus and twopatients (1.7%) had Down’s syndrome. The mean weightwas 87.5 kg (standard deviation (SD) 18.3, range 51–161 kg). 40 patients (34.8%) were obese (BMI > 30).The mean 51Cr-EDTA GFR was 116.3 ml/min (SD26.1) and 96.9 ml/min/1.73 m2 (SD 17.4) when correctedfor body surface area. Full data were available for 111patients, three patients had missing height and weightmeasurements and one patient had missingbiochemistry.

3.2. Performance of estimating GFR formulae

Differences between measured GFR and eGFR areshown in Table 3 and were compared graphically usingthe Bland–Altman Method (Fig. 1). CG tended to over-estimate GFR using both ABW and IBW (134.1 and107.1 ml/min, respectively) however, when correctedfor 1.73 m2 BSA CGIBW underestimated the GFR(90.7 ml/min/1.73 m2-).

CKD-EPI also tended to overestimate GFR (meaneGFR 101.0 ml/min/1.73 m2) whereas MDRD tended tounderestimate GFR (mean eGFR 93.6 ml/min/1.73 m2).Bias, the mean difference between measured and estimatedGFR, was greatest using the CGABW formula (�17.6 ml)and similar using MDRD and CKD-EPI formulae (+3.1and �4.3 ml/min/1.73 m2, respectively). Based on the SD

Mean Standard deviation (SD)

40.3 ±10.187.5 ±18.3

177.5 ±8.22.0 ±0.2

27.8 ±5.882.0 ±12.8

116.4 ±26.196.9 ±17.4

988.2 ±173.3

Table 3Performance of estimated glomerular filtration rate (eGFR) compared against chromium-51 ethylene diamine tetra-acetic acid (Cr-EDTA) GFRmeasurements.

GFR (mean ± standard deviation(SD))

Biasa Precisionb Root mean square oferrorc

P30 n

(%)d

51Cr EDTA (ml/min) 116.3 (26.1) – – – –51Cr EDTA per 1.73 m2 Body Surface Area

(BSA)(ml/min/1.73 m2)

96.9 (17.4) – – – –

Cockcroft–Gault (CG)ABWe (ml/min) 134.1 (35.9) –17.6 21.1 16.3 52 (46.8)

CGABWe per 1.73 m2 BSA (ml/min/1.73 m2) 112.6 (21.8) –15.6 21.7 16.1 60 (54.0)

CGIBWf (ml/min) 107.1 (22.6) 10.1 21.0 16.7 84 (75.6)

CGIBWf per 1.73 m2 BSA (ml/min/1.73 m2) 90.7 (21.5) 6.3 22.4 16.4 85 (76.6)

Management of Diet in Renal Disease(MDRD)(ml/min/1.73 m2)

93.6 (17.2) 3.1 18.9 16.1 101 (88.5)

Chronic Kidney Disease-Epidemiology(CKD-EPI)UNCORR (ml/min)

119.5 (21.7) –3.8 21.1 16.7 101 (88.5)

CKD-EPI (ml/min/1.73 m2) 101.0 (15.1) –4.3 17.1 15.7 103 (90.4)

a Bias is the mean difference between eGFR and isotope measured value.b Precision is the standard deviation of the mean differences.c From linear regression model, see methods for detail.d Percentage of estimates within 30% of the measured GFR.e Cockcroft–Gault calculated using actual body weight.f Cockcroft–Gault calculated using ideal body weight.

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of the bias, precision was greatest using the CKD-EPIformula (±17.1 ml/min/1.73 m2), whereas CGIBW norma-lised to 1.73 m2 had the least precision (±22.4 ml/min/1.73 m2). Based on the root mean square of error andP30, CKD-EPI had the greatest accuracy of the GFRestimating formulae, 103 (90.4%) had an eGFR within30% of the measured value.

3.3. Effect of estimating GFR on carboplatin prescribing

Using GFR obtained from 51Cr-EDTA, mean carbo-platin AUC7 dose calculated using the Calvert formulawas 988.2 mg. Doses calculated using eGFR formulae

Fig. 1. (a) and (b) Bland and Altman plots comparing each of the predictio(b) Management of Diet in Renal Disease (MDRD) studied with ethylene dEach value of estimated glomerular filtration rate (eGFR) is compared tobetween these two values, and the x axis, the average of the two values, for eagreement between the two methods are illustrated as dotted lines, and th

are summarised in Table 4. For CG, using ABW meandose of carboplatin was 1113.7 mg and 925.0 mg usingIBW. Mean calculated doses were 829.9 and 881.3 mgfor MDRD and CKD-EPI, respectively (Fig. 2). Byuncorrecting for BSA mean calculated dose usingCKD-EPIUNCORR was 1013.1 mg. Using paired t-test-ing; we tested the null hypothesis that there was no sta-tistically significant difference between the means ofdoses calculated using 51Cr-EDTA and eGFR formu-lae. There was no statistically significant differencebetween the mean 51Cr-EDTA calculated dose and themean dose obtained using the CKD-EPIUNCORR

formulae (p = 0.16). In contrast, mean dose calculated

n equations (a) Chronic Kidney Disease-Epidemiology (CKD-EPI) andiamine tetra-acetic acid (EDTA)-measured GFR corrected to 1.73 m2.the corresponding measured value. The y axis shows the differences

ach patient (in ml/min/1.73 m2). The resulting upper and lower limits ofe middle line illustrates bias.

Table 4Carboplatin area under the concentration curve (AUC)7 doses calculated using the Calvert formulae and various glomerular filtration rate (GFR)estimating methods with comparison of error with doses obtained using the 51Cr-ethylene diamine tetra-acetic acid (EDTA) method.

GFR measure Carboplatin dose (mg), mean(standard deviation (SD))

t-testa PE (%)b,mean (SD)

APE (%)c

mean (SD)APE<10%d, n

(%)

APE<20%e, n

(%)

51Cr-EDTA (ml/min) 988.2 (173.3) – – – – –Cockcroft–Gault (CG)ABW (ml/min) 1113.7 (251.3) p < 0.001 13.4 (17.3) 17.3 (13.4) 45 (40.5) 73 (66.3)CGABW (ml/min/1.73 m2) 963.4 (152.9) p = 0.012 �0.8 (15.8) 12.9 (9.2) 46 (41.4) 87 (78.4)CGIBW (ml/min) 925.0 (158.0) p = 0.001 �4.5 (17.9) 14.8 (11.0) 49 (44.5) 74 (66.7)CGIBW (ml/min/1.73 m2) 809.9 (150.4) p < 0.001 �15.5 (21.2) 22.9 (12.8) 19 (17.1) 53 (47.7)Management of Diet in Renal Disease

(MDRD) (ml/min/1.73 m2)829.9 (120.5) p < 0.001 �13.8 (18.4) 19.5 (12.3) 27 (23.7) 61 (54.0)

Chronic Kidney Disease-Epidemiology(CKD-EPI)UNCORR (ml/min)

1013.1 (151.9) p = 0.160 4.13 (13.7) 11.6 (8.3) 51 (45.9) 96 (86.4)

CKD-EPI (ml/min/1.73 m2) 881.3 (105.5) p < 0.001 �8.6 (16.8) 15.3 (11.2) 44 (39.6) 83 (74.8)

a Paired t-test comparing mean calculated dose with mean estimated dose, p < 0.05 indicates means are significantly different.b Percentage error between doses calculated with 51Cr-EDTA and those calculated with estimating formulae.c Absolute percentage error between doses calculated with 51Cr-EDTA and those calculated with estimating formulae.d Number of patients with absolute percentage error within 10% of actual dose of carboplatin.e Number of patients with absolute percentage error within 20% of actual dose of carboplatin.

Fig. 2. Box and whisker plots showing (a) carboplatin doses calculated using the Calvert method with different estimating formulae and (b)Percentage error (PE) in carboplatin dosing using different estimated glomerular filtration rate (eGFR) formulae, data between the two bold ordotted x-axis reference lines represent patients receiving within 10% or 20% of the correct carboplatin dose, respectively. Positive PE indicatesoverdosing of patients.

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by the MDRD and all CG formulae was statistically dis-similar (p < 0.05).

Doses calculated using estimating formulae werecompared to those obtained using the gold-standardusing percentage error. CGABW corrected to 1.73 m2

had the lowest mean PE (�0.8%). MDRD tended tounder dose patients (mean PE �13.8). CG calculatedusing IBW tended to overdose patients (median PE+13.4) but with correction for 1.73 m2, CGIBW tendedto underestimate the dose of carboplatin. The CKD-EPIUNCORR formula had the lowest absolute percentageerror (mean 8.3%) and MDRD and CGIBW per 1.73 m2

had the highest APE (mean 19.5% and 22.9%, respec-tively). Patients with an APE <10% were considered tohave received an equivalent dose of carboplatin; 45.9%of patients would have received equivalent dose of car-boplatin using CKD-EPIUNCORR compared to just23.7% of patients using MDRD. If the acceptable

APE is increased to within 20% of the measured dose,86.4% of patients would have received an equivalentdose.

Table 5 demonstrates the proportions of patients whowould have received too-little, too-much and equivalentdoses of carboplatin using the various formulae.Although CKD-EPIUNCORR was the most accurate,13.5% of patients would have received too littlecarboplatin and 40.5% would have received too much.Using MDRD, 67% of patients would have beenunder-dosed and using the CGABW formula, 55.0% ofpatients would have received too much carboplatin.Based on CKD-EPIUNCORR eGFR, patients predictedto receive an inadequately low carboplatin dose had alarger BSA (p = 0.035) and were obese (body massindex > 30) (p = 0.013), whilst there were no obviouspredictors of the 40.5% who would have received toogreat a dose.

Table 5Comparison of carboplatin doses calculated using eGFR formulae versus 51Cr-EDTA, demonstrating the number of patients who would receivethe same, higher or lower dose of carboplatin using a 10% and 20% margin of acceptability.

Estimating formula Same dose n (%) Overdosed n (%) Underdosed n (%)

10% error 20% error 10% error 20% error 10% error 20% error

Cockcroft–Gault (CG)ABW (ml/min) 45 (40.5) 73 (66.3) 61 (55.0) 37 (33.4) 5 (4.5) 1 (0.9)CGABW/1.73 m2 (ml/min/1.73 m2) 46 (41.4) 87 (78.4) 28 (25.2) 12 (9.5) 37 (33.3) 12 (9.5)CGIBW (ml/min) 49 (44.5) 74 (66.7) 42 (37.8) 23 (20.7) 20 (18.0) 14 (12.6)CGIBW/1.73 m2 (ml/min/1.73 m2) 19 (17.1) 53 (47.7) 15 (13.5) 8 (6.6) 77 (69.4) 50 (45)Management of Diet in Renal Disease (MDRD)

(ml/min/1.73 m2)27 (24.1) 61 (54.0) 10 (8.9) 5 (4.4) 75 (67.0) 48 (42.5)

Chronic Kidney Disease-Epidemiology (CKD-EPI)UNCORR

(ml/min)51 (45.9) 96 (86.4) 45 (40.5) 12 (10.8) 15 (13.5) 4 (3.6)

CKD-EPI (ml/min/1.73 m2) 44 (39.6) 80 (72.0) 11 (10.0) 7 (6.3) 60 (54.0) 24 (21.6)

950 S.T.C. Shepherd et al. / European Journal of Cancer 50 (2014) 944–952

4. Discussion

A single dose of adjuvant carboplatin AUC7 hasemerged as a standard option in the management ofstage 1 seminoma. Accurate GFR estimation is essentialfor correct dosing and safe prescribing in this group ofpatients. The MRC TE19/EORTC 30982 protocol rec-ommended isotopic measurement of GFR and thiswas performed in approximately 62% of enrolledpatients. The remainder had a urinary 24 h creatinineclearance measured. The use of CG or other estimatingformulae was not permitted. The current gold-standardis chromium 51 EDTA GFR, however it is not alwayspractical to perform this test prior to the initiation ofchemotherapy and a formula for estimating GFR basedon routinely collected clinical parameters would simplifythe pathway for these patients. Various formulae havebeen used to estimate creatinine clearance and GFR,however, none have been validated for the prescriptionof chemotherapy. In our study of 115 male subjectswho received adjuvant carboplatin AUC7 for stage 1seminoma between 2007 and 2012 at a single tertiaryoncology centre, we found that the CKD-EPI formulahad most clinical utility in predicting accurate carbo-platin dosing as well as closest overall correlation withmeasured GFR. Perhaps surprisingly, CKD-EPI, whichcorrects for body surface area was most closely alignedwith measured GFR uncorrected for body surface area,as assessed by bias. Numerically CKD-EPIUNCORR wasclosest to measured GFR. Measured GFR is the mea-sure used for carboplatin dosing using the Calvertmethod.

We assume that carboplatin dosing predicted by51Cr-EDTA GFR using the Calvert formula, remainsthe ‘gold-standard’ for achieving cure with minimal riskof nephrotoxicity and myelosuppression. Whilst, theCKD-EPI or CKD-EPIUNCORR formula was able topredict dosing accurately in a proportion of patients,the majority would have received an inaccurate dosewith both over and underdosing possible. Althoughthe clinical significance of such variation in carboplatindosing is uncertain, it is relevant that an exploratory

analysis of MRC TE19/EORTC 30982 raised the possi-bility of a clinically significant reduction in efficacy withunderdosing of just 10%. Specifically, the protocol man-dated a dose reduction of 10% in those patients whosecarboplatin dose was calculated using urinary creatinineclearance rather than isotope GFR although the meanGFR obtained by both methods was, in fact, similar[3]. A trend (HR, 0.51; 95% confidence interval (CI),0.24–1.07; p = 0.08) towards poorer outcome wasobserved in the subgroup with the dose reduction.Therefore, delivery of an accurate AUC7 dose may beimportant in reducing recurrence rates in men with stage1 seminoma and underdosing should be avoided. In ourcohort, at a 10% margin of error, CKD-EPIUNCORR

would calculate an equivalent, or larger, dose of chemo-therapy in 86.5% of patients but 13.5% would still beunderdosed.

Development of convenient, inexpensive and accu-rate methods for estimation of renal function for theprescription of chemotherapy is extremely appealing.To date, radioisotopic methods remain the most wide-spread method for calculation for GFR in this setting,However, they are relatively time consuming with bloodsampling required over at least a four hour period. Theyalso require access to specialised equipment (a gammacounter) and involve the handling and disposal of radio-active materials and are relatively expensive. Usually,these issues are dealt with by the local Nuclear MedicineDepartment although not all centres have access to thesefacilities and expertise. Radiocontrast methods, e.g.iohexol clearance, offer a potential alternative for accu-rate assessment of renal function, and whilst these areoften used in research studies, these have not translatedinto widespread clinical practice for chemotherapy pre-scribing. Inulin clearance remains the gold-standardfor measurement of renal function but this is not usedclinically, as this is expensive, time consuming and diffi-cult to measure.

Other studies have examined this issue, specificallyaddressing the needs of oncology patients. Ainsworthet al. studied the performance of the CG and MDRDequations in a larger oncology cohort, as well as

S.T.C. Shepherd et al. / European Journal of Cancer 50 (2014) 944–952 951

investigating the accuracy of the Wright and Jeliffe equa-tions, which were specifically derived from oncologycohorts [21–23]. Their findings suggest that the CG for-mula may have merits for calculating GFR (approxi-mated by CrCl), but only if specific adjustment is madein patients with an actual body weight 30% greater thantheir ideal body weight. This study did not address thepotential impact on carboplatin dose prescribed whichis a more important measure than the accuracy of theformula. It is clear that whilst the MDRD formula iswidely used in the general population for the diagnosisof chronic kidney disease, due to its systematic underes-timation of GFR at normal and near-normal levels ofkidney function, it has no place in the determination ofGFR for prescription of carboplatin.

In order to address the limitations of the MDRDequation, the CKD-EPI formula has emerged (in trutha set of eight equations with the equation used depen-dent on the age, race, gender and serum creatinine inthe individual patients). Unlike MDRD, which wasderived in patients with chronic kidney disease, CKD-EPI was derived from a large population of patientswith a range of renal function and this has resulted inan equation, which is more accurate in patients withnormal renal function. This has since been recom-mended as the routine method for estimated GFR(eGFR) in adults in routine clinical practice [9].

The performance of the CKD-EPI equation has beenexamined in a small number of oncology patients. Craiget al. found all estimating equations (MDRD, CKD-EPI, CG) to be associated with carboplatin overdosing(in 60–80% of cases) in a wide spectrum of oncologypatients with the majority of subjects having gynaeco-logical, lung, lymphoma and upper GI cancers [24]. Thisstudy highlights the difficulties in using estimating equa-tions to calculate carboplatin doses in oncology patients.All the estimating equations depend on creatinine as themajor endogenous variable representing excretory renalfunction. Creatinine varies widely between individualsdependent mainly on muscle mass, but also dependson dietary protein intake. Therefore, it is inappropriate,to broadly apply eGFR equations to all cancer patients,where sarcopaenia is common and dietary intake may bepoor. Oedema may be present, so actual body weightmay not reflect muscle mass, limiting the performanceof the CG equation. Although both the Wright and Jel-liffe formulae were derived specifically attempted toaddress the needs of cancer patients, our data, combinedwith others [21,24] highlight the challenges using derivedeGFR formulae in this group, which are at least as, ifnot more heterogeneous, as the various populationsused to generate the CKD-EPI and MDRD formulae.CKD-EPI was generated from a dataset of over 8000subjects and it would be challenging to generate a simi-lar dataset to reliably address the prescribing needs of alloncology patients.

In contrast to these previous studies, we examined theperformance of the various estimating equations in afairly homogenous group of men being prescribed car-boplatin as adjunctive therapy stage 1 seminoma.Appropriate carboplatin dose could be calculated in45.9% of patients. Although patients who were likelyto receive an inadequate dose were more likely to beobese, we did not find the overall performance ofCKD-EPI formula eGFR based prescribing to increaseby only studying non-obese subjects, using a BMI cutpoint of 30. Our homogenous study cohort representsa strength, demonstrating that in patients, with limitedco morbid disease, no tumour burden and no evidenceof cachexia, CKD-EPI based calculation of carboplatindose will appropriate in nearly half of cases. By alteringthe threshold for accurate dosing to within 20% of thatindicated by radioisotopic measured GFR, CKD-EPIwill predict an appropriate carboplatin dose in 86.4%of cases. However, caution needs to be exerted, priorto omitting isotopic GFR using these thresholds, giventhe risk of reduced cure rate if underdosed, and myelo-suppression if overdosed.

Our study is limited by its relatively small size andretrospective nature. A prospective study in a validationcohort would be required to confirm that eGFR doeslead to similar carboplatin dosing as isotopic methods.These results are unlikely to be generalisable to otheroncology patients, including older patients, those withcomorbid disease, cachexia and more advanced malig-nancy. Therefore it seems likely that eGFR based carbo-platin dosing should be reserved to well defined groupsof patients free of conditions likely to influence musclemass (and hence serum creatinine).

In conclusion we have demonstrated that the CKD-EPI formula can be used to calculate an accurate doseof adjuvant carboplatin in many patients with stage 1seminoma. Importantly, however, a majority of patientswould experience incorrect-dosing of a magnitude com-patible with clinical sequelae if CKD-EPIUNCORR wereto be used. By contrast only 13.5% would have beenunderdosed. Other formulae, including CG, were notreliable in this cohort. Further work to identify predic-tors of those patients who require measurement of true,rather than estimated GFR, may allow a reduction inthe use of isotopic GFR measurement whilst maintain-ing optimal dosing of adjuvant carboplatin.

Conflict of interest statement

None declared.

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