Performance of formulae based estimates of glomerular filtration rate for carboplatin dosing in stage 1 seminoma
Introduction
Stage 1 seminoma is the most common presentation of testicular germ cell tumour (GCT) and accounts for approximately 40% of all occurrences [1]. The management of stage 1 seminoma historically included adjuvant radiotherapy, however following orchidectomy, cases can be managed by surveillance alone or single agent carboplatin adjuvant therapy [2], [3]. Carboplatin is a platinum based alkylating agent that interferes with DNA processes and is used in the treatment of several malignancies [4]. The main therapeutic and toxic effects of carboplatin are related to its cytotoxicity. The most important dose-limiting toxicity of carboplatin exposure is myelosuppression, particularly thrombocytopaenia. Carboplatin exposure, defined as the area under the plasma concentration versus time curve (AUC), is associated with both severity of toxicity and anti-tumour effect [5]. Carboplatin is mainly eliminated by the kidneys. In patients with normal renal function, approximately 60–70% of an administered carboplatin dose is excreted by the kidneys within 24 h of administration. Carboplatin clearance is poorly associated with body surface area (BSA) but has a linear relationship with glomerular filtration rate (GFR) [5], [6].
The Calvert formula is widely used for dosing carboplatin and incorporates GFR as its key variable [6]. It is therefore essential to establish an accurate GFR. Clinical data are suggestive of a dose–response curve across therapeutically deliverable doses of carboplatin [4]. Consistent with these data, an exploratory analysis of the MRC TE19/EORTC 30982 study, a randomised trial comparing carboplatin with radiotherapy (RT) as adjuvant treatment for stage 1 seminoma, found a higher risk of relapse in patients where carboplatin dose was calculated based on creatinine clearance with an arbitrary 10% dose reduction applied, in comparison to those patients dosed according to isotopic GFR [3]. This highlights the importance of accurate assessment of GFR and hence carboplatin dose in this setting. In the UK current oncological practice commonly employs isotopic methods to calculate measured GFR such as the chromium-51 ethylene diamine tetra-acetic acid (EDTA) clearance method (51Cr-EDTA) [7], [8]. 51Cr-EDTA is accurate, reproducible, is validated for prescription of chemotherapy, and is considered ‘gold-standard’ in this setting. However, it is relatively time consuming, requires access to specialised equipment (a gamma counter), nuclear medicine expertise and involves the handling and disposal of radioactive materials. Centres without access to a nuclear medicine department may experience logistical difficulties in obtaining the estimation of renal function for accurate prescription of chemotherapy.
A number of methods of deriving GFR based on estimating equations have been developed. The most widespread in routine clinical practice in the general population is the 4-point MDRD (Management of Diet in Renal Disease (MDRD)) formula, which calculates estimated glomerular filtration rate (eGFR) [9]. This formula is widely used for the diagnosis and classification of chronic kidney disease [10]. This takes into account age, gender, race (white or Afro-Caribbean) and serum creatinine. A calculated MDRD eGFR is issued with all biochemistry reports measuring the biochemical panel of urea, creatinine and electrolytes in the United Kingdom. Whilst well validated as a measure of kidney function, this formula was derived from patients with known kidney disease and has not been robustly validated in patients without renal impairment, and is generally considered inadequate for use in calculating drug dosing. In addition to kidney function, serum creatinine is influenced by other factors including diet, muscle mass (low in the elderly, cachexia and amputees) and drugs (e.g. trimethoprim impairs tubular secretion of creatinine). Whilst eGFR reporting has improved detection and management of chronic kidney disease, the MDRD formula tends to underestimate eGFR at higher levels of kidney function [11]. To address the limitations of the MDRD formula the Chronic Kidney Disease-Epidemiology (CKD-EPI) formula has emerged to derive an eGFR, demonstrating less bias, greater accuracy and improved precision [12] and it is likely that this will be widely adopted as the standard measure of kidney function in all adult patients, following its endorsement in the most recent Kidney Disease Improving Global Outcomes (KDIGO) guidelines [10].
The Cockcroft–Gault (CG) formula is still widely used for the calculation of renal function to guide dosing for many drugs (e.g. gentamicin). Cockcroft–Gault calculates creatinine clearance (CrCl) rather than GFR [13]. In general CrCl tends to overestimate GFR due to tubular secretion of creatinine, particularly at lower levels of kidney function. Moreover, with obese patients, who have a relatively lower muscle mass, if actual body weight is used, CG will overestimate GFR, whilst if ideal body weight is used (as recommended by CG), GFR may be underestimated. In the absence of access to isotopic measurement of GFR, many centres employ Cockcroft–Gault derived CrCl to calculate carboplatin dosing.
We determined to investigate the accuracy of the Cockcroft–Gault, MDRD and CKD-EPI formulae in estimating GFR compared with the gold standard measurement of GFR using the 51Cr-EDTA method in a relatively homogenous population comprising men with stage 1 seminoma. We also report the impact of using these formulae on carboplatin dosing in this cohort.
Section snippets
Patients
We retrospectively identified all men who had received adjuvant carboplatin AUC7 for stage 1 seminoma at our institution between January 2007 and August 2012 using chemotherapy prescribing software (Chemocare vers 5.2, CIS Healthcare, Belfast, United Kingdom (UK)). Patient demographics and co-morbidities were recorded from initial visit. Body Mass Index (BMI) [14], Body Surface Area (BSA using the DuBois formula) [15] and Ideal Body Weight (IBW) were calculated [16]. The West of Scotland
Patient characteristics
We identified 115 male subjects who had received adjuvant 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 patients were Caucasian. The majority of patients had no comorbidity (90.4%). Eight patients (7%) had hypertension, two patients (1.7%) had diabetes mellitus and two patients (1.7%) had Down’s syndrome. The mean weight was 87.5 kg (standard deviation (SD) 18.3, range 51–161 kg). 40 patients
Discussion
A single dose of adjuvant carboplatin AUC7 has emerged as a standard option in the management of stage 1 seminoma. Accurate GFR estimation is essential for correct dosing and safe prescribing in this group of patients. The MRC TE19/EORTC 30982 protocol recommended isotopic measurement of GFR and this was performed in approximately 62% of enrolled patients. The remainder had a urinary 24 h creatinine clearance measured. The use of CG or other estimating formulae was not permitted. The current
Conflict of interest statement
None declared.
References (24)
- et al.
Testicular non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Ann Oncol
(2010) Application of the area under the curve of carboplatin in predicting toxicity and efficacy
Cancer Treat Rev
(1998)- et al.
Dissecting and refining the staging of chronic kidney disease
Kidney Int
(2009) - et al.
Indices of relative weight and obesity
J Chronic Dis
(1972) - et al.
Geometric method for measuring body surface area: a height–weight formula validated in infants, children, and adults
J Pediatr
(1978) - et al.
Evaluation of glomerular filtration rate estimation by Cockcroft-Gault, Jelliffe, Wright and Modification of Diet in Renal Disease (MDRD) formulae in oncology patients
Ann Oncol
(2012) - et al.
The changing presentation of germ cell tumours of the testis between 1983 and 2002
BJU Int
(2005) - et al.
Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214)
J Clin Oncol
(2011) - et al.
New perspectives on an old friend: optimizing carboplatin for the treatment of solid tumors
Oncologist
(1998) - et al.
Carboplatin dosage: prospective evaluation of a simple formula based on renal function
J Clin Oncol
(1989)