title: Relevant risk of carboplatin underdosing in cancer patients with normal renal function using estimated GFR: lessons from a stage I seminoma cohort.
abstract: BACKGROUND
  Seminoma stage I is the most frequent testis cancer and single-dose carboplatin (AUC7) is an effective and widely used adjuvant treatment. Underdosing of carboplatin by 10% has been shown to almost double the rate of relapse and hence correct dosing based on accurate GFR measurement is crucial. The gold standard of GFR measurement with a radiolabelled isotope is expensive and not readily available. In many institutions, it is replaced by GFR estimation with the Cockcroft-Gault formula, which might lead to significant carboplatin underdosing and potentially inferior clinical outcome.
  
  
  METHODS
  Retrospective analysis of all patients with stage I seminoma treated with adjuvant carboplatin between 1999 and 2012. All patients had serum creatinine measured and underwent GFR measurement with a radioisotope ((51)Cr EDTA or (99m)Tc DTPA), which was compared with seven standard GFR estimation formulae (Cockcroft-Gault, CKD-EPI, Jelliffe, Martin, Mayo, MDRD, Wright) and a flat dosing strategy. Bias, precision, rates of under- and overdosing of GFR estimates were compared with measured GFR. Bland-Altman plots were done.
  
  
  RESULTS
  A total of 426 consecutive Caucasian male patients were included: median age 39 years (range 19-60 years), median measured GFR 118 ml/min (51-209), median administered carboplatin dose 1000 mg (532-1638). In comparison to isotopic GFR measurement, a relevant proportion of patients would have received ≤ 90% of carboplatin dose through the use of GFR estimation formulae: 4% using Mayo, 9% Martin, 18% Cockcroft-Gault, 24% Wright, 63% Jelliffe, 49% MDRD and 41% using CKD-EPI. The flat dosing strategy, Wright and Cockcroft-Gault formulae, showed the smallest bias with mean percentage error of +1.9, +0.4 and +2.1, respectively.
  
  
  CONCLUSIONS
  Using Cockcroft-Gault or any other formula for GFR estimation leads to underdosing of adjuvant carboplatin in a relevant number of patients with Seminoma stage I and should not be regarded as standard of care.
authors.affiliation: Oncology/Haematology, Kantonsspital Graubünden, Chur richard.cathomas@ksgr.ch.
authors.forename: R
authors.initials: R
authors.lastname: Cathomas
authors.affiliation: SAKK (Swiss Group for Clinical Cancer Research) Coordinating Centre, Berne, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Klingbiel
authors.affiliation: Medical Oncology, Poole and Royal Bournemouth Hospitals, Bournemouth.
authors.forename: T R
authors.initials: TR
authors.lastname: Geldart
authors.affiliation: Departments of Medical Oncology.
authors.forename: G M
authors.initials: GM
authors.lastname: Mead
authors.affiliation: Medical Oncology, Poole and Royal Bournemouth Hospitals, Bournemouth.
authors.forename: S
authors.initials: S
authors.lastname: Ellis
authors.affiliation: Departments of Medical Oncology.
authors.forename: M
authors.initials: M
authors.lastname: Wheater
authors.affiliation: Departments of Medical Oncology.
authors.forename: P
authors.initials: P
authors.lastname: Simmonds
authors.affiliation: Nuclear Medicine, University Hospital Southampton, Southampton, UK.
authors.forename: N
authors.initials: N
authors.lastname: Nagaraj
authors.affiliation: Oncology/Haematology, Kantonsspital Graubünden, Chur.
authors.forename: R
authors.initials: R
authors.lastname: von Moos
authors.affiliation: Departments of Medical Oncology Medical Oncology and Haematology, Kantonsspital St Gallen, St Gallen, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Fehr
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016190:Carboplatin / Q000008:administration & dosage*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000209:etiology; D009367:Neoplasm Staging; D012189:Retrospective Studies; D012306:Risk; D018239:Seminoma / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D016190:Carboplatin
keywords: GFR estimation; GFR measurement; adjuvant treatment; carboplatin; seminoma stage I