Cancer & the Kidney Theory to Practice Brussels, Belgium 14 - 15 April 2015 Plenary Session 1 Cancer & the Kidney Theory to Practice

How to evaluate the renal function in cancer patients Dr. Vincent LAUNAY-VACHER, PharmD Service ICAR Pitié-Salpêtrière University Hospital Paris, France

Disclosure Past 3 years Pharmaceutical industry: Amgen, Bayer-Schering, Boehringer-Ingelheim, Daiichi-Sankyo, Gilead, Helsinn, Hospira, Ipsen, Leo Pharma, Roche, TEVA, Vifor Pharma (direct and/or indirect) French Health Authorities: Haute Autorité de Santé (HAS), Institut National du Cancer (INCa) (direct) Principles and definitions1: Links of interest can generate conflicts of interest Every link of interest does not necessarily result in a conflict of interest 1Haute Autorité de Santé. Guide des déclarations d’intérêts et de gestion des conflits d’intérêts. Juillet 2013

Short introduction Clinical Pharmacologist Nephro-Pharmacology Onco-Pharmacology Founded Service ICAR in 1999 With Pr. Gilbert Deray, Head of Nephrology Department ICAR = Information and Counselling on drug Adjustments in Renal disease Director of SiteGPR® www.sitegpr.com online Guidelines on how to Prescribe in Renal disease President of C-KIN www.c-kin.org Cancer & the Kidney International Network

How to evaluate renal function Measuring the Glomerular Filtration Rate (GFR) IV administration of a marker of GFR Inulin, 51Cr-EDTA, 99mTC-DTPA, … Urine and blood samples Calculation of the renal clearance of the marker => GFR Limits: Time-consuming Requires expert and trained staff Costs Constraining for the patient

How to evaluate renal function Measuring the Glomerular Filtration Rate (GFR) Not for routine clinical practice Creatinine clearance (CrCl) Endogenous Only excreted unchanged in the urine (not metabolized) Renal clearance of creatinine = Renal function (GFR) Advantage: does not require the administration of a radioisotope Limits: Require a 24-hour urine collection Constraining and often incomplete CrCl is not linearily linked to GFR

How to evaluate renal function Measuring the Glomerular Filtration Rate (GFR) Not for routine clinical practice Creatinine clearance (CrCl) Serum creatinine (SCr) Creatinine plasma concentration is stable Thus: If SCr ⬈ => Renal function ⬊

SCr and renal function Serum creatinine Creatinine production Muscle SCr production must be evaluated with: Weight Gender Age Creatinine production Muscle catabolism = Serum creatinine Creatinine elimination Glomerular filtration =

SCr and renal function SCr 75 µmol/L Renal function ~ 100 mL/mn Age: 37 Weight: 58 kg Age: 72 Weight: 53 kg SCr 75 µmol/L Renal function ~ 100 mL/mn Renal function ~ 50 mL/min

Important decrease in GFR SCr and renal function SCr Small increase in SCR GFR Important decrease in GFR

Formulae to estimate renal function Measuring the Glomerular Filtration Rate (GFR) Not for routine clinical practice Creatinine clearance (CrCl) Serum creatinine (SCr) Should not be used at all anymore as an index of normal/abnormal renal function Estimates of GFR with formulae

Formulae to estimate renal function Units Year Jeliffe1 CrCl ml/min 1973 Cockcroft-Gault2 1976 MDRD3 GFR ml/min/1.73m2 2000 Wright4 2001 CKD-EPI5 2009 Which formula to use in cancer patients ? 1Jelliffe RW. Ann Intern Med. 1973; 2Cockcroft DW, Gault MH. Nephron 1976; 3Levey AS et al. Ann Intern Med 1999 + J Am Soc Nephrol 2000 (poster); 4Wright JG, et al. Br J Cancer 2001; 5Levey AS, et al. Ann Intern Med 2009

Formulae to estimate renal function In non-cancer patients: aMDRD equation is recommended. In cancer patients: confounding evidence Example from the most recent literature: Authors’ conclusion: aMDRD understimates GFR in cancer patients… What should we do in clinical practice ?

Formulae to estimate renal function Always look at the Methods: Ainsworth’s study1: “*the raw results of aMDRD calculation in mL/min/1.73m2 were compared to measures of the actual GFR in mL/min and other formulae estimates in mL/min.” 50% of the patients had a BSA > 1.88 m2 1Ainsworth NL et al. Ann Oncol 2012; *Not mentionned in the article. Personal communication from Nicola Ainsworth.

Formulae to estimate renal function Comparisons with appropriate units: aMDRD is more precise Faluyi’s study: authors converted aMDRD raw result into mL/min using the actual BSA of the patients and then compared to CG and isotopic GFR. “the MDRD equation was observed to provide more accurate GFR estimates than the C&G equation” 1Faluyi OO et al. Med Oncol 2011

Formulae to estimate renal function Performance of formulae in special populations Adults Age < 65 Normal BMI Elderly (Age ≥ 65) High BMI (≥ 30) Low BMI (< 18.5) Cockcroft-Gault Correct False Not recommended MDRD More precise Accurate CKD-EPI ≈ MDRD Froissart et al. J Am Soc Nephrol 2005; Holweger K et al. Ann Pharmacother 2008; Barraclough LH et al. Clin Oncol 2008; Kleber M et al. Ann Oncol 2007; Launay-Vacher V et al. Ann Oncol 2007; Flamant M, et al. Am J Kidney Dis 2012; Michels WM, et al. Clin J Am Soc Nephrol 2010

Formulae to estimate renal function When BMI is lower than 18.5 No formula is precise enough Renal function cannot be estimated => Measured CrCl Cockcroft-Fault formula should be abandoned Modern formulae are as precise in young adults with normal BMI Modern formulae can be used when BMI > 30 (CG is false) Modern formulae ca be used when Age is ≥ 65 (CG false) Either MDRD or CKD-EPI can be used

Formulae to estimate renal function Comparing MDRD and CKD-EPI in the general population 116’321 subjects included in KEEP (Kidney Early Evaluation Program) Similar prevalence of eGFR < 60 mL/min/1.73m2 with MDRD or CKD-EPI Respectively 16.8% vs. 14.3% Stevens LA et al. Am J Kidney Dis 2011

Formulae to estimate renal function When BMI is lower than 18.5 => Measured CrCl No formula is precise enough Cockcroft-Fault formula should be abandoned Modern formulae are as precise in young adults with normal BMI Modern formulae can be used when BMI > 30 (CG is false) Modern formulae ca be used when Age is ≥ 65 (CG false) MDRD or CKD-EPI must be used

International definition and stratification of chronic kidney disease Stage Description eGFR (mL/min/1.73m²) At Increased Risk Risk factors for kidney disease (e.g., diabetes, high blood pressure, family history, older age, ethnic group) ≥ 90 1 Kidney damage (protein in the urine) and Normal GFR 2 Kidney damage and Mild decrease in GFR 60 to 89 3 Moderate decrease in GFR 30 to 59 4 Severe decrease in GFR 15 to 29 5 Kidney failure (dialysis or kidney transplant needed) Less than 15 K/DOQI : National Kidney Foundation. Am J Kidney Dis 2002.; KDIGO : Levey AS, et al. Kidney Int 2005.

Why evaluate the renal function ? CKD is highly frequent in cancer : 12 to 25% CKD is associated with reduced survival and increased cancer-related mortality Why and how CKD may impair survival ?

CKD impacts survival in other conditions CKD is a risk factor for mortality in a number of chronic diseases or acute conditions: Type 1 diabetes1 HIV infection2 Patients hospitalized for upper GI bleeding3 Atrial fibrillation4 Non-cardiac surgery5 Coronary heart disease and mortality6 Type 2 diabetes mellitus, especially in the elderly7 …/… 1Groop PH et al. Diabetes 2009; 2Ibrahim F et al. Am J Kidney Dis. 2012; 3Sood P et al. Am J Nephrol. 2012; 4Nakagawa K et al. Am J Cardiol 2011; 5Mathew A et al. Kidney Int 2008; 6Astor BC et al. Am Heart J. 2006; 7 Drion I et al. Age Ageing. 2012

How CKD may impact survival in cancer CKD patients are at risk for cardiovascular mortality Deaths CV events Hospit. HR : 1,0 1,2 1,8 3,2 5,9 HR : 1,0 1,4 2,0 2,8 3,4 HR : 1,0 1,1 1,5 2,1 3,1 1’120’295 subjects included… Go AS et al. N Engl J Med 2004

How CKD may impact survival in cancer CKD patients are at risk for cardiovascular mortality RR for venous thromboembolism increases as eGFR decreases RR becomes significant when eGFR is below 88 mL/min/1.73m2 Especially when eGFR < 60 mL/min/1.73m2 A: Mahmoodi BK. Circulation 2012

How CKD may impact survival in cancer CKD patients are at risk for cardiovascular mortality B Reduced survival in CKD patients experiencing venous thromboembolism / pulmonary embolism B: Parikh AM. Am J Kidney Dis 2011

How CKD may impact survival in cancer CKD patients are at risk for cardiovascular mortality Cancer patients with CKD may present with higher CV mortality => Reduced overall survival CKD patients are at risk for non-optimal drug management

How CKD may impact survival in cancer CKD patients are at risk for non-optimal drug management If Kidney Disease has not been identified OR If Kidney Disease has been diagnosed, but no dosage adjustment performed If Kidney Disease has been diagnosed but dose too much reduced UNDER-DOSE Lack of efficacy OVER-DOSE Toxicity delayed courses, treatment modification palliative care, …

How CKD may impact survival in cancer CKD patients are at risk for cardiovascular mortality Cancer patients with CKD may present with higher CV mortality => Reduced overall survival CKD patients are at risk for non-optimal drug management Overdosage => Toxicity => Reduced survival Under-dosage => Lack of efficacy => Reduced survival

CONCLUSIONS In cancer patients, renal function must be evaluated with MDRD or CKD-EPI formulae Except in patient with BMI < 18.5 => Measured CrCl CKD cancer patients: Are probably at risk for CV increased morbi-mortality Require dosage adjustments For curative treatments For supportive care treatments For any other associated treatments

GFR estimate with MDRD or CKD-EPI formula at cancer diagnosis before each treatment course eGFR < 90 ? NO Normal renal function Usual care eGFR < 60 eGFR ≥ 60 YES Determine the appropriate dose: SmPC Evidence-based tools Dosage adjustment may be required Increased risk for renal toxicity Prevention measures Monitor GFR and SCr EXCEPTION: Carboplatin Dose is adjusted to the GFR in the Calvert formula, whatever the GFR No dosage adjustment required

Thank you for your attention! Vincent Launay-Vacher Service ICAR Pitié-Salpêtrière University Hospital vincent.launay-vacher@psl.aphp.fr