Imprecise Kidney Function Thresholds in Cancer Clinical Trials and the Potential for Harm

Abstract

Current guidance for evaluation of kidney function and drug dosing emphasize using measured or estimated glomerular filtration rate (GFR) rather than measured or estimated creatinine clearance or serum creatinine (Scr) alone. We assessed the definitions of kidney function thresholds for eligibility in cancer clinical trials. A random sample of active Phase I–III trials with cisplatin (n = 465) and studies in cancer with decreased kidney function (n = 74) were identified from clinicaltrials.gov. Among cisplatin trials, kidney function thresholds were defined by Scr alone or a composite of Scr or creatinine clearance in 46% (212/465) of studies. Only 2% (n = 11) used GFR. Among trials in participants with decreased kidney function, the proportion utilizing GFR (14%, 10/74) was modestly higher. Imprecise and logically inconsistent kidney function thresholds are in frequent use in clinical trials in cancer and may cause harm from either toxicity or impaired efficacy. We recommend the adoption and harmonization of recommended standards.

Performance of Glomerular Filtration Rate Estimating Equations Before and After Bariatric Surgery

“…However, in the setting of bariatric surgery, clinicians should consider using eGFR cr-cys or direct measurement of GFR when more accurate estimation of GFR is required (ie, drugs excreted by the kidney with narrow therapeutic windows). 26 , 28 , 29 Results from other literature also suggest that eGFR cr-cys may be preferable in severely obese patients undergoing bariatric surgery, though we found overall higher accuracy, 10 , 30 which may reflect the rigor of our methods of measuring GFR in a research setting at a single site. Other studies of severely obese (non–bariatric surgery) individuals have shown either overestimation, underestimation, or minimal bias when using creatinine-based estimating equations.…”

A prospective cross-sectional study estimated glomerular filtration rate from creatinine and cystatin C in adults with solid tumors

“…Currently, GFR evaluation is not standardized in clinical oncology practice; treatment protocols use Scr, estimated creatinine clearance using the CG equation, and eGFRcr using the MDRD Study or CKD-EPI equations. 20 It has been estimated that a threshold of Scr or estimated creatinine clearance with the CG equation, alone or in combination, are the most commonly used criteria in cancer clinical trials, often in a logically inconsistent manner. Indeed, only 2% of all cancer clinical trials and 14% of cancer clinical trials in the setting of decreased kidney function utilize an estimation of the GFR.…”

“…Indeed, only 2% of all cancer clinical trials and 14% of cancer clinical trials in the setting of decreased kidney function utilize an estimation of the GFR. 20 The CG equation was developed in 1976, 4 and estimated creatinine clearance using this equation was recommended for use in pharmacokinetic studies in drug development programs by regulatory agencies in 1998. 21 It remains commonly used for the prescription of cancer chemotherapy, despite increasing evidence of its limitations (Supplementary Table S19).…”

GFR Measurement and Chemotherapy Dosing in Patients with Kidney Disease and Cancer

“…Despite this fact, almost half of all active clinical trials involving chemotherapeutic drugs use kidney function thresholds defined by serum creatinine alone or a composite of serum creatinine or creatinine clearance. In one comprehensive study of all active phases 1-3 cisplatin trials obtained from the www.clinicaltrials.gov website, 212 of 465 studies (46%) used serum creatinine alone or a composite of serum creatinine or creatinine clearance, and many trials had inadequate information on kidney function thresholds (52).…”