Estimation of Kidney Function in Oncology: Implications for Anticancer Drug Selection and Dosing

Abstract

Estimation of kidney function in patients with cancer directly affects drug dosing, agent selection, and eligibility for clinical trials of novel agents. Overestimation of kidney function may lead to overdosing or inappropriate agent selection and corresponding toxicity. Conversely, underestimation of kidney function may lead to underdosing or inappropriate agent exclusion and subsequent therapeutic failure. It would seem obvious that the most accurate estimates of kidney function should be used to reduce variability in decision making and ultimately, the therapeutic outcomes of toxicity and clinical benefit. However, clinical decision making is often more complex. The Cockcroft-Gault formula remains the most universally implemented estimator of kidney function in patients with cancer, despite its relative inaccuracy compared with the Chronic Kidney Disease Epidemiology Collaboration equation. The Chronic Kidney Disease Epidemiology Collaboration equation is a more precise estimator of kidney function; however, many currently used kidney function cutoff values were determined before the development of the Chronic Kidney Disease Epidemiology Collaboration equation and creatinine assay standardization using Cockcroft-Gault estimates. There is a need for additional studies investigating the validity of currently used estimates of kidney function in patients with cancer and the applicability of traditional anticancer dosing and eligibility guidelines to modern and more accurate estimates of kidney function. In this review, we consider contemporary calculation methods used to estimate kidney function in patients with cancer. We discuss the clinical implications of using these various methods, including the potential influence on drug dosing, drug selection, and clinical trial eligibility, using carboplatin and cisplatin as case studies.

Keywords: Cockcroft-Gault; cancer; chemotherapy; cisplatin; clinical trial; creatinine; creatinine clearance; glomerular filtration rate; kidney dysfunction; pharmacokinetics; renal dysfunction.

Figure 1.

Many anticancer drugs are dosed according to body surface area (BSA), but they are dose adjusted according to measures of absolute kidney function (i.e., estimated creatinine clearance as milliliters per minute) as opposed to BSA-indexed measures of kidney function (i.e., eGFR as milliliters per minute per 1.73 m²). (A) This practice will likely alter dose assignments of patients at the extremes of body size (patients who are obese and patients who are cachectic) compared to patients with BSA of 1.73 m². (B) Larger patients (BSA>1.73 m²) are already receiving a larger dose of BSA-dosed drugs due to their increased BSA. Use of an absolute kidney function value may preclude necessary dose reduction, because the absolute kidney function value of patients with BSA>1.73 m² will be greater than the BSA-indexed value and may be above a dose-adjustment breakpoint. (C) Smaller patients (BSA<1.73 m²) are already receiving a smaller dose of BSA-dosed drugs due to their decreased BSA. Use of an absolute kidney function value may lead to additional unnecessary dose reduction, because the absolute kidney function value of patients with BSA<1.73 m² will be less than the BSA-indexed value and may be below a dose-adjustment breakpoint. Bleomycin dosing of 10 U/m² was on the basis of manufacturer recommendations (41). Absolute eGFR values (milliliters per minute) were calculated by multiplying the BSA-indexed eGFR (milliliters per minute per 1.73 m²) by (patient’s BSA/1.73 m²).

Figure 2.

Area under the curve (AUC)–targeted dosing of carboplatin using either the Cockcroft–Gault formula or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to inform kidney function may result in different doses and exposures. The CKD-EPI equation estimates a body surface area (BSA)–normalized GFR value from assumed steady-state serum creatinine (SCr) and anthropomorphic variables. This estimate is converted to an absolute value using the patient’s BSA. Similarly, the Cockcroft–Gault formula estimates an absolute value for creatinine clearance, which is then used as a surrogate of GFR. The GFR value is imputed into the Calvert equation with a target AUC (often 6 mg/ml per min), which results in a carboplatin dose to be administered to the patient. On the basis of the true carboplatin clearance of the patient, an exposure is observed. On the basis of a probability of response (green curve) or toxicity (red curve), the exposure and corresponding probability of response and toxicity can be quite different depending on the kidney function estimate used and the corresponding carboplatin dose administered.