Fundamental problems with pediatric adaptive dosing of carboplatin using nuclear‐medicine‐based estimates of renal function

Abstract

Background Carboplatin is often adaptively dosed based on glomerular filtration rate (GFR), usually estimated by nuclear medicine tests. At least five pediatric adaptive dosing formulas have been developed. In an effort to standardize dosing in Children's Oncology Group protocols, we explored methodologic variation in GFR estimation and adaptive‐dosing formula performance. Procedure Nuclear medicine GFR data from published series of ≥100 children with cancer were compared. Data from patients for whom body surface area, weight, GFR, and tracer half‐life were available were used to compare formulas. Results Differences in methods used to estimate GFR in children with cancer resulted in highly variable population results, with median GFRs ranging from 96 to 150 mL/min/1.73m2. The choice of adaptive formula had a major impact on calculated dose. When targeting an area under the curve of 7.9 mg/mL • min, the median difference between the formula yielding the lowest and highest carboplatin dose for individual subjects was 289 (range 96‐1 737) mg/m2. Conclusions Wide variation in GFR obtained with nuclear‐medicine‐based tests in children with cancer primarily results from systematic methodologic errors. Formulas for calculating carboplatin dose produce additional and substantial variation that may place children with cancer at unnecessary risk for excessive toxicity or underdosing. These findings indicate a need for the development of a uniform, validated method for GFR determination in children that should be utilized in all centers. Currently, adaptive dosing of carboplatin based on GFR has serious limitations and in most clinical settings should arguably not be used in place of body‐surface‐area‐based dosing.

Children's Oncology Group's 2023 blueprint for research: Pharmacy

“…Discipline members participate in COG efforts to harmonize protocols across disease states and committees to standardize chemotherapy and supportive care where feasible with the goal of optimizing patient care, minimizing the risk of medication errors, and establishing a treatment standard upon which clinical trials can be designed. Discipline members played an active role in the Chemotherapy Standardization Task Force that developed Solid Tumor and Leukemia Lymphoma Chemotherapy Guidelines and in COG‐led efforts to harmonize complex dosing of carboplatin 7,8 . These guidelines pioneered the development of infant dosing tables that parallel a gradual transition from historic weight‐based dosing (mg/kg) to body surface area‐based dosing (mg/m 2 ) to ensure medications are appropriately dosed on the patient's size while avoiding significant dose adjustments due to slight age, length, or weight changes.…”

“…Pharmacy Discipline impact on Children's Oncology Group (COG) clinical trials.Chemotherapy Guidelines and in COG-led efforts to harmonize complex dosing of carboplatin 7,8. These guidelines pioneered the development of infant dosing tables that parallel a gradual transition from historic weight-based dosing (mg/kg) to body surface area-based dosing (mg/m 2 ) to ensure medications are appropriately dosed on the patient's size while avoiding significant dose adjustments due to slight age, length, or weight changes.…”

Clinical pharmacology of cytotoxic drugs in neonates and infants: Providing evidence-based dosing guidance

“…However, carboplatin dosing based on renal function poses a substantial challenge in neonates and infants because a reliable estimate of GFR is often unavailable. In addition, there is no standardised method of GFR determination across treatment centres, which can lead to marked variations in dose calculation [ 107 ]. Therefore, alternative strategies, such as dosing based on BSA, have been developed, where an AUC of 1.325 mg/mL∗min is typically achieved per 100 mg/m 2 dosed [ 102 ].…”

Over a decade of experience with carboplatin therapeutic drug monitoring in a childhood cancer setting in the United Kingdom

“…This study also highlighted the importance of considering changes in renal function that occur during the first weeks and months of life when dosing with carboplatin, a topic that will be discussed later in this article. While renal function‐based dosing has become a well‐established approach for carboplatin administration, more recently, concerns have been raised about the reliability of GFR estimation, in terms of variability between clinical centres on which carboplatin doses are based 10 . In addition, in a recent study designed to re‐evaluate paediatric carboplatin dosing formulas in patients aged 1–8 years, weight‐based dosing was shown to provide a more feasible alternative to renal function‐based dosing across a range of GFR values 11 .…”

“…While renal function-based dosing has become a well-established approach for carboplatin administration, more recently, concerns have been raised about the reliability of GFR estimation, in terms of variability between clinical centres on which carboplatin doses are based. 10 In addition, in a recent study designed to re-evaluate paediatric carboplatin dosing formulas in patients aged 1-8 years, weight-based dosing was shown to provide a more feasible alternative to renal function-based dosing across a range of GFR values. 11 Table 2 provides examples of carboplatin dosing regimens for a range of tumour types and currently used dose adjustments for neonates and infants.…”