Carboplatin Dosing on the Basis of Renal Function: 30+ Years after Calvert

Although the pharmacotherapy of cancer has changed dramatically over the past three decades (targeted therapy, immunotherapy, etc.), a study published 35 years ago has influenced carboplatin dosing, remarkably remaining unchanged to this day. Calvert and colleagues performed a co-modeled pharmacokinetic–pharmacodynamic study, which examined carboplatin pharmacokinetics and toxicity (thrombocytopenia). They produced a safe, yet effective formula using the drug concentration/time area under the curve (AUC) and drug clearance to determine carboplatin dosing.¹

In this study, 31 patients received 40 courses of carboplatin therapy. Carboplatin pharmacokinetics were studied, and pharmacokinetic variables were calculated, most notably AUC and total body clearance. Each patient's GFR was measured by determining ⁵¹CrEDTA clearance. It was found that the total body clearance of carboplatin was equal to the GFR (ml/min) (renal clearance) plus 25 ml/min (nonrenal clearance). When the resulting AUC is considered, the formula derived was dose (mg)=target AUC ([mg/ml]×min)×(GFR+25) (ml/min).

For the pharmacodynamic aspect of the study, the major adverse effect of thrombocytopenia was examined. In patients previously treated with chemotherapy, carboplatin prescribed in an AUC range of 4–6 was well tolerated (for previously untreated patients, an AUC range of 5–7). Thus, by measuring the GFR and setting an appropriate AUC, safe and effective carboplatin therapy could be prescribed.

Subsequent to its publication, the Calvert formula has been universally adopted as the optimal strategy for carboplatin dosing regimens. Institutions and various professional societies (e.g., the National Comprehensive Cancer Network²) have incorporated it into their clinical practice guidelines. However, in reality, the Calvert formula has been modified/distorted from the original and advances in nephrology (specifically the assessment of renal function) not accounted for (Figure 1). This perspective will review these developments and suggest changes in the utilization of the Calvert formula.

Figure 1.

Time line of the evolution of the assessment of kidney function (GFR) and the Calvert equation—CKD-EPI is CKD Epidemiology Collaboration. KDIGO, Kidney Disease Improving Global Outcomes.

As previously reviewed, the Calvert formula was derived by measuring the GFR, not the creatinine clearance (CRCL) (or estimated CRCL). Calvert specifically states that in patients who received nephrotoxic chemotherapy previously (e.g., cisplatin) or who exhibit changes in renal function during therapy, the relationship between CRCL and GFR is not valid, and ⁵¹CrEDTA clearance or similar techniques are the method of choice for determining GFR (although pretreatment CRCL might be used for initial dosing in those patients not previously treated with nephrotoxic chemotherapy or who develop changes in renal function during therapy).

Yet in clinical practice (at least in the United States), CRCL (or usually estimated CRCL) is used as a surrogate for GFR. Although CRCL can be measured by obtaining a 24-hour urine collection and serum creatinine, the most common method is to estimate it by using the Cockcroft–Gault equation. However, CRCL is not the GFR because creatinine is both filtered and secreted, with an increasing proportion of its clearance because of secretion with a decreasing GFR. Thus, CRCL may be 10%–40% higher than the GFR as the GFR decreases.³ Subsequently, a carboplatin dose using CRCL will be higher than that obtained using the GFR. The clinical importance of this is clear when one keeps in mind that routine dose changes of 10% or more are deemed clinically important.

Other considerations to bear in mind include changes in the assessment of renal function (GFR), which have appeared subsequent to 1976 (Cockcroft–Gault). The Modification of Diet in Renal Disease equations (1999 and 2006), and CKD Epidemiology Collaboration (CKD-EPI) formulas (2009, 2012, and subsequently 2021) both provide better estimates of the GFR than Cockcroft–Gault.^4,5 The National Kidney Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases both recommend that the CKD-EPI equations (2021 version) be used to estimate the GFR, and the National Kidney Foundation states that CRCL not be used clinically, but only in the research setting. Internationally, Kidney Disease Improving Global Outcomes (KDIGO) also recommends the CKD-EPI formula to estimate GFR.⁶

An additional factor to consider is the creatinine assay currently used in all US clinical laboratories as of the end of 2010. Before the utilization of creatinine assays traceable to isotope dilution mass spectrometry (IDMS), non-creatinine moieties could contribute to detectable creatinine in the serum. With the implementation of the IDMS standardized assay, serum creatinine values decreased an average of 10%–20%, thus elevating Cockcroft–Gault estimated CRCL and subsequent carboplatin doses, even without a real change in renal function. The latest CKD-EPI equations use the current assay so that GFR estimates (and carboplatin doses) are not altered by the change in assay.

With the preceding discussion in mind, it might be asked what the practical relevance of these changes might be in carboplatin dosing? Has the use of the estimated GFR shown to be superior to using estimated CRCL in the setting of carboplatin dosing using the Calvert formula and real clinical (carboplatin pharmacokinetic) data? One study best answers this question.⁷

Carboplatin pharmacokinetic data obtained from studies of 491 patients with cancer were used in this study, specifically the measured carboplatin clearance. The measured carboplatin clearance was then compared with the predicted carboplatin clearance as gauged by the Calvert formula (five formulas for estimated GFR) and two other formulas for estimating carboplatin clearance (non-Calvert). The criteria examined and compared for the actual measured and predicted measured carboplatin clearance were mean percentage error, mean absolute percentage error, and percentage of patients with a prediction error above 20% (P20).

Although the mean absolute percentage error and P20 were the lowest using the Calvert/CKD-EPI cystatin formula, among the formulas using only creatinine (cystatin C not commonly measured in clinical laboratories), the Calvert CKD-EPI and Calvert–Janowitz formulas were the best. The authors concluded, “The Calvert CKD-EPI equation seems to be the most suitable creatinine-based formula to predict carboplatin clearance homogeneously in all subgroups of patients.” It should be noted that because this study was published in 2020, it did not include the most recent iteration of the CKD-EPI equations, CKD-EPI 2021, which does not include a race coefficient. However, data from a study of a multiracial cohort of 1200 adults with solid tumors support the application of CKD-EPI 2021 equations in assessing GFR and demonstrated its superiority over CRCL (Cockcroft–Gault). The authors concluded that the use of CKD-EPI 2021 was acceptable when compared with the previous CKD-EPI equations.⁸

Although this perspective specifically deals with carboplatin dosing, it should be acknowledged that it might also apply to the dosing of other chemotherapeutic drugs (Table 1) and all medications whose clearance is dependent on kidney function (GFR). The National Kidney Foundation, the National Institute of Diabetes and Digestive and Kidney Diseases, and KDIGO all advocate using estimated GFR and not CRCL. KDIGO more than 10 years ago stated that CRCL/Cockcroft–Gault cannot be used for drug dosing, shortly after widespread adoption of IDMS referenced creatinine assays.

Table 1.

Chemotherapeutic agents whose dosing is dependent on kidney function (GFR)

Timetable
Anthracyclines (except doxorubicin)
Bleomycin
Carboplatin
Cisplatin
Cladribine
Clofarabine
Dacarbazine
Eribulin
Etoposide
Fludarabine
Ifosfamide
Irinotecan
Mercaptopurine
Methotrexate
Oxaliplatin
Pemetrexed
Topotecan

Data supporting actual measurement of GFR, as opposed to the use of the Cockcroft–Gault formula, in carboplatin dosage determination concluded that a measured GFR avoided under or overdosing carboplatin and was the preferred method.⁹

The American Society of Nephrology in its 2022 annual meeting had a session advocating and explaining how to incorporate GFR measurement into clinical practice (https://www.asn-online.org/education/kidneyweek/2022/program-session-details.aspx?sessId=419156). Another session described measuring GFR by transdermal detection of a fluorescent GFR tracer agent, relmapirazin (https://www.asn-online.org/education/kidneyweek/2022/program-abstract.aspx?controlId=3766355).

Multiple international societies, including KDIGO and the National Cancer Institute's Organ Dysfunction Working Group, have developed the International Consensus Guideline on Anticancer Drug Dosing in Kidney Disease. It specifically recommends estimation of GFR using the CKD-EPI formula, and eGFR guidance of dosing for drugs where dose depends on kidney function (in the absence of a measured GFR) (https://www.eviq.org.au/clinical-resources/addikd-guideline/4174-anticancer-drug-dosing-in-kidney-dysfunction). Actual measurement of GFR is recommended in certain situations, including extremes in patient body composition, for example, size, muscle mass, amputation, paraplegia, and eGFR <45 ml/min per 1.73 m².

To summarize, there have been many developments in nephrology and oncology since the publication 35 years ago of the Calvert formula. Recommended carboplatin dosing strategies should reflect and incorporate these changes for optimal patient care. A measured GFR or estimated GFR using the CKD-EPI formulas (routinely reported by clinical laboratories) should be used in dosing carboplatin.

Disclosures

The author has nothing to disclose.

Funding

None.

Author Contributions

Conceptualization: Michael H. Schwenk.

Data curation: Michael H. Schwenk.

Formal analysis: Michael H. Schwenk.

Investigation: Michael H. Schwenk.

Methodology: Michael H. Schwenk.

Project administration: Michael H. Schwenk.

Resources: Michael H. Schwenk.

Software: Michael H. Schwenk.

Supervision: Michael H. Schwenk.

Validation: Michael H. Schwenk.

Visualization: Michael H. Schwenk.

Writing – original draft: Michael H. Schwenk.

Writing – review & editing: Michael H. Schwenk.