Carboplatin-based chemotherapy remains the mainstay of treatment for many patients with gynecologic malignancies. In routine practice, the carboplatin dose is calculated using an estimated creatinine clearance that is derived from formulas that incorporate the patient’s serum creatinine. In the past, multiple assays were used to measure serum creatinine, resulting in considerable interlaboratory variability in the reporting of creatinine values.
In 2006, in an effort to standardize serum creatinine reporting across North America, the National Kidney Disease Education Program published recommendations to recalibrate serum creatinine assays to an isotope dilution mass spectrometry (IDMS) traceable reference method. All laboratories were expected to comply by December 31, 2010. In some patients with normal renal function, the new standardized IDMS method produced creatinine values that were on average 10 to 20 percent lower than older, non-IDMS values. Therefore, in patients with relatively low serum creatinine the IDMS method generated abnormally low values, leading to an overestimation of creatinine clearance and consequently higher calculated carboplatin doses.
Various formulas have been used to estimate renal function. The Cockcroft-Gault equation is the most common formula recommended by pharmaceutical manufacturers to determine drug dosages for patients with impaired renal function. Historically, the Gynecologic Oncology Group (GOG) used a different formula, the Jelliffe equation, to estimate creatinine clearance for carboplatin dosing. Unlike the Cockcroft-Gault formula, the Jelliffe formula does not require the patient’s weight. Both formulas were developed and validated using non-IDMS creatinine values.
More recently, the Modification of Diet in Renal Disease (MDRD) formula was developed to estimate the glomerular filtration rate (GFR) in order to identify patients with early-stage renal impairment. The MDRD-estimated GFR is now commonly reported by many laboratories whenever a serum creatinine is ordered. Numerical values for estimated GFRs greater than 60ml/min/1.73m2 are not reported as the formula was derived in patients with renal impairment. The MDRD formula has been re-expressed using the new IDMS creatinine values but cannot be used for carboplatin dosing as it has not been validated for this purpose.
The Calvert formula incorporates GFR to calculate the patient’s carboplatin dose. Although the creatinine clearance is always slightly higher than the GFR, the two estimates of renal function are used interchangeably in the Calvert formula.
Following the switch to the IDMS method of serum creatinine measurement, the National Cancer Institute's Cancer Therapy Evaluation Program (NCI/CTEP) noted a potential for an increase in carboplatin-related adverse events. This led to the publication of an action letter on guidelines for carboplatin dosing in October 2010.(1) In this action letter, the NCI/CTEP made the following recommendations:
- They advised that the GFR used in the Calvert formula for carboplatin dosing should not exceed 125 ml/min.
- They recommended capping the maximum carboplatin dose based on target area under the curve (AUC).
- Back-conversion of IDMS creatinine to non-IDMS values was NOT permitted for carboplatin dosing
This prompted the GOG to switch from the Jelliffe to Cockcroft-Gault formula for estimation of GFR in carboplatin dosing. The Cockcroft-Gault equation was found to overestimate the creatinine clearance in obese patients or in patients with abnormally low creatinine values. Overestimation of patients’ renal function could result in higher than intended carboplatin doses with a potential for increased toxicity. These concerns for patient safety led the GOG to make further recommendations for carboplatin dosing.(2)
- In patients with abnormally low serum creatinine they recommended using a minimum serum creatinine value of 0.6 mg/dL when estimating GFR. This minimum value was subsequently increased to 0.7 mg/dL to reflect the fact that the newer IDMS values tend to be lower than non-IDMS.
- Surgery and/or aggressive intravenous hydration can lead to artificially low serum creatinine values, so for postoperative patients they indicate that clinicians could consider using a more appropriate (higher) value from the preoperative period when estimating GFR.
- They recommend using an “adjusted” rather than actual body weight in patients who are overweight (those with BMI ≥ 25kg/m2). Actual weight is used for patients with BMI < 25kg/m2
- Patients who have ≥ 10% weight change from baseline or who experience CTCAE ≥ grade 2 renal toxicity (serum creatinine > 1.5 ULN) require recalculation of the carboplatin dose for subsequent cycles.
- In patients who require carboplatin dose modification, if the creatinine at the time of dose modification is lower than the baseline creatinine that was used, they recommend using the prior (higher) creatinine value. If the creatinine at the time of dose modification is higher than the baseline creatinine value, they recommended using the current (higher) value. This is to ensure that patients receive the intended dose reduction.