Safety and Survival Outcomes in Lung Cancer Patients Receiving Carboplatin: Impact of Uncapped Dosage

The prescription of carboplatin is commonly based on the Calvert formula, and low serum creatinine values can lead to an overestimation of the glomerular filtration rate and of the carboplatin dose. Limited data recommend to cap carboplatin dose at 800 mg, but the risk of suboptimal carboplatin dose is concerning. This study compared hematologic toxicity occurrence and survival outcomes in lung cancer patients receiving carboplatin &#x3e; or &#x3c;800 mg based on the Calvert formula (target area under the curve = 5 mg/mL min). Our results show more severe cytopenia in patients receiving carboplatin &#x3e;800 mg with significant difference for all grades of thrombocytopenia in the uncapped group (37% patients vs. 3%, <i>p</i> = 0.02). For metastatic non-small-cell lung cancer patients, we also observed hematologic toxicity in the uncapped group with more severe anemia (30% of patients vs. 0%, <i>p</i> = 0.03) and all grades of thrombocytopenia (39 vs. 0%, <i>p</i> = 0.02) than the capped group. Concerning the secondary endpoint, we obtained a trend of lower progression-free survival and overall survival in patients receiving carboplatin &#x3e;800 mg, but no significant difference appears for the both survival criteria. This study aims to improve the determination of carboplatin dosage to know the real impact of carboplatin capping and to find the optimum balance between excessive toxicity and substandard therapeutics outcomes.

Cisplatin and carboplatin pharmacokinetics in a pediatric patient with hepatoblastoma receiving peritoneal dialysis

Purpose Cisplatin and carboplatin are frequently used drugs in the treatment of pediatric hepatoblastoma. Dosing guidelines for these drugs in children requiring peritoneal dialysis are lacking. Here, we describe the case of a 3-year-old boy with pre-existing end-stage renal disease on peritoneal dialysis, requiring treatment with cisplatin and carboplatin for hepatoblastoma. Methods Pharmacokinetic data were generated to support clinical dosing decisions, with the aim of adequate exposure and minimal toxicity. In the first chemotherapy cycle, 25% of the standard cisplatin dose and 75% of the carboplatin dose, calculated using the pediatric Calvert formula, were administered. Free platinum concentrations were determined in plasma ultrafiltrate and dialysate samples drawn after administration of cis- and carboplatin. Results Cisplatin was well tolerated and the observed AUC of cisplatin were 15.3 and 14.3 mg/L h in cycles 1 and 3, respectively. The calculated AUC of carboplatin in cycle 1 (9.8 mg/mL min) exceeded target AUC of 6.5 mg/mL min and toxicity was observed; therefore, the dose was reduced in cycles 2 and 3. The observed AUC in cycles 2 and 3 was 5.4 and 5.7 mg/mL min respectively. Platinum concentrations in the dialysate showed that 3–4% of the total dose of cisplatin and 10–12% of the total dose of carboplatin were excreted via peritoneal dialysis. Chemotherapy enabled extended hemihepatectomy and complete remission was achieved. Conclusion This report shows that it is feasible to measure AUCs for both drugs and to individualize the dose of these drugs according to the PK results and clinical parameters. Our advice for future cases would be to calculate the starting dose of carboplatin using the (pediatric) Calvert formula, assuming a dialytic clearance of zero, and to adjust the dose if required, based on therapeutic drug monitoring.

Analysis of carboplatin dosing in patients with a glomerular filtration rate greater than 125 mL/min: To cap or not to cap? A retrospective analysis and review

The use of the Calvert formula to calculate carboplatin doses allows clinicians to achieve the appropriate carboplatin area under the concentration (AUC) curve. Thrombocytopenia is the dose limiting toxicity of carboplatin and optimizing AUC minimizes the risk of thrombocytopenia. Carboplatin clearance directly correlates with glomerular filtration rate (GFR) and, therefore, an accurate estimation of the renal function is needed. The Calvert formula was designed using the GFR measured by 51Cr-EDTA; however, many clinicians substitute estimated creatinine clearance (CrCl) as calculated by the Cockcroft–Gault (C–G) equation. The potential for overestimating AUC occurs when clinicians substitute actual weight in obese patients or use a low serum creatinine when calculating C–G estimated CrCl. In 2010, the National Cancer Institute recommended the GFR value within the Calvert formula should not exceed 125 mL/min, thereby capping the carboplatin dose. However, there are studies demonstrating that certain patients’ actual GFR values do exceed 125 mL/min. Therefore, capping the carboplatin dose in these patients may lead to underestimating the carboplatin AUC. A single-center, retrospective study was performed to evaluate the change in platelet count pre- and post-carboplatin exposure in patients with C–G estimated CrCl greater than 125 mL/min receiving capped versus uncapped carboplatin doses. A review of carboplatin dosing strategies is also presented. This study indicated there was a larger mean difference in pre- and post-platelet count in patients receiving uncapped carboplatin compared to patients receiving capped carboplatin with no differences in toxicities. Dose capping this patient population will likely lead to a lower AUC rather than the intended AUC target, which could ultimately lead to substandard outcomes.

Evaluation of carboplatin toxicities and efficacy using different body weight descriptors in the Calvert formula.

e14017 Background: Carboplatin dosing is calculated using the Calvert formula that includes glomerular filtration rate (GFR). In practice, GFR is often substituted by creatinine clearance (CrCl) with the Cockcroft-Gault (CG) equation. However, there is no standardization of which body weight descriptors should be utilized. Data suggest use of total body weight (TBW) may overestimate CrCl in overweight patients, while adjusted body weight may better estimate CrCl. The primary objective is to determine the impact of using different weight descriptors (DWD) in place of TBW for carboplatin dosing. Methods: This was a single-center, retrospective cohort study. Patients over 18 who were intended to receive at least 6 cycles of carboplatin with target area under the curve (AUC) of 5 or 6 and paclitaxel 175 to 225 mg/m2 were included. DWD included: adjusted body weight for overweight and obese patients, ideal body weight for normal weight patients and TBW for underweight patients. Primary endpoint was the composite of grade 3 or 4 anemia, thrombocytopenia and neutropenia (hematologic toxicity). Secondary endpoints included individual parameters of the primary endpoint, dose delays, dose reductions, progression-free survival, overall survival and objective response rate. Results: A total of 117 patients were included (DWD: n = 39; TBW: n = 78). Results on survival analysis, anemia and dose reductions are pending. Conclusions: To our knowledge, this is the first evaluation of patient outcomes specifically comparing carboplatin dosing calculations. Although there is a trend toward decreased grade 3 and 4 hematologic toxicities in the DWD group, there is no statistically significant difference in this under powered cohort. However, there was a significant decrease in treatment delays and days of treatment delay (p < 0.001) in the DWD group. Further studies are needed to evaluate the impact of DWD on carboplatin dosing. [Table: see text]