Carboplatin's fourth decade: still searching for its sweet spot.

Carboplatin, also called JM8, was characterized in preclinical testing in the 1970s as being potentially less nephrotoxic and emetogenic that cisplatin. Initial phase I studies were done with dose escalations calculating the dose based on body surface area and defined dose-limiting toxicity at a dose of ∼400 mg/m 2 every 21–28 days as myelosuppression, predominantly thrombo-cytopenia, but which was dependent on patients' renal function [1, 2]. The dosing of carboplatin in clinical practice was rendered unique by the work of Hilary Calvert and others in producing a nomogram for dosing the drug based on myelosup-pression and renal function [3]. This has been widely adopted so that most oncologists using carboplatin formulate dose based on a calculated area under the concentration/time curve (AUC; milligrams of carboplatin per ml/min derived from the patient's renal function rather than based on calculated body surface area as is the norm for most cytotoxic drugs). Many oncologists used and still use other formulae to calculate the creatinine clearance incorporating serum creatinine, weight and age. This approach was promoted using 'chemotherapy calculation slide rules' in the 1980s with transition to online calculators more recently. Some oncolo-gists do a more formal and accurate measurement of the creatinine clearance using a 24-h urine collection or using the radionuclide-labeled ligand such as [ 99M ]Tc-DTPA to assess glomerular filtration rate (GFR) method to place into the Calvert formula but these are more costly and logistically difficult for the patient. The work by Calvert and colleagues defined the risk of significant thrombocytopenia in single-agent carboplatin doses designed to produces AUCs in the range from 4–6 and 6–8 mg/ml for patients with a measured GFR range of 33–135 ml/min. Doses of carboplatin are calculated in milligrams by adding 25 to the GFR and then multiplying by the target AUC. Before this work, trials had been designed to test the substitution of carboplatin 500 mg/m 2 (generally equivalent to target AUC in the lower 4–6 mg/ml range) in each cycle for cisplatin combined with eto-poside in regimens for advanced germ-cell tumors. The carbo-platin regimen was definitively inferior for relapse-free survival in good risk category advanced patients [4], leaving cisplatin as the standard. Despite this carboplatin was developed in combination with etoposide in higher dose protocols (carboplatin 2100 mg/m 2 or AUC target 21–24 mg/ml in three divided doses on three successive days every 14–21 days) for poor risk and relapsed patients with positive …