Evaluation of a 24-hour infusion of etidronate disodium for the treatment of hypercalcemia of malignancy.

Abstract

Hypercalcemia is a serious and common complication of malignancy. Etidronate, a known inhibitor of osteoclastic bone resorption, is approved in the therapy of hypercalcemia of malignancy (HCM) at a dose of 7.5 mg/kg/day infused during a period of 2-4 hours on 3 consecutive days. A multicenter study was conducted to evaluate the safety and efficacy of a single 24-hour infusion of etidronate disodium in patients with HCM. Selected patients with HCM had disease refractory to at least 24-hours of intravenous fluid (more than 3 l/day) with two albumin-adjusted serum calcium concentrations greater than 11.5 mg/dl drawn 24 hours apart before etidronate treatment. Thirty patients were enrolled; 13 received 25 mg/kg for 24 hours, 12 received 30 mg/kg for 24-hours, 3 received incorrect doses (2 overdoses, and 1 underdose) and 2 died of disease-related complications before day 7. Of the 25 evaluable patients, 15 were men and 10 were women. Median age was 53 years (range, 20-75 years). Twelve patients (6 in each treatment group) had confirmed skeletal metastases. During the week after treatment, the 25 mg/kg group had adjusted serum calcium levels fall from a mean preinfusion baseline of 13.3 +/- 0.3 mg/dl (plus or minus the standard error of the mean) to a mean nadir of 10.9 +/- 0.4 mg/dl (the average of each patient's lowest calcium values). The 30 mg/kg group had adjusted serum calcium levels fall from a mean preinfusion baseline of 13.8 +/- 0.4 mg/dl to a mean nadir of 10.5 +/- 0.3 mg/dl. The average day that nadir occurred was day 5.7 for the 25 mg/kg group and day 5.6 for the 30 mg/kg group. The mean maximum reduction (delta) derived from the patients' nadirs in the 25 mg/kg dose group was 2.5 +/- 0.4 mg/dl and 3.3 +/- 0.3 mg/dl for the 30 mg/kg dose. Time to effect (either a partial response defined as a 15% or greater decrease in the adjusted serum calcium from the preinfusion value or a complete eucalcemic response defined as a reduction to the laboratory's eucalcemic range) occurred on average on day 4.6 in the 25 mg/kg group and day 3.7 in the 30 mg/kg group. Nine of the 13 (69%) patients in the 25 mg/kg treatment group had either partial or complete response to the 24-hour infusion. Five of these patients (38% of the 13 patients) of the 25 mg/kg group had serum calcium levels fall to their laboratory's eucalcemic range before day 7 (a complete response), 4 (31%) had partial response only, and 4 had no response. In the 30 mg/kg group, 11 of 12 (92%) patients had at least partial responses. Eight of the 12 (67%) patients had adjusted serum calcium concentrations fall to the eucalcemic range by day 7, 3 (25%) had a partial response, and 1 had no response. Reported adverse experiences generally were attributable to the underlying disease. The reduction in the serum calcium throughout the week for the 30 mg/kg dose group was significantly greater than that for the 25 mg/kg group (analysis of variance, P < 0.0001). Etidronate, when administered intravenously at 30 mg/kg during a period of 24 hours, apparently was safe and effective in this study for treatment of hypercalcemia in patients with a wide variety of tumor types. This regimen may offer a more convenient method of administration than does standard etidronate therapy for the treatment of HCM.