Dose-response study of ibandronate in the treatment of cancer-associated hypercalcaemia

Abstract

Summary Hypercalcaemia is an important cause of morbidity in malignant disease. We studied the efficacy and safety of intravenous ibandronate (a new, potent bisphosphonate) in a multicentre study of 147 patients with severe cancer-associated hypercalcaemia which had been resistant to treatment with rehydration alone. Of 131 randomized patients who were eligible for evaluation, 45 were allocated to receive 2 mg ibandronate, 44 patients to receive 4 mg and 42 patients to receive 6 mg. Serum calcium values fell progressively in each group from day 2, reaching a nadir at day 5, and in some patients normocalcaemia was maintained for up to 36 days after treatment. The 2-mg dose was significantly less effective than the 4-mg or 6-mg dose in correcting hypercalcaemia, as the number of patients who achieved serum calcium values below 2.7 mm after treatment was 50% in the 2-mg group compared with 75.6% in the 4-mg group and 77.4% in the 6-mg group (P < 0.05; 2 mg vs others). In a logistic regression analysis, three factors were found to predict response; ibandronate dose (higher doses were more effective), severity of presenting hypercalcaemia (severe hypercalcaemia was associated with less complete response) and tumour type (patients with breast carcinoma and haematological tumours responded better than those with other tumours). Ibandronate was generally well tolerated and no serious drug-related adverse events were observed. We conclude that ibandronate is a safe, well tolerated and effective treatment for cancer-associated hypercalcaemia, which should prove a useful addition to the current range of therapies available to treat this condition.

Is there a dose response relationship for clodronate in the treatment of tumour induced hypercalcaemia?

“…O'Rourke et al (1993) found a differential response rate of only 50% in patients with humoral hypercalcaemia compared to 74% in patients with bone metastases and 100% in myeloma patients (one sixth of patients recruited). This effect has been reported by other studies (Body et al, 1987;Body and Dumon, 1994;Thiebaud et al, 1988;Ralston et al, 1997). In this study, no significant difference in response rate was seen between tumour types and patients with or without bone metastases but the number of patients in each group was small.…”

“…Several studies have explored dose response relationships for different bisphosphonates and degree of hypercalcaemia (Body et al, 1987(Body et al, , 1994(Body et al, , 1999Thiebaud et al, 1988;Nussbaum et al, 1993;Pecherstorfer et al, 1996;Ralston et al, 1988Ralston et al, , 1997. There have been few studies however exploring this dose response relationship for single dose clodronate, the majority of which have involved consecutive daily clodronate infusions rather than single dose comparisons (Adami et al, 1987;Urwin et al, 1987;Bonjour et al, 1988;Kanis et al, 1990).…”

Ibandronate in the treatment of prostate cancer associated painful osseous metastases

“…6 The rationale to use a dose of 6 mg ibandronate derives from the dose -response studies in the treatment of cancer-associated hypercalcemia. 20 -23 These investigations reported on a significantly reduced efficacy to restore normocalcemia in tumors other than breast cancer and hematological tumors since the osteolytic process responsible for hyperclacemia appears to be predominantly humeral in solid tumors; 21 hematological malignancies show mainly local osteolytic mechanisms and breast cancer demonstrates a mixed osteolytic process involved in hypercalcemia. 22,23 These hypothetical findings are paralleled by measurable disturbances in calcium metabolism in patients with PCA.…”

Safety and Convenience of a 15-Minute Infusion of Zoledronic Acid

“…Single doses of ibandronate ranging from 0.2-6 mg via 2-to 4-hour infusions have been investigated in trials involving more than 300 patients [12]. A dose of 4-6 mg ibandronate (via a 2-hour infusion) was required to effectively normalize serum calcium levels in 75%-80% of patients with moderate-to-severe HCM (serum calcium ≥12 mg/dl) [36]. Serum creatinine elevations were reported in <1% of patients treated with ibandronate in those studies [12].…”