Although intravenous (i.v.) bisphosphonates are the standard of care for metastatic bone disease, they are less than ideal for many patients due to infusion-related adverse events (AEs), an increased risk of renal toxicity and the inconvenience of regular hospital visits. The use of oral bisphosphonate therapy is limited by concerns over efficacy and gastrointestinal (GI) side effects. There remains a clinical need for an oral bisphosphonate that offers equivalent efficacy to i.v. bisphosphonates, good tolerability and dosing convenience. Oral ibandronate, a highly potent, third-generation aminobisphosphonate, has been evaluated in phase III clinical trials of patients with bone metastases from breast cancer. In two pooled phase III studies, patients with breast cancer and bone metastases were randomised to receive oral ibandronate 50 mg (n ¼ 287) or placebo (n ¼ 277) once daily for up to 96 weeks. The primary end point was the skeletal morbidity period rate (SMPR), defined as the number of 12-week periods with new skeletal complications. Multivariate Poisson's regression analysis was used to assess the relative risk of skeletal-related events in each treatment group during the study period. Oral ibandronate 50 mg significantly reduced the mean SMPR compared with placebo (0.95 vs 1.18, P ¼ 0.004). There was a significant reduction in the mean number of events requiring radiotherapy (0.73 vs 0.98, Po0.001) and events requiring surgery (0.47 vs 0.53, P ¼ 0.037). Poisson's regression analysis confirmed that oral ibandronate significantly reduced the risk of a skeletal event compared with placebo (hazard ratio 0.62, 95% CI ¼ 0.48, 0.79; P ¼ 0.0001). The incidence of mild treatment-related upper GI AEs was slightly higher in the oral ibandronate 50 mg group compared with placebo, but very few serious drug-related AEs were reported. Oral ibandronate 50 mg is an effective, well-tolerated and convenient treatment for the prevention of skeletal complications of metastatic bone disease.

From January 1991 to August 1993,237 women with metastatic breast cancer were recruited into a multicentric phase II clinical trial designed to assess the cardioprotective activity of Cardioxane (ICRF-187). All patients were treated with 5-fluorouracil 500 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m² (FDC) and Cardioxane 1000 mg/m², in cycles repeated every 3–4 weeks. Cardiac functions were assessed at baseline by physical examination, ECG, and resting ultrasound left ventricle ejection fraction (LVEF). The same tests were repeated regularly after the 3rd, 6th, 8th cycle and every additional 100 mg/m² of doxorubicin. At the end of the study there were 212 evaluable patients. Prior to analysis, patients were stratified according to the presence of cardiac risks at study entry. One hundred thirty-three patients (63%) bore one or more cardiac risks. The average total cumulative dose of doxorubicin administered to the group was 311 mg/m² (range: 200–900 mg/m²). Overall response (CR + PR) was 49.5% (105/212), with 12% of patients entering complete remission. General toxicity (WHO grading) was mild and tolerable; no excessive myelosuppression or related symptoms were observed. Three patients from the risk group experienced cardiotoxity, with an LVEF fall below 45%, and had to be removed from the study. Another 3 patients (1 from the risk group) were removed from the study due to clinically documented congestive heart failure after 200, 300 and 400 mg/m2 of doxorubicin. In our study, Cardioxane (ICRF-187) did not influence the antitumor efficacy of FDC chemotherapy, nor did concomitant administration of Cardioxane and chemotherapy result in any other or severer toxicity than that already known for this regimen. Finally, the observation that 51 % of patients with preexisting cardiac risks received doxorubicin at dose range of 450–900 mg/m² without significant clinical or laboratory signs of cardiotoxicity supports the evidence that Cardioxane provided cardiac protection offering the possibility of longer doxorubicin chemotherapy.