Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer

Abstract

Bone metastases occur in most women with advanced breast cancer and can lead to considerable morbidity and a rapid deterioration in the patient's quality of life. It was the aim of the present study to assess changes in quality of life and bone pain due to intravenous (i.v.) ibandronate, a potent third-generation bisphosphonate. In a phase III randomised, double-blind, placebo-controlled trial in patients with bone metastases due to breast cancer, 466 women were randomised to receive placebo, 2 mg ibandronate or 6 mg ibandronate for up to 96 weeks. Treatment was administered i.v. at 3- or 4-weekly intervals. Clinical endpoints included the incidence of adverse events, quality of life (assessed using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Scale – Core 30 questionnaire (QLQ-C30)), and bone pain (assessed on a 5-point scale from 0=none to 4=intolerable). Ibandronate was generally well tolerated. Compared with baseline measurements, the bone pain score was increased at the last assessment in both the placebo and 2 mg ibandronate groups, but was significantly reduced in the patients receiving 6 mg ibandronate (−0.28 ± 1.11, P<0.001). A significant improvement in quality of life was demonstrated for patients treated with ibandronate (P<0.05) for all global health status. Overall, at the last assessment, the 6 mg ibandronate group showed significantly better functioning compared with placebo (P=0.004), and had significantly better scores on the domains of physical, emotional, and social functioning, and in global health status (P<0.05). Significant improvements in the symptoms of fatigue and pain were also observed in the 6 mg ibandronate group. I.v. ibandronate treatment leads to significant improvements in quality of life, and is an effective and well-tolerated palliative treatment in patients with bone metastases due to breast cancer.

Introduction

Bone metastases occur in up to 80% of women with advanced breast cancer [1], [2]. This leads to major skeletal complications including bone pain, fractures and hypercalcaemia. Combined, these manifestations can cause significant morbidity and deterioration in the patient's quality of life. The management of the secondary complications of metastatic breast cancer is therefore important from patient welfare and societal care perspectives [3], [4], [5].

Treatment options in metastatic bone disease can be divided into local (irradiation and surgery) or systemic (hormone therapy, chemotherapy and bisphosphonates) treatments. The primary goal of antiosteolytic treatment with bisphosphonates is the reduction of skeletal-related complications such as hypercalcaemia, pathological fractures and spinal cord compression [6]. These effects are mainly achieved by the osteoclast-inhibiting property of bisphosphonates, and possibly by a direct anti-tumour action. Bisphosphonates are a class of pyrophosphate analogues characterised by a central PCP backbone. Bisphosphonates bind strongly on bone surface, particularly in zones with activated turnover. Incorporated into osteoclasts (or other cells), bisphosphonates may induce apoptotic or necrotic cell death [7], [8].

Oral (p.o.) (e.g. clodronate) and intravenous (i.v.) (e.g. pamidronate) bisphosphonates are currently the standard treatment for metastatic bone disease due to breast cancer. Bisphosphonates are known to delay skeletal-related events and improve bone pain, and may also be expected to improve overall quality of life [9], [10], [11], [12], [13]. However, there is limited data on this latter point as few studies have directly measured the effects of bisphosphonate treatment on quality of life. Furthermore, previous studies that incorporated these measurements, have generally failed to show a direct correlation between reduction in skeletal events and improved quality of life [11], [13]. Therefore, to improve overall quality of life in patients with metastatic bone disease, additional issues may be important. These could include improvement of other disease symptoms, overall functioning, and ease of therapy administration.

Ibandronate is a potent, third-generation bisphosphonate that is effective in the treatment of hypercalcaemia of malignancy [14], [15], [16]. Ibandronate has also been evaluated in patients with metastatic bone disease due to breast cancer. A phase II dose-finding study indicated that i.v. doses of 2 and 6 mg, once every 4 weeks, were effective and sufficiently well tolerated for further evaluation [15], [17]. A subsequent phase III study was initiated to evaluate the tolerability and efficacy of i.v. ibandronate administered at 2 and 6 mg, once every 3 or 4 weeks, for at least 60 weeks. Primary efficacy results from this study have recently been reported [18]. Treatment with 6 mg ibandronate was associated with significant clinical benefits. In addition to reducing the rate of skeletal complications, the 6 mg dose extended the time to the first skeletal event by more than 4 months.

Since reducing the incidence of skeletal events and minimising bone pain would be expected to lower disease burden, we report secondary efficacy results from the phase III study to assess the effect of ibandronate on the patient's quality of life.