Academic Unit of Clinical Oncology, Yorkshire Cancer Research Centre, Weston Park Hospital, Sheffield, UK
* Correspondence to: Dr R. E. Coleman, MD, Academic Unit of Clinical Oncology, Yorkshire Cancer Research Centre, Weston Park Hospital, Whitham Road, Sheffield S10 2SJ, UK. Tel: +44-114-226-5213; Fax: +44-114-226-5678; Email: r.e.coleman{at}sheffield.ac.uk
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Abstract |
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Key words: bisphosphonates, bone metastases, pamidronate, placebo, skeletal complications, zoledronic acid
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Introduction |
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Bisphosphonates for the treatment of bone metastases |
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The clinical benefits of bisphosphonate therapy have been evaluated in a large number of clinical trials designed to capture data on skeletal complications (Table 1) [8, 14
23
]. The majority of these trials have used a composite end point defined as a skeletal-related event (SRE) or bone event, which includes pathologic fracture, radiation therapy for bone pain or to treat or prevent a fracture, surgery to stabilize bone fractures, spinal cord compression and HCM. Such composite end points capture data on all clinically relevant events and are more likely to detect therapeutic benefits when treatment effects and disease morbidity are multifaceted [24
].
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In contrast, multiple analyses account for non-constant event rates and are able to model all events and the time between events. Therefore, multiple event analyses are able to account for inter- and intrapatient variations in event rates and provide a statistically robust and comprehensive assessment of skeletal morbidity throughout the entire length of follow-up [28]. Andersen-Gill multiple event analysis calculates a hazard ratio that indicates the risk of skeletal events between two treatment groups. A hazard ratio <1 indicates a favourable treatment effect. Recently, non-parametric methods for multiple event analysis have also been described by Ghosh and Lin [29
] and by Cook and Lawless [30
]. These models calculate the cumulative incidence of skeletal complications and allow for right-censored data, thus accounting for death or study discontinuation for other reasons. Collectively, both first-event and multiple-event statistical analyses provide sensitive and comprehensive assessments of the clinical benefit of bisphosphonates in patients with bone metastases.
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Bisphosphonates approved for the treatment of bone metastases from breast cancer |
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Oral clodronate
The safety and efficacy of oral clodronate (1600 mg/day) were evaluated in a double-blind, placebo-controlled trial that enrolled 173 patients (Table 2) [14, 33
]. This study assessed the number of HCM episodes, courses of radiotherapy to bone, and pathologic fractures (expressed as events per 100 patient-years). After a median follow-up of approximately 14 months, there was no statistical difference between treatment groups in the percentage of patients with either HCM, radiotherapy to bone, or fractures. In contrast, clodronate compared with placebo significantly reduced the event rate for HCM (P <0.01), vertebral fractures (P <0.025), vertebral deformity (P <0.001), and the combined event rate for all events (218.6 versus 304.8 events per 100 patient-years; P <0.001). However, the statistical methodology used in this trial has been criticised because of the potential for overestimation of treatment effects [34
]. This is a particular concern given that the majority of patients died before they completed the 18-month study. Time to first SRE was later updated by Pavlakis and Stockler [33
] based on an analysis of 185 patients. In the updated analysis, time to first bone event was significantly delayed (9.9 months for the clodronate group versus 4.9 months for placebo; P=0.022).
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Intravenous pamidronate
The efficacy and safety of i.v. pamidronate (90 mg via 2 h infusion every 34 weeks) for the treatment of bone metastases secondary to breast cancer were established in the mid 1990s based on two large multicentre, randomised, placebo-controlled trials involving 754 patients [17, 18
]. These trials each individually showed that pamidronate significantly reduced the incidence and delayed the onset of SREsdefined as pathologic fractures, spinal cord compression, surgery to treat or prevent fractures, HCM, and need for radiation to bonecompared with placebo [17
, 18
]. In the study reported by Hortobagyi et al. [17
], pamidronate delayed SREs for up to 24 months in patients with breast carcinoma and osteolytic lesions receiving chemotherapy. Likewise, in the study reported by Theriault et al. [18
], pamidronate significantly delayed and reduced SREs in patients receiving hormonal therapy. A pooled analysis of these trials at 2 years follow-up demonstrated that pamidronate significantly reduced the percentage of patients with
1 SRE (51% versus 64% for placebo; P <0.001), extended the median time to first SRE by nearly 6 months (12.7 versus 7.0 months for placebo; P <0.001), and reduced the mean skeletal morbidity rate (2.5 versus 4.0 SREs/year for placebo; P <0.001; Table 3) [8
]. Pamidronate also significantly improved bone lesion response (32% versus 22% for placebo; P=0.002) and significantly reduced pain scores (P=0.015) compared with placebo. Given these results, which are based on conservative clinical end points, i.v. pamidronate quickly became established as the international standard of care for women with bone metastases from breast cancer.
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Pamidronate has also been shown to be effective in delaying the time to progression of bone lesions in 295 women treated with either 45 mg pamidronate or placebo via 1 h infusion every 3 weeks (median, 249 days versus 168 days for placebo; P=0.02) [19]. This study also showed that significantly more patients treated with pamidronate reported decreased pain (44% versus 30% for placebo; P=0.025). Skeletal-related events were not assessed in this study.
Intravenous zoledronic acid
Zoledronic acid has been compared directly with pamidronate and was shown by multiple-event analysis to be significantly more effective at reducing the risk of SREs among breast cancer patients (Table 4) [3537
]. Zoledronic acid reduced the risk of developing an SRE by an additional 20% over that achieved with pamidronate (P=0.025) and by an additional 30% in patients receiving hormonal therapy (P <0.01).
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Summary of clinical trials |
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Effects on pain
Several bisphosphonate trials have reported statistically significant improvements in pain compared with placebo [33], and bisphosphonates reduce the need for radiotherapy to bone, which serves as a surrogate for bone pain. In a systematic review of 25 randomised trials in metastatic breast cancer in which pain was evaluated, bisphosphonates generally had a beneficial effect [41
]. The recent trial of zoledronic acid in Japanese women provides the most comprehensive evaluation of change from baseline score across time using the Brief Pain Inventory. Zoledronic acid consistently reduced bone pain from baseline at every monthly evaluation throughout the 12-month study [23
]. Currently, however, there is insufficient evidence to recommend bisphosphonates as first-line therapy for the treatment of bone pain [42
], and the American Society of Clinical Oncology guidelines recommend that the current standard of care for cancer pain should not be displaced by bisphosphonates [43
]. Nevertheless, bisphosphonates are an important adjunct to analgesics and/or radiotherapy for the management of painful bone metastases.
Quality-of-life benefits
Bone pain and skeletal morbidity can lead to a rapid decline in a patient's quality of life (QoL). Therefore, reducing skeletal complications and improving a patient's QoL are intimately linked. Current data suggest that bisphosphonates can result in improvements in QoL or reduce declines in QoL in patients with metastatic breast cancer [41]. For example, a significant improvement in QoL was demonstrated for patients treated with 6 mg ibandronate for 96 weeks compared with placebo [44
]. In a study by Weinfurt et al. [45
], women receiving zoledronic acid or pamidronate for the prevention of SREs experienced an overall increase in health-related QoL scores. Collectively, these studies suggest that bisphosphonate therapy may have previously unappreciated benefits in terms of improved QoL during the course of treatment.
Effects on biochemical markers of bone metabolism
Bisphosphonates have profound effects on bone cell function that can be monitored using specific biochemical markers. In particular, markers of type 1 collagen breakdown have been evaluated in an attempt to both predict clinical outcome and identify a surrogate marker for individual patient benefit. Early small studies suggested a link between bone resorption rates and both pain relief [46] and the risk of fracture [47
] during treatment with pamidronate. Subsequently, a larger study in bisphosphonate-naïve patients demonstrated a rapid increase in the relative risk of an SRE in patients with elevation of the resorption marker, urinary n-telopeptide (NTX), suggesting it may be possible to identify a population of patients at increased risk for skeletal complications [48
]. More recently, evidence from the large phase III trials of zoledronic acid has confirmed the relationship between bone resorption (as measured by urinary NTX) and skeletal morbidity, disease progression and death across a broad range of tumours affecting bone both with [49
] and without [50
] concomitant bisphosphonate treatment. The potential use of biochemical markers to refine the selection of patients for bisphosphonate treatments, and optimise both the schedule of administration and cost-effectiveness of bisphosphonate therapy is a current area of active research.
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Antitumour effects of bisphosphonates |
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Strategies for cost effectiveness and economic implications of bisphosphonate treatment |
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A recent systematic review of the cost effectiveness of bisphosphonates for the treatment of SREs found no cost effectiveness analyses for HCM. However, based on expert opinion the review suggested that it is more cost effective to prevent HCM than to treat HCM because of the extended hospitalization time associated with the treatment [59]. Bisphosphonates are highly effective agents for the prevention of HCM and, therefore, could be expected to reduce these costs. Similarly, these analyses suggest that bisphosphonates appear to be more cost effective for the prevention of skeletal morbidity in breast cancer patients with bone metastases because these patients have a high incidence of SREs.
In conclusion, bisphosphonates clearly improve selected outcomes in women with metastatic breast cancer and appear to be cost effective. Further study is needed, given the complexities of cancer treatment, to assess comprehensively the cost effectiveness of bisphosphonates and to determine the best use of finite health care resources.
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Conclusions |
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Received for publication October 26, 2004. Revision received January 4, 2005. Accepted for publication January 7, 2005.
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