Bisphosphonates for breast cancer.
BACKGROUND
Bone is the most common site of metastatic disease associated with breast cancer, and affects more than half of women during the course of their disease. Bone metastases are a significant cause of morbidity due to pain, pathological fractures, hypercalcaemia and spinal cord compression, and contribute to mortality. Bisphosphonates, which inhibit osteoclast-mediated bone resorption, are standard care for tumour-associated hypercalcaemia, and have been shown to reduce bone pain, improve quality of life, and to delay skeletal events and reduce their number in patients with multiple myeloma. Several randomized controlled trials have evaluated the role of bisphosphonates in breast cancer.


OBJECTIVE
The aim of this systematic review was to identify, describe and summarize high-quality evidence regarding the effect of bisphosphonates on skeletal events, bone pain, quality of life and survival in women with early and advanced breast cancer.


METHODS
Randomized controlled trials were identified in the specialized register maintained by the secretariat of the Cochrane Breast Cancer Group (the search was applied to the databases Medline, Central/CCTR, Embase, CancerLit, and included handsearches from a number of other relevant sources). See: Cochrane Collaboration Collaborative Review Group in Breast Cancer search strategy.


METHODS
Randomized controlled trials evaluating skeletal events in women with metastatic breast cancer and in women with early breast cancer comparing: 1. treatment with a bisphosphonate with the same treatment without a bisphosphonate 2. treatment with one bisphosphonate with treatment with a different bisphosphonate.


METHODS
Studies were selected by two independent reviewers. Studies fulfilling the eligibility criteria were evaluated for quality, particularly concealment of allocation to randomized groups. Data were extracted from the published papers or abstracts independently by the two primary reviewers for each of the specified endpoints (skeletal events, bone pain, quality of life and survival). Data on skeletal events and survival were presented as numbers of events, risk ratios and ratios of event rates. Meta-analyses were based on the fixed-effects model (Mantel-Haenszel). Subjective qualitative ratings were used to summarize the quality of life and pain data.


RESULTS
From 37 reports considered in detail after screening of the 117 reports identified by our search, 19 randomized studies were included. In eight studies that included 1962 women with advanced breast cancer and existing bone metastases, bisphosphonates reduced the risk of developing a skeletal event by 14% (RR 0.86; 95% confidence interval (CI) 0.80-0.91; P < 0.00001). This effect was more modest, but still highly significant if episodes of hypercalcaemia were excluded (6 studies, 1553 women, RR 0.88; 95% CI 0.81-0.96; P = 0.004). For intravenous pamidronate the reduction in the risk of skeletal event was greatest with a dosage of 90 mg (RR 0.77; 95% CI 0.69-0.87). Oral bisphosphonates reduced the risk of a skeletal event by 17% (pooled RR 0.83; 95% CI 0.73-0.94, P = 0.004). Oral clodronate reduced the risk of a skeletal event by 16% in women with advanced breast cancer and clinically evident bone metastases (pooled RR 0.84; 95% CI 0.72-0.98; P = 0.03). Compared with placebo or no bisphosphonate, with bisphosphonates the skeletal event rate was lower in all of eight studies (median reduction of 30%, range 20-48%); statistically significant reductions were reported in six trials (three intravenous pamidronate, two oral clodronate and one intravenous ibandronate). All studies of intravenous pamidronate and oral clodronate in women with advanced breast cancer and clinically evident bone metastases showed significant delays in the median time to a skeletal event. Event-free survival was reported to be longer in women receiving 6 mg of ibandronate compared with control women. Compared with placebo or no bisphosphonate, with bisphosphonates significant improvements in pain were reported in four studies, and improvements in quality of life were reported in two studies. Treatment with bisphosphonates does not appear to affect survival in women with advanced breast cancer. Intravenous zolendronate (4 mg) appeared to have equivalent efficacy when compared with intravenous pamidronate in a single randomized double-blind study. In the three studies of bisphosphonates in 320 women with advanced breast cancer without clinically evident bone metastases, there was no significant reduction in the incidence of skeletal events (RR 0.99; 95% CI 0.67-1.47; P > 0.9). In three studies of oral clodronate that included 1680 women with early breast cancer, there was borderline evidence of a reduction in the risk of developing skeletal metastases (RR 0.73; 95% CI 0.55-0.98; P = 0.04), but there was significant heterogeneity among these studies (P = 0.035). Toxicity or adverse events were described in 14 of the 19 studies. In general, few adverse events were reported.


CONCLUSIONS
In women with advanced breast cancer and clinically evident bone metastases, the use of bisphosphonates (oral or intravenous) in addition to hormone therapy or chemotherapy, when compared with placebo or no bisphosphonates, reduces the risk of developing a skeletal event and the skeletal event rate, as well as increasing the time toskeletal event. Bisphosphonates may also reduce bone pain in women with advanced breast cancer and clinically evident bone metastases. In women with early breast cancer the effectiveness of oral clodronate in reducing the incidence of bone metastases remains an open question for research.
Pavlakis
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Department of Medical Oncology (Faculty of Medicine), Royal North Shore Hospital (University of Sydney), Pacific Highway, St Leonards, NSW, Australia, 2065. pavlakis@med.usyd.edu.au
Stockler
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M
D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D001943:Breast Neoplasms; D004164:Diphosphonates / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D016032:Randomized Controlled Trials as Topic
D000970:Antineoplastic Agents; D004164:Diphosphonates