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Use of bisphosphonates in women with breast cancer |
Warr D, Johnston M, Breast Cancer Disease Site Group |
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CRD summary This review assessed bisphosphonates for women with breast cancer. The authors concluded that bisphosphonates did not improve survival but did reduce pain and skeletal problems in women who have had bone metastases. There was no evidence that bisphosphonates benefited women who had breast cancer without bone metastases. Based on the evidence presented, the conclusions are probably reliable. Authors' objectives To assess whether bisphosphonates should be used in women with breast cancer. Searching The authors searched MEDLINE (from 1976 to February 2004), the Cochrane Library (Issue 1, 2004), conference proceedings of the American Society of Clinical Oncology (1997 to 2003) and the San Antonio Breast Cancer Symposium (2001 to 2003), and bibliographies. The search terms were reported and the searches were not restricted by language. Study selection Study designs of evaluations included in the reviewRandomised controlled trials (RCTs) and trial data from meta-analyses were eligible for inclusion. Specific interventions included in the reviewStudies were eligible for inclusion if they compared bisphosphonate treatment with placebo or no treatment, different bisphosphonates, or different doses or routes of administration of the same bisphosphonate. Clodronate, pamidronate, ibandronate and zoledronate were used in the included studies. The treatment regimens varied between trials. Zoledronate was administered intravenously; the other drugs were administered intravenously or orally. Participants included in the reviewStudies were eligible if they included mainly patients (male or female) with early stage or advanced breast cancer. Eligible studies could also have included patients with other solid tumours or myeloma, as long as they were not the majority. The included studies were of women with bone metastases due to breast cancer, women with locally advanced breast cancer or breast cancer metastatic to sites other than bone, or women with early breast cancer. Outcomes assessed in the reviewStudies were eligible for inclusion if they reported survival, quality of life, or adverse effects. Other outcomes were bone pain, skeletal events other than hypercalcaemia, and the development of bone metastases in patients with no diagnosis at trial entry. Bone pain was measured on a pain scale or by analgesic consumption. How were decisions on the relevance of primary studies made?The authors did not state how the papers were selected for the review, or how many reviewers performed the selection. Assessment of study quality The authors did not state that they assessed validity. This review was developed using the Practice Guidelines Development Cycle (see Other Publications of Related Interest nos.1-2). Data extraction The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. The data extracted for an analysis of survival were the number of patients who died and the number randomised. Data on skeletal event rates, median time to skeletal event, and median survival time from trials included in an existing meta-analysis were extracted from the original report (see Other Publications of Related Interest no.3). Other outcomes data were extracted from individual trial reports. Methods of synthesis How were the studies combined?The authors used the existing meta-analysis (see Other Publications of Related Interest no.3) to reanalyse survival data in the patient groups of interest; a fixed-effect model was used to be consistent with the original analysis. A narrative synthesis was used for the other findings. How were differences between studies investigated?Sensitivity analyses were performed by separating trials in advanced breast cancer from those in patients with and without bone metastases. In the narrative synthesis of outcomes in women with bone metastases, the studies were grouped according to the review question addressed and tabulated by the specific intervention. Differences in the route, dose, frequency and planned duration of treatment, and the assessment of pain relief, were also tabulated. Results of the review Twenty-eight RCTs in patients with bone metastases from breast cancer (5,417 evaluable patients), three in locally advanced or extraskeletal disease (320 evaluable patients) and three in early stage disease (1,653 evaluable patients) were included. Nineteen of these trials had been summarised in an existing meta-analysis of women with breast cancer (see Other Publications of Related Interest no.3). Oral clodronate and intravenous pamidronate significantly reduced skeletal events and pain in women with breast cancer metastatic to bone. Direct comparisons found 4 mg zoledronate equivalent to 90 mg pamidronate given intravenously every 3 to 4 weeks. There was no significant difference in adverse effects between those receiving bisphosphonates and controls. However, bisphosphonates did not prolong survival in patients with bone metastases. There was no evidence that bisphosphonates reduce skeletal events in patients with locally advanced breast cancer or breast cancer that is metastatic to sites other than bone. Detailed analyses, broken down by type of bisphosphonate and bisphosphonate comparisons, were reported in the review. Cost information None. However, references for four relevant economic analyses were given. Authors' conclusions Bisphosphonates did not improve survival but did reduce skeletalevents and pain in women with breast cancer metastatic to bone. There was no evidence that bisphosphonates reduce skeletal events in locally advanced breast cancer or breast cancer that is not metastatic to bone. CRD commentary This review had clear research questions and inclusion criteria. Several relevant sources were searched to identify trials, without inherent language bias in the strategy. The report did not provide reassurance that the study selection process was unbiased, nor did it provide any information to enable a judgement of the quality of the included trials. Pertinent study characteristics were presented with further details in the narrative synthesis. The use of an existing Cochrane Review as the basis for the sensitivity meta-analysis seemed sensible, and the quality of those trials might have been more assured. The data presented appeared to support the authors' conclusions. Implications of the review for practice and research Practice: The authors stated that women with breast cancer and bone metastases who are expected to survive more than 6 months should be offered oral clodronate or intravenous pamidronate or zoledronate. Zoledronate may be favoured over pamidronate if a shorter infusion time is preferable. Bisphosphonates are not recommended for the prevention of bone metastases or to improve survival in women with locally advanced breast cancer or non-skeletal metastases. There was insufficient evidence to support using bisphosphonates as adjuvant therapy in women with early stage breast cancer, either to prevent skeletal events or improve survival. Research: The authors stated that there was limited evidence from clinical trials about the optimal duration of bisphosphonate use, the efficacy of bisphosphonates in men with breast cancer, and whether it is appropriate to switch from clodronate to pamidronate if a skeletal event occurs. The authors suggested that, given the cost of prolonged bisphosphonate therapy, it would be worthwhile investigating whether it is beneficial to continue bisphosphonates in patients who experience skeletal events. They identified one ongoing trial of clodronate in women with early stage breast cancer. Funding Cancer Care Ontario; Ontario Ministry of Health and Long-term Care. Other publications of related interest 1. Browman GP, Levine MN, Mohide EA, Hayward RS, Pritchard KU, Gafni A, et al. The practice guidelines development cycle: a conceptual tool for practice guidelines development and implementation. J Clin Oncol 1995;13:502-12. 2. Bloomfield D, Warr D, Whelan T, Pritchard K, Levine M, Breast Cancer Disease Site Group. Use of bisphosphonates in patients with bone metastases from breast cancer. Curr Oncol 1999;6:144-54. 3. Pavlakis N, Stockler M. Bisphosphonates in breast cancer (CochraneReview). In: The Cochrane Library, Issue 1, 2002. Oxford: Update Software. 4. Warr D, Johnston M, Breast Cancer Disease Site Group. Use of bisphosphonates in women with breast cancer. Ontario: Cancer Care Ontario Practice Guidelines Initiative; 2002. (accessed 21/11/2005). Available from: URL: https://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=34182 Indexing Status Subject indexing assigned by CRD MeSH Antineoplastic Agents; Breast Neoplasms /drug therapy; Diphosphonates /administration & Female; dosage AccessionNumber 12003008192 Date bibliographic record published 31/08/2005 Date abstract record published 31/08/2005 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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