Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an assessment report. The assessment report for this technology appraisal was prepared by the School of Health and Related Research (ScHARR), University of Sheffield (See the "Availability of Companion Documents" field.)
Clinical Effectiveness
Search Strategy
The search aimed to identify all studies relating to anastrozole, letrozole and exemestane for the treatment of early stage breast cancer. The following databases were searched: Medline, the Excerpta Medica Database (EMBASE), Cumulative Index of Nursing and Allied Health Literature (CINAHL), Biosciences Information Service (BIOSIS), the Cochrane Database of Systematic Reviews, the Cochrane Controlled Trials Register, the Science Citation Index and the National Health Service (NHS) Centre for Reviews and Dissemination databases (Database of Abstracts of Reviews of Effectiveness [DARE], National Health Service Economic Evaluation Database [NHS EED], HTA) and OHE Health Economic Evaluations Database (HEED). Pre-Medline was also searched to identify any studies not yet indexed on Medline. Current research was identified through searching the National Research Register, the Current Controlled Trials register, the Medical Research Council Clinical Trials Register and the proceedings of the American Society for Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO) and the San Antonio Breast Cancer Symposium (SABCS). Any industry submissions, as well as any relevant systematic reviews were hand-searched in order to identify any further clinical trials. Searches were not restricted by language, date or publication type. The MEDLINE search strategy is presented in Appendix 2 of the Assessment Report (see the "Availability of Companion Documents" field).
Inclusion and Exclusion Criteria
Systematic reviews and Phase III randomised controlled trials were included. Reviews of primary studies were not included in the analysis. Studies which were considered methodologically unsound were excluded from the review.
Studies randomising only the following population groups were included: postmenopausal women who have had surgery for early stage breast cancer (stages I and II of the American Joint Committee of Cancer [AJCC] system), whose tumours are oestrogen-receptor positive and: (a) who are hormonal therapy-naïve; (b) who have survived disease-free after two to three years of tamoxifen; or, (c) who have survived disease-free after five years of adjuvant tamoxifen. Studies designed to evaluate the experimental interventions in the following population groups were excluded: men; pre-menopausal women, women with ductal carcinoma in situ, advanced stage breast cancer or oestrogen receptor negative tumours.
Studies randomising only to the following experimental interventions were included: any one of the following aromatase inhibitors: anastrozole, letrozole, or exemestane, administered adjuvant to surgical resection. This review considers any treatment strategy containing one of the above aromatase inhibitors, regardless of the point of randomisation in the study or the length and structure of the treatment programme. Studies randomising to the following interventions were excluded: aromatase inhibitors administered as neoadjuvant treatment; aromatase inhibitors administered in the adjuvant setting where the women in the comparator arm are not offered the current standard treatment of five years' single agent tamoxifen (regardless of the point of randomisation).
Studies randomising only to the following comparators were included: tamoxifen alone, where trials randomise women who are hormonal therapy-naïve or have survived disease-free after two to three years of tamoxifen; placebo, where trials randomise women who have survived disease-free after five years of adjuvant tamoxifen. Studies randomising to other comparators were excluded.
Studies designed to assess the following outcomes were included: overall survival (the review's primary outcome), defined as the hazard of death from any cause after any follow-up, or the time to death from any cause expressed in months; disease-free survival however defined; recurrence, however defined; adverse events and toxicity however defined; and, health-related quality-of-life, however defined.
Where outcome data was available the following subgroups were analysed separately: node positive versus node negative tumours; expression of other molecular markers where available.
Economic Analysis
Identification of Studies
The aim of the search was to provide as comprehensive a retrieval as possible of economic evaluations of the hormonal therapies - anastrozole, letrozole and exemestane in the treatment of early breast cancer.
Sources Searched
Eight electronic databases were searched providing coverage of the biomedical and health technology assessment literature (BIOSIS, CINAHL, EMBASE, OHE HEED, HTA, Medline and PreMedline, and the NHS EED). The ASCO and ESMO conference abstracts and two current research registers (Current Controlled Trials and National Research Register) were also searched. The websites of the following organizations were also searched The Agency for Healthcare Research and Quality (AHRQ), Canadian Coordinating Office for Health Technology Assessment (CCOHTA), eMC, European Agency for the Evaluation of Medicinal Products (EMEA), International Network of Agencies for Health Technology Assessment (INAHTA) Clearinghouse, National Guidelines Clearinghouse, The National Coordinating Centre for Health Technology Assessment (NCCHTA) and The Scottish Intercollegiate Guidelines Network (SIGN). The economic assessments submitted by sponsors were identified as studies for inclusion in the review. In addition, the sponsor submissions were hand-searched for further references to studies.
Keyword Strategies
The keyword strategies developed in the review of clinical effectiveness were used, with the randomized controlled trial (RCT) methodological filter being replaced by a filter aimed at restricting search results to economic and cost related studies. An example search strategy for the Medline database is provided in Appendix 2 of the Assessment Report (see "Availability of Companion Documents" field).
Search Restrictions
The same limits and restrictions used in the review of clinical effectiveness were applied with the exception of the methodological filter as described above. All searches were undertaken in June 2005.
Inclusion and Exclusion Strategy
Studies were selected for inclusion according to pre-determined inclusion and exclusion criteria. Studies were included if they reported the cost-effectiveness of aromatase inhibitors in the adjuvant treatment of early breast cancer. Studies which were considered to be methodologically unsound, that were not reported in sufficient detail or that did not report an estimate of costs-effectiveness (e.g., costing studies) were excluded.
Two reviewers independently screened all titles and abstracts. Disagreement was settled through discussion. Full paper manuscripts were obtained for any titles/abstracts that were considered relevant or where the title/abstract information was not sufficient to make a decision.
Reviews discussing cost-effectiveness studies of aromatase inhibitors were not included in this review but were retained for use in discussion.