The review found that aromatase inhibitors used as adjuvant therapy for postmenopausal hormone receptor positive breast cancer had a small benefit on disease-free (but not overall) survival compared to tamoxifen. Limitations of the review methodology and the modest effect size bring into question the reliability of the results of the review.

To assess the effectiveness of third generation aromatase inhibitors (anastrozole, letrozole and exemestane) as adjuvant therapy for post-menopausal women with early stage hormone receptor positive breast cancer.

MEDLINE, Excerpta Medica, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews were searched to May 2007. Search terms were described in the review. The proceedings of two American oncology meetings and bibliographies of identified papers were searched. Searches were limited to trials published in English.

Randomised controlled trials (RCTs) or meta-analyses that compared aromatase inhibitors with tamoxifen or placebo as adjuvant therapy in post-menopausal women with early-stage hormone receptor-positive breast cancer were eligible for inclusion. Only trials in which clinical efficacy outcomes (some measure of survival) were reported were eligible.

In the included trials, the following daily doses were used: tamoxifen 20mg; anastrozole 1mg; letrozole 2.5mg; and exemestane 25mg.

Where reported, the median age of the included women ranged from 61 to 64 years. Fifty per cent to 100% were node positive. Between 44% and 64% of tumours were less than or equal to 2cm. In all but two studies, all women had oestrogen and/or progesterone receptor positive breast cancer. The primary therapy varied between studies, including mastectomy (23% to 52%), radiotherapy (0 to 72%) and chemotherapy (0 to 67%). The definition of post-menopause varied between studies and was reported in the review.

The authors stated neither how the validity assessment was performed nor how many reviewers performed the assessment, but some details of study quality were reported.

Hazard ratios and confidence intervals for disease-free overall survival and adverse event rates were extracted, where possible. The authors did not state how many reviewers performed the extraction.

The studies were combined using a narrative synthesis grouped according to the drug comparison being made. Forrest plots were used to display the results from individual studies, but no meta-analysis was conducted.

Validity: Most studies reported appropriate randomisation procedures (two failed to report the method of randomisation). Most studies were double blinded (one was open label and one did not report blinding). All but one trial used intention-to-treat analysis.

Nine RCTs (n=27,202) and one meta-analysis (n=3,674) were included in the review. The meta-analysis was based on three of the nine included trials.

Aromatase inhibitors alone versus tamoxifen alone: Two trials found beneficial effects on disease-free survival, time to recurrence and time to distant recurrence, but not on overall survival.

Aromatase inhibitors after tamoxifen versus tamoxifen alone: Four trials each found beneficial effects on disease-free survival, but not on overall survival.

Aromatase inhibitors after five years of tamoxifen: Three trials found that aromatase inhibitors improved disease free survival, though in two of these trials the significance was borderline. Based on results from two of the three trials, aromatase inhibitors did not affect overall survival.

Side effects of aromatase inhibitors: The rates of cardiovascular, cerebrovascular and thromboembolic events were generally similar between the aromatase inhibitor and tamoxifen groups in six studies; aromatase inhibitors were associated with higher levels of fractures and osteoporosis and lower levels of gynaecological toxicities (including endometrial cancer) compared to tamoxifen.

Aromatase inhibitors provided an alternative to tamoxifen as adjuvant therapy for postmenopausal hormone-receptor positive breast cancer patients.

The review addressed a clear research question. Intervention and outcome inclusion criteria were all stated. The lack of clear participant inclusion criteria meant that the studies in the review included two in which not all patients had hormone receptor positive breast cancer. Although the search strategy included a range of relevant databases, the exclusion of non English-language trials and the lack of attempting to identify unpublished data meant that the results could be affected by language or publication bias. The authors did not appear to take steps to minimise error or bias during study selection, validity assessment or data extraction. The authors noted that the magnitude of the effect of aromatase inhibitors was modest. The limitations bring into question the reliability of the results of the review.

Practice: The authors stated that aromatase inhibitors provided an alternative to tamoxifen as adjuvant therapy for postmenopausal hormone receptor positive breast cancer patients. Treatment options included: five years of anastrazole or letrozole; and anastrazole or exemestane after two or three years of tamoxifen. Five years of letrozole should be considered following five years of tamoxifen. Patients should be monitored for bone mineral density and cardiovascular disease risk.

Research: Longer follow-up of published and ongoing trials, and meta-analysis, would indicate whether the results in this review were robust.

Trudeau AE, Shelley W, Sinclair S, et al. The role of aromatase inhibitors in adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: guideline recommendations. Ottawa, ON, Canada: Cancer Care Ontario and the Ontario Ministry of Health and Long-term Care. Evidence-based Series #1-18(sections 1-3).2008.

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.