Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women

Abstract

Hormonal treatments for advanced or metastatic breast cancer, such as tamoxifen and the progestins megestrol acetate and medroxyprogesterone acetate, have been in use for many years. Aromatase inhibitors (AIs) are a class of compounds that systemically inhibit oestrogen synthesis in the peripheral tissues. Aminoglutethimide was the first AI in clinical use (first generation) and had a similar tumour-regressing effect to other endocrine treatments, which showed the potential of this alternative type of therapy. Other AIs have since been developed and the third generation AIs anastrozole, exemestane and letrozole are in current use. Randomised evidence on response rates and side effects of these drugs is still limited. To compare aromatase inhibitors to other endocrine therapy in the treatment of advanced breast cancer in postmenopausal women. The Cochrane Breast Cancer Group Specialised Register was searched on 3 December 2004 using the codes for "advanced" and "endocrine therapy". Details of the search strategy applied to create the Register and the procedure used to code references are described in the Cochrane Breast Cancer Group module on The Cochrane Library. The search was updated to 30 September 2005 and additional publications were included. Experts were consulted to determine that no relevant studies had been excluded. Randomised trials comparing the effects of any aromatase inhibitor versus other endocrine therapy, no endocrine therapy or a different aromatase inhibitor in the treatment of advanced (metastatic) breast cancer. Data from published trials were extracted by two independent review authors. A third independent author then carried out a further cross check for accuracy and consistency. Hazard ratios (HR) were derived for analysis of time-to-event outcomes (overall and progression-free). Odds ratios (OR) were derived for objective response and clinical benefit (both analysed as dichotomous variables). Toxicity data were extracted where present and treatments were compared using odds ratios. All but one of the studies included data on one or more of the following outcomes: overall survival, progression-free survival, clinical benefit and objective response. Thirty studies were identified, twenty five of which were included in the main analysis of any AI versus any other treatment (9416 women). The pooled estimate showed a significant survival benefit for treatment with an AI over other endocrine therapies (HR 0.89, 95%CI 0.82 to 0.96). A subgroup analysis of the three commonly prescribed AIs (anastrozole, exemestane, letrozole) also showed a similar survival benefit (HR 0.88, 95%CI 0.80 to 0.96). The results for progression-free survival, clinical benefit and objective response were not statistically significant and there was statistically significant heterogeneity across types of AI. There were very limited data to compare one AI with a different AI, but these suggested an advantage for letrozole over anastrozole. All the trials of AIs used exclusively as first-line therapy were against tamoxifen. There was an advantage to treatment with AIs in terms of progression-free survival (HR 0.78, 95% CI 0.70 to 0.86) and clinical benefit (OR 0.70, 95% CI 0.51 to 0.97) but not overall survival or objective response. There was considerable heterogeneity across studies when considering clinical benefit (P = 0.001). Use of an AI as second-line therapy showed a significant benefit in terms of overall survival (HR 0.80, 95% CI 0.66 to 0.96) but not for progression-free survival (HR 1.08, 95% CI 0.89 to 1.31), clinical benefit (OR 1.00, 95% CI 0.87 to 1.14) or objective response (OR 0.96, 95% CI 0.81 to 1.14). This is difficult to interpret due to the extreme heterogeneity across AIs for progression-free survival but not the other endpoints.AIs have a different toxicity profile to other endocrine therapies. For all AIs combined, they had similar levels of hot flushes (especially when compared to tamoxifen) and arthralgia, increased risks of nausea, diarrhoea and vomiting, but a decreased risk of vaginal bleeding and thromboembolic events compared with other endocrine therapies. A similar pattern of risks and benefits was still seen when analyses were limited to the currently most-prescribed third generation AIs. In women with advanced (metastatic) breast cancer, aromatase inhibitors including those in current clinical use show a survival benefit when compared to other endocrine therapy.