Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women

Advanced (or metastatic) breast cancer is cancer that has spread beyond the breast and regional lymph node areas. Breast cancer can progress to metastatic disease despite the person undergoing a range of therapies given after initial treatment, such as surgery, chemotherapy or radiation therapy. Metastatic breast cancer is treatable but it is not curable. Most breast cancer is sensitive to the female hormone oestrogen. Sensitive cancer cells need oestrogen to stay alive and removal of oestrogen from the body, or stopping any circulating oestrogen getting to the cancer cells, is very effective treatment for hormone-sensitive breast cancers. Endocrine (hormonal) therapy removes the influence of oestrogen on breast cancer cells. Hormonal treatments for advanced breast cancer include tamoxifen, the progestins megestrol acetate and medroxyprogesterone acetate, and aromatase inhibitors (AIs). AIs reduce the body's ability to make (synthesise) oestrogen and have tumour-regressing effects. The AIs in current clinical use include anastrozole, exemestane, and letrozole.

The aim of this systematic review was to compare AIs to other endocrine therapy in the treatment of advanced (metastatic) breast cancer. A systematic search was conducted which identified 37 controlled trials in which over 14,000 women were randomised to treatment groups. Treatment with an AI improved survival for women with metastatic disease by 10%. The overall benefits on disease-free survival and response of the tumour were however unclear based on the studies included in this review. Trials using AIs as first-line and second-line therapy reported benefits of therapy that varied with the different AIs and measures of effectiveness. We were unable to identify specific subgroups of women who may benefit from AI use.

Toxicity (negative side effects) was not well reported in the trials. Where it was reported, there was variation as to the method used for reporting, the type of toxicities reported, as well as the criteria used to assess toxicity. Nevertheless, toxicity data were available for 26 of the 32 trials where an AI was compared with a non-AI. AIs had similar levels of arthritic pain (arthralgia) and hot flushes (especially when compared to tamoxifen); increased risks of rash, diarrhoea, nausea and vomiting; but decreased risk of vaginal bleeding and blood clotting (thromboembolic) events compared with other endocrine therapies. Limited quality of life (QOL) data were provided and, as such, no conclusions can be drawn by this review as to the effect on QOL related to an AI versus a non-AI. This is due to the differences between participants and the side-effect profiles of the agents used, different methods of drug application (injection versus tablets), and use of four different QOL instruments at several different timepoints, some which provided results of responders versus non-responders rather than by treatment group. Some QOL measures were based on clinician-reported rather than patient-reported symptoms.

Authors' conclusions: 

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.

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Background: 

Endocrine therapy removes the influence of oestrogen on breast cancer cells and so hormonal treatments such as tamoxifen, megestrol acetate and medroxyprogesterone acetate have been in use for many years for advanced breast cancer. Aromatase inhibitors (AIs) inhibit oestrogen synthesis in the peripheral tissues and have a similar tumour-regressing effect to other endocrine treatments. Aminoglutethimide was the first AI in clinical use and now the third generation AIs, anastrozole, exemestane and letrozole, are in current use. Randomised trial evidence on response rates and side effects of these drugs is still limited.

Objectives: 

To compare AIs to other endocrine therapy in the treatment of advanced breast cancer in postmenopausal women.

Search strategy: 

For this update, the Cochrane Breast Cancer Group Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) and relevant conference proceedings were searched (to 30 June 2008).

Selection criteria: 

Randomised controlled trials in postmenopausal women comparing the effects of any AI versus other endocrine therapy, no endocrine therapy, or a different AI in the treatment of advanced (metastatic) breast cancer. Non-English language publications, comparisons of the same AI at different doses, AIs used as neoadjuvant treatment, or outcomes not related to tumour response were excluded.

Data collection and analysis: 

Data from published trials were extracted independently by two review authors and cross-checked by a third. Hazard ratios (HR) were derived for analysis of time-to-event outcomes (overall and progression-free survival). Odds ratios (OR) were derived for objective response, clinical benefit, and toxicity.

Main results: 

Thirty-seven trials were identified, 31 of which were included in the main analysis of any AI versus any other treatment (11,403 women). No trials were excluded due to inadequate allocation concealment. The pooled estimate showed a significant survival benefit for treatment with an AI over other endocrine therapies (HR 0.90, 95% CI 0.84 to 0.97). 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). There were very limited data to compare one AI with a different AI, but these suggested an advantage for letrozole over anastrozole.

AIs have a different toxicity profile to other endocrine therapies. For those currently prescribed, and for all AIs combined, they had similar levels of hot flushes and arthralgia; increased risks of rash, nausea, diarrhoea and vomiting; but a 71% decreased risk of vaginal bleeding and 47% decrease in thromboembolic events compared with other endocrine therapies.

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