Elsevier

The Breast

Volume 26, April 2016, Pages 106-114
The Breast

Review
Aromatase inhibitors alone or sequentially combined with tamoxifen in postmenopausal early breast cancer compared with tamoxifen or placebo – Meta-analyses on efficacy and adverse events based on randomized clinical trials

https://doi.org/10.1016/j.breast.2016.01.006Get rights and content

Highlights

  • Monotherapy with AI improves DFS and OS compared with tamoxifen.

  • AI sequentially combined with tamoxifen improves DFS compared with tamoxifen alone.

  • The effect of sequenced therapy with AI on DFS is not significant in studies with randomization before any endocrine therapy.

  • Extended therapy with AI improves disease-free survival.

  • Cardiovascular events related to AI treatment cannot be ruled out.

Abstract

Tamoxifen (TAM) and aromatase inhibitors (AI) are adjuvant therapy options for postmenopausal women with estrogen receptor positive (ER+) breast cancer. This systematic review of seven randomized controlled studies comparing TAM and AI, and one study comparing extended therapy with an AI with placebo after about 5 years of tamoxifen, aims to assess long-term clinical efficacy and adverse events. The literature review was performed according to the principles of the Cochrane Collaboration. The search included common databases up to 2013-01-14. Studies of high or moderate quality were used for grading of evidence. Revman™ software was utilized for meta-analyses of published data. Disease free survival (DFS) and overall survival (OS) were improved with AI monotherapy compared to TAM with high and moderate quality of evidence respectively. Sequenced therapy with AI → TAM (or vice versa) improved DFS compared with TAM with moderate quality of evidence, but did not improve OS (low quality of evidence). However, if only studies on sequenced AI therapy with randomization before endocrine therapy were considered, no improvement of DFS could be found. Fractures are more frequently associated with AI whereas the risk of endometrial cancer and venous thromboembolism are higher with TAM. For cardiovascular events no difference was found between AI (mono- or sequenced therapy) and TAM, whereas sequenced therapy compared with AI had lower risk of cardiovascular events (moderate level of evidence).

AIs are superior to TAM as adjuvant hormonal therapy for postmenopausal ER-positive breast cancer. TAM can be considered for individual patients due to the different toxicity profile compared with AI. Cardiovascular events related to AI treatment deserve further attention.

Introduction

Hormonal therapy is the cornerstone of adjuvant systemic treatment for patients with ER- positive breast cancer. The efficacy of adjuvant tamoxifen (TAM) for 5 years, irrespective of menopausal status, compared to placebo has repeatedly been reported in terms of disease-free (DFS) and overall survival (OS) [1]. The side effects of TAM are well documented including increased risk of thromboembolic events and endometrial cancer [1]. For postmenopausal women, adjuvant endocrine therapy with TAM has been challenged during the last decade by third-generation AI showing improvement of DFS compared to TAM in ER-positive breast cancer [2], [3].

Trials comparing adjuvant aromatase inhibitors (AI) with TAM have used different schedules: 5 years of monotherapy; sequenced therapy, i.e. TAM for 2–3 years followed by AI to a total of 5 years or vice versa with either TAM or an AI as the comparator; and extended therapy with AI compared to placebo after 5 years of TAM (Fig. 1) [2], [3], [4], [5], [6], [7], [8], [9]. The adjuvant randomized controlled trials (RCT) of AI have included over 35,000 women worldwide and long-term follow-up data have been reported for some of the largest trials suggesting that AI also increases OS compared to TAM [2], [4]. AI has consistently been reported to increase the risk of fractures compared to TAM [10], [11], and to symptoms related to estrogen deprivation such as musculoskeletal- and genitourinary discomfort, whereas potentially negative effects on cardiovascular events are not fully elucidated.

In 2005 the Swedish Council on Health Technology Assessment and Assessment of Social Services (SBU) published a systematic review on the effects of AI in metastatic breast cancer together with data on adjuvant and neo-adjuvant treatment with AI in early breast cancer [12]. At that time point, no long-term data was available.

The aim of the present systematic review was to analyze long-term follow–up data from RCTs with AI (mono-, sequenced- and extended therapy) compared with TAM or placebo in order to provide a comprehensive update on efficacy (DFS and OS) and side effects including available data from on- and off-treatment.

Section snippets

Literature search and selection of articles

This article is based on a Health Technology Assessment reported by The Swedish Council of Health Technology Assessments and Assessment of Social Services, SBU [13], whose methods are in line with the Cochrane Collaboration Handbook for Systematic Reviews (http://handbook.cochrane.org/). The methods used in this review article are essentially the same as recommended in the Prisma Checklist (http://www.prisma-statement.org/statement.htm). The search strategy along with the text words (TW) and

Selection of studies

Seven-hundred-eighty-six abstracts met the search criteria; 559 of them were excluded due to: a) the PICO – criteria, b) available as abstract only and c) too short follow-up time, which left two-hundred-and-twenty-seven abstracts for further evaluation. An additional 12 articles were manually retrieved, resulting in 239 published full text articles that were assessed regarding scientific quality using the SBU checklist [13].

Two-hundred and seven were excluded due to low quality or not

Discussion

This systematic review shows that DFS and OS were improved with five years of AI monotherapy compared to five years of TAM with high and moderate quality of evidence respectively. However, the absolute differences in effects are relatively small, around 3% for DFS and 1% for OS. For sequenced AI therapy with TAM as comparator, DFS was superior with moderate level of evidence, whereas the effect on OS was non-significant. Sequenced therapy compared with AI monotherapy did not prove to be

Conclusions

AI monotherapy improves DFS and OS compared with TAM. Sequenced therapy with AI and extended therapy with 5 years of AI after 5 years of TAM improves DFS. Due to differences in toxicity profile, TAM is an appropriate option for some women. An elevated risk for cardiovascular events with AI treatment cannot be completely ruled out and therefore warrants further research in studies without TAM as comparator.

Ethical statement

An ethical approval has not been judged as necessary since this is a systematic review using only anonymous group level data that have been published before.

Conflict of interest statement

None of the authors declares any conflicts of interest.

Acknowledgment

The study was supported by the Swedish Council on Health Technology Assessment and Assessment of Social Services, SBU.

References (24)

  • F. Boccardo et al.

    Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial

    Ann Oncol

    (2006)
  • M. Kaufmann et al.

    Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 study

    J Clin Oncol

    (2007)
  • Cited by (0)

    1

    First authorship shared between Rydén L and Heibert Arnlind M.

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