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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Fulvestrant for systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women: guideline recommendations

J Flemming, Y Madarnas, and J Franek. Breast Cancer Disease Site Group.

Review published: 2008.

Link to full article: [Journal publisher]

CRD summary

This review concluded that fulvestrant was not proven to be either superior or non-inferior to tamoxifen as first-line therapy for metastatic breast cancer in postmenopausal women, but may be considered as an alternative to anastrazole or exemestane in some subgroups of hormone-receptor positive women. The conclusions accurately reflected the evidence and are likely to be reliable.

Authors' objectives

To evaluate fulvestrant as a first-line or subsequent treatment for locally advanced or metastatic breast cancer in postmenopausal women.

Searching

MEDLINE (to June 2008), EMBASE (to April 2008), Cochrane Central Register of Controlled Trials (CENTRAL) (to first quarter 2008) and Cochrane Database of Systematic Reviews (to first quarter 2008) were searched from 1996. Search terms were reported. Two relevant sets of conference proceedings were searched up to 2007. Canadian Medical Association Infobase and the National Guidelines Clearing House were searched, as were ClinicalTrials.gov and Cancer.gov (National Cancer Institute) databases. References from identified studies were checked. Only studies reported in English were eligible for inclusion. Full papers and abstracts were eligible.

Study selection

Phase II or III randomised controlled trials (RCTs) that evaluated fulvestrant for the treatment of post-menopausal women with locally advanced (stage IIIB or greater) or metastatic breast cancer were eligible for inclusion in the review. Trials were required to report one of the following outcomes: time to progression; time to treatment failure; objective or complete response rate; progression-free survival; overall survival; compliance and continuation; and toxicities.

Included studies used fulvestrant at a dose of 250mg/month intramuscularly. Comparators were tamoxifen, anastrazole and exemestane. Included studies used differing criteria on prior treatment of participants, with considerable variation in whether therapy for advanced disease was acceptable.

The authors stated neither how the papers were selected for the review nor how many reviewers performed the selection.

Assessment of study quality

The authors assessed the validity of the RCTs using the criteria of blinding, randomisation, power calculation, achievement of planned sample size and use of intention-to-treat (ITT) analysis. The authors did not state how many reviewers performed the assessment.

Data extraction

Hazard ratios (HR) with 95% confidence intervals (CI) were extracted for each outcome. It appeared that data were extracted using standardised forms.

The authors did not state how many reviewers performed the data extraction.

Methods of synthesis

Studies were combined in a narrative synthesis, due to heterogeneity of reported outcomes. Results of a combined analysis of two trials were reported in place of individual trial results.

Results of the review

Four phase III superiority RCTs (n=2,131) were included in the review. Three RCTs were double-blinded double-dummy designs, three used an intention-to-treat analysis and three reported sample-size calculations. Randomisation methods were poorly described.

Fulvestrant versus tamoxifen: One RCT (n=587) found no significant differences between treatments on any outcome. Non-inferiority on the primary endpoint of time to progression was not confirmed (the upper confidence interval of the hazard ratio did not meet the predefined criterion of being 1.25 or lower). Unadjusted analyses showed a statistically significant benefit for tamoxifen in overall survival (HR 1.29, 95% CI 1.01 to 1.64, p=0.04). Results for subgroups of women with oestrogen receptor positive and or progesterone-receptor positive tumours showed no difference in overall survival between treatment groups. There were no significant differences in adverse events between the groups, except that patients on tamoxifen experienced more hot flashes (p=0.0501).

Fulvestrant versus anastrazole: Two RCTs (n=851) were combined. There were no significant differences between the groups on any primary outcome. Following the failure to show superiority of fulvestrant, an unplanned non-inferiority analysis was conducted. This showed non-inferiority for time to progression (5.5 months versus 4.1 months, HR 0.95, 95% CI 0.82 to 1.10) and objective response rate (difference of 2.75%, 95% CI 2.27% to 9.05%) compared to anastrazole. The duration of response was significantly longer in the fulvestrant groups at 22.1 months follow-up (ratio 1.30, 95% CI 1.13 to 1.50, p<0.01) in all patients and in responders only (16.7 versus 13.7 months). The only significant difference in adverse effects was a higher incidence of joint disorders in patients treated with anastrazole (12.8% versus 8.3%, p=0.02).

Fulvestrant versus exemestane: One RCT (n=693) found no statistically significant differences on any primary or secondary efficacy outcomes and no significant differences in adverse effects. Both treatments appeared well tolerated (only 2% of fulvestrant patients and 2.6% of exemestane patients withdrew as a result of adverse events).

Authors' conclusions

Fulvestrant was not proven to be either superior or non-inferior to tamoxifen as first-line therapy for metastatic breast cancer. It may be considered as an alternative to anastrazole in hormone-receptor-positive metastatic breast cancer in postmenopausal women who had progressed or recurred on prior tamoxifen therapy. It may also be considered as an alternative therapy to exemestane in patients with hormone-receptor positive and locally advanced or metastatic breast cancer who had progressed on prior third-generation non-steroidal A1 therapy. However, comparability of fulvestrant to other A1s and its performance in other settings have yet to be determined. There was a decreased risk of joint disturbances compared with anastrazole and improved compliance over an oral therapy.

CRD commentary

The review question and the inclusion criteria were clear and specific. The authors searched several relevant databases and other sources. The inclusion of unpublished studies reduced the chances of publication bias, but the decision to limit the review to studies reported in English may have introduced language bias and caused some relevant studies to be missed. The authors did not report using methods designed to reduce reviewer bias and error at any stage of the review process. The authors appeared to assess study validity using an appropriate tool. The decision to use a narrative synthesis appeared appropriate. The conclusions accurately reflected the results of the review. Despite poor reporting of some aspects of the review process, the conclusions appear likely to be reliable.

Implications of the review for practice and research

Practice: The authors stated that fulvestrant may be considered as an alternative to anastrazole in hormone-receptor-positive metastatic breast cancer in postmenopausal women who have progressed or recurred on prior tamoxifen therapy. It may also be considered as an alternative therapy to exemestane in patients with hormone-receptor positive and locally advanced or metastatic breast cancer who have progressed on prior third-generation non-steroidal A1 therapy.

Research: The authors did not state any implications for further research.

Funding

Cancer Care Ontario, supported by the Ontario Ministry of Health and Long-term Care.

Bibliographic details

Flemming J, Madarnas Y, Franek J, Breast Cancer Disease Site Group. Fulvestrant for systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women: guideline recommendations. This paper is produced by Cancer Care Ontario Practice Guidelines Initiative. The series is published on the Internet and regularly updated. To ensure that you are viewing the most up to date version, go to the Cancer Care Ontario website at: https://www.cancercare.on.ca/toolbox/qualityguidelines/

Indexing Status

Subject indexing assigned by CRD

MeSH

Antineoplastic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Estradiol; Estrogen Antagonists; Female; Humans; Postmenopause

AccessionNumber

12009102944

Database entry date

24/03/2010

Record Status

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.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

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