CRD summary

This review of individual patient data concluded that in women with hormone-receptor-positive breast cancer, the addition of luteinising-hormone-releasing hormone (LHRH) agonists to tamoxifen, chemotherapy, or both, reduces the risk of recurrence and death after recurrence and that LHRH agonists are as effective as chemotherapy. This review had some methodological weaknesses that may undermine the reliability of the results.

Authors' objectives

To evaluate the efficacy of luteinising-hormone-releasing hormone (LHRH) agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer.

Searching

PubMed and SpringerLink were searched; the search terms were reported. The abstracts from breast cancer meetings, the database of the Oxford overview group, and references from published reports of known trials were checked, and investigators from known studies were contacted to identify additional studies. A steering committee was established to undertake the meta-analysis.

Study selection

Assessment of study quality

The authors did not state how the validity of each trial was assessed. Results data were checked for internal consistency with published results and for outliers. If required, the data were updated or amended after contact with the trialists.

Data extraction

Investigators were contacted, if necessary, to obtain additional information and to verify the finalised data.

Methods of synthesis

Results of the review

IPD from 16 trials (including IPD for 11,906 women; 9,022 women were hormone-receptor positive) were included in the review. The authors stated that one other eligible trial was identified, but the investigator could not be contacted and the data were therefore not available.

Adjuvant treatments were provided without any blinding in all of the included studies.

Hormone-receptor-positive women. LHRH agonist alone (n=338).

There was no significant difference between LHRH agonists and no systemic adjuvant therapy for recurrence (% change in HR -28.4, 95% CI: -50.5, 3.5, p=0.08), death after recurrence (% change in HR -17.8, 95% CI: -52.8, 42.9, p=0.49) or any death (% change in HR -22.9, 95% CI: -44.1, 6.4, p=0.11), but they were associated with a significant reduction in the risk of the combined outcome of recurrence or death (% change in HR -25.2, 95% CI: -40.6, -5.8, p=0.01).

LHRH agonist plus tamoxifen and/or chemotherapy versus tamoxifen and/or chemotherapy (n=3,754). The addition of an LHRH agonist to tamoxifen, chemotherapy, or both significantly reduced the risk of recurrence (% change in HR -12.7, 95% CI: -21.9, -2.4, p=0.02), death after recurrence (% change in HR -15.1, 95% CI: -26.7, -1.8, p=0.03) and any death (% change in HR -13.6, 95% CI: -24.9, -0.6, p=0.04).

LHRH agonist versus chemotherapy. There was no significant difference between LHRH agonist and chemotherapy in the risk of recurrence (% change in HR 3.9, 95% CI: -7.7, 17.0, p=0.52), death after recurrence (% change in HR -6.7, 95% CI: -20.7, 9.6, p=0.40) and any death (% change in HR -14.9, 95% CI: -27.7, 0.1, p=0.05).

Details of other treatment comparisons were discussed in the text.

Women with negative, poor oestrogen-receptor or unknown status. In patients with negative or poor oestrogen-receptor status and either negative or unknown progesterone-receptor status (n=1,681), the addition of an LHRH agonist to any adjuvant treatment did not reduce the risk of recurrence or death after recurrence. Compared with chemotherapy alone, LHRH agonists were associated with a higher risk of recurrence (% change in HR 67.7, 95% CI: 22.2, 129.9, p=0.001), with similar rates for death after recurrence and all deaths.

Authors' conclusions

In women with hormone-receptor-positive breast cancer, the addition of LHRH agonists to tamoxifen, chemotherapy, or both, reduces the risk of recurrence and death after recurrence. LHRH agonists do not appear to be effective in women with hormone-receptor-negative tumours.

CRD commentary

This meta-analysis of IPD addressed a well-defined question in terms of the participants, intervention, outcomes and study design. The authors searched two databases, although the precise timeframe of the bibliographic search was not stated. Publication bias was not assessed, but the authors did attempt to retrieve unpublished trials. The authors checked the internal consistency of the IPD, but it was unclear whether the adequacy of randomisation to study treatment and allocation concealment or the comparability of treatment groups were evaluated in each trial. The number of excluded studies, as well as the number of participants in trials for which data could not be retrieved, were specified. It was not stated how many members of the steering committee participated in the selection of the studies, or whether trial investigators were contacted to check each trial's eligibility for inclusion. No information was provided on how the data were acquired, or if any recoding or transformation of the data prior to the analysis was performed.

Statistical heterogeneity was not assessed, which leaves it unclear as to whether the authors' decision to pool the studies in a meta-analysis was appropriate. However, the influence of various factors on the results was explored. The authors' conclusions appear to reflect the evidence presented, but the incomplete reporting of review methods means it is not possible to assess their reliability.

Implications of the review for practice and research

Practice: The authors did not state any implication for practice.

Research: The authors stated that future trials should compare the combination of an LHRH agonist and tamoxifen against chemotherapy and tamoxifen. The efficacy of LHRH agonists should be better evaluated according to oestrogen and progesterone receptor status.

Funding

Cancer Research UK.

Bibliographic details

Cuzick J, Ambroisine L, Davidson N, Jakesz R, Kaufmann M, Regan M, Sainsbury R. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet 2007; 369: 1711-1723. [PubMed: 17512856]

Other publications of related interest

Early Breast Cancer Trialists' Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687-717.

Indexing Status

Subject indexing assigned by NLM

MeSH

Adult; Antineoplastic Agents, Hormonal /therapeutic use; Antineoplastic Combined Chemotherapy Protocols /therapeutic use; Breast Neoplasms /drug therapy /mortality /pathology; Chemotherapy, Adjuvant; Drug Interactions; Female; Gonadotropin-Releasing Hormone /agonists; Goserelin /therapeutic use; Humans; Middle Aged; Multicenter Studies as Topic; Neoplasm Recurrence, Local /mortality /prevention & control; Premenopause; Randomized Controlled Trials as Topic; Tamoxifen /therapeutic use

AccessionNumber

12007008137

Database entry date

29/02/2008

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.