LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women.
BACKGROUND
Approximately 60% of breast cancer tumours in premenopausal women are hormone sensitive (ER+). These patients may be suitable for hormonal treatment. The goal of hormonal therapy is to reduce the availability of oestrogen to the cancer cell. This can be achieved by blocking oestrogen receptors with drugs such as tamoxifen, suppression of oestrogen synthesis by LHRH agonists, or ovarian ablation either surgically or by radiotherapy. Chemotherapy can also have a hormonal action by inducing amenorrhoea in premenopausal women.


OBJECTIVE
To assess LHRH agonists as adjuvant therapy for women with early breast cancer.


METHODS
The specialised register of the Cochrane Breast Cancer Group was searched on 19 December 2006. The reference lists of related reviews were checked. A final check of the list of trials maintained by the Early Breast Cancer Trialists' Collaborative Group was made in January 2008.


METHODS
Randomised trials of LHRH agonist versus LHRH agonist and tamoxifen, LHRH agonist versus chemotherapy, LHRH agonist versus ovarian ablation, or LHRH agonist versus LHRH agonist and chemotherapy, that recruited premenopausal women with early breast cancer.


METHODS
Data were collected from trial reports. We report estimates for the differences between treatments on recurrence free survival, overall survival, toxicity and quality of life using data available in the reports of each trial. Meta-analyses were not performed because of variability in the reporting of the trials and the need for more mature data.


RESULTS
We identified 14 randomised trials, involving nearly 12,000 premenopausal women with operable breast cancer, most of whom were ER+. The LHRH agonist in most of these trials was goserelin. For most of the treatment comparisons there are too few trials, too few randomised patients or too little follow-up to draw reliable estimates of the relative effects of different treatments. Four trials (nearly 5000 women) addressed the integration of LHRH agonists into adjuvant hormonal therapy, showing that a combination of an LHRH agonist and tamoxifen might be better than either alone. Insufficient data are available to inform a choice between tamoxifen and goserelin as sole adjuvant therapy. We included twelve trials (more than 10,000 women) of the integration of LHRH agonists into adjuvant chemo-hormonal therapy. Four trials assessed the effects of an LHRH agonist compared to chemotherapy and three other trials investigated a combination of an LHRH agonist and tamoxifen versus chemotherapy. One trial assessed the effects of adding chemotherapy to an LHRH agonist, five trials compared a combination of an LHRH agonist and chemotherapy versus chemotherapy alone, and three trials compared the combination of LHRH agonist, tamoxifen and chemotherapy versus chemotherapy alone. No trials compared an LHRH agonist containing regimen against chemotherapy and tamoxifen. No significant differences in recurrence free survival or overall survival were found between LHRH agonists, with or without adjuvant tamoxifen, and chemotherapy for premenopausal women with ER+ tumours, but hormonal therapy had fewer distressing side effects. The trials point to reductions in recurrence and death for premenopausal women with ER+ tumours who take LHRH agonists, with or without tamoxifen, along with chemotherapy.


CONCLUSIONS
For premenopausal women with early breast cancer who are not known to be ER negative, the use of an LHRH agonist, with or without tamoxifen as adjuvant therapy is likely to lead to a reduction in the risk of recurrence and a delay in death. The evidence is insufficient to support the LHRH agonists over chemotherapy, or vice versa, in regard to recurrence free survival and overall survival, but LHRH agonists have fewer or less severe adverse effects. Further follow-up of women in these trials is needed to provide reliable evidence on long term outcomes. Direct randomised comparisons of different durations of LHRH agonists (for example, two years versus longer) and, in the presence of uncertainty, of different LHRH agonists among ER+ or ER unknown premenopausal women are also needed. It is also uncertain how the findings from the CMF-based trials in this review would relate to the use of LHRH agonists with more modern chemotherapy regimens or the comparison of LHRH agonist containing regimens with combinations such as chemotherapy and tamoxifen.
Sharma
Rohini
R
Department of Medical Oncology, Hammersmith Hospital Trust, Du Cane Road, London, UK, W12 0HS. r.sharma@imperial.ac.uk
Hamilton
Anne
A
Beith
Jane
J
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists*; D017273:Goserelin / Q000627:therapeutic use; D006801:Humans; D010052:Ovariectomy; D017697:Premenopause; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use
D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D017273:Goserelin; D007987:Gonadotropin-Releasing Hormone