Ovarian suppression with LHRH agonists (such as goserelin) for treating premenopausal women with early breast cancer

More than half of the premenopausal women who develop breast cancer have a type of cancer that is sensitive to hormones, termed 'oestrogen receptor positive' or ER+ disease. To slow the growth of any cancer cells that remain after surgery, hormonal therapy can be used to reduce the availability of the natural hormone oestrogen to the cells. This can be done by blocking the oestrogen receptors on the cells with drugs such as tamoxifen, by suppressing the production of oestrogen by drugs called luteinising hormone releasing hormone (LHRH) agonists, or by removing the ovaries with surgery or impairing their ability to produce hormones using radiotherapy. A new class of drugs called aromatase inhibitors work by stopping the production of oestrogen, but can only be safely used in premenopausal women if their ovarian cycling is suppressed (either by LHRH agonists, surgery, or radiotherapy). Chemotherapy, designed to kill cancer cells, can also have a hormonal action by bringing on early menopause. This review examined the role of LHRH agonists for women with early stage breast cancer. It looked at comparisons of LHRH agonists versus other types of hormonal treatment and versus chemotherapy. We also examined the role of combined LHRH agonist plus tamoxifen therapy, combined LHRH agonist plus chemotherapy, and combined LHRH agonist plus tamoxifen plus chemotherapy. A total of 14 randomised trials that involved over 13,000 women were found, but only a small number of these were relevant to each of the comparisons in this review. The LHRH agonist in the trials was usually goserelin, used for a couple of years.

We found seven trials comparing LHRH agonist therapy (alone) to other treatments. There is not enough evidence to compare LHRH agonists directly to tamoxifen. Four of the trials compared an LHRH agonist to a now superseded chemotherapy regimen. For ER+ women, these trials showed no significant differences between LHRH agonists and chemotherapy on recurrence and death, but LHRH agonists had fewer side effects.

Six trials compared LHRH agonists in combination with tamoxifen to other treatments. There is currently insufficient information to reliably compare this combination with tamoxifen alone. The LHRH agonist plus tamoxifen combination may reduce the risk of breast cancer recurrence, but not death, when compared to an LHRH agonist alone or chemotherapy alone. There is insufficient evidence to know whether an LHRH agonist plus an aromatase inhibitor is better or worse than an LHRH agonist plus tamoxifen.

Three trials compared combining an LHRH agonist plus chemotherapy plus tamoxifen to chemotherapy alone. There was a reduction in the risk of breast cancer recurrence, and possibly death, with the combination treatment.

It is important to note that the current standard of care for premenopausal women with ER+ breast cancer is five years of tamoxifen, often with chemotherapy. We found no trials of LHRH agonist-containing regimens versus this standard. The women in the trials in this review need to continue to be followed up so that the longer-term effects can be investigated, to 10 and more years after diagnosis. More research is also needed to help choose between different types of LHRH agonist, and to find out if the length of time that the drug is used makes a difference. It is also unknown whether there are important differences between the effects of LHRH agonists and ovarian ablation by surgery or radiotherapy.

Authors' conclusions: 

Overall, the data from currently published clinical trials of LHRH agonists in the adjuvant setting for premenopausal women with endocrine-sensitive breast cancer are supportive of clinical benefit. Nonetheless, definitive comparisons against current clinical standards of care that include third generation chemotherapy regimens and tamoxifen are required before their place in the adjuvant setting can be properly defined. The authors conclude that the current data strongly support the continuation of current trials that definitively compare a variety of combinations of LHRH agonists and anti-oestrogenic strategies to the current standard of five years of tamoxifen.

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Background: 

Approximately 60% of breast cancers amongst premenopausal women express the nuclear oestrogen receptor (ER+ breast cancer). Adjuvant endocrine therapy is an integral component of care for ER+ breast cancer, exerting its effect by reducing the availability of oestrogen to micrometastatic tumour cells. Endocrine strategies in premenopausal women include oestrogen receptor blockade with tamoxifen, temporary suppression of ovarian oestrogen synthesis by luteinising hormone releasing hormone (LHRH) agonists, or permanent interruption of ovarian oestrogen synthesis with oophorectomy or radiotherapy. Aromatase inhibitors are also available with concurrent suppression of ovarian oestrogen synthesis, either through LHRH agonists, surgery, or radiotherapy. Chemotherapy can also have an endocrine action in premenopausal women by interrupting ovarian oestrogen production, either temporarily or permanently. International consensus statements recommend single agent tamoxifen as the current standard adjuvant endocrine therapy for premenopausal women (often preceded by chemotherapy), and the role of LHRH agonists remains under active investigation.

Objectives: 

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

Search strategy: 

The Cochrane Breast Cancer Group Specialised Register was searched on 19 February 2009. This register incorporates references from CENTRAL (The Cochrane Library) (to 2002), MEDLINE (1966 to July 2008), EMBASE (until 2002); and handsearches of abstracts from the San Antonio Breast Cancer Symposium, American Society of Clinical Oncology Annual Meeting, and the Clinical Oncological Society of Australia Annual Meeting. MEDLINE references (from August 2008 to 19th February 2009) were checked by the authors. 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.

Selection criteria: 

All randomised trials assessing LHRH agonists as adjuvant treatment in premenopausal women with early stage breast cancer were included. Specifically, we included trials that compared:

(A) LHRH agonists (experimental arm) versus another treatment;

(B) LHRH agonists + anti-oestrogen (experimental arm) versus another treatment;

(C) LHRH agonists + chemotherapy (experimental arm) versus another treatment;

(D) LHRH agonists + anti-oestrogen + chemotherapy (experimental arm) versus another treatment.

Data collection and analysis: 

Data were collected from trial reports. We reported 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.

Main results: 

We identified 14 randomised trials that involved over 13,000 premenopausal women with operable breast cancer, most of whom were ER+. The numbers of trials making the different comparisons were:

(A) i. LHRH versus tamoxifen (three trials),

ii. LHRH versus chemotherapy (four trials);

(B) i. LHRH + tamoxifen versus tamoxifen (two trials),

ii. LHRH + tamoxifen versus LHRH (three trials),

iii. LHRH + tamoxifen versus chemotherapy (two trials),

iv. LHRH + aromatase inhibitor versus LHRH + tamoxifen (one trial);

(C) i. LHRH + chemotherapy versus LHRH (one trial),

ii. LHRH + chemotherapy versus chemotherapy (five trials);

(D) LHRH + tamoxifen + chemotherapy versus chemotherapy (three trials).

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.

(A) LHRH monotherapy: results suggest that adjuvant LHRH agonist monotherapy is similar to older chemotherapy protocols (eg. CMF) in terms of recurrence-free and overall survival in ER+ patients. There are insufficient data to compare LHRH agonist monotherapy to tamoxifen alone, but available results suggest that these treatments are comparable in terms of recurrence-free survival.

(B) LHRH + anti-oestrogen therapy: there are insufficient data to compare the combination of an LHRH agonist plus tamoxifen to tamoxifen alone. Results suggest that the LHRH agonist plus tamoxifen combination may be superior to an LHRH agonist alone or to chemotherapy alone, but the chemotherapy protocols tested are outdated. The data comparing LHRH agonists plus aromatase inhibitors to LHRH agonists plus tamoxifen are currently inconclusive.

(C) LHRH + chemotherapy: there are insufficient data to compare the LHRH + chemotherapy combination to an LHRH agonist alone, although results from a single study suggest comparable efficacy in ER+ patients. There is a trend towards improved recurrence-free and overall survival in patients who received an LHRH agonist plus chemotherapy combination in comparison to chemotherapy alone.

(D) LHRH agonist + chemotherapy + tamoxifen: there is a trend towards improved recurrence-free and overall survival in patients who received an LHRH agonist plus tamoxifen plus chemotherapy in comparison to chemotherapy alone.

There are insufficient data to assess the effect of the addition of LHRH agonists to the current standard treatment of chemotherapy plus tamoxifen.

Endocrine therapy with LHRH agonists appears to have fewer side-effects than the forms of chemotherapy assessed. The optimal duration of LHRH therapy in the adjuvant setting is unclear.

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