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Erschienen in:
01.12.2005 | Adis Drug Evaluation
Goserelin
A Review of its Use in the Treatment of Early Breast Cancer in Premenopausal and Perimenopausal Women
Erschienen in: Drugs | Ausgabe 18/2005
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Abstract
Goserelin (Zoladex®), a gonadotropin-releasing hormone analogue, reduces plasma/serum estrogen levels in pre- or perimenopausal women (to postmenopausal levels), and is indicated in hormone receptor-positive early breast cancer in this population group.
Adjuvant goserelin monotherapy has similar efficacy to adjuvant chemotherapy in pre- or perimenopausal women with early, hormone receptor-positive breast cancer. Furthermore, the addition of goserelin to adjuvant chemotherapy appeared to offer an advantage over chemotherapy alone in younger patients. Fewer patients remained amenorrheic after goserelin therapy than after chemotherapy. Complete endocrine blockade provided by the addition of tamoxifen to therapy including goserelin appears to improve outcomes.
Thus, goserelin offers a valuable addition to the currently available options for treating pre- or perimenopausal women with hormone therapy-responsive early breast cancer, particularly for women wishing to regain ovarian function after treatment.
Pharmacological Properties
Goserelin is a gonadotropin-releasing hormone (GnRH) analogue. Initial occupation of GnRH receptors by goserelin results in a transient increase in plasma/ serum luteinising hormone and follicle-stimulating hormone levels. The subsequently decline to pretreatment levels or lower within 3 weeks of continued goserelin administration because of drug-induced downregulation of the anterior pituitary gland. This results in a decrease in plasma/serum estradiol levels to within the postmenopausal range generally within 14 days of depot administration.
Formulated as a biodegradable sustained-release depot injection, goserelin 3.6mg is administered subcutaneously every 28 days. In women with gynaecological disorders, the mean peak serum concentration (1.35–1.84 μg/L) was reached 12–15 days after administration of goserelin; there was no accumulation of the drug with monthly injections for up to 6 months. Protein binding of goserelin in human plasma is low. The release of goserelin from the depot formulation was complete over a 4-week period.
After extensive metabolism, goserelin is excreted primarily in the urine. Mean total body clearance in women with gynaecological disorders was 8.68–9.65 L/h after goserelin 3.6mg administered as single or multiple depot injections.
Therapeutic Efficacy
The efficacy of goserelin in the adjuvant treatment of early breast cancer in premenopausal or perimenopausal women has been evaluated in several randomised, multicentre, nonblind trials (n = 244–2710), which included patients with hormone receptor-positive (GROCTA 02, ABCSG 5 and INT 0101 trials) or mixed receptor status (IBCSG VIII, ZIPP, ZEBRA and MAM1 trials) disease.
Goserelin was equivalent to chemotherapy in terms of disease-free survival in women with hormone receptor-positive early breast cancer in the ZEBRA and IBCSG VIII trials. While adjuvant chemotherapy followed by goserelin was no better than chemotherapy alone in the overall trial population with hormone receptor-positive breast cancer (INT 0101 and IBCSG VIII), the addition of goserelin may have improved outcomes for a subgroup of women aged <40 years, possibly due to the induction of amenorrhoea in women who still remain premenopausal after chemotherapy.
Two trials (INT 0101 and MAM1) indicated that the addition of tamoxifen to chemotherapy plus goserelin would improve outcomes in women with early breast cancer. Adjuvant therapy with goserelin with or without tamoxifen improved standard care; goserelin plus tamoxifen was superior to chemotherapy in women with hormone receptor-positive breast cancer in the ABCSG 5 trial and outcomes were improved by the addition of goserelin to chemotherapy with or without tamoxifen in the ZIPP trial.
Goserelin is not effective in women with hormone receptor-negative, early breast cancer. In subgroup analyses, chemotherapy was superior to goserelin monotherapy (ZEBRA trial), and chemotherapy followed by goserelin was superior to goserelin monotherapy (IBCSG VIII).
Tolerability
Subcutaneous goserelin (alone or in combination with oral tamoxifen) was well tolerated in the treatment of early breast cancer in premenopausal or perime-nopausal women. The most common adverse events in the goserelin-containing treatment arms were those related to the pharmacological effects of estrogen suppression (e.g. vaginal dryness and hot flashes [flushes]).
In the 2-year ZEBRA trial, the incidence of menopausal-like adverse events (e.g. vaginal dryness and hot flashes) was higher in the goserelin than cyclophosphamide, methotrexate and fluorouracil (CMF) treatment groups at 24 weeks and 2 years (i.e. when most goserelin recipients had amenorrhoea). There was a marked reduction in menopausal-like adverse events 1 year after the cessation of goserelin treatment, which corresponded with the reversal of amenorrhoea in most patients.
Bone mineral density (BMD) loss is associated with ovarian suppression that results in amenorrhoea. Reductions in BMD were generally significantly greater in patients receiving goserelin than in those receiving CMF. Partial recovery of BMD was evident with the return of ovarian function in most patients 1 year after the cessation of goserelin treatment, whereas BMD losses continued in patients in the CMF treatment arm. The demineralising effects of goserelin may be reduced with the addition of tamoxifen to treatment regimens.