Goserelin

Summary

Synopsis

Goserelin is a synthetic analogue of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH); or gonadorelin] which stimulates gonadotrophin and sex hormone release in the short term, and then causes suppression with continued administration. Goserelin is given as a subcutaneous biodegradable depot incorporating 3.6mg of the drug, which is released continuously at an average rate of 120 jug/day over 4 weeks.

Monthly goserelin depot therapy produces partial disease remission or stabilisation in about 75% of men with previously untreated prostatic cancer, a rate equivalent to that achieved with orchidectomy or diethylstilbestrol (stilboestrol). The response to goserelin is more rapid than to diethylstilbestrol, and goserelin is better tolerated. About 30 to 45% of premenopausal women with breast cancer responded to goserelin using objective assessment criteria, suggesting comparability to ovariectomy. In benign hormone-dependent conditions, preoperative goserelin aids surgical removal of uterine leiomyoma [fibroids) and reduces blood loss, and 6 months of therapy relieves the signs and symptoms of endometriosis.

The elevation in testosterone at the beginning of goserelin therapy can result in disease ‘flare’ in men with prostate cancer, and sex steroid suppression with continued treatment results in hot flushes and loss of libido in most patients.

Thus, goserelin is an effective alternative to surgery or estrogen therapy in prostatic cancer palliation, and possibly to ovariectomy in premenopausal breast cancer. Other gynaecological conditions reliant on the pituitary-gonadal axis also appear amenable to hormone manipulation with goserelin.

Pharmacodynamic Properties

The synthetic GnRH analogue goserelin acts as an agonist that is about 100 times more potent than the naturally occurring hormone. When given in the short term, goserelin stimulates the anterior pituitary gland to release luteinising hormone (LH) and follicle-stimulating hormone (FSH). With continual administration, GnRH receptor numbers decrease, the pituitary becomes desensitised and gonadotrophin release declines.

In both men and women, serum LH and FSH levels initially increase following subcutaneous bolus or slow-release depot goserelin administration, reaching a peak after 2 or 3 days. Levels decrease to pretreatment values or below within 14 days if goserelin administration is continued. Suppression of LH release is usually greater than that of FSH, and the biological activity of LH may be diminished. The pituitary response to exogenous GnRH is also considerably blunted by goserelin administration.

As a result of the effects on LH, testicular testosterone synthesis is maximal within 4 days of beginning goserelin administration, and then decreases to routinely reach castrate levels (≤ 2 nmol/L) within a month. Goserelin depot 3.6mg administered subcutaneously every 28 days results in a more rapid and consistent suppression of testosterone release than lower depot doses or daily subcutaneous injections of 100 or 250μg. Prolonging the interval between depots beyond 4 weeks can lead to a re-establishment of pituitary sensitivity to endogenous GnRH and normal LH and hence testosterone production. With continued treatment, castrate levels have been sustained for 2.5 years or more.

In women, goserelin depot 3.6mg inhibits ovarian androgen production, but persistent serum levels of dihydroepiandrosterone sulphate, and to a lesser extent androstenedione, demonstrate that adrenal androgen synthesis is preserved.

Ovarian estradiol release increases slightly 3 days after administration of goserelin 3.6mg depot in premenopausal women and then decreases within 2 weeks to levels normally found during the early follicular phase of the cycle. Ovulation and luteinisation are prevented and progesterone synthesis abolished. Estrogen production is inhibited to a lesser extent in postmenopausal women, since it occurs largely through peripheral aromatisation of androgens.

Goserelin has demonstrated in vitro activity against the estrogen-dependent MCF-7 human breast cancer cell line and LNCaP-2 prostate cancer cells. In vivo, mammary tumours induced by dimethylbenz(α)anthracene (DMBA), and the Dunning R3327H prostate tumours are sensitive to goserelin. The activity of goserelin 1 or 10 Mg/day was equivalent to tamoxifen 100 μg/day in estrogen-dependent DMBA-induced tumours.

Pharmacokinetic Properties

Goserelin is inactivated if given orally because of degradation by gastrointestinal peptidases, and is therefore administered subcutaneously. Daily injections with an aqueous solution of the drug have been superseded by a depot formulation injected subcutaneously in the abdominal wall which releases goserelin 3.6mg at a continuous mean rate of 120 μg/day from a biodegradable poly (d,/-lactide-co-glycolide) polymer rod over a period of 28 days. There is an initial evanescent peak serum concentration of 0.2 to 2 μg/L within 2 to 8 hours of administering a goserelin 3.6mg depot, and a second peak 14 to 15 days later of about 2 to 3 μg/L. The serum drug concentration then steadily declines as the depot becomes exhausted. Fluctuation in serum concentrations is negligible, giving a satisfactory degree of pituitary-gonadal axis suppression.

Goserelin is distributed into extravascular fluid, and has a volume of distribution approximating the extracellular fluid volume, implying limited plasma protein binding. Following subcutaneous administration to animals, several hexa- and heptapeptide metabolites of goserelin have been detected in serum and urine; in animals and humans, excretion is mainly in the urine. Total body clearance is reduced by about 75% and elimination half-life increased 2- or 3-fold in patients with severe renal impairment, but dosage adjustment is not deemed necessary.

Therapeutic Use

Treatment with monthly subcutaneous depots of goserelin 3.6mg is now established in prostate cancer palliation, and has been investigated in women with breast cancer, and the benign gynaecological conditions of uterine leiomyoma (fibroids) and endometriosis.

The original dosage and formulation of goserelin, subcutaneous injections of 250 μg/day, yielded objective, mainly partial, responses in 60 to 80% of men with previously untreated prostatic cancer in early trials. The advent of the sustained release subcutaneous depot of goserelin 3.6mg, injected every 4 weeks, rendered the daily injection regimen obsolete. Phase II studies show that monthly depot administration of goserelin 3.6mg produces a partial objective remission in about 50% of patients and disease stabilisation in another 25%, although the relative proportion of patients assigned to one or other of these categories may depend on the assessment criteria. Complete responses have occurred in 3 to 15% of men with stage D prostate cancer. Objective responses are noted within 8 to 12 weeks of commencing therapy, and persist for a median of 5 to 14 months. Patients with histologically well differentiated tumours respond more frequently and for longer periods than do their counterparts with anaplastic tumours. Nearly 70% of symptomatic patients respond subjectively to goserelin therapy, as defined by a decrease in bone pain, analgesic use and urinary outlet obstruction, or improvement in performance status. Randomised phase III clinical trials reveal that goserelin is of equivalent efficacy to orchidectomy, but is psychologically more acceptable to most patients. Similarly, goserelin is comparable to oral diethylstilbestrol 1mg 3 times daily or fosfestrol (diethylstilbestrol diphosphate) 300mg daily in producing disease remission or stabilisation and symptom relief, but induces an objective response more rapidly. Concomitant use of an antiandrogen, such as flutamide 750 mg/day, does not appear to improve response rates or prolong survival but may aid symptom relief and attenuate disease ‘flare’ at the beginning of goserelin treatment in previously untreated patients. Goserelin plus an antiandrogen may elicit a partial response or stabilisation in some of the 20 or 30% of patients who fail to respond to goserelin alone, although this requires confirmation in larger studies.

About 30 to 45% of premenopausal women, mostly with metastatic breast cancer, have demonstrated an objective remission during monthly treatment with goserelin 3.6mg depot, and 8 to 28% had disease stabilisation, a rate apparently similar to that achieved with ovariectomy, although direct comparative data are lacking. Far fewer postmenopausal women have benefited from goserelin, but the period of remission or stabilisation is similar (at least 6 months) irrespective of menopausal status. Women assessed as having estrogen receptor (ER)-positive tumours are more likely to respond to goserelin therapy than those with ER-negative tumours. The predominant mechanism of action of goserelin in premenopausal women with ER-positive disease is estrogen suppression. However, a direct antitumour effect has also been proposed, since postmenopausal women occasionally responded to goserelin without a substantial change in circulating estrogens compared with nonresponders, as did several premenopausal women assessed as having ER-poor or ER-negative tumours.

Preliminary data suggest that coadministration of an aromatase inhibitor may be beneficial in some pre- and postmenopausal patients in whom the low level of estrogens produced peripherally (and therefore relatively unaffected by goserelin) is sufficient to sustain tumour progression. However, this approach has not been investigated sufficiently to recommend its use at present. The clinical benefit of giving tamoxifen to women in whom the menopause has been simulated by goserelin therapy also requires further qualification, but preliminary data imply an extension of time to disease progression compared with goserelin alone.

A promising use for goserelin depot is in the pretreatment of women undergoing surgery for leiomyoma (fibroid) removal. Three or 4 months’ preoperative goserelin therapy facilitated surgical excision of myomas and reduced intraoperative blood loss by 15 to 40%. This adjunctive role is likely to be the main use for goserelin in women with fibroids. Although the uterine volume of women with myomas was decreased by a mean of 40 to 55% after 3 to 6 months’ depot administration of goserelin 3.6mg, individual responses were highly variable. Most of the shrinkage occurred during the first 4 months of treatment. Importantly, the pretreatment uterine volume was regained and menses resumed within 3 months of stopping therapy, indicating a need for continuous goserelin treatment to maintain leiomyoma degeneration. Longer term goserelin therapy should thus be reserved for treating women with myomas who are not candidates for surgery or those nearing the menopause, since prolonged estrogen suppression should be avoided if possible. Oral hormone replacement therapy with medroxyprogesterone or conjugated estrogens and progestins, after myomas have regressed during goserelin monotherapy, limits hypoestrogenism, thus allowing long term treatment. Goserelin plus tamoxifen resulted in a less marked decrease in uterine volume than goserelin alone, but symptoms were relieved.

Goserelin appears as effective as danazol in women with endometriosis, and seems better tolerated. After 6 months’ goserelin treatment, nearly 70% of women with endometriosis were asymptomatic. The Revised American Fertility Society (RAFS) disease severity score decreased by at least 50%, laparoscopic classification improved and amenorrhoea was established in practically all women.

Small groups of women with polycystic ovary disease, dysfunctional uterine bleeding and/or menorrhagia improved symptomatically during 3 to 4 months’ goserelin treatment, and the drug has been used successfully to facilitate augmented ovulation in an in vitro fertilisation programme.

Adverse Effects

Most of the unwanted effects of goserelin are a result of changes in sex hormone levels. About 4 to 10% of men with prostate cancer experience a ‘flare’ in symptoms, usually bone pain, caused by the initial surge in testosterone synthesis in the first 1 or 2 weeks of goserelin treatment. Ureteric obstruction and spinal cord compression have also occurred rarely. Including an antiandrogen, or diethylstilbestrol, at the start of treatment may limit the severity of ‘flare’

Hot flushes occur in 60 to 80% of men and women as sex hormone synthesis is suppressed by further goserelin therapy. Over 70% of men became impotent or less libidinous, a rate similar to that reported following orchidectomy. Reduced libido and vaginal dryness in women was relatively infrequent; a decrease of 1.5 to 3.7% in spinal and hip bone mineral density has been reported. Gynaecomastia was experienced by 5 to 9% of men with prostatic cancer during goserelin treatment, a significantly lower incidence than with diethylstilbestrol (70% in 1 trial). Goserelin also does not produce the severe cardiovascular adverse effects sometimes associated with diethylstilbestrol. Injection of the goserelin depot occasionally caused pain or bruising, but a local anaesthetic was rarely requested.

Dosage and Administration

In men with prostate cancer, and women with breast cancer, fibroids, endometriosis or other benign sex hormone-related conditions, goserelin is injected subcutaneously into the anterior abdominal wall as a sustained release biodegradable depot of 3.6mg every 4 weeks. Dosage adjustment is not needed in the elderly or renally impaired. Careful consideration should be given to the use of goserelin in men with prostate cancer at risk of developing ureteric obstruction or spinal cord compression. Antiandrogens or diethylstilbestrol 1mg 3 times daily for 1 week before and 1 week after the first depot may reduce the chance of ‘flare’ development in men, and hormone replacement therapy appears to diminish the incidence of hot flushes in women.