I was under the impression that the oral availabilty was quite low thus the need for a transdermal delivery.
FORMESTANE
SUMMARY SHEET
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TRADE NAME: Lentaron
Licensed Indications:
‘Treatment of advanced breast cancer in women with natural or artificially induced post-menopausal status’.
Background Information
In western societies breast cancer is the most common form of cancer in women, with 10-12% of women developing the disease and 3-5% dying from it.1 There are about 25,000 new cases of breast cancer diagnosed annually in the UK, resulting in 13-15,000 deaths each year; two-thirds of these cases occur in women over the age of 50.2
Advanced breast cancer is an incurable disease with a poor prognosis. The growth of a large proportion of metastatic breast tumours is dependent on hormonal stimulation. Endocrine therapy, therefore, plays a key role in the treatment of breast cancer, reducing the oestrogen supply to the tumour cell. In postmenopausal women, oestrogens are produced mainly by the conversion of androstenedione and testosterone to oestrone and oestradiol respectively. Aromatase inhibitors prevent the peripheral conversion of androgens to oestrogens by inhibiting the aromatase enzyme.
Current first-line endocrine treatment is with oral tamoxifen, an antioestrogen. Tamoxifen causes tumour regression in approximately 30% of patients treated, and about 60% of patients whose tumours are oestrogen receptor (ER) positive.3,4 However, some patients fail to respond to tamoxifen (‘de novo resistance’) or relapse after responding (‘acquired resistance’). In these cases, subsequent hormonal treatment should be investigated.
Dosage and administration
Oral formestane does not suppress aromatase to the same degree as parenteral treatment. Administration is therefore by depot intramuscular injection given every two weeks.
Clinical Efficacy
In early studies, formestane was investigated as second or third-line therapy in women who had been heavily pre-treated with tamoxifen, progestogens or aminoglutethamide. More recently, the efficacy of formestane has been compared with that of tamoxifen as first-line endocrine therapy for advanced breast cancer.
In these trials the efficacy of formestane was usually evaluated in terms of ‘complete’ and ‘partial’ response to therapy according to the criteria adopted by the World Health Organisation (WHO)5:-
Complete response(CR): disappearance of all known disease
Partial response (PR): ³ 50% reduction in measurable lesions and no appearance of new lesions or progression of any lesion
Objective response (OR): sum of complete and partial responses
Disease stabilisation/No change (NC): < 50% decrease or < 25% increase in the size of measurable lesions
Progressive disease (PD): ³ 25% increase in size of one or more measurable lesions or the appearance of new lesions.
Efficacy as second- or third-line endocrine therapy
In phase II non-comparative trials6-9 investigating the efficacy of formestane, objective response rates (complete + partial response) ranged from 22 to 39% in patients treated with formestane 250mg i.m. every two weeks. The percentage of patients experiencing a complete response ranged from 0 to 12% and partial responses were reported in 16 to 39%. Responses were maintained for a median of 8 to 13 months.
Efficacy as first-line endocrine therapy.
One randomised, controlled study of 409 patients compared formestane with tamoxifen as first-line hormonal therapy in postmenopausal women with advanced breast cancer of unknown receptor status.10 An objective response was reported in 33% of patients treated with formestane and 37% treated with tamoxifen. A complete response was reported in 8% and 6% and a partial response in 25% and 31% of patients respectively. The median duration of response was 458 and 604 days respectively. There were no statistically significant differences between therapy in any of these response rates. There was no statistically significant difference between treatments for survival (35 months for formestane and 38 months for tamoxifen). For time to disease progression and time to treatment failure, however, tamoxifen was statistically superior (p £ 0.01) to formestane.
Adverse Effects
Intramuscular formestane was well tolerated in clinical trials by the majority of postmenopausal patients with advanced breast cancer. Local adverse effects at the injection site have been reported in about 7% of patients. The most common adverse events experienced by patients treated with formestane were hot flushes, nausea and vomiting, lethargy, skin rash/itching. Other adverse events reported include dizziness, drowsiness, headache, peripheral oedema, thrombophlebitis, muscle cramps, arthralgia and, rarely, anaphylactoid reactions. There has been one report of hypoglycaemia associated with formestane treatment.11
Conclusion
Formestane showed similar systemic efficacy and tolerability to tamoxifen as first-line therapy. Tamoxifen, being orally administered and well established, is generally more acceptable for first-line therapy. As second or third-line therapy, phase II non-comparative studies showed an objective response rate with formestane of between 22 and 39%. No published studies have directly compared formestane with other second-line therapies.
References
Harris JR, Lippman ME, Veronesi U & Willett W. Breast Cancer (First of Three Parts). NEJM. 1992; 327: 319-28.
Smellie WJB & Sacks NPM. Recent advances in the treatment of breast cancer. Postgrad.Med.J. 1994; 70: 243-246
Pritchard K. Breast cancer: the real challenge. Lancet 1997; 349: (124-126)
Jones A. Hormonal Therapy and Immunotherapy for Cancer. Medicine 1995; 430-432.
Miller AB, Hoogstraten B, Staquet M & Winkler A. Reporting results of cancer treatment. Cancer, 1981; 47: 207-214.
Bajetta E, Zilembo N, Buzzoni R, et al. Endocrinological and clinical evaluation of two doses of formestane in advanced breast cancer. Br J Cancer 1994; 70: 145-150.
Possingere K, Jonat W & Hoffken K. Formestane in the treatment of advanced postmenopausal breast cancer. Ann.Onc. 1994; 5 (Suppl.7): S7-S10.
Murray R & Pitt P. Treatment of advanced breast cancer with formestane. Ann.Onc. 1994; 5 (Suppl.7): S11-S13.
Bajetta, Zilembo N, Buzzoni R, et al. Formestane: Effective therapy in postmenopausal women with advanced breast cancer. Ann.Onc. 1994; 5 (Suppl.7): S15-S17.
Perez Carrion R, Alberola Candel V, Calabresi F, et al. Comparison of the selective aromatase inhibitor formestane with tamoxifen as first-line hormonal therapy in postmenopausal women with advanced breast cancer. Ann.Onc. 1994; 5 (Suppl.7): S19-S24.
Brankin E, Gallagher A & Soukop M. Hypoglycaemia associated with formestane treatment. BMJ 1997; 314: 869-870.
Date: September 1997 SS97/20
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