Tamoxifen: A Review of its Pharmacological Properties and Therapeutic Use in the Treatment of Breast Cancer

Abstract

Synopsis: Tamoxifen1 is a triphenylethylene oestrogen antagonist which has partial oestrogen agonist activity in some species. Most therapeutic trials with tamoxifen have involved postmenopausal women with advanced breast cancer, about 25 to 60% of patients showing some improvement while receiving treatment (usually 20 or 40mg daily); however, poorly defined assessment criteria in some studies make it difficult to compare the results of different authors. 7 to 18% of patients have had complete clinical remissions lasting for a few months to several years. Although few comparative studies with other treatments have been done, it nevertheless appears that tamoxifen is at least as effective as standard oestrogen or androgen therapy in postmenopausal women, while producing a lower incidence of troublesome adverse effects. In the only comparison with a cytotoxic treatment regimen, the response rates with tamoxifen and cytotoxic therapy were similar (41% versus 50%) in patients who were more than 5 years postmenopausal and had primarily soft-tissue involvement; but in patients who were within 2 to 5 years of their last menstrual period cytotoxic treatment was more effective. Similarly, most authors have reported a higher response rate with tamoxifen in women several years postmenopausal than in those more recently postmenopausal. Tumours which contain oestrogen receptors respond more often to tamoxifen than those which do not. Administering tamoxifen concomitantly with other chemotherapeutic agents such as cytotoxic drugs appears to increase the response rate, but as might be expected also increases the incidence of adverse reactions. When used alone tamoxifen has been relatively well tolerated in all studies, the overall withdrawal rate due to side-effects being less than 3 %. Pharmacodynamic Studies: In most animal species tamoxifen exerts antioestrogenic actions, although in some tests in rodents it produces weak or atypical oestrogenic reactions and it has appeared to produce some oestrogen-like effects in a few women receiving therapeutic doses. Tamoxifen inhibited or reversed the growth of some chemically-induced tumours in rats and decreased the frequency of tumour development when given concurrently with the carcinogenic agent dimethylbenzanthracene. In in vitro studies using human mammary tumour cell cultures, tamoxifen inhibited cellular reproduction when added to the culture medium of tumours containing oestrogen receptors, but had little or no effect in the absence of oestrogen receptors. The mechanism of its antioestrogenic as well as its antitumour activity probably involves competition with oestradiol for oestrogen receptor sites, preventing typical oestrogenic actions including oestrogen-stimulated nucleic acid synthesis. Pharmacokinetic Studies: The absorption of orally-administered tamoxifen has not been well studied in humans, but maximum plasma levels of drug appear to occur several hours after oral ingestion. Distribution studies showing the extent of tumour uptake of tamoxifen have not been done. In animals the ovaries retained more radioactivity than other reproductive organs after a single labelled dose; and in the small number of patients who have been thus studied radioactivity in the uterus was higher than in serum 4 to 96 hours after a labelled dose. Metabolism studies in animals have shown hydroxylation to be the major metabolic route, the monohydroxylated metabolite being more active as an antioestrogen than tamoxifen, while the dihydroxylated metabolite was only weakly active. In animals the bile was an important route of elimination of radioactivity after a labelled dose, with subsequent reabsorption of some of the biliary radioactivity. Excretion in humans appears to occur slowly, primarily via the faeces, the elimination half-life being more than 7 days in the few patients studied thus far. Therapeutic Trials: Most trials with tamoxifen have been noncomparative studies in postmenopausal women with advanced, recurrent breast cancer. In many studies, varying criteria of response and a lack of sufficient information on factors such as time of evaluation and type and time of stopping previous treatment make comparisons of the individual study results difficult. However, in most studies about 25 to 60 % of patients have shown some response to treatment and 7 to 18% of patients have achieved complete remissions lasting for a few months to as long as several years. It thus appears that tamoxifen is at least as effective as standard hormonal therapy in postmenopausal women, although direct comparisons with these agents have not yet been reported. In a single comparison with a cytotoxic regimen, tamoxifen and cytotoxic treatment were comparably effective (41% and 50% response rates, respectively) in women more than 5 years postmenopausal who had primarily soft-tissue involvement; but cytotoxic therapy was more effective in women who were within 2 to 5 years of their last menstrual period. Indeed, many other authors have similarly reported that women several years postmenopausal respond more frequently to tamoxifen than those more recently postmenopausal. The number of premenopausal women treated to date is too small to clearly determine their response rate as compared with postmenopausal patients. In most trials in which oestrogen receptor studies were done, there was a correlation between the presence of oestrogen receptors and a response to tamoxifen, although a few patients with oestrogen receptor-negative tumours have responded. As with other hormonal treatments of breast cancer, visceral metastases have responded less frequently than soft tissue, skin or, in some cases, bone involvement. Combining tamoxifen with cytotoxic chemotherapy or with other hormonal agents, appears to increase the response rate as well as the incidence of serious adverse effects. Side-Effects: Tamoxifen has been well tolerated in most postmenopausal patients studied, the overall incidence of withdrawal from treatment due to adverse effects being less than 3%. The most common side-effects are due to the drug’s antioestrogenic actions, and include hot flushes (10 to 20%) and less frequently pruritus vulvae and vaginal bleeding or discharge. Nausea and vomiting have been reported in about 10% of patients. Pain from bone metastases, especially during the early stage of therapy, has been reported by some patients but was often followed by a response to tamoxifen. Transient blood abnormalities (thrombocytopenia, mild leukopenia, decreased haemoglobin) have occurred but have not necessitated discontinuing treatment. Pulmonary emboli have been reported in a few cases during tamoxifen administration, but a causal relationship with drug treatment has not been clearly established. Dosage: The recommended starting dosage of tamoxifen is 10mg twice daily. If a response does not occur within 1 month, the dose should be increased to 20mg twice daily. © 1978, ADIS Press. All rights reserved.