Tamoxifen

Abstract

Tamoxifen, a non-steroidal antioestrogen, represents a significant advance in treatment of female breast cancer. In trials of tamoxifen as postsurgical adjuvant treatment of early breast cancer, disease-free survival is consistently prolonged, representing an enhanced quality of life in association with tamoxifen’s favourable adverse effect profile. Moreover, overview analysis indicates a survival benefit of approximately 20% at 5 years for all women, most clearly evident in women over 50 years, while a survival benefit independent of menopausal, nodal or oestrogen receptor status has been demonstrated in some individual trials. Thus, for postmenopausal women, tamoxifen is clearly optimal adjuvant treatment, although the relative benefit of adjuvant chemotherapy in node-negative patients requires clarification. A survival benefit for women under 50 has not been clearly demonstrated in overview analysis, but is not precluded by these rather limited data, and adjuvant treatment of premenopausal women with tamoxifen may also warrant serious consideration. Response rates to tamoxifen in advanced breast cancer are around 30 to 35%, increasing with patient selection for oestrogen receptor positivity. Tamoxifen must be regarded as first-line endocrine treatment in postmenopausal women, and may represent an alternative to first-line ovarian ablation in premenopausal women. An emergent role in primary therapy of elderly and frail patients with operable disease is apparent. Tamoxifen is also of benefit following surgery in male breast cancer, and may have a role as first-line endocrine treatment. Tamoxifen also has a potential role in other hormone-sensitive malignancies such as pancreatic carcinoma, and in treatment of benign breast disease. Finally, tamoxifen has a place in treatment of male and female infertility. Tamoxifen is very well tolerated, and discontinuation of therapy because of adverse effects is rarely necessary. The most frequent adverse effects are related to the drug’s anti-oestrogenic activity, and include hot flushes, nausea and/or vomiting, vaginal bleeding or discharge, and menstrual disturbances in premenopausal patients. Thus, tamoxifen continues to play a major role in management of female breast cancer in both early and advanced stages of disease, with a place also in treatment of male breast cancer and of infertility. Tamoxifen is the trans isomer of a triphenylethylene derivative, and is administered orally as the citrate salt. Tamoxifen exhibits complex pharmacological properties, acting as an oestrogen antagonist, or partial or full agonist, depending on the target tissue and the species studied. Predominantly antioestrogenic and partial oestrogenic effects are apparent in humans and in rats, antioestrogenic effects in the chick, and fully oestrogenic effects in the mouse and in the dog. A number of metabolites are active; the N-demethyl metabolite may contribute to the activity of the parent compound in vivo. The tumour growth inhibitory actions of tamoxifen have been investigated in vitro principally using the oestrogen-responsive MCF-7 human breast cancer cell line; in addition there has been extensive research using the DMBA-induced rat mammary carcinoma model. The precise mechanism of tamoxifen’s antitumour activity remains elusive. The classical account involves competitive blockade by tamoxifen of sites on the oestrogen receptor; however, recently the emphasis of research has shifted to address effects of tamoxifen on tumour growth of which postulated mediators include polypeptide growth factors, a specific anti-oestrogen binding site, protein kinase C, and calmodulin. Tamoxifen has complex effects at the hypothalamic-pituitary level, the clinical significance of which is unclear. An elevation in plasma oestrogen levels has been observed in premenopausal patients. Tamoxifen generally exerts weak oestrogen-like effects in postmenopausal patients, with reduction in circulating gonadotrophin and prolactin levels and increases in serum pregnancy zone protein and sex hormone-binding globulin. Other effects reported, of uncertain clinical significance, include reduction in functional antithrombin III activity and increases in serum high density lipoprotein cholesterol; tamoxifen appears not to exert adverse effects on bone mineral content. Data regarding the pharmacokinetics of tamoxifen in humans are incomplete. Following administration of a single oral dose, maximum plasma concentrations of the parent drug and the demethyl metabolite are achieved within several hours. However, with chronic administration, steady-state concentrations are not attained for 3 to 4 weeks. Tamoxifen is highly plasma protein bound at therapeutic concentrations. It undergoes extensive hepatic metabolism; N-demethylation is the principal metabolic pathway, with subsequent sidechain deamination to the primary alcohol. The fraction of the dose excreted as unchanged drug in urine is negligible. Biliary excretion is the main route of elimination; elimination appears to be biphasic, with an initial phase of 7 to 14 hours, and a terminal phase of around 7 days. During the past decade, tamoxifen has been the subject of extensive clinical research in the treatment of female breast cancer. Over 40 trials of tamoxifen as postsurgical adjuvant therapy of early breast cancer are currently in progress. Results published so far consistently indicate prolonged disease-free survival with tamoxifen monotherapy vs no adjuvant treatment or tamoxifen as treatment of first relapse. Furthermore, significant benefit in overall survival is now apparent. An overview analysis of 28 adjuvant trials in a total of 16,513 women reported a reduction in 5-year mortality of 16% among women of all ages. The effect was most...