Tamoxifen

Summary

Synopsis

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.

Pharmacodynamic Studies

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.

Pharmacokinetic Studies

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.

Therapeutic Trials

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 apparent in women over 50 years, in whom a highly significant 5.7% absolute difference from controls in 5-year survival was observed. Although a clear benefit in survival was not demonstrated for women under 50, it was not precluded by the limited available data, which involved only 1062 younger women receiving tamoxifen alone without chemotherapy. More prolonged adjuvant therapy with tamoxifen appeared to be more effective, but not significantly so. In several recently published trials an overall survival benefit was observed, independently of menopausal and oestrogen-receptor status, although other trials have reported a highly significant correlation of treatment effect with oestrogen receptor status. In a comparison with adjuvant irradiation menopause in premenopausal patients, a trend towards increased overall survival with tamoxifen was apparent. Adjuvant trials comparing cytotoxic chemotherapy with chemotherapy plus tamoxifen have provided evidence of significant benefit in overall survival with the combination regimen only in women 50 years of age or older, with some indication of an adverse effect of the regimen including tamoxifen on survival of women younger than 50 whose primary tumours were oestrogen or progesterone receptor-negative. The inclusion of tamoxifen has significantly prolonged disease-free survival in most trials, particularly in patients who were postmenopausal, those oestrogen receptor-positive, and those with a greater degree of nodal involvement. Further enhancement of disease-free survival was apparent in a trial which extended the duration of adjuvant treatment to a third year, with the benefit accruing principally to patients 50 years and older, irrespective of the degree of nodal involvement. Trials of chemoendocrine adjuvant therapy with or without concomitant tamoxifen have not so far conclusively indicated benefit with the addition of tamoxifen, but further follow-up is required. The addition of tamoxifen to chemotherapy may be disadvantageous in younger receptor-negative patients. A trial comparing tamoxifen plus radiotherapy with radiotherapy alone in 961 postmenopausal patients demonstrated significantly greater relapse-free survival at 6 years with tamoxifen, especially in oestrogen receptor-positive patients, those with well-differentiated primary tumours, with 4 or more nodes involved, and patients aged 50 to 59 years. There was, however, no significant difference in overall survival according to treatment regimen.

In treatment of advanced breast cancer, response rates to tamoxifen and ovarian ablation in premenopausal patients are similar, at 20 to 40%, with a similar duration of response. In postmenopausal patients, the response rate, which increases with patient selection for oestrogen receptor positivity, is similar to that observed with oestrogens, progestins and androgens, and with the aromatase inhibitor aminoglutethimide, but the incidence of adverse effects reported with other additive endocrine therapies is significantly greater than that observed with tamoxifen. Use of combination therapy with fluoxymesterone has provided no advantage over tamoxifen alone in 1 study while a greater number of adverse effects of combination treatment were reported. Trials comparing tamoxifen plus cytotoxic chemotherapy with tamoxifen or chemotherapy alone in postmenopausal patients have not demonstrated any advantage of concurrent treatment, over sequential tamoxifen and chemotherapeutic regimens. Uncontrolled trials have indicated tamoxifen to be of benefit in primary treatment of elderly and frail patients. One recent report of a randomised comparison with surgery described similar rates of local relapse or progression with either treatment, but a second randomised study reported a higher rate of local progression with tamoxifen and a requirement for subsequent surgery in 40% of patients receiving tamoxifen. A trial comparing tamoxifen with radiotherapy in such patients reported a similar incidence of disease progression at 6 months with either therapy, with no difference in time to development of distant metastases or in survival at 30 months’ follow-up.

Response rates to tamoxifen in a small number of male patients with breast cancer were around 40%, with a benefit in survival apparent in a trial of tamoxifen following surgery. Survival benefit was also demonstrated in 2 small trials of tamoxifen in pancreatic carcinoma, while responses in small trials in prostatic, ovarian, renal and colorectal carcinomas have not been impressive, and preliminary data regarding the use of tamoxifen in malignant melanoma are inconclusive.

Ovulation is achieved in around 70% of patients with anovulatory infertility following tamoxifen treatment, with rates of subsequent pregnancy, where assessed, ranging from 15 to 60%. Administration of tamoxifen to men with idiopathic oligospermia has been associated with subsequent pregnancy rates in partners of 20 to 34%.

There is at present considerable interest in the potential of tamoxifen in treatment of benign breast disease. Resolution of symptoms was apparent in 70 to 90% of patients with mastalgia receiving tamoxifen, in 2 preliminary controlled trials, and further investigations are in progress.

Adverse Effects

Tamoxifen is in general very well tolerated, and discontinuation of therapy because of adverse effects is rarely necessary. The most frequent adverse effects include hot flushes, nausea and/or vomiting, and vaginal bleeding or discharge, while menstrual disturbances occur in a significant proportion of premenopausal patients. Haematological changes such as thrombocytopenia and leucopenia are reported infrequently, but the relationship to treatment is uncertain. CNS disturbances including dizziness, lethargy and depression have also been described, although infrequently. Disease ‘flare’ is apparent in a number of patients early in therapy, but is not necessarily an indication for treatment withdrawal. Thromboembolic events have been reported very rarely, and in contrast, potentiation of the anticoagulant effect of warfarin; ocular disturbances, generally in association with very high dosages, have also been described in rare instances.

Dosage and Administration

The recommended dosage of tamoxifen, in advanced breast cancer and as adjuvant therapy, is 10mg twice daily, administered orally, increasing to 20mg twice daily if no response. The optimal duration of adjuvant therapy remains to be established, but at present it appears that longer, or indeed indefinite, treatment may be desirable. Tamoxifen should not be administered during pregnancy.