Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the 'nordic' phase III study

Abstract

SummaryThe study was planned to compare, in a prospective double-blind randomized trial, the efficacy and safety of toremifene (TOR) and tamoxifen (TAM) in post-menopausal patients with advanced breast cancer who have not had prior systemic therapy for advanced disease. Four hundred and fifteen post-menopausal patients with oestrogen receptor (ER)-positive or ER-unknown advanced breast cancer were randomly assigned to receive daily either 60 mg TOR or 40 mg TAM. The patients were stratified to measurable and non-measurable but evaluable groups. They were assessed for response to therapy, time to progression (TTP), time to treatment failure (TTF), response duration, overall survival and drug toxicity. Two hundred and fourteen patients were randomized into TOR and 201 into TAM treatment. The response rate (complete + partial) was 31.3% for TOR and 37.3% for TAM (P = 0.215). The 95% confidence interval (Cl) for the 6% difference was -15.1% to 3.1%. The median TTP was 7.3 months for TOR and 10.2 months for TAM (P = 0.047). The 95% Cl for the hazard ratio of 0.80 was 0.64-1.00. A percentage of the TOR patients (9.8%) and the TAM patients (18.9%) discontinued the treatment prematurely (P = 0.011) for various reasons. Consequently, the median TTF of 6.3 vs 8.5 months did not differ significantly (P = 0.271). The hazard ratio was 0.89 and the subsequent 95% Cl 0.73-1.09. The median overall survival was 33.0 months for TOR and 38.7 months for TAM (P = 0.645). The hazard ratio was 0.94 with 95% Cl of 0.73-1.22. The transient difference in TTP may be related to an imbalance in ER content of the tumours. When only patients with ER-positive tumours were considered (n = 238), no difference between two treatments was seen (P = 0.578). TAM was associated with an overall slightly higher frequency of adverse drug reactions than TOR (44.3 vs 39.3%) and a higher discontinuation rate due to these events (3.5% vs 0.9%). Treatment-emerged moderate dizziness (P = 0.026) and cataracts (P = 0.026) were more frequent among TAM than among TOR patients. In conclusion, TOR (60 mg day1) and TAM (40 mg day-1) are equally effective and safe in the treatment of advanced post-menopausal ER-positive or ER-unknown breast cancer.Keywords: antioestrogen; post-menopausal women; advanced breast cancer Tamoxifen (TAM) is the most common alternative for initial endocrine therapy of patients with recurrent or metastatic breast cancer. The overall response rate of post-menopausal women to TAM varies from 20% to 60% (Jaiyesimi et al, 1995). This wide range is largely due to the variability of prognostic factors in different study populations and to heterogeneous quality assessment. TAM, when given as an adjuvant treatment, is associated with a 20% mortality reduction (Santen et al, 1990; Early Breast Cancer Trialists' Collaborative Group, 1992).The presence of oestrogen receptors (ERs) in the breast cancer cells is the most important factor associated with successful treatment with TAM. Approximately 70% of al primary breast cancers

Toremifene in the treatment of breast cancer

“…Fever and chills were significantly more common among tamoxifen-treated patients [35] . A safety analysis in the Finnish Breast Cancer Study Group data also illustrates the similar tolerability and safety profiles of toremifene; sweating and hot flashes being observed in more than half of the patients, followed by vaginal dryness and discharge with itching and depression observed in more than 20% of patients [32] . (Table 4) In no case were significant differences between toremifene and tamoxifen observed.…”

“…A Nordic study compared toremifene 60 mg with tamoxifen 40 mg in 415 postmenopausal women with advanced breast cancer in a double-blind randomized manner [32] . Response rates were similar in toremifene and tamoxifen groups (31.5% vs 37.3%).…”

“…There have been ten randomized controlled studies comparing toremifene with tamoxifen [29][30][31][32][33][34][35][36][37][38] . Collectively, these studies, which include a total of more than 5500 patients show rather clearly that toremifene is not less effective than tamoxifen.…”

Role and pharmacologic significance of cytochrome P‐450 2D6 in oxidative metabolism of toremifene and tamoxifen

“…As TOR is equally effective to TAM in breast cancer treatment, the approximately fivefold greater plasma exposure of TOR and NDM TOR relative to TAM and NDM TAM (resulting from the higher clinical dose at 60 mg for TOR vs. 20 mg for TAM) may offset the difference in the contribution of the active metabolites. [4][5][6][7] In conclusion, we found that CYP2D6 is not an essential enzyme in the metabolism and disposition of TOR or its primary metabolite NDM TOR. Although 4-OH TOR and 4-OH-NDM TOR were up to 360-fold more antiestrogenic than TOR and NDM TOR, the combined plasma concentrations of these highly potent and active 4-OH metabolites are likely clinically irrelevant.…”

“…3 TOR is equally effective in breast cancer treatment. [4][5][6][7] However, TOR may have reduced genotoxicity and lower potential to induce secondary endometrial cancers 8,9 and may therefore be considered as an alternative to TAM as firstline therapy for patients with ER-positive advanced breast cancer.…”