Multicenter phase II efficacy trial of toremifene in tamoxifen-refractory patients with advanced breast cancer.

Vogel, Charles L.; Shemano, Irving; Schoenfelder, John R.; Gams, Richard A.; Green, Mark R.

doi:10.1200/jco.1993.11.2.345

Cited by 104 publications

(26 citation statements)

References 9 publications

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“…In a larger retrospective study in which the efficacy of 120 mg TOR was analyzed with AI-failure cases (n=80), ORR and CB were 15 and 45%, respectively (19). In cases where tamoxifen preceded AI, high-dose TOR was effective for tamoxifenresistant breast cancer (20)(21)(22). The majority of the patients in that study as well as ours tolerated the side effects and experienced a more favorable quality of life during treatment.…”

Section: Discussionmentioning

confidence: 99%

High-dose toremifene as first-line treatment of metastatic breast cancer resistant to adjuvant aromatase inhibitor: A multicenter phase II study

et al. 2011

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Abstract. There is currently no standardized therapy available for metastatic breast cancer in patients with aromatase inhibitor (AI)-resistant breast cancer. We conducted a prospective study to examine the efficacy and safety of high-dose toremifene (TOR) treatment for the first-line treatment of metastatic breast cancer following AI adjuvant therapy. A multicenter phase II study was designed (Registry no.: UMIN000000489). Inclusion criteria comprised hormone-responsive postmenopausal women who had received adjuvant AI postoperatively for >1 year and had relapsed during the treatment or within 12 months of completion of adjuvant therapy. Treatment comprised oral intake of 120 mg TOR once a day. The primary endpoint was objective response rate (ORR). The secondary endpoints were evaluations of clinical benefit (CB), progression-free survival (PFS) and toxicity. A total of 13 patients were enrolled. ORR was 7.7% (1/13) [95% CI, 0.2-36.0%]. In total, 7 patients (53.8%) had stable disease (SD), 5 of whom were long SD, and 5 patients (38.5%) experienced progressive disease (PD). The CB rate was 46.2% (6/13) [95% CI, 19.2-74.9%]. The median time to PFS was 5.9 months. No serious adverse events were observed. Patients with HER2-positive disease exhibited marginally poorer PFS (p= 0.08). Patients with PD had a relatively short duration of AI treatment in contrast to responders, who had a longer period of AI treatment (p=0.02). High-dose TOR as a first-line treatment following AI adjuvant therapy was effective and well tolerated. A longer duration of adjuvant AI therapy and negative HER2 overexpression may, with further studies, be beneficial as positive predictive factors for the effectiveness of TOR treatment.

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Section: Discussionmentioning

confidence: 99%

High-dose toremifene as first-line treatment of metastatic breast cancer resistant to adjuvant aromatase inhibitor: A multicenter phase II study

et al. 2011

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“…The dose has ranged from 20 mg to 400 mg day-' (Valavaara et al, 1988;Valavaara and Pyrhonen, 1989;Hietanen et al, 1990;Pyrhonen et al, 1990;Hamm et al, 1991). TOR has been used as first-, second-or third-line treatment after previous hormonal or cytotoxic treatment has failed (Valavaara et al, 1988;Valavaara and Pyrhonen, 1989;Hietanen et al, 1990;Pyrhonen et al, 1990;Hamm et al, 1991;Jonsson et al, 1991;Tominaga et al, 1993;Vogel et al, 1993;Pyrhonen et al, 1994). At a dose of 40-240 mg day-', TOR has been well tolerated as first-line treatment in advanced ER-positive or undetermined breast cancer.…”

mentioning

confidence: 99%

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

Pyrhönen

Valavaara²,

Modig³

et al. 1997

Br J Cancer

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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

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“…The reason for the reduced adduct formation observed with idoxifene is still not clear. However, there is a major interspecies difference in idoxifene metabolism between rats and humans with the 4'-hydroxy derivative of idoxifene being the major metabolite in rats in vitro and in vivo (Vogel et al, 1993). This metabolite is so far undetected in human plasma (Coombes et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…For these reasons, much work has been done to develop novel antioestrogens. These include LY117018 (Scholl et al, 1983), droloxifene (Bruning, 1992), toremifene (Vogel et al, 1993) and ICI 182, 780 (Wakeling, 1991), the last one showing properties of a pure antioestrogen. Some of these compounds would be unsuitable as preventive agents.…”

mentioning

confidence: 99%

Idoxifene is equipotent to tamoxifen in inhibiting mammary carcinogenesis but forms lower levels of hepatic DNA adducts

Pace

Jarman²,

Phillips³

et al. 1997

Br J Cancer

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Summary Tamoxifen is an effective agent preventing mammary carcinogenesis in rats but causing liver tumours. Idoxifene is a more potent antioestrogen and is effective in patients with advanced breast cancer. We therefore compared the effects of idoxifene with tamoxifen on mammary carcinogenesis and hepatic DNA adduct formation. To do this, we undertook a study designed to compare tamoxifen with idoxifene as a chemopreventive agent in rats inoculated with Mmethyinitrosourea (MNU) and also measured hepatic adduct formation. We examined the time to mammary tumour development in 272 female Ludwig/Wistar/Olac rats treated with MNU followed by tamoxifen (5 mg kg-'), equimolar idoxifene or vehicle three times a week for up to 24 weeks. To determine duration of effect, a second study was carried out whereby all of the 129 animals surviving at the end of treatment were entered into a surveillance programme for 27 weeks after the end of the administration period. Hepatic DNA adduct formation was examined by 32P-postlabelling in a group of rats after 24 weeks' treatment. In the first study, both idoxifene and tamoxifen were effective in preventing tumour growth as only 2 out of 21 (10%) MNU and vehicle-treated animals were alive and tumour free after 24 weeks compared with 13 out of 22 (59%) animals receiving MNU followed by idoxifene or tamoxifen (P < 0.001). The second study showed that, in both idoxifene-and tamoxifen-treated animals, a progressive regrowth of tumours occurred after cessation of therapy, as by the end of the observation period only four idoxifene-treated animals and one tamoxifen-treated animal were free from disease. In the subset of animals tested, tamoxifen-treated animals had approximately 100 times higher levels of DNA hepatic adducts than idoxifene-treated animals. Adducts were not seen in the control group. These results indicate that idoxifene is as effective a chemopreventive agent as tamoxifen in the rat while causing only very low levels of DNA adducts in liver tissue and suggest that idoxifene may be a well-tolerated chemopreventive agent in women who are at increased risk of breast cancer.

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Multicenter phase II efficacy trial of toremifene in tamoxifen-refractory patients with advanced breast cancer.

Abstract: We conclude that there is major cross-resistance between tamoxifen and toremifene and that only occasional tamoxifen-refractory patients will have objective responses to toremifene.

Cited by 104 publications

References 9 publications

High-dose toremifene as first-line treatment of metastatic breast cancer resistant to adjuvant aromatase inhibitor: A multicenter phase II study

High-dose toremifene as first-line treatment of metastatic breast cancer resistant to adjuvant aromatase inhibitor: A multicenter phase II study

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

Idoxifene is equipotent to tamoxifen in inhibiting mammary carcinogenesis but forms lower levels of hepatic DNA adducts

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