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PubMed1996

[Hormone therapy of advanced renal cancer with high-dose toremifene (Fareston)].

Toremifene (Fareston)-a novel antiestrogenic drug with a triphenylethylene structure-has been effective in the treatment of postmenopausal breast cancer patients. It is safely administered even in high doses up to 300 mg/day. The purpose of the study was to investigate the effect and tolerability of high dose toremifene in the treatment of patients with advanced renal cell carcinoma (RCC). Thirty six patients started the treatment with toremifene 300 mg/day. There were 26 males and 10 females. Mean age was 56.0 years, range 35-75 years. Nineteen patients were nephrectomized. One patient was not evaluable for response because of too short treatment time. The response rate was 17.1%, including 1 CR (2.9%) lasting for 121 + weeks and 5 PR (14.3%) with the mean duration of 39.8 + weeks. Ten cases of NC (28.6%) had the mean duration of 23.7 weeks. There were no significant differences in response rate when patients with lung metastases only were compared to patients with metastases of other sites with or without lung metastases. Total pain control was achieved in 45% and partial control in 20% of those patients who had pains in the beginning of the treatment. Ten patients (27.8%) had adverse reactions which led to discontinuation of the treatment in one case. It can be concluded that high-dose toremifene is an effective and safe means of palliative treatment in advanced RCC.

Adult↗
PubMed1997

Evolving role of toremifene in the adjuvant setting.

The Finnish Breast Cancer Group (FBCG) started the first multicenter trial of toremifene (Fareston) in the adjuvant setting in 1992. The primary aim of the trial is to compare the efficacy and side effects of toremifene and tamoxifen (Nolvadex) as adjuvant therapies for postmenopausal node-positive breast cancer patients. About 830 patients have been enrolled in the trial to date. An interim analysis of the first 500 patients, performed after a mean follow-up of 18 months, showed no significant difference between toremifene and tamoxifen with regard to efficacy or side effects. The study includes additional protocols aimed at examining some side effects, including ocular problems and the formation of DNA adducts in the endometrium and leukocytes, as well as possible additional benefits, such as effects on lipid levels and bone density. Toremifene also is being studied in two other trials in Europe. These studies, which are being coordinated by the International Breast Cancer Study Group (IBCSG), have enrolled approximately 600 patients to date.

Aged↗
PubMed1997

[Complete tumor regression obtained by chemoendocrine therapy including toremifene in two cases of pulmonary metastasis of breast cancer with a history of tamoxifen treatment].

Two cases of recurrent breast cancer, for which combined therapy using toremifene and oral chemotherapeutic agents were effective, are reported. In case 1, high-dose toremifene (120 mg/day) and 5'-DFUR were administered to a forty-seven-year-old woman with lung metastasis of estrogen-receptor positive breast cancer, who had been previously treated with polychemotherapy and tamoxifen. A complete response was obtained after six months of treatment and this condition has remained for longer than one year. In case 2, a fifty-year-old woman developed liver and lung matastasis of breast cancer with increased tumor marker levels. Forty mg/day of toremifene and oral cyclophosphamide was started and transarterial embolization of the hepatic artery using lipiodol, adriamycin and mitomycin C was performed. Both hepatic and pulmonary metastasis disappeared, and the tumor maker level was normalized one month later. No regrowth of the tumors has been observed for more than six months. The chemosensitizing effect of toremifene might be responsible for the favorable effects on these matastases of breast cancer.

Adenocarcinoma↗
PubMed2002

Toremifene metabolism in rat, mouse and human liver microsomes: identification of alpha-hydroxytoremifene by LC-MS.

The in vitro metabolism of toremifene has been studied in liver microsomal preparations from rat, mouse and human sources using high-performance liquid chromatography-electrospray ionisation mass spectrometry (HPLC-ESIMS). The metabolites detected were N-desmethyltoremifene (m/z 392), 4-hydroxytoremifene (m/z 422), 4'-hydroxytoremifene (m/z 422) and toremifene N-oxide m/z 422). In addition, a new polar metabolite with a protonated molecule at m/z 422 has been detected in all three species. The compound was identified by tandem MS-MS as alpha-hydroxytoremifene, an analogue of alpha-hydroxytamoxifen. The results showed that alpha-hydroxylation is a common feature of tamoxifen and toremifene metabolism and that alpha-hydroxytamoxifen is unlikely to be the reactive metabolite responsible for the hepatocarcinogenesis in rat, as widely believed.

Animals↗
PubMed2002

Effects of transforming growth factor-beta1 and tumour necrosis factor-alpha on cultured fibroblasts from skin fibroma as modulated by toremifene.

To determine how toremifene, an anti-oestrogen triphenylethylene derivate, reduces tumour mass, we investigated its modulation of TGF-beta1 and TNF-alpha in fibroma fibroblasts. Normal and fibroma fibroblasts, isolated from patients affected by Gardner's syndrome without or with fibroma manifestation, were cultured in vitro. Secretion of GAG, collagen and TGF-beta1 was increased in fibroma fibroblasts compared to healthy cells. The increase in TGF-beta1 secretion into the medium was associated with a parallel increase in TGF-beta1 gene expression and receptor number. Receptor cross-linking studies using radiolabelled TGF-beta1 revealed more receptors, particularly types I and II, in fibroma fibroblasts than in normal cells. Normal and fibroma fibroblasts did not synthesise TNF-alpha, but they had TNF-alpha membrane receptors, as shown by TNF-alpha assay. TNF-alpha secreted by human monocytes, which may be present in the peritumoral area, increased cell proliferation and GAG accumulation and was, in turn, enhanced by TGF-beta1 treatment. Both growth factors increased angiogenesis, as shown by the CAM assay. Toremifene reduced TGF-beta1 secretion by fibroma fibroblasts and TNF-alpha secretion by monocytes, thus downregulating cell proliferation, ECM macromolecule accumulation and angiogenic progression. We hypothesise that increased TGF-beta1 gene expression and TGF-beta1 secretion in fibroma fibroblasts as well as the subsequent rise in TNF-alpha production by monocytes may facilitate fibroma growth and that toremifene inhibits autocrine and paracrine growth factor production.

Animals↗
PubMed2002

Tamoxifen and toremifene treatment of breast cancer and risk of subsequent endometrial cancer: a population-based case-control study.

A population-based case-control study was performed to evaluate the risk of endometrial cancer related to tamoxifen or toremifene treatment. All patients with breast cancer diagnosis since 1980 in Finland who subsequently developed an endometrial cancer by the end of 1995 and 3 matched controls were identified among the 38,000 breast cancer patients of the Finnish Cancer Registry database. Detailed information on treatment of breast cancer and potential confounders was collected from hospital records. The OR for tamoxifen treatment (59 cases), adjusted for significant cofactors (increased risk associated with obesity, low parity and PR positivity) was 2.9 (95% CI 1.8-4.7). The OR for toremifene (3 cases) was 0.9 (95% CI 0.3-3.9). The OR related to adjuvant tamoxifen treatment reached its maximum 2-5 years after the beginning of treatment (OR 5.1, 95% CI 2.1-13), while the OR for tamoxifen used for palliative treatment of advanced breast cancer was especially high after a lag of over 5 years (OR 9.5, 95% CI 2.5-36). The risk increase due to tamoxifen was slightly higher if the age at initiation was below 55, and risk was more pronounced among patients with well-differentiated endometrial cancer than patients with cancers of clinical grades 2 or 3. According to our results, treatment with tamoxifen increases the risk of endometrial cancer. Due to the rare use of toremifene up to the mid-1990s, the risk assessment concerning it was inconclusive.

Breast Neoplasms↗
PubMed1994

High dose toremifene in advanced breast cancer resistant to or relapsed during tamoxifen treatment.

Fifty patients with advanced breast cancer refractory to prior tamoxifen therapy were assigned to investigational treatment with high-dose toremifene administered 120 mg orally twice a day. Treatment was generally well tolerated. The majority (80%) of the patients had no side effects, and among the remaining 10 patients reported side effects were mostly mild and/or transient. Two objective tumor responses were observed: one complete response (CR), duration 6.2 months, and one partial response (PR), duration 8 months. The response rate was thus 4% (95% CI: 0.5 to 14%). In addition 3 patients experienced a mixed response, some metastatic sites responding, while at other sites disease progressed; 22 patients had disease stabilization for > 2 months. A subset analysis disclosed that a small subgroup of patients, including 7 patients in this study, who had achieved CR at some of the sites during preceding tamoxifen therapy, experienced a long progression-free time during high dose toremifene treatment. The median time to progression in this subgroup of patients was 9.4 months (95% CI: 3.8 to 9.4) as opposed to 2.1 months (95% CI: 2.0 to 2.8) for all the remaining 43 patients, which is a significant decrease in disease progression (p < 0.03). Such results reveal that although this kind of second-line hormonal treatment with high dose toremifene cannot be recommended for all tamoxifen failures, there might be a subset of patients, i.e. those who achieve CR in some lesion during tamoxifen therapy, who benefit from this type of treatment.

Adult↗
PubMed1990

Phase I study of the tolerance and pharmacokinetics of toremifene in patients with cancer.

Toremifene is a triphenylethylene derivative structurally and pharmacologically similar to tamoxifen. This Phase I trial assessed the safety, pharmacokinetics, anti-estrogenic, and estrogenic effects of toremifene at six dose levels (10, 20, 40, 60, 200, and 400 mg/day). The most common side-effects associated with therapy included gastrointestinal (nausea/vomiting 43%), anti-estrogenic (hot flashes 29%), and CNS (dizziness/vertigo 12%). Three patients with bone metastases from breast cancer developed hypercalcemia. At doses greater than or equal to 40 mg/day a decline in LH and FSH occurred which was not statistically significant. At all doses tested SHBG rose during therapy. A dose dependent estrogenic blockade was seen on the vaginal epithelium following challenge with transdermal estradiol. Steady-state concentrations of toremifene were reached within 4 weeks, and at doses greater than or equal to 60 mg/day ranged from 879-3445 ng/ml. The half-life was found to be 5 days, and at three weeks following discontinuation of treatment concentrations greater than 24 ng/ml were detected. The N-desmethyl and 4-hydroxy metabolites achieved steady state levels within 4 weeks and had half-lives of 6 and 5 days respectively. Partial responses were seen in 4 patients, 3 with breast cancer treated at 200 mg/day and 1 with endometrial cancer treated at 400 mg/day.

Adult↗
PubMed2000

Dose-dependent hormonal effects of toremifene in postmenopausal breast cancer patients.

PURPOSE: The purpose of the study was to compare hormonal effects of three toremifene doses, 20 mg (TOR20), 40 mg (TOR40) and 60 mg (TOR60) administered daily, in postmenopausal women with advanced breast cancer. METHODS: The study was randomized and open label in three parallel groups. Biochemical variables were identified as the serum concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH) and sex hormone binding globulin (SHBG). The changes were compared with objective clinical responses and to progression-free time. Adverse reactions and liver function test (aspartate aminotransferase, ASAT) were assessed for safety. RESULTS: A total of 260 patients were randomly grouped (90 to TOR20, 81 to TOR40 and 89 to TOR60). Of these patients 29, 29 and 22 completed at least 3 months of treatment and the results were analyzed for biochemical variables. All treatments had intrinsic estrogen agonist activity by decreasing of serum FSH and LH and by increasing of SHBG during the first 3 months (P < 0.01). Dose TOR20 showed slightly longer times to exert maximum estrogenic effects than did the two higher doses. No increases in liver function tests were seen in any of the groups. Objective response rates were 24.4, 39.5 and 32.6% (P = 0.01) and median times-to-progression were 206, 189 and 196 days in TOR20, TOR40 and TOR60, respectively (P = 0.913). Fewer responses were observed in the TOR20 group than in TOR40 (P = 0.05). Adverse events were reported in 19, 23 and 30 patients in the treatment groups (P = 0.20). The most frequently reported events were hot flushes and nausea. These were mostly mild or moderate, and only 1.5% of treatments was discontinued due to toxicity. CONCLUSIONS: Toremifene doses of 40 and 60 mg daily were effective and safe treatments of breast cancer in postmenopausal women, and no differences in their biochemical or clinical effects were seen. Toremifene at 20 mg/day had similar but slightly less potent antiestrogenic and estrogenic effects than the two higher doses.

Aged↗
PubMed1990

In vitro and in vivo binding of toremifene and its metabolites in rat uterus.

The in vitro binding affinities of toremifene (TOR), 4-hydroxy toremifene (4-OH-TOR) and several other metabolites for the rat uterine cytosolic estrogen receptor were compared with those of tamoxifen (TAM) and 4-hydroxy tamoxifen (4-OH-TAM). Only small differences were observed and the binding affinities of both 4-hydroxy metabolites were similar to that of estradiol (E2). Uterine uptake and subcellular distribution of [3H]TOR and [3H]TAM were then compared at 1, 8 and 72 h after administration to castrated rats. The uptake and retention of both antiestrogens were similar at all times. In each case the amount of nuclear bound radioactivity declined to low levels at 8 and 72 h but the ratios of 4-OH-TAM/TAM and 4-OH-TOR/TOR determined by HPLC analysis increased dramatically at 72 h. The level of radioactivity in both plasma and uterine cytosol at 72 h was significantly higher following [3H]TAM administration. However, most of the radioactivity appeared to be in a conjugated form since it was not extractable with solvent. Finally, the ability of prior administration of each antiestrogen (100 mg/kg) to block uterine [3H]estradiol uptake was examined at 3 and 7 days. It was found that uterine wet weights were higher than control one week after administration of both compounds. Prior administration of TOR increased nuclear uptake of [3H]E2 whereas TAM had no effect. The results of these experiments suggest that toremifene and tamoxifen have very similar in vitro and in vivo binding properties but differences in metabolism exist that may be important.

Animals↗
PubMed1990

Effect of toremifene on clinical chemistry, hematology and hormone levels at different doses in healthy postmenopausal volunteers: phase I study.

Toremifene was given within the dose range of 3-680 mg as a single dose or on five consecutive days to 72 postmenopausal volunteers. Blood samples for clinical chemistry were taken hourly up to 7 h and 1, 2, 3, 7, 10 and 15 days after the last dose of toremifene. The concentrations of serum bilirubin, creatinine, amylase, free thyroxine, cortisol, prolactin, electrolytes and blood glucose remained unchanged at all dose levels. A statistically significant decrease was observed in liver enzymes (ASAT, ALAT, ALP) at the dose levels of 220-680 mg, whereas gamma-GT remained unchanged. A decrease in the concentration of LH and FSH was observed at the dose levels of 46 mg or higher and 220 mg or higher, respectively. These hormonal changes including the increase of SHBG at the dose levels of 220-680 mg and the decrease of antithrombin III (220-680 mg) may be attributed to a weak estrogen-like effect of toremifene. Side effects were minimal: pulse rate, blood pressure and ECG remained unchanged during the test period. Only two patients on 680 mg dose suffered from nausea and vertigo, and one of them discontinued the medication.

Adult↗
PubMed1990

Effect of toremifene on estrogen primed vaginal mucosa in postmenopausal women.

The antiestrogenic effect of 20 mg toremifene daily for 7 days and 68 mg for 5 days was studied in postmenopausal women volunteers primed for 7 days with estradiol valerate (2 mg daily orally) which was continued throughout the study. A control group received estrogen only and a reference group estrogen with 60 mg tamoxifen for 5 days. No treatment opposed the action of the estrogen on the endometrium but both 68 mg toremifene and 60 mg tamoxifen statistically significantly decreased the maturity index of vaginal cells on day 13. A decrease was also evident on day 18 with 20 mg toremifene.

Biopsy↗
PubMed1990

Toremifene, a new antiestrogenic compound in the treatment of metastatic mammary cancer. A phase II study.

Toremifene is a new antiestrogenic compound. Toremifene has definite antitumor effect in advanced breast cancer. The response rate in the present phase II study among postmenopausal women, mostly not pretreated with systemic therapy and with ER positive or not determined ER status in tumor tissue, was 11/23 (48%; 95% confidence interval 37-59%) including 6 complete responses. The toxicity profile was similar to that of tamoxifen. It is concluded that toremifene is at least as active as tamoxifen in advanced breast cancer and that a randomized study between these two antiestrogens is indicated.

Aged↗
PubMed1990

Hormonal effects of toremifene in breast cancer patients.

The effect of toremifene treatment on the serum levels of sex steroids (estradiol, progesterone, testosterone), FSH, LH, prolactin, TSH, T3, T4 and SHBG was investigated. Basal prolactin level and the "prolactin reserve capacity" of the hypophysis was also studied by the TRH functional test. Steroid hormone receptors were detected in the patients where a tumor biopsy could be obtained. In a randomized trial patients were treated by 60 and 300 mg of toremifene per os, daily. Hormone levels were assayed prior to treatment and at the 2nd, 6th, 8th and 12th week of tormifene therapy. The hormonal effects of toremifene were the most marked at the 2nd and at the 8th week. Estradiol decreased continuously, SHBG increased slightly and the high initial value of basal prolactin level decreased. The TRH-induced prolactin release was suppressed by tormifene after an 8-week period. No clinical response-related tendency was found.

Adult↗
PubMed1988

Toremifene, a new antiestrogenic compound, for treatment of advanced breast cancer. Phase II study.

Forty-six postmenopausal women with estrogen receptor positive advanced breast cancer were treated with the novel antiestrogen toremifene in this phase II study. The patients had no prior or concurrent hormonal or cytostatic treatment. Sixty milligrams of toremifene was given as a single daily dose for a minimum treatment period of 6 weeks. Eight patients (17%) achieved complete response, 17 (37%) partial response and 12 (26%) showed no change. The median durations of responses were 93, 66 and 24 weeks, respectively. Three patients still continue the treatment in complete response, four patients in partial response. No significant differences in response rates could be seen when related to different estrogen receptor concentrations. The treatment was well tolerated, only two patients had remarkable side-effects; one of the patients interrupted the treatment mainly because of tremor. Our conclusion is that toremifene is an effective, safe and in clinical practice easily applied choice of treatment in estrogen receptor positive advanced breast cancer.

Aged↗
PubMed1989

Liquid chromatographic-atmospheric pressure ionization mass spectrometric analysis of toremifene metabolites in human urine.

A liquid chromatographic-atmospheric pressure ionization mass spectrometric method has been developed for the analysis of toremifene metabolites in human urine after oral administration. This ionization source is a useful device for studying metabolites of toremifene because the total effluent from high-performance liquid chromatography is fed through an interface with a direct heating nebulizer and vaporizer at atmospheric pressure. To obtain good sensitivity the use of the right mobile phase is very important: ammonium acetate in methanol in the case of toremifene and its metabolites. Four unconjugated and three glucuronide-conjugated metabolites were detected in human urine. The majority of these were new and distinguishable from known metabolites.

Antineoplastic Agents↗
PubMed1991

High-performance liquid chromatographic method for the determination of toremifene and its major human metabolites.

A high-performance liquid chromatographic method has been developed for the measurement of toremifene and its major human metabolites in plasma and urine. We have simplified other published methods, such that our assay uses protein precipitation in place of organic extraction, and ultraviolet detection instead of photochemical activation followed by fluorescence detection. In a stability study toremifene and metabolites remained unchanged for up to seven weeks at -70 degrees C. This simple and specific assay allowed toremifene and three metabolites to be quantitated for pharmacokinetic analyses in a high-dose Phase I trial.

Chromatography, High Pressure Liquid↗
PubMed1997

Comparisons of the binding of [14C]radiolabelled tamoxifen or toremifene to rat DNA using accelerator mass spectrometry.

Tamoxifen, widely used as adjuvant therapy in the treatment of breast cancer, is now undergoing trials as a cancer chemopreventative agent. Previous work has shown an association between 32P-postlabelled adducts in rat liver DNA and the development of liver tumours. With the use of accelerator mass spectrometry, [14C]tamoxifen was shown to bind to liver DNA of female rats in a dose-dependent manner and was linear over 0.1-1 mg/kg, compatible with the therapeutic dose used in women (20 mg/person per day). Radiolabel could also be detected in extrahepatic organs, including reproductive and GI-tract, where levels were about 18 and 46%, respectively those seen in liver. Following enzymatic hydrolysis of liver DNA, normal nucleotides by HPLC showed < 2% incorporation of the [14C]radioactivity while > 80% appeared as non-polar products. In contrast, when animals were given an equivalent dose of [14C]toremifene, binding to DNA was an order of magnitude lower than that seen with tamoxifen and no evidence of non-polar adducted nucleotides following HPLC. However, in vitro, using human, rat or mouse liver microsomal preparations, NADPH-dependent binding of both toremifene and tamoxifen to calf thymus DNA could be demonstrated, suggesting that under favourable circumstances toremifene is capable of undergoing conversion to reactive intermediates.

Animals↗