The effect of toremifene therapy on serum immunoglobulin levels in breast cancer.

Estrogens and anti-estrogens enhance the number of immunoglobulin (Ig)-secreting cells in pokeweed mitogen (PWM)-stimulated lymphocyte cultures. Lymphocytes from patients who have received anti-estrogen therapy show similar enhancement of Ig-secreting cells after PWM stimulation. In this study the effect of anti-estrogen (toremifene) therapy on serum immunoglobulin (IgA, IgM, IgG) levels in breast cancer patients was investigated. Serum Ig levels were followed up to two years after or during the therapy. An unexpected finding was that the Ig levels decreased during the follow-up period. This decrease was seen in patients who responded to the therapy as well as in those who did not.     

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

The 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 (CI) 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% CI 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% CI 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% CI 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 day(-1)) 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.     

Effects of monoamine oxidase inhibition by selegiline on concentrations of noradrenaline and monoamine metabolites in CSF of patients with Alzheimer's disease

Summary A double-blind, cross-over trial with 12 patients with Alzheimer's disease (AD) was carried out primarily to test the suitability of this design in the investigation of the clinical, effects of selegiline (10 mg/day) in AD. Cerebrospinal fluid (CSF) samples for the determination of concentrations of noradrenaline (NA) and several monoamine metabolites were collected at baseline and at the end of both four-week treatment periods (placebo and selegiline). The severity of dementia was assessed using Ferm's and Gottfries-Bråne-Steen (GBS) dementia scales. The concentrations of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and the NA metabolites, 3,4-dihydroxyphenylglycol (DHPG), and 3-methoxy-4-hydroxyphenyl glycol (MHPG) decreased significantly during selegiline treatment. There was a clear trend of reduction in concentrations of homovanillic acid (HVA) during selegiline treatment, whereas the concentrations of NA, 5-hydroxyindoleacetic acid (5-HIAA), and tryptophan did not differ significantly. The study design was not suitable for the analysis of the clinical results as there was a significant carry-over effect in both scales. As only the first period data could be used in the analysis, there were no significant differences in the scores of Ferm's or GBS scales, but clear positive trends could be detected in favour of selegiline.     

Endocrine mechanism of action of toremifene at the level of the central nervous system in advanced breast cancer patients

Purpose: To differentiate the antagonistic and agonistic effect of toremifene at the level of the hypothalamus-hypophysis axis a leutinizing hormone-releasing hormone (LHRH) test was performed during a phase II clinical trial. Methods: In 15 postmenopausal patients with advanced breast cancer, follicle-stimulating hormone (FSH) and LH release – induced by an LHRH agonist (Suprefact injection, 0.5 mg s.c.) – was monitored during a 16-week period of toremifene treatment (60 mg/day p.o.). Prolactin, estradiol, and sex hormone-binding globulin (SHBG) levels were also measured. The functional test was carried out prior to toremifene therapy and then 4, 8, 12, and 16 weeks afterward. Results: The drug sensitized the pituitary to the action of the gonadotrophins; the LHRH-induced FSH and LH release showed a considerably increasing tendency during the toremifene therapy. Estradiol levels decreased statistically significantly and SHBG levels showed a statistically significant increase. A decreased level of prolactin is the sign of an antiestrogenic effect of toremifene on the hypophysis and, as a result, provides evidence for a direct influence of toremifene upon the pituitary. An increase in LH and prolactin release in response to the LHRH test was characteristic in the responders. Conclusion: According to the LHRH test, the antagonistic effect of toremifene seems to be more dominant than the concomitantly existing agonistic property. Neither clinical nor endocrinological side effects could be observed at the level of the CNS during a prolonged period of toremifene administration. Received: 13 July 1997 / Accepted: 17 February 1998     

The effects of anti-estrogen therapy on lymphocyte functions in breast cancer patients.

The effects of anti-estrogen therapy (tamoxifen or toremifene) on in vitro lymphocyte functions were investigated in breast cancer patients. We found that the amount of DNA synthesis, with or without PWM stimulation, was decreased in all cancer patient groups compared to normal controls. The number of Ig-secreting cells was enhanced in unstimulated peripheral blood lymphocyte cultures but decreased in PWM-stimulated cultures. This occurred in all cancer patient groups investigated, with or without anti-estrogen therapy, as compared to healthy controls. On the other hand, subsequent samples with two-month intervals showed that anti-estrogens can increase PFC responses and inhibit DNA synthesis of peripheral blood lymphocytes in more than half of the patients. Interestingly, the enhancing dexamethasone effect, which usually causes an increase in the number of Ig-secreting cells in PWM-stimulated cultures, was also seen more often in anti-estrogen-treated patients. These results suggest that anti-estrogens may have immunoregulatory effects in vivo.     

Toremifene: an evaluation of its safety profile

Toremifene has been in clinical use for 8 years for the treatment of advanced hormone-sensitive breast cancer and the adjuvant treatment of early breast cancer. More than 350,000 patient treatment years have accumulated, sufficient to allow evaluation of its longer-term safety profile in comparison with tamoxifen and, where possible, with raloxifene and aromatase inhibitors. We reviewed all preclinical and clinical safety data from 1978 to 2004 and comparative clinical safety data between October 1995 and the end of 2004. Secondary endometrial cancer incidence was lower with toremifene than with tamoxifen and was similar to that with raloxifene. It is speculated that toremifene may unmask existing endometrial tumors rather than induce new events. The risk of stroke, pulmonary embolism, and cataract may be lower with toremifene than with tamoxifen and the risk of pulmonary embolism and deep vein thrombosis lower than with raloxifene. Beneficial estrogen agonistic effects were equivalent to those of tamoxifen regarding bone mineral density and superior regarding lipid profiles.     

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

Summary 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 progressionfree 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.