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.

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.

Influence of toremifene on the endocrine regulation in breast cancer patients.

In a combined phase I-II study, the hormonal effects of toremifene (TOR) were investigated in 30 patients. Half of the patients received continuous therapy of TOR 60 mg and half 300 mg of TOR orally daily. Serum concentrations of oestradiol (E2), progesterone (PROG), testosterone (TE), follicle stimulating hormone (FSH), luteinising hormone (LH), prolactin (PRL), human growth hormone (hGH) and sex hormone binding globulin (SHBG) were monitored prior to the treatment and at the second, sixth, eighth and twelfth weeks. The influence of TOR upon the hypothalamo-hypophyseal axis was investigated by the TRH (thyroid-stimulating hormone releasing hormone) functional test using 400 micrograms intravenous injection of TRH for stimulation of PRL secretion. The concentration of E2 decreased during the TOR therapy with 60 mg and 300 mg causing 82 and 71% decreases, respectively (non-significant). PRL was significantly (P < 0.001) suppressed. Both these effects reflect the anti-oestrogenic action of TOR. SHBG increased significantly at both doses of TOR, probably due to a direct oestrogen-like effect of TOR in the liver. TE decreased as a consequence of the elevated SHBG. The TRH-induced PRL release was suppressed by both doses of TOR. There were 17 and 27% reductions at 12 weeks in the 60 and 300 mg groups, respectively. Other hormones measured were not significantly affected by TOR. The hormonal effects of 60 and 300 mg doses of TOR did not differ significantly. Anti-oestrogenic (i.e. decrease of E2), and partially oestrogenic (i.e. increase of SHBG) properties as well as the antiprolactinic effects of TOR may have an overall beneficial effect in the clinical management of breast cancer patients.

Cisplatin containing combination chemotherapy of advanced germ cell line testicular tumours.

One hundred ninety patients with germ cell line testicular tumours were treated according to the modified Einhorn scheme. The response rate was 67.9%. The most favourable results were found in the embryonal histologic type (RR = 76.9%) in the biological markers (beta-HCG and AFP) negative (RR = 97.4%) and in the minimal pulmonary extent group (RR = 94.1%). The authors treated 112 patients with including these VPB-resistant germ cell testicular tumour and those with recurrence after this treatment. The patients' mean age was 28.8 (limits 19 to 44) years. Patients were given Vepeside (100 mg/m in infusion for days 1-5), Adriablastin (40 mg/m in infusion on day 1) and Cisplatin (20 mg/m in infusion) for day 1-5. The treatment resulted in CR with 18 patients (16.1%) and PR with 42 (37.5%) (RR = 53.6%). The best results were obtained with the seminoma patients who were marker-negative and had small-volume metastasis. CR developed in 4 of 7 seminoma patients (57%) and in 7 of 25 marker-negative individuals (28%), and PR developed in 11 patients (44%) (RR = 72%). Out of 12 patients with small volume metastatis four (33%) showed CR and five revealed PR (41.7%), their RR turned out to be 74.6%. The average remission period was 37 (range 4-70) months in CR but merely 6.1 (range 2-38) months in PR. It can be stated that fairly good results can be achieved with second-line VpAP treatment in case of resistance developed to primary VPB therapy or subsequent relapse. The efficacy of combined chemotherapy of Vepesed+Holoxan +/- Adriablastin as third-choice was studied in advanced testicular cancer patients refractory to, or recurrent after, first- and second-line cytostatic therapy. Between September 1981 and January 1988 49 evaluable patients were treated with Vepesid (VP-16213--100 mg/m2 days 1-5), Holoxan (40 ml/kg days 1-5), hydration, urine-alkylation + Uromitexan +/- Adriablastin (40 mg/m day 1). The single dose of Uromitexan was 20% of the daily dose of Holoxan, and the patients received it i.v. just prior to Holoxan administration (h 0), the 4 and 8 h later. Two patients got into CR and 10 to PR. The rate of remission was 24.5%. The most severe side effect was leukopenia. The elevation of BUN and se. creatinine was transient and mild. In those cases where Holoxan was not included in the first- or second-line regimens, when combined with Vepesid and Adriablastin as third-choice therapy one could achieve further improvement. In case of CR the prolongation of life is also noteworthy. The first-, second- and third-line therapy plus salvage RLA and/or pulmonary metastasectomy achieved long-term survival only in one quarter of the patients.

[The anti-estrogenic effect of 4-chloro-1,2-diphenyl-1-(4-[2-(N,N-dimethylamino)ethoxy]phenyl)1-butene (Toremifene) on the endocrine regulation in breast cancer patients]. / Az antiösztrogén hatású 4-kloro-1,2-difenil-1-(4-[2-(N,N-dimetilamino)etoxi]fenil)-1-butén (Toremifene) hatása emlörákos betegek endokrin regulációjára.

In a combined phase I-II study the hormonal effects of Toremifene were investigated in 15-15 patients at two dose levels: 60 mg and 300 mg per os, daily. Serum estradiol, progesterone, testosterone, follicle-stimulating hormone, luteinizing hormone, prolactin, human growth hormone were monitored by radioimmunoassay and sexual hormone binding globulin by immunoradiometric assay prior to treatment and at the 2nd, 8th and 12th weeks. The influence of Toremifene upon the hypothalamo-hypophyseal axis was also controlled by a tirotropin releasing hormone functional test using 400 micrograms tirotropin releasing hormone injection iv. Estradiol, progesterone, follicle-stimulating hormone, luteinizing hormone and prolactin decreased proving the antiestrogenic activity of the drug. Sexual hormone binding globulin significantly (p less than 0.002) increased by week 12 at both doses, probably due to a direct effect of Toremifene upon the liver. The increase in sexual hormone binding globulin suggests the partial estrogenic effect of the drug. The tirotropin releasing hormone induced prolactin release was also suppressed. On the basis of hormonal changes and the clinical response of patients 60 mg of Toremifene proved to be as effective as 300 mg.

Effect of toremifene in breast cancer patients. Preliminary communication.

Toremifene, an antiestrogenic drug administered at three dose levels (60, 120, and 300 mg/day) was investigated in 17 postmenopausal patients with advanced breast cancer previously treated with hormonal and/or cytostatic therapy. The drug proved to be well tolerated at all dose levels without any serious side effects even on prolonged administration. Neither response nor side effects have shown any dose dependency in this small group of patients.

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.

Multiple myeloma arising from solitary plasmacytoma of bone.

Double (kappa + lambda), Bence Jones (BJ) proteinuria was detected in a male patient of 73 years. The disease started as a solitary plasmacytoma in bone and transformed into multiple myeloma. At the beginning, isolated BJ lambda proteinuria was observed which was soon accompanied by transient excretion of BJ kappa protein.

Vinblastine, cisplatin and bleomycin treatment of advanced nonseminomatous testicular tumors.

Between December 1979 and July 1986, 190 patients with nonseminomatous germ-cell testicular tumors were treated according to the modified Einhorn scheme. The response rate was 67.89%. The most favorable results were found in the embryonal histologic type (RR = 76.9%), in the biological marker (AFP, HCG) negative (RR = 97.43%) and in the minimal pulmonary extent group (RR = 94.12%).

Activity of epirubicin and dibromodulcitol in advanced breast cancer. Results of the South-East European Oncology Group Study.

The therapeutic efficacy of the combination of epirubicin + dibromodulcitol was evaluated in 108 previously treated or untreated patients with advanced breast cancer. The overall response rate was 39.8%, complete remission 3.7% (mean duration 6.3 months) and partial remission 36.1% (mean duration 3.5 months). The response was rated in function of age, menopausal status, performance status and previous therapy. Toxicity (in case of 115 patients) was evaluated according to the WHO recommendation. The similar therapeutic effectiveness and less toxicity of the above drug combination compared to ADM + DBD regimen are demonstrated.

Comparative evaluation of two administration schedules of cis-dichlorodiammineplatinum (DDP) in ovarian and head and neck cancers: a CMEA chemotherapy group study.

The therapeutic effectivity of two administration schedules of DDP were compared. The dose was either 100 mg/m2 infused for 4 h or 20 mg/m2 infused for 1 h on 5 consecutive days. The combined objective remission rate of the two regimens were 37/53 (23% CR ++ 44% PR) for ovarian cancer and 8/35 (9% CR + 14% PR) for head and neck cancer. WHO Grade 1-2 myelo- and nephrotoxicity was observed in 26% and 20%, respectively, out of the 105 cases evaluable for toxicity in the two groups. Nausea and vomiting was moderate to severe. Neither the remission rate nor the toxicity of the two schedules were significantly different.

Activity of epirubicin in combination chemotherapy of advanced ovarian cancer. Results of the South-East European Oncology Group (SEEOG) Study.

The therapeutic efficacy of the combination of cyclophosphamide + epirubicin + cisplatin was evaluated in 107 previously treated or untreated patients with advanced ovarian cancer. The overall response rate was 58.8%, complete remission 36.4% (mean duration-7.62 months) and partial remission 22.4% (mean duration-6.74 months). The response was rated in function of age, menopausal status, performance status and previous therapy. Toxicity (in case of 109 patients) was evaluated according to the WHO recommendation. The similar therapeutic effectiveness and less toxicity of the above drug combination compared to CAP regimen is demonstrated.

Phase I-II trial of aclacinomycin A given in a four-consecutive-day schedule to patients with solid tumours. A South-East European Oncology Group (SEEOG) Study.

Aclacinomycin A (ACM) in a daily dose of 30 mg/m2 was infused over 1 h on 4 consecutive days to 50 patients. Myelotoxicity was acceptable, nausea and vomiting was frequent, hair loss was mild. Grade 1-2 cardiac rhythm abnormalities were observed in 12% of the patients. Between days 1 and 4 the heart rate and the corrected Q-T interval increased while the amplitude of the T wave decreased significantly, cardiac contractility remained unchanged. In 24 evaluable breast cancer patients 1 complete remission (4%) and 2 partial remissions (8%) lasting for only 2-3 months were seen. None of the 8 patients suffering from ovarial cancer benefitted from ACM therapy.

Pain killing with calcitonin in patients with malignant tumours.

The most essential role of Miacalcic (Calcitonin Sandoz), a 32-amino-acids peptide, is the preservation of osseal integrity. Based on this physiological fact it is assumed that this hormone may have a bone-regenerating effect in bone metastasis formation and sometimes in other malignancies. Though no considerable calcium incorporation could be revealed in our 58 patient treated with Miacalcic, a marked relief of pain was observed in 65.5% of the patients. For objectivation of the subjective pain sensation, the decrease in the quantity of other analgetics used daily, duration of pain and changes of its intensity were studied. These figures were 35.4% on the average, from 12.5-6 h and 23.6%, respectively. The pain-killing character of Miacalcic cannot be explained, but the following assumptions are made: (1) it partially inhibits the synthesis of algogenous peptides; (2) with its possibly cytostatic effect it inhibits the cell proliferation in loco and normalizes the internal pressure of the destroyed region, and (3) by conversion into beta-endorphin it exerts its effect centrally. Compared to the pain-killing effect, the simultaneous improvement of the quality of life seems to be even more essential. It has been proved earlier that a hormone physiologically present, when applied in a high dose, has an analgetic effect, i.e. by utilizing the endogenous substance of the organism, relief of pain can be achieved. We should like to point out that Miacalcic is the only analgetic agent capable of ensuring relief of pain with a simultaneous improvement of the quality of life. Accordingly, the application of Miacalcic in patients suffering from malignant tumours is highly recommended.

Relation between dose, plasma concentration and toxicity in a phase I trial using high dose intermittent administration of an alkylating agent, diacetyldianhydrogalactitol (DADAG).

Diacetyldianhydrogalactitol (DADAG), a new alkylating sugar alcohol derivative, was administered as single, 30-min infusions in doses ranging from 390 to 1200 mg/m2. The dose-limiting toxicity was myelosuppression. The median times to WBC nadir and regeneration were 16 and 21 days, and to platelet nadir and recovery 20 and 27, respectively. Nausea and vomiting occurred frequently and were of moderate severity. For phase II studies 900 mg/m2 DADAG given every 4-6 weeks is recommended. The area under the plasma concentration time curve (AUC) for DADAG did not increase in proportion with dose escalation; it changed only from 235.5 +/- 70.7 to 262.4 +/- 71.5 micrograms h ml-1 between doses of 690 and 1050 mg/m2. No correlations between the dose administered and the nadir values for haemoglobin concentration, WBC and platelet counts, or the number of episodes of vomiting were demonstrable in this dose range. Such an association was revealed, however, when the above biological variables were related to the individual AUC for DADAG.

Hormonal changes during a prolonged tamoxifen treatment in patients with advanced breast cancer.

The effect of tamoxifen (TAM) on the serum levels of sexual hormones and on the sex hormone-binding globulin (SHBG) was investigated in 30 postmenopausal patients with advanced breast cancer. To study the 'prolactin reserve capacity' of the pituitary gland, thyrotrophin-releasing hormone (TRH) and sulpiride-induced prolactin release were measured prior to TAM treatment, then in the 2nd and 8th week of the therapy. The TRH (400 micrograms i.v.)-induced prolactin secretion was significantly suppressed by TAM after an 8-week treatment, but only in responding cases. Maximal prolactin stimulation occurred at the 15th min after TRH injection, being equal to 5,600 +/- 800 mlU/l in cancer patients, and decreasing to 2,400 +/- 150 mlU/l after 8 weeks. TAM did not suppress the sulpiride-inducable prolactin release either in responders or in nonresponders.

A sensitive assay for the pharmacokinetic investigation of a rapidly hydrolyzing alkylating agent Lycurim (ritrosulfan; R-74; NSC-122 402).

Lycurim [1,4-di(2'-methanesulfonyloxyethylamino)-1,4-dideoxymesoerythri tol dimethane sulfonate] is rapidly hydrolyzed in aqueous media to inactive products according to a second-order reaction. The respective rate constants are: k1 = 9.82 X 10(-2) and k2 = 1.76 X 10(-2) mumol/ml/min. The concentrations of the parent compound and alkylating intermediate(s) were measured by chemical trapping with N,N-diethyldithiocarbamic acid (DDTC). The rate of this reaction is substantially higher: k1 = 2.61 X 10(-1) and K2 = 4.76 X 10(-2) mumol/ml/min. By using 35S-labeled DDTC, alkylating compounds in concentrations as low as 0.04 microgram/ml could be detected in spiked plasma samples. After intracavitary application of 60 mg Lycurim no alkylating activity could be demonstrated in the plasma of patients at any time point.