Predictive initial parameters for response of stage D prostate cancer to treatment with the luteinizing hormone-releasing hormone agonist goserelin

One hundred eighteen patients with stage D (D1 or D2) prostate cancer with a mean age of 69 years were treated with monthly goserelin (Zoladex; ICI 118, 630; ICI Americas Inc, Wilmington, DE, property of Imperial Chemical Industries PLC) injections and the data were analyzed for predictive parameters for best response and time to treatment failure (National Prostatic Cancer Project [NPCP] and Eastern Cooperative Oncology Group [ECOG] criteria). For best response in a univariate analysis, the performance status (PS 0-1 v 2-3) (P = .01), hematocrit (P = .04), and pain (P = .04) were significant. For time to treatment failure by univariate analysis, ECOG performance status (0-1 v 2-3) was most predictive (P less than .0001), followed by pain at entry (P = .0002), initial testosterone (T) level (greater than 250 ng/dL) (P = .0005), age less than 69 years (P = .02), alkaline phosphatase (less than 115 IU/L) (P = .03), hemoglobin (less than 14 g/dL) (P = .03), whereas normal acid phosphatase (less than 3 IU/mL) (P = .29) was not predictive. In multivariate analysis for time to treatment failure, only the ECOG performance status was of significance (P = .01). Estimated median time to treatment failure for PS of 0-1 was 88 weeks and for PS of 2-3 was 31 weeks.     

Anti-tumour activity of ICI 118630, a new potent luteinizing hormone-releasing hormone agonist.

Experiments were undertaken with DMBA-induced mammary tumours of the rat to determine the anti-tumour properties of a new and potent luteinizing hormone releasing hormone (LH-RH) agonist, [D-Ser(But) 6Azgly10]-LH-RH (ICI 118630). Tumours were classified according to their oestrogen-receptor (ER) content. Twice daily i.m. injections of either 5 micrograms or 0.5 micrograms ICI 118630 in saline were as effective as ovariectomy or tamoxifen therapy in causing the regression of ER+ DMBA-induced mammary tumours. ER- mammary tumours showed a more equivocal overall response to ICI 118630, some tumours progressing, others regressing. About one-third of the ER+ tumours disappeared in the 20-day treatment period. Those tumours which did regrow after the cessation of treatment proved to be hormone-dependent. In addition to the inhibitory effects of the LH-RH agonist on pre-existing tumours, ICI 118630 also reduced the total number of new tumours formed during and after treatment.     

A luteinizing hormone-releasing hormone agonist for the prevention of chemotherapy-induced ovarian follicular loss in rats

In an attempt to prevent chemotherapy-induced ovarian follicular loss, [D-Leu6, des-Gly10-NH2]-luteinizing hormone-releasing hormone ethylamide (LHRHa) was given subcutaneously to Sprague-Dawley cycling female rats in two daily doses of 2.5 micrograms starting 2 days prior to and concomitant with cyclophosphamide (CTX) (5 mg/kg/day for 21 days). Four groups of female cycling rats (10 in each) received either no treatment, CTX alone, CTX + LHRHa, or LHRHa alone. One ovary from each animal was serially sectioned, stained, and examined for the number and size of follicles. CTX produced a significant reduction in the total number of follicles. The pool of growing follicles (medium to large, greater than 30 microns in diameter) appeared to be vulnerable to the cytotoxic effect of CTX. LHRHa resulted in a significant reduction in the number of medium-to-large follicles and an increase in the number of small follicles. When given in combination with CTX, LHRHa significantly further reduced the number of medium-to-large follicles, significantly increased the number of small follicles, and resulted in an increase in the total number of follicles. Chronic LHRHa treatment resulted in functional deprivation of follicles from gonadotropins, thus halting the process of recruitment from the quiescent pool of primordial follicles into the CTX sensitive pool and thereby preserving the functional potential of the ovary.     

Potentiation of the gonadotoxicity of Cytoxan in the dog by adjuvant treatment with a luteinizing hormone-releasing hormone agonist

This study evaluates the effect on spermatogenesis of coadministration of Cytoxan (cyclophosphamide) and nafarelin, a luteinizing hormone-releasing hormone agonist. Nafarelin causes complete aspermatogenesis in dogs by interrupting the hypothalamic-pituitary-gonadal axis, which might protect against the testicular cytotoxicity associated with cyclophosphamide. The four treatment groups, each consisting of 2 mature male beagle dogs, were (a) no drug; (b) cyclophosphamide (p.o. 3x weekly for 43 and 48 wk for a total dose of 582 and 709 mg/kg, with dose varying according to weekly hematological profile); (c) nafarelin (2 micrograms/kg s.c. daily for 48 and 52 wk); and (d) cyclophosphamide plus nafarelin [same schedule as above with cyclophosphamide (570 and 698 mg/kg total dose) starting 7 wk after beginning nafarelin]. Plasma testosterone, spermatogenesis, and ejaculate volume were completely suppressed by nafarelin prior to starting cyclophosphamide. By 2 wk after cessation of treatment (posttreatment, PT), plasma testosterone reached normal levels, and at 5 wk PT ejaculates appeared which reached normal volumes 2 to 3 wk later. Normally motile ejaculated spermatozoa were noted at 6 to 8 wk PT in nafarelin-only-treated animals; normal sperm numbers were reached at 14 wk PT. The animals receiving cyclophosphamide plus nafarelin were azoospermic for the entire 65-wk PT period, and at 65 wk PT no germinal cells were found upon evaluation of testicular histology. Sperm numbers in cyclophosphamide-only-treated animals began to rise 10-11 wk PT and reached 150 x 10(6) sperm/ejaculate at approximately 65 wk PT (contemporaneous control dogs had sperm numbers of approximately 300-600 x 10(6)/ejaculate). Spermatogenesis in these cyclophosphamide-only-treated animals was normal in most seminiferous tubules at this time. The addition of nafarelin to cyclophosphamide treatment thus exacerbated the deleterious effects of cyclophosphamide on the testes, suggesting caution for use of such a protocol clinically.     

Aggressive angiomyxoma of the inguinal region

Aggressive angiomyxoma is a distinctive and very rare soft tissue tumor occurring almost exclusively in women. Only seven cases occurring in men have been previously reported. We herein report a case of a 74-year-old man who was admitted to our hospital presenting with a huge right inguinal mass that had grown over a 14-year period, in order to undergo surgical treatment for gastric cancer. The inguinal tumor was well-defined and demonstrated a glistening appearance on the cut surface. Histologically, the tumor was composed of bland-looking spindle and stellate cells with delicate cytoplasmic processes, which sparsely populated the fibromyxoid matrix. A prominent vascular component was also present. Immunohistochemically, the stromal cells stained consistently for vimentin and variably for muscle-specific actin, but not for alpha-smooth muscle actin, desmin, and S-100 protein. The gastric cancer was microscopically diagnosed to be papillary adenocarcinoma with serosal invasion and showing immunoreactivity for p53 protein, but not for aggressive angiomyxoma.     

Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials.

PURPOSE: The logic behind the application of luteinizing hormone-releasing hormone (LHRH) agonists in combination with tamoxifen in premenopausal women is that LHRH agonists on the one hand suppress the tamoxifen-induced stimulation of the pituitary-ovarian function and, on the other hand, seem as effective as surgical castration. This meta-analysis combines all randomized evidence to compare the combined treatment with LHRH agonist alone with respect to overall survival, progression-free survival, and objective response in premenopausal women with advanced breast cancer. PATIENTS AND METHODS: Four clinical trials randomizing a total of 506 premenopausal women with advanced breast cancer to LHRH agonist alone or to the combined treatment of LHRH agonist plus tamoxifen were identified. Meta-analytic techniques were used to analyze individual patient data from these trials. RESULTS: With a median follow-up of 6.8 years, there was a significant survival benefit (stratified log-rank test, P = .02; hazards ratio [HR] = 0.78) and progression-free survival benefit (stratified log-rank test, P = .0003; HR = 0.70) in favor of the combined treatment. The overall response rate was significantly higher on combined endocrine treatment (stratified Mantel Haenszel test, P = .03; odds ratio = 0.67). CONCLUSION: The combination of LHRH agonist plus tamoxifen is superior to LHRH agonist alone in premenopausal women with advanced breast cancer. Therefore, if a premenopausal woman with advanced breast cancer is thought to be suitable for endocrine treatment, it is proposed that the combination of a LHRH agonist plus tamoxifen be considered as the new standard treatment.     

Comparison of efficacy and safety of 1- and 3-month luteinizing hormone-releasing hormone agonist depots as initial therapies for prostate cancer

Background

We compared the efficacy and safety of 1- and 3-month depots of the luteinizing hormone-releasing hormone (LH-RH) agonist goserelin acetate in prostate cancer patients.

Methods

Patients were randomly assigned to the Direct Group that received the goserelin 3-month depot or the Switch Group that began with the 1-month depot for the first 3 months and then switched to the 3-month depot. All patients were co-administered the antiandrogen agent bicalutamide. Serum testosterone and prostate-specific antigen (PSA) levels and adverse events were recorded at weeks 4, 8, 12, and 24.

Results

Baseline testosterone levels in the Direct and Switch Groups were 4.98 and 5.07 ng/mL, respectively (P = 0.798). At each week, the levels in both groups were ≤0.50 ng/mL (castration level) with no significant differences between them. All of the patients in the Switch Group and 98.1 % in the Direct Group had achieved castration levels at week 12, and 100 % had achieved such levels at week 24. Baseline PSA levels in the Direct and Switch Groups were 52.37 and 46.72 ng/mL, respectively (P = 0.793). Levels in both groups dropped continuously, to about 1.0 ng/mL at week 24, with no significant differences between the groups at any time. Three patients in the Direct Group experienced adverse events that were attributed to the co-administered bicalutamide.

Conclusions

There was no difference in the efficacy or safety between the 1- and 3-month depots of goserelin when given as initial prostate cancer treatment in combination with bicalutamide. Patients must be monitored for adverse events associated with bicalutamide.     

Prevention of severe menorrhagia in oncology patients with treatment-induced thrombocytopenia by luteinizing hormone-releasing hormone agonist and depo-medroxyprogesterone acetate

BACKGROUND: Menorrhagia is a serious complication in young female oncology patients who suffer from severe thrombocytopenia during myelosuppressive treatment. To the authors' knowledge, little is known regarding the incidence of this complication or the effectiveness of possible therapies for its prevention. METHODS: In this retrospective clinical study, after a thorough gynecologic evaluation, young female oncology patients with regular menstrual cycles undergoing myelosuppressive treatments received either depo-medroxyprogesterone acetate (DMPA), or D-tryptophan-6-luteinizing hormone-releasing hormone depot treatment (gonadotropin-releasing hormone agonist [GnRH-a]), or no treatment before the administration of myelosuppresive chemotherapy. Only patients who later developed severe thrombocytopenia (<25,000 platelets per muL) were included in the study. Daily blood counts, menorrhagia, nonvaginal bleeding episodes, and the need for blood products, gynecologic consultations, and other medical interventions were determined. RESULTS: Of 101 women with cancer who met the inclusion criteria, 42 patients received DMPA, 39 patients received GnRH-a, and 20 patients remained untreated. The mean duration (+/- standard deviation) of severe thrombocytopenia was 24.76 +/- 23.6 days. Four patients were not included because of significant gynecologic pathologies. General bleeding from nongynecologic sites was similar for all groups and was not associated with vaginal bleeding. Severe or moderate menorrhagia was documented in none of the 39 women who received GnRH-a, in 9 patients (21.4%) who received DMPA, and in 9 untreated patients (40%; P = .02). Fewer calls for urgent gynecologic consultations were documented in the GnRH-a group compared with the untreated group (P < .0001). CONCLUSIONS: Female patients undergoing myelosupressive therapy are at high risk of developing significant menorrhagia during prolonged, severe thrombocytopenia. Pretreatment gynecologic evaluation can detect significant pelvic pathologies. GnRH-a treatment effectively prevented menorrhagia, whereas DMPA administration was less effective.     

Inhibition of prostate carcinogenesis in probasin/SV40 T antigen transgenic rats by leuprorelin, a luteinizing hormone-releasing hormone agonist

The effects of leuprorelin acetate, a luteinizing hormone-releasing hormone agonist (LHRH-A), on prostate carcinogenesis in probasin/SV40 Tag transgenic rat was investigated. Fifteen weeks after administration of 0.28 and 2.8 mg/kg leuprorelin, prostate weights and serum testosterone levels were significantly decreased compared to values for transgenic controls. Histopathological findings revealed that the incidence of prostatic adenocarcinomas was significantly reduced in ventral, dorsal and lateral lobes of the prostate, correlating with decreased expression of SV40 Tag oncoprotein as well as inhibition of DNA synthesis and proliferation of epithelial cells in neoplastic lesions of the ventral prostate. Microarray analysis further showed leuprorelin acetate to significantly inhibit testicular steroidogenesis, suppressing the expression of SV40 Tag oncoprotein and altering the expression of a large number of genes which might be involved in the inhibition of prostate cancer progression in this rat model.     

Zoladex: a sustained-release, monthly luteinizing hormone-releasing hormone analogue for the treatment of advanced prostate cancer

Zoladex, a sustained-release luteinizing hormone--releasing hormone (LHRH) analogue administered by subcutaneous injection every 28 days, was evaluated at three dose levels in 46 men with untreated advanced prostate cancer. All three Zoladex doses yielded similar endocrinologic effects. After initial transient increases in serum luteinizing hormone, follicle-stimulating hormone, and testosterone concentrations, serum testosterone was suppressed uniformly to castration levels within 22 days. At a median follow-up of 41 weeks, Zoladex had maintained persistent suppression of serum testosterone. Measurements of serum Zoladex levels indicated that release of the drug from the injected depot was sustained over a period of 1 month and that there was no drug accumulation as evaluated over an initial 3-month period. No antibodies to Zoladex were detected. Tumor regression rates and side effects with Zoladex therapy were similar to those reported with daily injections of subcutaneous LHRH therapy. Signs and symptoms consistent with a brief tumor flare after the first injection of the LHRH analogue were noted in eight (17%) of the study entrants. Spinal cord compression was observed in two patients within 1 week from the onset of therapy. Zoladex is considered to be an effective, sustained-release LHRH analogue for the treatment of patients with prostate cancer.     

Growth inhibition of mouse MXT mammary tumor by the luteinizing hormone-releasing hormone antagonist SB-75

Female BDF1 mice bearing MXT mammary adenocarcinomas were treated for 3 weeks with the luteinizing hormone-releasing hormone (LH-RH) antagonist [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10]-LH-RH (SB-75), with the agonist D-Trp6-LH-RH, with tamoxifen (5 micrograms per animal per day subcutaneously), with the combination of D-Trp6-LH-RH and tamoxifen, or by surgical ovariectomy. SB-75 and D-Trp6-LH-RH were administered in the form of microcapsules releasing 25 micrograms/day. The reduction in tumor weights after treatment with SB-75, D-Trp6-LH-RH, D-Trp6-LH-RH plus tamoxifen, or ovariectomy was 84%, 64%, 33%, and 67%, respectively. Tamoxifen alone was ineffective. Histologically, the regressive changes in the treated tumors were characteristic of apoptosis (programmed cell death). In view of its potency and its immediate inhibitory effect, the LH-RH antagonist SB-75 should be considered as a possible new hormonal agent for the treatment of breast cancer.     

Effects of high doses of a series of new luteinizing hormone-releasing hormone analogues in intact female rats.

A new series of LH-RH analogues containing an Azgly10 modification and having potent agonist properties were given in high concentration to intact female rats. Plasma LH and FSH were raised to extremely high levels after 14 days' administration of the compounds (5.0 and 0.5 microgram/rat twice daily), but plasma oestradiol concentrations were reduced to those in ovariectomized rats. The weights of the ovary and uterus were also markedly reduced, suggesting that these compounds are, on this treatment regime, producing the effects of chemical castration.     

Overview of luteinizing hormone-releasing hormone agonists in early breast cancer-benefits of reversible ovarian ablation

Goserelin ('Zoladex'), a luteinizing hormone-releasing hormone (LHRH) agonist induces reversible ovarian ablation in premenopausal women. It is the most extensively studied LHRH agonist for the treatment of breast cancer and data from a large clinical trial program show that, alone or in combination with tamoxifen, goserelin is at least as effective as cyclophosphamide-methotrexate-5-fluorouracil (CMF) chemotherapy in patients with hormone-sensitive, early disease. Furthermore, goserelin has been shown to add benefit when used in addition to standard adjuvant therapy (surgery +/- radiotherapy +/- chemotherapy +/- tamoxifen) and may be beneficial when used after chemotherapy. In patients with hormone-sensitive, early breast cancer, treatment-induced amenorrhea has been associated with an improved prognosis and goserelin provides a highly effective and reliable method of achieving amenorrhea. The reversibility of amenorrhea upon cessation of goserelin treatment may confer long-term advantages compared with permanent methods of ovarian ablation. Ultimately, patients should be provided with sufficient information on the risks and benefits of the treatment options available to them so that they can be involved in treatment decisions.     

Regression of nitrosamine-induced pancreatic cancers in hamsters treated with luteinizing hormone-releasing hormone antagonists or agonists

Groups of 15 female Syrian golden hamsters with N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancers were treated for 2 mo with microcapsules of the luteinizing hormone-releasing hormone (LH-RH) antagonist [Ac-D-Nal(2)1-D-Phe(4Cl)2-D-Pal(3)3,D-Cit6,D-Ala10] LH-RH (SB-75) releasing 8 micrograms/day or with the microcapsules of the LH-RH agonist D-tryptophan-6-luteinizing hormone-releasing hormone (D-Trp-6-LH-RH) releasing 8 micrograms/day or 25 micrograms/day. Chronic treatment with SB-75 resulted in 70% inhibition of pancreatic tumor weight; D-Trp-6-LH-RH in doses of 8 micrograms/day and 25 micrograms/day produced 66% and 62% inhibition, respectively. The number of animals with pancreatic tumors was reduced by about 50% in each treated group. Tumorous ascites were found in seven control hamsters and in one hamster in each group treated with D-Trp-6-LH-RH but not in the group given SB-75. Reduction in serum luteinizing hormone levels and ovarian as well as uterine weights indicated that an inhibition of the pituitary-gonadal axis occurred during chronic SB-75 and D-Trp-6-LH-RH treatment. Membrane receptor assays showed a significant decrease of the concentration of binding sites for LH-RH in tumor cells after SB-75 or D-Trp-6-LH-RH treatment. Insulin-like growth factor I receptors, but not epidermal growth factor receptors, were down-regulated by D-Trp-6-LH-RH. SB-75 did not influence the concentration or the binding capacity of insulin-like growth factor I and epidermal growth factor receptors in the tumor cells. The inhibitory effect of chronic treatment with SB-75 and D-Trp-6-LH-RH on tumor growth was mediated by enhanced apoptosis (programmed cell death) induced by the change in hormonal environment. Apoptosis was also produced in hamsters with N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancers by acute treatment (3 to 6 days) with high doses of D-Trp-6-LH-RH or SB-75. In view of its potency and an immediate powerful inhibitory effect, the LH-RH antagonist SB-75 might be considered as a possible new hormonal agent for the treatment of exocrine pancreatic cancer.     

Evaluation of binding of cytotoxic analogs of luteinizing hormone-releasing hormone to human breast cancer and mouse MXT mammary tumor

The binding characteristics of several cytotoxic analogs of luteinizing hormone-releasing hormone (LH-RH) developed in our laboratory were examined in membranes from human breast cancer and estrogen independent MXT mammary cancer. Specific binding of [¹²⁵I]D-Trp⁶-LH-RH and the cytotoxic LH-RH analog [¹²⁵I]T-98 ([D-Lys⁶]LH-RH coupled to glutaryl-2-(hydroxymethyl)anthraquinone) (HMAQG) was demonstrated in membrane preparations from human breast and MXT mammary tumor cells. Ligand binding of T-98 was specific, saturable, and dependent on temperature, time, and plasma membrane concentration. Analysis of the binding data showed that in human breast cancer, interaction of [¹²⁵I]T-98 was consistent with the presence of two classes of LH-RH receptors, one class showing high affinity and low capacity, and the other class showing low affinity and high capacity binding. In membranes from MXT mammary cancer, T-98 bound to one class of saturable, specific, noncooperative binding sites with high affinity and low capacity. The rates of association and dissociation for [¹²⁵I]T-98 were calculated to be 4.757×10⁸ M^–1 min^–1 and 0.016 min^–1 (t_1/2=38.7) in membranes from MXT mammary cancer. In human breast cancer, association rate constants (K_1a and K_1b) were 2.3×10⁶ M^–1 min^–1 for binding to high affinity and 1.8×10⁴ M^–1 min^–1 for binding to low affinity binding sites. Dissociation rate constants were K_–1a=0.0801 min^–1 (t_1/2a=63.4 min) and K_–1b=0.0467 min^–1 (t_1/2b=23.5 min), respectively. [¹²⁵I]T-98 was not displaced by either unlabeled somatostatin or epidermal growth factor, but was displaced completely by unlabeled T-98 or [D-Trp⁶]LH-RH. The analysis of displacement curves of [D-Trp⁶]LH-RH by cytotoxic agonists and antagonists of LH-RH synthesized in our laboratory showed that T-121, AJ-11, T-120, T-133, and T-98 were the most potent in displacing [¹²⁵I]D-Trp⁶-LH-RH from breast and MXT cancer membranes. Binding kinetics and analyses of displacement curves of [¹²⁵I]D-Trp⁶-LH-RH and [¹²⁵I]T-98 in membranes of human breast cancer and estrogen independent MXT mouse mammary cancer suggest that binding of the cytotoxic analog T-98 to the LH-RH receptor proceeds reversibly like that of its congeners without cytotoxic radicals. Our findings may provide a stimulus for further studies with LH-RH analogs carrying cytotoxic radicals. Such analogs could be targeted to breast cancer and other cancers that have membrane receptors for LH-RH. Because the antitumor action may be exerted to a greater degree at more selective sites that have the cell membrane receptors, the peripheral toxicity could be reduced.On leave of absence from Department of Pharmacology, Medical School, University of Tuzla and Military Technical Institute, Belgrade, Yugoslavia