goserelin and nilutamide

Ever since prostatic carcinoma was discovered to be dependent on the hormone androgen for its proliferation, androgen deprivation has been the treatment of choice for advanced cases of prostate cancer. Originally, treatment was limited to surgical castration or estrogen therapy. However, the introduction of luteinizing hormone-releasing hormone analogues, antiandrogens, and newer treatment modalities, such as combined androgen blockade, has made choosing a treatment strategy more complex. Assuming that each modality is equally effective, emphasis should be placed on increasing patient tolerance and compliance by the use of long-acting, nontoxic treatments with simple dosing regimens and minimal side effects. This review focuses on the factors influencing the final choice of treatment strategy.

Topics: Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Flutamide; Goserelin; Humans; Imidazoles; Imidazolidines; Male; Nitriles; Prostatic Neoplasms; Tosyl Compounds

The aim of the study was to evaluate the efficacy of antiandrogen therapy on overall survival and response in unresectable hepatocellular carcinoma (HCC).. A total of 244 patients with unresectable HCC were included in this multicentric double-blind trial. According to a two-by-two factorial design, patients were randomly assigned to receive one of the following treatments: pure antiandrogen plus placebo (A+P group, 60 patients); luteinizing hormone-releasing hormone (LHRH) agonist plus placebo (LHRH+P group, 62 patients); pure antiandrogen plus LHRH agonist (A+LHRH group, 62 patients); or placebo plus placebo (P+P group, 60 patients). Pure antiandrogen consisted of Anandron (Roussel-Uclaf Laboratory, Romainville, France) administered orally (300 mg daily for 1 month, then 150 mg daily). LHRH consisted of goseriline acetate (3.6 mg) or triptoreline (3.75 mg) administered monthly by subcutaneous injection. Treatment was given until death. Response was evaluated every 8 weeks according to World Health Organization (WHO) criteria.. Six patients were considered ineligible. One patient had a complete response (A+P arm) and three had a partial response (two in the LHRH+P arm and one in the A+LHRH arm). An overall log-rank test did not demonstrate any significant difference in survival among the four arms. Taking the factorial design into account, comparison of survival showed no significant difference between Anandron-containing regimens and others, or between LHRH-containing regimens and others. No serious side effects occurred for any regimen.. This controlled study shows clearly the lack of efficacy of androgen treatment in unresectable HCC.

Topics: Androgen Antagonists; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Double-Blind Method; Female; Gonadotropin-Releasing Hormone; Goserelin; Humans; Imidazoles; Imidazolidines; Liver Neoplasms; Male; Survival Rate; Triptorelin Pamoate

This trial compares Casodex (ICI 176,334) monotherapy with the combination of castration (medical or surgical) plus nilutamide. The trial is now closed to entry, 270 patients having been recruited from 32 French centres. As it is too early to present efficacy data, only patient characteristics and interim tolerability data appear in this paper. In the combined treatment group, interstitial pneumonitis (4.5%) was observed, leading to withdrawal from the trial. Other adverse events leading to withdrawal included dyspnoea and ocular problems. There was also 1 case of hepatitis in this treatment group. In the Casodex treatment group, only 6 patients (as compared with 13 in the combined treatment group) withdrew from the trial because of adverse events. As expected with this group, the adverse events were mainly pharmacological effects of an anti-androgen as monotherapy. In the majority of patients, the effects of gynaecomastia and breast tenderness did not result in withdrawal.

Topics: Aged; Androgen Antagonists; Anilides; Antineoplastic Agents; Combined Modality Therapy; Goserelin; Humans; Imidazoles; Imidazolidines; Male; Nitriles; Orchiectomy; Prostatic Neoplasms; Tosyl Compounds

There is no consensus on the association between the use of androgen deprivation therapy (ADT) and the risk of developing depression. This study investigated the association between ADT use and the development of depression, outpatient psychiatric services, inpatient psychiatric services, and suicide in a homogeneous group of men with prostate cancer (PC) treated with definitive radiation therapy (RT) after controlling for multiple sources of selection bias.. This was a retrospective, observational cohort study of 39,965 veterans with PC who were treated with definitive RT and were diagnosed by the US Department of Veterans Affairs health care system between January 1, 2001, and October 31, 2015. Exposure was ADT initiation within 1 year of the PC diagnosis. The primary outcome was new development of depression. Secondary outcomes were outpatient psychiatric use, inpatient psychiatric use, and suicide.. During follow-up, 934 patients were newly diagnosed with depression, 7825 patients used outpatient psychiatric services, 358 patients used inpatient psychiatric services, and 54 patients committed suicide. In the multivariable competing risks regression model, ADT was associated with the development of depression (subdistribution hazard ratio [SHR], 1.50; 95% confidence interval [CI], 1.32-1.71; P < .001). ADT was also associated with outpatient psychiatric utilization (SHR, 1.21; 95% CI, 1.16-1.27; P < .001). Finally, ADT was not associated with inpatient psychiatric utilization or suicide.. An increase in the risk of depression and the use of outpatient psychiatric services was observed in a large cohort of men with PC who received ADT with definitive RT. These results may provide further evidence for the long-term risks of ADT for psychiatric health in the treatment of PC.

Topics: Aged; Aged, 80 and over; Ambulatory Care; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Depression; Depressive Disorder; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Hospitalization; Humans; Imidazolidines; Leuprolide; Male; Mental Health Services; Middle Aged; Nitriles; Oligopeptides; Prostatic Neoplasms; Radiotherapy; Retrospective Studies; Suicide; Tosyl Compounds

As androgen deprivation therapy (ADT) is increasingly being used in men with localised prostate cancer, our goal was to examine the association between ADT and the risk of cardiovascular disease (CVD).. We conducted a prospective cohort study using records of a large health-care system in California. The study included men with newly diagnosed localised prostate cancer (1998-2008) who initially underwent active surveillance (N=7637) and were followed through 2010. We examined 10 individual CVD outcomes. Cox proportional hazard models incorporated time-varying treatment variables and controlled for race/ethnicity, age, and tumour characteristics, recurrence risk, CVD medication use, and CVD risk factors.. Of the 7637 subjects, nearly 30% were exposed to ADT. In the multivariable analyses, ADT was associated with an increased risk of heart failure (adjusted HR=1.81, 95% CI 1.40-2.32) in men without preexisting CVD. Elevated risks of arrhythmia (adjusted HR=1.44, 95% CI 1.02-2.01), and conduction disorder (adjusted HR=3.11, 95% CI 1.22, 7.91) were only observed among patients with preexisting CVD.. In men with clinically localised prostate cancer who were initially under active surveillance, ADT was associated with a greater risk of heart failure in men without any preexisting CVD. We also found an increased risk of arrhythmia and conduction disorder in men with preexisting CVD. This study provides the basis for identifying high-risk men treated with ADT who might benefit from regular cardiac monitoring and lifestyle modification recommendations.

Topics: Aged; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Arrhythmias, Cardiac; California; Cardiovascular Diseases; Cohort Studies; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Heart Failure; Humans; Imidazolidines; Leuprolide; Male; Middle Aged; Multivariate Analysis; Neoplasm Grading; Nitriles; Proportional Hazards Models; Prospective Studies; Prostatic Neoplasms; Risk Factors; Tosyl Compounds

The meta-analysis of maximal androgen blockade (MAB) concluded that there is no survival advantage of MAB over castration alone. However, the results from the largest trials yield conflicting results.. The design and results of three trials were examined.. Most studies were planned to detect an over-optimistic difference in survival and immature data were published. The survival curves show that statistical assumptions are not fulfilled. Excluding from the meta-analysis all trials where a negative impact of disease flare on survival could not be excluded resulted in no difference in survival between MAB and castration.. Trials of MAB should be planned to detect differences of no more than 5-10% in median survival. The analyses should only be carried out on mature data and should take into account the possibility of a negative impact on survival due to disease flare if no anti-androgen has been given initially with an LH-RH agonist.

Topics: Androgen Antagonists; Anilides; Clinical Trials, Phase III as Topic; Cyproterone Acetate; Factor Analysis, Statistical; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Humans; Imidazoles; Imidazolidines; Leuprolide; Male; Meta-Analysis as Topic; Nitriles; Orchiectomy; Prognosis; Prostatic Neoplasms; Research Design; Survival Analysis; Tosyl Compounds; Treatment Outcome

To study the effect of androgens on somatic testicular cells, rats were rendered germ cell depleted by prenatal irradiation (RX). Adult RX rats were treated with a desensitizing dose of a GnRH agonist (GnRHa; Zoladex), combined with an antiandrogen (Nilutamide) to preclude all androgen effects, or combined with testosterone or hCG to restore androgen action. The effect of these treatments for 3 weeks on the weight of testes and accessory sex glands, hormones (LH, FSH, testosterone, inhibin), testicular proteins, the pattern of incorporation of [35S]-methionine into testicular proteins (studied by two dimensional gel electrophoresis) and steady state mRNA levels for transferrin and androgen-binding protein (ABP) were evaluated. Combined treatment with GnRHa and antiandrogen virtually eliminated gonadotrophins, androgens and androgen effects. Testicular weight was reduced to 50% of that observed in RX controls. Treatment with GnRHa and testosterone resulted in supraphysiological levels of testosterone and testicular weights comparable to those observed in RX controls. FSH levels in these animals, however, were in the normal range. A low dose of hCG also restored testicular weight in the presence of low concentrations of serum testosterone and low normal levels of FSH. Neither polyacrylamide gel electrophoresis of total testicular proteins nor two dimensional gel electrophoresis of [35S]-methionine labelled proteins revealed striking changes in distinct testicular proteins as a result of androgen withdrawal or androgen treatment. Dot blot hybridization showed a three-fold increase in the mRNA level for ABP (expressed per microgram total RNA) in the Sertoli cell enriched testes of RX rats. This level was barely influenced by androgen withdrawal or androgen administration. The mRNA level for transferrin was increased six-fold in RX rats. A 50% reduction of this level was observed after combined treatment with GnRHa and antiandrogen. It is concluded that, in the germ cell-depleted testis, the major effect of androgens is an overall increase in protein and RNA synthesis rather than a very important and selective increase of a few gene products.

Topics: Androgen Antagonists; Androgens; Animals; Base Sequence; Body Weight; DNA Primers; Female; Follicle Stimulating Hormone; Goserelin; Imidazoles; Imidazolidines; Luteinizing Hormone; Male; Molecular Sequence Data; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Protein Biosynthesis; Proteins; Rats; Rats, Wistar; RNA; Spermatozoa; Testis; Testosterone

Topics: Androgen Antagonists; Buserelin; Flutamide; Goserelin; Humans; Imidazoles; Imidazolidines; Leuprolide; Male; Orchiectomy; Prostatic Neoplasms

The effects of the s.c. administration of a depot formulation of the luteinizing hormone-releasing hormone (LHRH) analogue Zoladex were studied in normal male rats, alone and in combination with three drugs with "antiandrogenic" action (ketoconazole, cyproterone acetate, and RU 23908) on prostatic weight and on circulating hormone levels in order to investigate whether these antiandrogens might prevent the LHRH-A-induced initial increase in these parameters. These effects were compared with those caused by surgical castration. In addition the effects of the antiandrogens on the activity of the hypothalamic-pituitary-adrenal axis were investigated. The depot LHRH analogue caused an initial increase in ventral prostatic weight after 4 days but suppressed the prostatic and testicular weights, the pituitary luteinizing hormone (LH) content, and plasma LH and testosterone levels after 10 and 17 days. All three antiandrogenic drugs used prevented the initial LHRH analogue-induced rise in prostatic weight, while RU 23908 suppressed its weight after only 4 days. After 10 and 17 days cyproterone acetate and RU 23908 had a similar significantly greater suppressive effect on prostatic and testicular weights than the LHRH analogue alone, while the additive inhibitory effect of ketoconazole was smaller. Surgical castration suppressed prostatic weight significantly more after 4 days, while its effects after 10 and 17 days were similar to that exerted by the combination of LHRH-A and RU 23908. The antigonadotropic effect of cyproterone acetate and the indirect gonadotropin-stimulating effects of ketoconazole and RU 23908 were not recognized in rats simultaneously treated with the LHRH analogue and did not interfere with the LHRH analogue-induced rapid depletion of the pituitary LH content and the decrease in circulating LH and testosterone levels. The LHRH analogue stimulated circulating progesterone and suppressed 17-hydroxyprogesterone levels. Ketoconazole and cyproterone acetate caused disorders in the pituitary-adrenal axis via different mechanisms: ketoconazole caused adrenal hypertrophy with normal circulating corticosterone levels caused by a compensatory increase in ACTH secretion; while cyproterone acetate exerted glucocorticoid-like effects causing a depletion of the pituitary adrenocorticotropic hormone content, adrenal atrophy, and lowered corticosterone levels. The addition of RU 23908 did not change the LHRH agonist-induced changes in adrenocortical activi

Topics: Adrenocorticotropic Hormone; Animals; Buserelin; Cyproterone; Cyproterone Acetate; Delayed-Action Preparations; Goserelin; Imidazoles; Imidazolidines; Ketoconazole; Luteinizing Hormone; Male; Orchiectomy; Organ Size; Prostate; Prostatic Neoplasms; Rats; Rats, Inbred Strains