Showing papers on "Bicalutamide published in 2001"

The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade: a double blind, randomized, placebo-controlled crossover study.

Abstract: BACKGROUND Prostate carcinoma therapy with combined androgen blockade may result in high bone-turnover with significant bone loss. This study was undertaken to evaluate the antiosteoporotic efficacy of intravenous pamidronate in a double blind, randomized, placebo-controlled, crossover study. METHODS Twenty-one consecutive men with metastatic prostate carcinoma who were receiving combined androgen blockade with a long-acting gonadotropin-releasing hormone agonist (gosarelin acetate) and an androgen antagonist (flutamide or bicalutamide) were evaluated at baseline and at 6 and 12 months after therapy. They were randomly assigned to receive a single intravenous infusion of 500 mL of normal saline solution diluted with either pamidronate (90 mg) or placebo at baseline and with a crossover at 6 months. Lumbar-spine bone-mineral densities (BMDs) were measured by spinal quantitative computed tomography (QCT), femoral neck BMDs were measured by dual-energy X-ray absorptiometry (DXA), and markers of bone turnover were measured by noninvasive methods. Data on 10 men with localized prostate carcinoma who were treated with radiotherapy alone, over the same period, was collected for comparison studies. RESULTS The mean age of the men was 75.1 years ± 1.6 years. One man withdrew from the study because of deteriorating health, and two died from metastatic disease within the first 6 months. Combined androgen blockade normalized serum prostate-specific antigen activities (from an initial mean value of 86.2 ng/mL ± 10.1 ng/mL) and maintained serum free testosterone concentrations in the hypogonadal range (< 2.2 pmol/L) in all men throughout the study. Treatment with pamidronate resulted in a 7.8% ± 1.5% increase in mean lumbar spine QCT from 79.4 mg/cm3 (95% confidence interval [CI], 64–94 mg/cm3) to 85.6 mg/cm3 (95% CI, 70–101 mg/cm3) (P = 0.0005) and a 2% ± 0.9% increase in mean total femoral neck DXA from 0.98 g/cm2 (95% CI, 0.90 –1.05 g/cm2) to 1.0 mg/cm2 (95% CI, 0.91–1.08 g/cm2) (P = 0.02). Conversely, treatment with placebo, resulted in a 5.7% ± 1.6% decrease in mean lumbar spine QCT and a 2.3% ± 0.7% decrease in mean total femoral neck DXA (P = 0.0001 and P = 0.0007 for the comparison of percentage change between the pamidronate and placebo treatments). After pamidronate therapy, serum bone Gla-protein concentrations decreased by 16.8% ± 5.9%, and urinary deoxypyridinoline excretion rates decreased by 18.5% ± 12.8% (P < 0.01 respectively for the comparison between pamidronate and placebo treatment). CONCLUSIONS This study demonstrated that a single intravenous infusion of pamidronate (90 mg) significantly reduced the high bone turnover and bone loss (for at least 6 mos) in men with prostate carcinoma who had been rendered hypogonadal with combined androgen blockade therapy. Cancer 2001;92:1444–50. © 2001 American Cancer Society.

Flare Associated with LHRH-Agonist Therapy.

Abstract: The most common form of hormonal treatment for prostate cancer is luteinizing hormone-releasing hormone (LHRH)-agonist therapy. During the first 1 to 3 weeks of LHRH-agonist therapy, an initial increase in testosterone is associated with a condition known as "flare." Blockade of flare can be accomplished with a number of agents, including flutamide, bicalutamide, nilutamide, diethylstilbestrol, ketoconazole, and cyproterone acetate. Evidence from the early use of LHRHagonists suggested that flare could be serious in nature, with an exacerbation of pain, increase in uremia, development of neurologic sequelae, and possibly death. These events have been uncommonly reported of late, most probably owing to the use of flare blockade in most patients with advanced disease, as well as the fact that many patients are currently being treated with much earlier disease. Evidence is conflicting as to whether flare makes a difference in less advanced disease. A few reports have noted complications during flare in patients in whom a blockade of flare was not required, including two deaths from one institution. Reported series, however, seem to suggest that with flare blockade, acute complications are extremely uncommon. Evidence suggests that 1) advanced disease should be blocked; 2) blockade should probably include an antiandrogen beginning about 1 week prior to administration of the LHRH-agonist; and 3) that patients without advanced disease but with very high PSA levels should be considered for flare blockade.

The bicalutamide Early Prostate Cancer Program. Demography.

Abstract: BACKGROUND: The optimal treatment for early prostate cancer has yet to be established. A well-tolerated hormonal therapy such as bicalutamide could be a useful treatment option in this setting, either as adjuvant or immediate therapy. A major collaborative clinical trials program was set up to investigate bicalutamide as a treatment option for local prostate cancer (localized or locally advanced disease). METHODS: The bicalutamide Early Prostate Cancer program comprises three randomized, double-blind, placebo-controlled trials of similar design that are being conducted in distinct geographical areas (North America; Australia, Europe, Israel, South Africa and Mexico; and Scandinavia). Men with T1b-4N0-1M0 (TNM 1997) prostate cancer have been randomized on a 1:1 basis to receive bicalutamide 150 mg daily or placebo. Recruitment to the program closed in July 1998, and follow-up is ongoing. Study endpoints include time to clinical progression, overall survival and tolerability. RESULTS: 8113 men aged 38 to 93 years (mean 66.9) were randomized over a 3-year period. 67.4% of the enrolled patients had localized disease (T1-2) and 66.4% had a Gleason score

Treatment of Localized Prostate Cancer With Intermittent Triple Androgen Blockade: Preliminary Results in 110 Consecutive Patients

Abstract: Objectives To determine the effectiveness of triple androgen blockade as an alternative to watchful waiting, radical prostatectomy or radiation therapy in the management of patients with clinical stage T1 to T3 prostate cancer Methods The records of 110 consecutive patients were retrospectively evaluated Patients were treated with a three-drug androgen blockade regimen, consisting of a luteinizing hormone-releasing hormone agonist (leuprolide or goserelin) plus an antiandrogen (flutamide or bicalutamide) plus finasteride (a 5-alpha-reductase inhibitor), followed by finasteride maintenance therapy, as the sole intervention All patients refused local therapy and had their prostates intact Determinants of efficacy included serum prostate-specific antigen (PSA) levels and disease-specific survival Results Patients were treated for a median of 13 months with triple androgen blockade At baseline, mean PSA level was 132 ± 12 ng/ml (range, 039-100 ng/ml), and mean Gleason score was 66 ± 01 (range, 4-10) During treatment, PSA levels declined to ≤01 ng/ml in all patients, with a median time of 3 months After a median follow-up of 36 months since initiation of treatment, PSA levels have remained stable in 105 of 110 patients (955%) At a median follow-up of 55 months (range, 38-125 months), the mean PSA level for the first 57 patients treated in this series is 188 ± 01 (range, 0-110 ng/ml) Only 9 of 110 (81%) patients have a PSA level ≥40 ng/ml To date, no patient has received a second cycle of hormone blockade Conclusions Although median follow-up is short, triple androgen blockade therapy followed by finasteride maintenance appears to be a promising alternative for the management of patients with clinically localized or locally advanced prostate cancer Further study of this approach is warranted The Oncologist 2001;6:177-182

Androgen receptor mutations in carcinoma of the prostate: significance for endocrine therapy.

Abstract: Endocrine therapy for advanced prostate cancer involves androgen ablation (orchiectomy or application of luteinizing hormone releasing hormone analogs) and/or blockade of the androgen receptor (AR) with either steroidal (cyproterone acetate) or nonsteroidal (hydroxyflutamide, bicalutamide and nilutamide) antiandrogens. These antagonists prevent androgen-induced conformational change and activation of the AR. During long term androgen ablation, the AR adapts to an environment with low androgen concentrations and becomes hypersensitive to low concentrations of androgens, either alone or in combination with various cellular regulators. Bicalutamide can switch from antagonist to agonist during long-term androgen withdrawal, as shown in prostate cancer LNCaP cells. AR point mutations were detected in metastatic lesions from human prostate cancer more frequently than in primary tumors. Although functional characterization of only some mutant AR detected in prostate cancer tissue has been performed, data available suggest that they are activated by dihydrotestosterone, its precursors and metabolites, synthetic androgens, estrogenic and progestagenic steroids and hydroxyflutamide. A direct association between AR mutations and endocrine withdrawal syndrome has been investigated in only one study thus far. There is no evidence at present that activation of any of the mutant AR genes detected in prostate cancer is enhanced in the presence of a nonsteroidal AR stimulator. Coactivators of the AR are proteins that associate with the receptor, possess histone acetylase activity and facilitate AR activation. The coregulatory proteins ARA70 and ARA160 differentially affected the activity of the mutated AR Glu(231)-->Gly, which was discovered in a mouse authochthonous prostate tumor. ARA70 enhanced receptor activation by both androgen and estradiol, whereas ARA160 augmented only androgen-induced AR activity. Novel experimental therapies that down-regulate AR expression have been developed; they include the application of ribozymes and antisense oligonucleotides.

Is there a role for antiandrogen monotherapy in patients with metastatic prostate cancer

Abstract: Castration is the most widely used form of androgen ablation employed in the treatment of metastatic (M1) prostate cancer. Non-steroidal antiandrogen monotherapy is a potential alternative treatment option for men for whom castration is unacceptable or not indicated. Of the three non-steroidal antiandrogens, bicalutamide (‘Casodex’), flutamide and nilutamide, only bicalutamide has been compared with castration in large, controlled, randomised, Phase III trials in M1 patients. A post-hoc analysis of these studies indicated that bicalutamide 150 mg/day monotherapy may be of benefit to M1 patients with a prostate specific antigen (PSA) level ≤400 ng/ml. Significant advantages for M1 patients treated with bicalutamide were observed in subjective response rate, maintenance of sexual interest and physical capacity. Patients with a higher disease burden (PSA >400 ng/ml) may decide that quality of life and symptomatic benefits outweigh the slight survival disadvantage seen in clinical trials and opt for bicalutamide monotherapy as an alternative to castration. .

Effects of finasteride and bicalutamide on prostatic blood flow in the rat.

Abstract: ObjectiveTo determine whether finasteride and bicalutamide, both currently used in the clinical management of patients with prostate diseases because they have anti-androgenic properties, have any effects on prostatic blood flow in a rat prostate model, as androgens are known to be involved in the regulation of prostatic blood flow and angiogenesis. Materials and methodsBoth finasteride and bicalutamide were supplied as oral suspensions in water and given daily to rats for 7 days by tube feeding. Blood flows to the ventral and dorsal prostates, and to the kidneys, were measured using the radioactive microsphere technique. In the bicalutamide experiments, some rats were treated with the Leydig cell toxin ethane dimethane sulphonate (EDS), to obtain a castration-like effect, and one group of these rats received testosterone. ResultsFinasteride induced a clear decrease in blood flow to the ventral and dorsal prostates after 7 days of treatment, with no significant changes in blood pressure or kidney blood flow. Bicalutamide inhibited the testosterone-induced increment of prostatic blood flow observed in EDS-treated animals. ConclusionsFinasteride, a blocker of 5α-reductase, decreases prostate blood flow after 7 days of administration. The response was slower than that after castration, but was of similar magnitude. Blood flow was also decreased after treatment with the androgen-receptor inhibitor bicalutamide. These observations suggest that prostatic blood flow is increased by dihydrotestosterone, and that the androgen receptor is responsible for mediating this effect.

Long‐term exposure of tumor necrosis factor α causes hypersensitivity to androgen and anti‐androgen withdrawal phenomenon in LNCaP prostate cancer cells

Abstract: BACKGROUND One of the mechanisms through which prostate cancers relapse during anti-androgen therapy may involve adaptation to low concentrations of androgen induced by anti-androgen therapies. Recent studies from our laboratory have reported that tumor necrosis factor-α (TNFα) is secreted from prostate cancer epithelial cells and LNCaP cells. We hypothesized that TNFα changes androgen-sensitivity in LNCaP cells. METHODS We cultured LNCaP cells for more than 3 months in the presence of 50 ng/ml TNFα and established TNFα-resistant LNCaP cells (LN-TR2). Sensitivity to androgen was examined by the cell proliferation assay. We also transfected LNCaP and LN-TR2 cells with a luciferase reporter plasmid driven by prostate-specific antigen (PSA) promoter and compared PSA promoter activity. Nuclear localization of AR protein that binds to target genes was also examined by Western blotting. RESULTS LN-TR2 cells had increased sensitivity to dihydrotestosterone (DHT) (i.e., proliferation and PSA promoter activation) than LNCaP cells. Total AR mRNA and AR protein levels were decreased in LN-TR2 cells. However, LN-TR2 cells demonstrated increased levels of nuclear AR compared to LNCaP cells. At 1 nM DHT, the anti-androgen bicalutamide stimulated LN-TR2 and inhibited LNCaP proliferation. CONCLUSIONS Long-term exposure of TNFα causes hypersensitivity to DHT in LNCaP and this was associated with increased nuclear AR protein. Furthermore, hypersensitivity to androgen caused anti-androgen withdrawal phenomenon in the presence of DHT although bicalutamide itself did not stimulate LNCaP proliferation without androgen. This result may be one possible mechanism for the anti-androgen withdrawal phenomenon. Prostate 46:319–326, 2001. © 2001 Wiley-Liss, Inc.

Pharmaceutical combination of bicalutamide and tamoxifen for providing an anti-androgenic effect and an anti-oestrogenic effect

Abstract: The present invention relates to a pharmaceutical product, daily dose or dose regimen comprising 4'-cyano-α',α',α'-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropriono-m-toluidide (compound I) and tamoxifen. The product comprises compound I and tamoxifen in a ratio of 25 to 350:0.5 to 100 respectively. The invention also relates to a method of providing an anti-antrogenic effect and an anti-oestrogenic effect in a patient, wherein the anti-oestrogenic effects is provided substantially without causing an additional increase in the levels of circulating androgens.

Androgen deprivation and other treatments for advanced prostate cancer.

Abstract: Among the issues discussed at this year's meeting on prostate cancer in Vail, Colorado, were several that specifically relate to the patient with advanced disease. Dr. E. David Crawford addressed the issue of the timing of hormone therapy, specifically reviewing several important trials that give a glimpse at the potential outcome of aggressive treatment in stage D1.5. The efficacy of antiandrogens, flutamide, bicalutamide, and nilutamide, when combined with chemical or surgical castration, was reviewed. Dr. Arturo Mendoza-Valdes reviewed the rationale behind intermittent (versus continuous) total androgen blockade, especially as related to quality of life. Dr. Paul Miller gave an update on the role of bisphosphonates as adjuvant therapy for prostate cancer. Also discussed was an important new agent for androgen deprivation, Abarelix, a sustained-release GnRH antagonist with low histamine-releasing potential which avoids testosterone and other hormone surge and flare.

Emerging pharmacologic therapies for prostate cancer.

Abstract: The last decade has seen explosive growth in the therapy of prostate cancer. Three areas of therapeutics are emerging: 1) new compounds with novel uses; 2) available compounds with new applications; and 3) new compounds applied to established indications. The novel compounds target specific receptor sites of cancer pathways and attack cancer cells with less effect on normal tissue. Earlyphase trials with compounds targeting the endothelin-A and EGF receptors have shown encouraging results in hormone-refractory prostate cancer. In addition, the Early Prostate Cancer Trial of over 8000 men is currently underway to determine the benefit of adjuvant androgen ablation with bicalutamide in men with localized prostate cancer. Early results show a significant 42% reduction in the progression of the disease in the bicalutamide treatment arm. Further, in large, phase 3 clinical trials in patients needing androgen ablation, the GnRH antagonist abarelix caused no testosterone surge and demonstrated a significantly more rapid decline in serum testosterone to the castrate level than did an LHRH agonist analogue. Abarelix should thus have application as a monotherapy in patients who need a rapid onset of action or are at high risk of complications from the clinical flare seen with LHRH agonists. Abarelix also uniquely caused a sustained decline in serum FSH levels, which have been shown in vitro to stimulate prostate cancer cell growth. If these favorable effects can be duplicated in patients, abarelix might also offer a survival benefit.

The effect of bicalutamide on prostate histology.

Abstract: BACKGROUND Nonsteroidal antiandrogens are commonly used in the treatment of prostate cancer, but more clinical and laboratory studies on patients with benign as well as malignant prostate diseases are required to define their exact role. METHODS Light microscopic examination of perineal prostate biopsies of 21 men with BPH was performed pretreatment, after 24 weeks of therapy with 50 mg bicalutamide (Casodex) or placebo and 24 weeks after end of treatment. We assessed whether it was possible to distinguish between patients having received bicalutamide or placebo based on a general histological examination. In addition, the volume fractions of the prostatic epithelial, luminal, and stromal compartments were determined by morphometry. RESULTS Histological changes following treatment were uncharacteristic and patients treated with bicalutamide were not identified. At morphometry prior to therapy, the prostates of the study participants consisted of 91.8% stroma (range 78.9–97.2), 5.5% epithelium (range 1.4–14.1) and 2.7% glandular lumen (range 0.8–7.5). Changes in the relative content of the three tissue components following treatment were not statistically significant. CONCLUSIONS We did not observe consistent morphological changes in the prostate following treatment with bicalutamide at a dose of 50 mg daily. However, this dose is lower than the 150 mg dose presently recommended for bicalutamide monotherapy. Prostate 46:275–280, 2001. © 2001 Wiley-Liss, Inc.

Effects of long‐term treatment with the anti‐androgen bicalutamide on human testis: an ultrastructural and morphometric study

Abstract: Aims: To assess the effects of more than 4 years' treatment with the anti-androgen bicalutamide on human testis by clinical, ultrastructural and morphometric analysis. Methods and results: Two patients (aged 74 and 69 years) with prostate cancer were treated for more than 4 years with bicalutamide 50 mg daily. Clinical characterization and follow-up included luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and prostate-specific antigen (PSA) measurements and clinical response of the tumours. Due to progression of the disease, patients underwent surgical orchidectomy as a further androgen withdrawal therapy. Testis biopsies were studied by light and electron microscopy and analysed by morphometry. Control samples were obtained from the normal testis of two patients with testicular cancer who underwent orchidectomy. Clinical follow-up showed a good response in the control of tumour growth and serum PSA decreased to < 4 ng/mL; concentrations of serum LH, FSH and testosterone were within the normal range. Testicular morphology of treated patients was unexpectedly well preserved; the organization of seminiferous tubules was normal with all the germ line elements and mature spermatozoa present. In some areas, a net increase of peritubular connective tissue was evident which may be a consequence of the age of the patients. Conclusions: Long-term bicalutamide (50 mg) treatment appears to have very little impact on testis ultrastructure and sperm maturation, while it is effective in the control of androgen-dependent prostatic tumours.

Pharmaceutical combination of bicalutamide and anastrozole for providing an anti-androgenic effect and aromatase inhibition

Abstract: The present invention relates to a pharmaceutical product, daily dose or dose regimen comprising 4′-cyano-α′,α′,α′-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methylpropriono-m-toluidide (compound I) and anastrozole. The invention also relates to a method of providing an anti-anrogenic effect and aromatase inhibition in a patient, wherein the aromatase inhibition is provided substantially without causing an additional increase in the levels of circulating androgens.

Effects of bicalutamide and leuprolide on prostate-specific antigen (PSA), acid phosphatase (ACP) and prostatic acid phosphatase (PAP) in men with benign prostatic hyperplasia (BPH).

Abstract: The effects of the nonsteroidal antiandrogen bicalutamide (Casodex(TM)) and the luteinizing hormone releasing hormone agonist leuprolide depot (Procren Depot(TM), Lupron Depot(TM)) on serum prostate-specific antigen (PSA), acid phosphatase (ACP), and prostatic acid phosphatase (PAP) in patients with benign prostatic hyperplasia (BPH) were determined. Thirty patients with BPH were randomised to receive bicalutamide 50 mg orally once daily or a placebo for 24 weeks, followed by 24 weeks of follow-up (bicalutamide study). In another study 55 men were randomised between 3.75 mg leuprolide depot intramuscularly at every 28 days for 24 weeks or placebo injections (leuprolide study). In both studies blood sampling was performed at baseline, at week 12 at week 24 and 24 weeks after the end of therapy. Androgen suppression with bicalutamide 50 mg daily for 24 weeks resulted in a median of 56% reduction of PSA (P<0.001 when compared to placebo). Acid phosphatase and PAP did not change. Leuprolide resulted in a median of 87% reduction of serum PSA (P<0.001) and a 39% reduction of PAP (P=0.023), whereas ACP was unchanged. Both bicalutamide and leuprolide induced a pronounced decline in serum PSA in BPH patients. The studies suggest a stronger androgen suppressive effect of leuprolide than of bicalutamide, but this difference might largely be due to too low a dosage of bicalutamide. ACP and PAP were relatively insensitive to androgen suppression. Our study suggests a different degree of androgen suppression on PSA originating from benign tissue versus cancer tissue, and that the direction of this discrepancy might be different for various androgen suppressive regimens.Prostate Cancer and Prostatic Diseases (2001) 4, 173-177.