leuprolide and Prostatic-Neoplasms

Relugolix (Orgovyx. Androgen deprivation therapy (ADT), a key component of prostate cancer treatment, reduces testosterone production to slow disease progression. Relugolix (Orgovyx

Topics: Androgen Antagonists; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms; Testosterone

Androgen deprivation therapy (ADT) has been a treatment of choice for prostate cancer in almost all phases, particularly in the locally advanced, metastatic setting in both hormone-sensitive and castration-resistant diseaseand in those who are unfit for any local therapy. Different ways of administering ADT comes in the form of surgical or chemical castration with the use of gonadotropin-releasing hormone (GnRH-agonists) being the foremost way of delivering ADT.. This review encompasses ADT history, use of leuprolide, degarelix, and relugolix, with contextual use of ADT in combination with androgen-signaling inhibitors and potential mechanisms of resistance. Novel approaches with regard to hormone therapy are also discussed.. The use of GnRH-agonists and GnRH-antagonists yields efficacy that is likely equivalent in resulting in testosterone suppression. While the side-effect profile with ADT are generally equivalent, effects on cardiovascular morbidity may be improved with the use of oral relugolix though this is noted with caution since the cardiovascular side-effects were a result of secondary subgroup analyses. The choice of ADT hinges upon cost, availability, ease of administration, and preference amongst physicians and patients alike.

Topics: Androgen Antagonists; Androgens; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms

Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (s) (GnRH-A) remains the backbone of advanced prostate cancer treatment. In this review, we assessed the efficacy, safety, and convenience of administration of various GnRH-A. All GnRH-A (goserelin, triptorelin, buserelin, histrelin, and leuprorelin) have comparable potential to suppress testosterone (T) levels (≤50 ng/dL in a month and ≤20 ng/dL in 3 months). However, goserelin has shown better efficacy in maintaining T levels ≤50 ng/dL compared with leuprolide. The incidences of T escape are lower with goserelin and leuprolide than buserelin. Goserelin also has maximum benefit in prostate-specific antigen suppression. In neoadjuvant setting, when only goserelin was used, the 10-year overall survival (OS) rate was 42.6% to 86%. When either goserelin or leuprolide was used, the 10-year OS rate was 62%. As an adjuvant to radical prostatectomy, goserelin had a 10-year survival rate of 87%, and triptorelin had an 8-year survival rate of 84.6%. Goserelin further showed an absolute survival rate of 49% when used as an adjuvant to radiotherapy. The survival rates further improved when GnRH-A are used as combined androgen blockade compared with monotherapy. The frequency and severity of adverse events (hot flushes, fatigue, sexual dysfunction) are comparable among the GnRH-A. Goserelin appears to be the most convenient of all the GnRH-A for administration. Lack of conclusive comparative evidence makes it imperative to have a holistic approach of considering the patient profile and the disease characteristics to select the appropriate GnRH-A for ADT in prostate cancer.

Topics: Androgen Antagonists; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms

This is a summary of a research study (known as a clinical trial) called HERO. The HERO study compared how well relugolix and leuprolide worked in lowering blood testosterone to sustained castration levels in men with advanced prostate cancer. Sustained castration is a blood testosterone level below 50 ng/dl from Day 29 through 48 weeks of treatment.. Researchers looked at 930 adult men with advanced prostate cancer: 622 of these men took relugolix (by mouth once daily) and 308 received leuprolide (injected every 3 months). The HERO study showed that more men taking relugolix (97%) achieved sustained castration through 48 weeks than men receiving leuprolide (89%). This decrease in testosterone also happened more quickly in men taking relugolix. In 184 men who were followed up for 90 days after completing treatment, blood levels of testosterone returned to normal in more men who took relugolix than men who received leuprolide. Side effects were similar among men taking relugolix or receiving leuprolide, and most were identified as mild or moderate in terms of how bad they were.. In men with advanced prostate cancer and compared with those receiving leuprolide, more men taking relugolix had lower levels of blood testosterone. ClinicalTrials.gov NCT number: NCT03085095.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Humans; Ipilimumab; Language; Leuprolide; Male; Melanoma; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Testosterone

The aim of this study was to determine whether gonadotropin-releasing hormone (GnRH) antagonists (an emerging class of drugs to suppress testosterone synthesis in the treatment of prostate cancer) cause less adverse cardiovascular events than the more commonly use GnRH agonists.. We conducted a systematic review to identify all randomized, controlled trials in which a GnRH antagonist was compared with a GnRH agonist in men with prostate cancer. We identified 10 eligible studies including two different GnRH antagonists, degarelix (n = 1681) and relugolix (n = 734), which were compared with the GnRH agonists, leuprolide (n = 714) and goserelin (n = 600). The pooled risk ratios (95% confidence intervals) among GnRH antagonist recipients for adverse cardiovascular events, cardiovascular death, and all-cause mortality were 0.57 (0.39-0.81); 0.49 (0.25-0.96); and 0.48 (0.28-0.83), respectively. Important limitations of the included trials were their short duration of follow-up, unblinded study design and (in most of the studies) the identification of adverse cardiovascular events through safety reporting mechanisms rather than as a pre-specified outcome. There was no evidence of heterogeneity of findings among the studies.. There is consistent but methodologically limited data to suggest that GnRH antagonists-a relatively new class of androgen deprivation therapy for prostate cancer-cause significantly less cardiovascular adverse effects than the more frequently used GnRH agonists.

Topics: Androgen Antagonists; Cardiovascular Diseases; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms

To review direct comparative studies of the gonadotrophin-releasing hormone (GnRH) agonists goserelin, triptorelin, and leuprorelin for the treatment of prostate cancer, and identify whether there are meaningful clinical differences between these agents. In June 2017, the following searches were performed independently by two reviewers in PubMed: (i) 'prostate cancer' and 'triptorelin' and 'leuprorelin', (ii) 'prostate cancer' and 'triptorelin' and 'goserelin', and (iii) 'prostate cancer' and 'goserelin' and 'leuprorelin', without time restriction. Duplicates were deleted. Relevant conference abstracts were also screened. A total of 16 direct comparative trials were identified: 12 reported on efficacy outcomes, four on safety/tolerability, and five on the convenience of administration/user perceptions. These studies are restricted in terms of patient numbers, formulations assessed, and endpoints measured; none were adequately powered for survival outcome measures. Studies reporting on efficacy endpoints did not show major differences in the ability of these GnRH agonists to reduce levels of testosterone or prostate-specific antigen. Some studies suggest differences in short- or long-term testosterone control, the rate of injection site adverse events, and patient/healthcare professional perceptions, but definitive conclusions cannot be drawn from the existing evidence. Few direct comparative trials of GnRH agonists have been conducted. Whilst GnRH agonists provide a similar castration effect, there is not enough evidence to show that GnRH agonists are equivalent.

Topics: Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms; Survival Rate; Testosterone; Treatment Outcome; Triptorelin Pamoate

To evaluate the effectiveness and harms of DES in treating prostate cancer compared to other forms of androgen deprivation therapy (orchiectomy, LHRH agonists, and anti-androgens).. We included clinical trials comparing DES with other forms of ADT (bicalutamide, flutamide, LHRH agonists, or orchiectomy) in PCa treatment. The primary outcomes were overall survival, cancer-specific survival, and progression-free survival, and secondary outcomes were cardiovascular effects. We searched in MEDLINE, EMBASE, Central, and Lilacs from inception to nowadays and saturated information for unpublished data in other sources. We performed a qualitative analysis of all included studies. It was not possible to perform meta-analysis due to low-quality trials and high heterogeneity.. Overall, 1700 references were scanned and 14 prospective randomized trials with a total of 3986 patients were included in the final analysis. Although trials showed DES as similarly effective to another forms of ADT, evidences about cardiovascular toxicity in out of date high doses have discouraged its use. In doses of 1 mg, DES has been used as secondary line PCa treatment with safety.. DES might be similarly effective to other forms of ADT on advanced PCa patients, with potential important roles. Intriguingly, the burden of severe cardiovascular toxicity is mainly related to old-fashioned doses of 5.0 and 3.0 mg. Modern PCa hormonal knowledge warrants stout high-quality prospective randomized trials in the low-dose 1 mg DES scenario.

Topics: Anilides; Antineoplastic Agents, Hormonal; Diethylstilbestrol; Estrogens, Non-Steroidal; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Nitriles; Orchiectomy; Prostatic Neoplasms; Tosyl Compounds

Topics: Adenocarcinoma; Aged, 80 and over; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Fatal Outcome; Humans; Leuprolide; Lower Urinary Tract Symptoms; Male; Nitriles; Prostatectomy; Prostatic Neoplasms; Tosyl Compounds

Hormone sensitive advanced prostate cancer (PCa) is an incurable disease that is treated with a variety of hormonal therapies targeting the androgen/androgen receptor signaling axis. For decades androgen deprivation therapy (ADT) by surgical or chemical castration is the gold standard for the treatment of advanced PCa. Areas covered: This review discusses the pharmacological features of Leuprolide, a luteinizing hormone-releasing hormone (LHRH) agonists/analog and the most commonly used drug in ADT. Expert opinion: Although Leuprolide has been on the market for more than 30 years it is still the leading option for ADT and serves as a basis for most multimodal therapy concepts. The fact that with the onset of castration-resistance in late stage metastatic disease, a prolongation of ADT in combination with a second line hormonal manipulation is recommended supports the importance of the compound for daily clinical practice.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Orchiectomy; Prostatectomy; Prostatic Neoplasms

Luteinizing hormone-releasing hormone agonists such as leuprolide acetate (LA) are the most frequently utilized treatment of advanced prostate cancer as the regimen for achieving androgen deprivation therapy (ADT). The efficacy of LA is determined by extent of testosterone (T) suppression in prostate cancer patients. Although, the historical castrate T suppression target has been defined as < 50 ng/dl, this level may not be as low as required to deliver equivalent suppression as achieved by surgical castration. Recent studies have demonstrated that a T level as low as 20 ng/dl may produce improved clinical outcomes.. LA is available in long-acting formulations that deliver active drug over the course of 1-6 months from a single-dose administration. The technologies utilized to provide sustained drug delivery differ: one mode of administration uses microspheres, which encapsulate the drug and are injected as a suspension intramuscularly; another mode of administration uses a liquid polymer that creates a single, solid depot after injection subcutaneously. This article will review the safety and efficacy of both 6-month LA formulations, as well as their impact in prostate cancer treatment.. As the understanding of optimal T castrate level evolves and may be refined pending new data from contemporaneous trials, achievement and maintenance of T levels well below 50 ng/dl may be important in evaluating potential differences in ADT regimens.

Topics: Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Drug Delivery Systems; Drug Design; Humans; Leuprolide; Male; Prostatic Neoplasms; Testosterone

Studies comparing the gonadotropin-releasing hormone antagonist, degarelix, with luteinising hormone-releasing hormone (LHRH) agonists indicate differences in outcomes.. To assess differences in efficacy and safety outcomes in a pooled analysis of trials comparing degarelix with LHRH agonists.. Data were pooled from five prospective, phase 3 or 3b randomised trials (n=1925) of degarelix and leuprolide or goserelin in men requiring androgen deprivation therapy for the treatment of prostate cancer. Patients received either 3 mo (n=467) or 12 mo (n=1458) of treatment.. Men were randomised to receive degarelix (n=1266), leuprolide (n=201), or goserelin (n=458).. Unadjusted Kaplan-Meier analyses were supported by the Cox proportional hazards model, adjusted for disease-related baseline factors, to estimate hazard ratios (HRs) of efficacy and safety outcomes. The Fisher exact test compared crude incidences of adverse events.. Prostate-specific antigen (PSA) progression-free survival (PFS) was improved in the degarelix group (HR: 0.71; p=0.017). For patients with baseline PSA levels >20 ng/ml, the HR for PSA PFS was 0.74 (p=0.052). Overall survival (OS) was higher in the degarelix group (HR: 0.47; p=0.023). OS was particularly improved with degarelix in patients with baseline testosterone levels >2 ng/ml (HR: 0.36; p=0.006). In terms of disease-related adverse events, there were, overall, fewer joint-related signs and symptoms, musculoskeletal events, and urinary tract events in the degarelix group.. These data indicate clinical benefits with degarelix, including a significant improvement in PSA PFS and OS, as well as reduced incidence of joint, musculoskeletal, and urinary tract adverse events, compared with LHRH agonists.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Clinical Trials, Phase III as Topic; Disease-Free Survival; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Survival Rate; Testosterone; Treatment Outcome

Non-steroidal antiandrogens and castration are the main therapy options for advanced stages of prostate cancer. However, debate regarding the value of these treatment options continues.. To assess the effects of non-steroidal antiandrogen monotherapy compared with luteinising hormone-releasing hormone agonists or surgical castration monotherapy for treating advanced stages of prostate cancer.. We searched the Cochrane Prostatic Diseases and Urologic Cancers Group Specialized Register (PROSTATE), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science with Conference Proceedings, three trial registries and abstracts from three major conferences to 23 December 2013, together with reference lists, and contacted selected experts in the field and manufacturers.. We included randomised controlled trials comparing non-steroidal antiandrogen monotherapy with medical or surgical castration monotherapy for men in advanced stages of prostate cancer.. One review author screened all titles and abstracts; only citations that were clearly irrelevant were excluded at this stage. Then, two review authors independently examined full-text reports, identified relevant studies, assessed the eligibility of studies for inclusion, assessed trial quality and extracted data. We contacted the study authors to request additional information. We used Review Manager 5 for data synthesis and used the fixed-effect model for heterogeneity less than 50%; we used the random-effects model for substantial or considerable heterogeneity.. Eleven studies involving 3060 randomly assigned participants were included in this review. The quality of evidence is hampered by risk of bias. Use of non-steroidal antiandrogens decreased overall survival (hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.05 to 1.48, six studies, 2712 participants) and increased clinical progression (one year: risk ratio (RR) 1.25, 95% CI 1.08 to 1.45, five studies, 2067 participants; 70 weeks: RR 1.26, 95% CI 1.08 to 1.45, six studies, 2373 participants; two years: RR 1.14, 95% CI 1.04 to 1.25, three studies, 1336 participants), as well as treatment failure (one year: RR 1.19, 95% CI 1.02 to 1.38, four studies, 1539 participants; 70 weeks: RR 1.27, 95% CI 1.05 to 1.52, five studies, 1845 participants; two years: RR 1.14, 95% CI 1.05 to 1.24, two studies, 808 participants), compared with medical or surgical castration. The quality of evidence for overall survival, clinical progression and treatment failure was rated as moderate according to GRADE. Predefined subgroup analyses showed that use of non-steroidal antiandrogens, compared with castration, was less favourable for overall survival, clinical progression (at one year, 70 weeks, two years) and treatment failure (at one year, 70 weeks, two years) in men with metastatic disease. Use of non-steroidal antiandrogens also increased the risk for treatment discontinuation due to adverse events (RR 1.82, 95% CI 1.13 to 2.94, eight studies, 1559 participants), including events such as breast pain (RR 22.97, 95% CI 14.79 to 35.67, eight studies, 2670 participants), gynaecomastia (RR 8.43, 95% CI 3.19 to 22.28, nine studies, 2774 participants) and asthenia (RR 1.77, 95% CI 1.36 to 2.31, five studies, 2073 participants). The risk of other adverse events, such as hot flashes (RR 0.23, 95% CI 0.19 to 0.27, nine studies, 2774 participants), haemorrhage (RR 0.07, 95% CI 0.01 to 0.54, two studies, 546 participants), nocturia (RR 0.38, 95% CI 0.20 to 0.69, one study, 480 participants), fatigue (RR 0.52, 95% CI 0.31 to 0.88, one study, 51 participants), loss of sexual interest (RR 0.50, 95% CI 0.30 to 0.83, one study, 51 participants) and urinary frequency (RR 0.22, 95% CI 0.11 to 0.47, one study, 480 participants) was decreased when non-steroidal antiandrogens were used. The quality of evidence for breast pain, gynaecomastia and hot flashes was rated as moderate according to GRADE. The effects of non-steroidal antiandrogens on cancer-specific survival and biochemical progression. Currently available evidence suggests that use of non-steroidal antiandrogen monotherapy compared with medical or surgical castration monotherapy for advanced prostate cancer is less effective in terms of overall survival, clinical progression, treatment failure and treatment discontinuation due to adverse events. Evidence quality was rated as moderate according to GRADE. Further research is likely to have an important impact on results for patients with advanced but non-metastatic prostate cancer treated with non-steroidal antiandrogen monotherapy. However, we believe that research is likely not necessary on non-steroidal antiandrogen monotherapy for men with metastatic prostate cancer. Only high-quality, randomised controlled trials with long-term follow-up should be conducted. If further research is planned to investigate biochemical progression, studies with standardised follow-up schedules using measurements of prostate-specific antigen based on current guidelines should be conducted.

Topics: Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Disease Progression; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Medication Adherence; Nitriles; Orchiectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Tosyl Compounds; Triptorelin Pamoate

Neuroendocrine (NE) differentiation in prostate carcinomas can be seen in two settings: as a focal finding in conventional acinar adenocarcinoma, identifiable by immunohistochemical staining, or as a primary NE tumor of the prostate gland, such as carcinoid, small cell carcinoma, or large cell NE carcinoma. Of particular interest is the large cell NE carcinoma, which had been previously reported in isolated cases or in limited case series. In this report, we describe a case of a large cell NE carcinoma diagnosed in a 48-year-old man who presented with difficulty in voiding and urine retention. A cystoscopy revealed an enlarged, elongated prostate with an intra-urethral obstructing mass in the prostatic urethra. Subsequently, a transurethral resection of prostate (TURP) was performed at an outside hospital under the clinical diagnosis of benign prostatic hyperplasia (BPH). Microscopic examination of the TURP specimen revealed several foci of low-grade transitional-zone-type adenocarcinoma corresponding to Gleason score 5 (3 + 2), and a focus of high-grade large cell NE carcinoma. Concurrent x-ray computed tomography scans of the chest, abdomen, and pelvis demonstrated an enlarged left pelvic lymph node, which was biopsied and the patient was diagnosed with metastatic large cell NE carcinoma. He subsequently underwent 8 cycles of neoadjuvant chemotherapy with Lupron, a laparoscopic robotic-assisted radical retropubic prostatectomy, and pelvic lymphadenectomy. He died of widely metastatic prostatic carcinoma with leptomeningeal metastases 13 months after radical prostatectomy. Here, we present a rare case of large cell NE carcinoma with a review of the published literature.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Biopsy; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Chemotherapy, Adjuvant; Cisplatin; Cystoscopy; Disease Progression; Etoposide; Fatal Outcome; Humans; Immunohistochemistry; Laparoscopy; Leuprolide; Lymph Node Excision; Lymphatic Metastasis; Male; Meningeal Neoplasms; Middle Aged; Neoadjuvant Therapy; Neoplasm Grading; Paclitaxel; Pelvis; Prostatic Neoplasms; Robotic Surgical Procedures; Time Factors; Tomography, X-Ray Computed; Transurethral Resection of Prostate; Treatment Outcome

For nearly three decades, gonadotropin-releasing hormone (GnRH) agonists, particularly leuprorelin acetate (LA), have served as an important part of the treatment armamentarium for prostate cancer. The introduction of LA depot formulations provided a significant improvement in the acceptance of this therapy; however, their indicated treatment duration of 1 to 4 months was still not long enough to satisfy all medical needs. For this reason some manufacturers developed new injectable formulations that provide testosterone suppression for 6 months. This review article assesses key publications in order to compare these long-acting, commercially available, LA depot formulations and their clinical performance. The literature search identified 14 publications; by excluding reviews, duplications, and non-English articles, only three original papers describing clinical trial remained for review: two focused on microsphere-based LA formulations with either a 30 mg or 45 mg dose and one focused on a gel-based leuprorelin acetate with a 45 mg dose. All products were tested in individual clinical trials and have demonstrated their efficacy and safety.

Topics: Antineoplastic Agents, Hormonal; Chemistry, Pharmaceutical; Humans; Leuprolide; Male; Prostatic Neoplasms

Gonadotropin-releasing hormone analog depots have been widely used for a variety of diseases including prostate cancer, breast cancer, endometriosis, uterine leiomyomas, and central precocious puberty. Most of the side/adverse effects of gonadotropin-releasing hormone analog depots, such as leuprorelin acetate depot, are related to hypotestosteronism in males. Anaphylaxis to gonadotropin-releasing hormone analog depot is extremely rare. We present the first case report of a Japanese man who developed anaphylaxis to leuprorelin acetate depot during the treatment of metastatic prostate cancer and recovered successfully by conservative treatment. A drug-lymphocyte stimulation test showed that not only leuprorelin acetate itself, but also its vehicle polylactic and glycolic acids, might be responsible for the anaphylaxis to leuprorelin acetate depot. Because anaphylaxis can be lethal, the present case suggests that one should bear in mind the possibility of anaphylaxis in all patients who receive gonadotropin-releasing hormone analog depot and monitor such patients carefully.

Topics: Aged; Anaphylaxis; Antineoplastic Agents, Hormonal; Drug Eruptions; Fatal Outcome; Humans; Immunosuppressive Agents; Leuprolide; Male; Prostatic Neoplasms

Thanks to recent advances in biotechnology, the use of peptides and proteins as drugs has become a concrete clinical reality, and consequently an interesting challenge has emerged for non-parenteral drug delivery. Leuprolide is a synthetic nonapeptide agonist to the luteinizing hormone-releasing hormone (LH-RH) receptor with principal clinical applications for prostate cancer. Although a large number of formulations available, they mainly consist in depot subcutaneous injections or implantable devices. Both of these routes of administration present multiple limitations considering the large clinical applications of this active substance.. The objective of this review is to critically discuss the formulations currently available on the market for leuprolide optimization and to consider how drug delivery plays an important role in improving the bioavailability of this compound.. Due to its physicochemical properties and its economical market, leuprolide is an interesting candidate for drug delivery to improve the efficacy of existing treatments, dose adjustments, and patient compliance and safety.

Topics: Administration, Cutaneous; Administration, Intranasal; Administration, Oral; Administration, Sublingual; Amino Acid Sequence; Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemistry, Pharmaceutical; Endometriosis; Female; Genital Diseases, Female; Gonadotropin-Releasing Hormone; Humans; Infusions, Parenteral; Injections, Subcutaneous; Leuprolide; Male; Prostatic Neoplasms; Puberty, Precocious; Receptors, LHRH

Gonadotropin-releasing hormone agonists and antagonists provide androgen-deprivation therapy for prostate cancer. Unlike agonists, gonadotropin-releasing hormone antagonists have a direct mode of action to block pituitary gonadotropin-releasing hormone receptors. There are two licensed gonadotropin-releasing hormone antagonists, degarelix and abarelix. Of these, degarelix is the more extensively studied and has been documented to be more effective than the well-established, first-line agonist, leuprolide, in terms of substantially faster onset of castration, faster suppression of prostate-specific antigen, no risk for testosterone surge or clinical flare, and improved prostate-specific antigen progression-free survival, suggesting a delay in castration resistance. Other than minor injection-site reactions, degarelix is generally well tolerated, without systemic allergic reactions and with most adverse events consistent with androgen suppression or the underlying condition. In conclusion, degarelix provides a rational, first-line androgen-deprivation therapy suitable for the treatment of prostate cancer, with faster onset of castration than with agonists, and no testosterone surge. Furthermore, data suggest that degarelix improves disease control compared with leuprolide, and might delay the onset of castration-resistant disease. In view of these clinical benefits and the lack of need for concomitant anti-androgen treatment, gonadotropin-releasing hormone antagonists might replace gonadotropin-releasing hormone agonists as first-line androgen-deprivation therapy in the future.

Topics: Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

Increased understanding of prostate cancer biology has led to new treatment strategies and promising new agents for treating prostate cancer, in particular peptide-based agonists and antagonists. In this review article, new therapy modalities and potential approaches for the treatment of advanced prostate cancer are discussed, including agonists and antagonists of luteinizing hormone-releasing hormone, antagonists of bombesin/gastrin-releasing peptide, and growth hormone-releasing hormone and somatostatin analogues. Though the prognosis of patients with prostate cancer is much improved by some of these treatment approaches, including combination treatment methods, extensive side-effects are still reported. These include sexual dysfunction, functional lesions of the liver and renal system, osteoporosis, anaemia and diarrhoea. Future studies should focus on new treatment agents and treatment approaches that can eliminate side-effects and improve quality of life in patients with prostate cancer on the basis of potent treatment efficacy.

Topics: Animals; Antineoplastic Agents, Hormonal; Bombesin; Clinical Trials as Topic; Humans; Leuprolide; Male; Neoplasms, Hormone-Dependent; Octreotide; Oligopeptides; Peptide Fragments; Prostatic Neoplasms; Sermorelin

Luteinizing hormone-releasing hormone (LHRH) agonists represent one of the main cost factors in the management of patients with metastatic prostate cancer. We compared the cost-effectiveness of the five different 3-month formulations of LHRH agonists currently available for advanced prostate cancer in Italy, because these differ both in their capacity to suppress testosterone and in their acquisition costs.. A probabilistic, patient-level simulation model was developed to compare the cost-effectiveness, from the perspective of the Italian National Health Service (INHS), of leuprorelin 11.25 mg and 22.5 mg, triptorelin 11.25 mg, buserelin 9.9 mg, and goserelin 10.8 mg. The model incorporated testosterone-dependent progression-free and cancer-specific survival functions, LHRH agonist effectiveness data, and national costs and tariffs. Cox's proportional hazard models were used to compute total and progression-free survival functions based on clinical data from 129 patients with metastatic prostate cancer treated in an Italian center. Bayesian random effects models were employed to summarize evidence from published literature on testosterone suppression obtained with the available LHRH agonists.. Estimated total survival was ≈5 years, with a maximum difference between treatment options of ≈2 months. There was a mean difference of almost €2,500 in lifetime total costs between the least costly option (leuprorelin 22.5 mg) and the most expensive (goserelin). In the incremental cost-effectiveness analysis, leuprorelin 22.5 mg dominated all alternatives except buserelin, which had an incremental cost-effectiveness ratio versus leuprorelin 22.5 mg of ≈€12,000 per life-month gained.. Based on modelling with meta-analysis of comparative survival data, leuprorelin 22.5 mg was the most cost-effective treatment of the available depot formulation LHRH agonists.

Topics: Aged; Antineoplastic Agents, Hormonal; Buserelin; Cost-Benefit Analysis; Decision Trees; Drug Costs; Gonadotropin-Releasing Hormone; Goserelin; Humans; Italy; Leuprolide; Male; Models, Econometric; Proportional Hazards Models; Prostatic Neoplasms; Survival Analysis; Triptorelin Pamoate

We report the case of a 60 year old male who complained of headache and blurry vision--that progressed to left ophthalmoplegia and ptosis--after receiving a dose of leuprolide for Prostate cancer therapy. Imaging showed a hemorrhagic sellar mass. The patient underwent transsphenoidal debulking, and the tissue obtained demonstrated immunohistochemical staining for LH. A literature review revealed nine previously reported cases of pituitary apoplexy after GnRH agonist therapy for prostate cancer. In most cases, the sellar tissues stained for LH, consistent with a gonadotropinoma. The pathophysiology of these events is unclear, but recent animal models suggest possible explanations. The predominance of gonadotropinomas is important because they do not usually present with hypersecretory symptoms. Particular attention to clinical findings suggestive of a non functioning pituitary tumor in patients receiving GnRH agonist therapy is critical as routine screening with MRI is not practical.

Topics: Adenoma; Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Pituitary Neoplasms; Prostatic Neoplasms; Sella Turcica; Stroke

A case of neuroendocrine (NE) differentiated prostate cancer is reported herein, which was progressed with NE differentiation during hormonal treatment in adenocarcinoma of the prostate. A 65-year-old man was admitted to our department with increased serum prostate specific antigen (PSA) (150 ng/ml). A prostate biopsy was performed and histological examinations indicated poorly differentiated adenocarcinoma with a Gleason score of 5 + 4 = 9. Further examinations showed metastases to systemic bones. The clinical stage was T3bN0M1b and hormonal therapy using leuprorelin was started. Eighteen months after hormonal therapy, the serum PSA level declined to 1.702 ng/ml. He subsequently experienced edema in his legs. Computed tomography (CT) demonstrated enlargement of the prostate and swelling of multiple pelvic lymph nodes. Immunohistochemical examination of a re-biopsy specimen revealed a neuroendocrine carcinoma. The neuron-specific enolase (NSE) level was 50.9 ng/ml. The treatment measure was changed from hormonal therapy to combination chemotherapy comprising cisplatin (CDDP) and irinotecan (CPT-11). Pelvic radiotherapy (50 Gy) was then performed. Two courses of the chemotherapy resulted in a great reduction of the tumor volume. However, he had liver metastases 3 months later. His condition worsened rapidly and he died at 8 months after definite diagnosis.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Cell Differentiation; Humans; Leuprolide; Male; Phosphopyruvate Hydratase; Prostate-Specific Antigen; Prostatic Neoplasms

To perform comparative analysis of the efficacy and the safety of six months formulation of LHRH analogues indicated for prostate cancer treatment.. Search in the PubMed database for clinical trials published between 2006 and 2009 using the following key words: "prostate cancer", "triptorelin or leuprorelin" and "66-month depot".. The efficacy of all 3 six months formulation of LHRH analogues currently approved is high (96-98%) for reducing testosterone levels down to below 50 ng/dl. As the patients included in the three trials are quite heterogeneous, and due to the variability in the way of presenting results, it is not possible to compare testosterone escapes and their effect on PSA levels. The incidence of adverse events (AE) reported across the three trials was high, but only 0.9% to 15.8% were severe. Only one trial reported patient withdrawal (2.5%) because of drug-related AEs.. Even though all the studies show and important variability in the analysis and data management, no significant efficacy and safety differences seem to exist.

Topics: Antineoplastic Agents, Hormonal; Drug Administration Schedule; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms; Time Factors; Triptorelin Pamoate

Hormonal deprivation therapy is well established for the treatment of locally advanced and metastatic prostate cancer, as well as the adjuvant treatment of some patients with localized disease. Long-acting gonadotropin releasing hormone (GnRH) agonists have become a mainstay of androgen deprivation therapy, due to their efficacy, tolerability, and convenience of use. One-month, 3-month, and 4-month depot leuprorelin formulations are well established and widely used to this end. Recently, a 6-month depot leuprorelin has been approved for use in advanced and metastatic prostate cancer patients. With similar efficacy and side effect profiles to earlier formulations, 6-month depot leuprorelin is a convenient treatment option for these patients. This review will highlight the role of GnRH agonists in the treatment of prostate cancer with a focus on the clinical efficacy, pharmacology, and patient-focused outcomes of the newer 6-month 45 mg depot leuprorelin formulation in comparison to available shorter-acting products.

Topics: Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Dose-Response Relationship, Drug; Humans; Leuprolide; Male; Prostatic Neoplasms; United States

Disseminated intravascular coagulation (DIC) is the most frequent coagulation disorder associated with metastatic prostate cancer. We report a case of a 60-year-old white man who was admitted in our department with ecchymoses and haematuria secondary to a DIC associated with metastatic prostate cancer. A review of this clinical scenario is also reported.

Topics: Adenocarcinoma; Anilides; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Diagnosis, Differential; Disseminated Intravascular Coagulation; Ecchymosis; Femur; Hematuria; Humans; Leuprolide; Male; Middle Aged; Nitriles; Prostatic Neoplasms; Tosyl Compounds; Treatment Outcome

High-risk prostate cancer can be defined as a cancer that, although clinically localized, will not be cured by monotherapy, whether surgery or radiation, and as a result will require some form of multimodal therapy, which will normally include luteinizing hormone-releasing hormone agonists. High-risk localized prostate cancer can be identified at three specific points during the management of the patient; before starting treatment (based on the profile of some predictive criteria, e.g. pathological features, prostate-specific antigen, PSA, level, and PSA velocity), on pathological evaluation of a surgical specimen taken during radical prostatectomy, or at the point of PSA relapse after radiotherapy or surgical therapy. Within Europe, therapeutic choice in patients identified as high-risk is normally made based on their age and life-expectancy. In those with a relatively long life-expectancy (>10 years) androgen suppression therapy (AST) should form part of a multimodal approach to treatment, but neoadjuvant hormonal therapy should be limited to use in combined hormonal therapy/radiotherapy protocols. AST can also be used to treat patients with PSA relapse. Several studies investigated the relative advantages of giving AST continuously vs intermittent therapy, but there are no notable differences between these approaches. AST monotherapy can be indicated in those patients with a shorter life-expectancy (<10 years), particularly if there are poor risk factors, e.g. a high PSA level (>50 ng/mL) or a short PSA doubling time (<12 months).

Topics: Antineoplastic Agents, Hormonal; Combined Modality Therapy; Europe; Humans; Leuprolide; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Factors

Data from the Japanese Urological Society showed that, in Japan, almost half of patients with localized prostate cancer are treated with hormone therapy (HT), regardless of disease stage, and that radiation therapy (RT) is also widely used to treat high-risk patients. A retrospective study was undertaken in Japan to evaluate the potential benefits of using primary HT in locally advanced prostate cancer. Of 628 patients in the study, 63.5% were treated with combined androgen blockade (CAB; luteinizing hormone-releasing hormone agonists plus an antiandrogen) and 36.5% with medical or surgical castration. CAB treatment was significantly better than hormone monotherapy for disease-specific survival. The results also showed that, even if a patient is classified as 'high-risk', a good prognosis could normally be predicted based on certain variables: if their initial prostate-specific antigen (PSA) level was < or = 20 ng/mL, their Gleason score was < or = 6, and their nadir PSA decreased to < or = 0.2 ng/mL within 6 months of HT. In this subgroup of 'good responders', any treatment, be it prostatectomy, RT or CAB, is likely to be effective. However, in 'poor responders', combined therapies with CAB and high-dose rate brachytherapy are likely to be needed for a clinical response. While HT is effective, it might be associated with a reduction in the patient's quality of life (QoL) due to adverse effects, e.g. a reduction in sexual function. Results from the analysis of QoL questionnaires completed by men of different ages with prostate cancer found that only sexual function, and not other QoL variables, in men aged 50-59 years appeared to be reduced in men who had HT, compared to age-matched controls.

Topics: Antineoplastic Agents, Hormonal; Disease-Free Survival; Humans; Japan; Leuprolide; Male; Multicenter Studies as Topic; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Retrospective Studies; Risk Factors

Prostate-specific antigen doubling time (PSA-DT) after surgery or radiotherapy (RT) is known to be a predictive factor for death from prostate cancer (prostate cancer-specific mortality, PCSM). An analysis of two multi-institutional databases, including 8669 men with prostate cancer treated with surgery or RT, found that a PSA-DT of <3 months, and the specific value of the PSA-DT when > or = 3 months, appeared to be surrogate endpoints for PCSM after surgery or RT. While many PSA failures occur after local therapy for localized prostate cancer, few of these patients go on to die from their disease, so it is important to identify other factors associated with PCSM, so that the subgroup of high-risk patients can be identified. An analysis was undertaken to determine whether patients at risk of PCSM could be identified using information available at diagnosis. The results showed that risk factors for PCSM were a PSA velocity of >2.0 ng/mL/year, a Gleason score of 8-10 and an increasing PSA level. However, the most important risk factor that had an impact on both PCSM and all-cause mortality was a PSA velocity of >2.0 ng/mL/year. PSA kinetics are being increasingly used in the setting of rising PSA levels after radical prostatectomy or RT, and several studies showed that the rate of increase in PSA level at the time of recurrence is closely associated with time to cancer death. A PSA-DT of <3 months is associated with a poor prognosis, and represents 15-20% of PSA failures in the general population and 6-7% of PSA failures in a screened population, such as those included in clinical trials. Better risk-assessment models are needed to help to identify at an early stage men who are at high risk of prostate cancer death and those who are at low risk, so that each subgroup can receive the most appropriate therapy for their disease.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Cohort Studies; Combined Modality Therapy; Humans; Leuprolide; Male; Middle Aged; Multicenter Studies as Topic; Neoplasm Staging; Prognosis; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Risk Assessment; Survival Analysis; United States

Stage C prostate cancer, where the tumour has extended beyond the capsule of the prostate, is typically a high-risk disease. According to the National Cancer Institute Physician Data Query the treatments of choice for stage C disease comprise external beam radiation therapy (with or without the addition of adjuvant hormone therapy), androgen deprivation by either surgery or hormone therapy, radical prostatectomy, or careful observation. From 2001, the Japanese Urological Association initiated computer-based registration of all patients with prostate cancer in Japan. Data show that overall, 57% of all patients and 46% of those with T1c to T3 disease had primary androgen deprivation therapy (PADT). Similarly, the Japanese Prostate Cancer Group undertook a large-scale epidemiological surveillance study in Japan and found that the most commonly used hormone therapy is PADT, regardless of disease stage. To date, two randomized, controlled trials of the effect of PADT on stage C prostate cancer in elderly (> or =75 years old) patients have been undertaken in Japan. The results showed that patients with locally advanced prostate cancer treated with PADT are likely to have a life-expectancy similar to that of the normal population. In one study, combined androgen blockade (CAB) with leuprorelin plus chlormadinone appeared to prolong time to disease progression when compared with leuprorelin monotherapy, but there was no difference in survival between these treatment groups. In a second study CAB with an luteinizing hormone-releasing hormone (LHRH) agonist plus bicalutamide was found to prolong time to progression when compared with LHRH agonist monotherapy, but survival results for these regimens are still awaited.

Topics: Aged; Androgen Antagonists; Anilides; Antineoplastic Combined Chemotherapy Protocols; Chlormadinone Acetate; Gonadotropin-Releasing Hormone; Humans; Japan; Leuprolide; Male; Neoplasm Staging; Nitriles; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Tosyl Compounds

Prostate cancer is the most common nonskin cancer in the United States, with more than 2 million men currently living with the disease (Prostate Cancer Foundation, 2005). Hormone ablation therapy has resulted in much improved outcomes for thousands of men with this disease; however, there are often side effects that impact patients' quality of life. An overview of the use of hormone ablation therapy and the critical role nurses play for patients undergoing this treatment is provided.

Topics: 5-alpha Reductase Inhibitors; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Drug Monitoring; Finasteride; Flutamide; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Mass Screening; Neoplasm Staging; Nurse's Role; Nursing Assessment; Oligopeptides; Patient Education as Topic; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Quality of Life; Treatment Outcome

Topics: Antineoplastic Agents, Hormonal; Consensus; Delayed-Action Preparations; Humans; Leuprolide; Luteinizing Hormone; Male; Professional Practice; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

Leuprolide acetate is a synthetic nonapeptide that is a potent gonadotropin-releasing hormone receptor (GnRHR) agonist used for diverse clinical applications, including the treatment of prostate cancer, endometriosis, uterine fibroids, central precocious puberty and in vitro fertilization techniques. As its basic mechanism of action, leuprolide acetate suppresses gonadotrope secretion of luteinizing hormone and follicle-stimulating hormone that subsequently suppresses gonadal sex steroid production. In addition, leuprolide acetate is presently being tested for the treatment of Alzheimer's disease, polycystic ovary syndrome, functional bowel disease, short stature, premenstrual syndrome and even as an alternative for contraception. Mounting evidence suggests that GnRH agonist suppression of serum gonadotropins may also be important in many of the clinical applications described above. Moreover, the presence of GnRHR in a multitude of non-reproductive tissues including the recent discovery of GnRHR expression in the hippocampi and cortex of the human brain indicates that GnRH analogs such as leuprolide acetate may also act directly via tissue GnRHRs to modulate (brain) function. Thus, the molecular mechanisms underlying the therapeutic effect of GnRH analogs in the treatment of these diseases may be more complex than originally thought. These observations also suggest that the potential uses of GnRH analogs in the modulation of GnRH signaling and treatment of disease has yet to be fully realized.

Topics: Animals; Endometriosis; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Humans; Leiomyoma; Leuprolide; Male; Prostatic Neoplasms; Puberty, Precocious; Receptors, LHRH

Leuprorelin is a well known luteinising hormone releasing hormone (LHRH) agonist. The drug is effective in the treatment of advanced prostate cancer and is well tolerated. This article reviews published literature (based on a search of PubMed, EMBASE and Biosis databases to the end of 2005) and other sources of data on a new formulation of leuprorelin acetate (Eligard) for use in the treatment of hormone-dependent advanced prostate cancer. This product takes advantage of a novel delivery system (Atrigel) which forms an implant in situ that is capable of delivering double doses of leuprorelin consistently to provide better, more sustained testosterone suppression compared with a microsphere leuprolide acetate formulation. Two formulations, 7.5 mg and 22.5 mg, are currently available with duration of action of 1 and 3 months, respectively. The 2-week stability at room temperature prior to mixing facilitates its use and reduces the potential for waste.. In clinical studies of the new leuprorelin acetate formulation reviewed here, all patients achieved testosterone levels < or = 50 ng/dL and up to 98% of patients showed levels comparable to those resulting from surgical bilateral orchidectomy (< or = 20 ng/dL). Both formulations showed minimal breakthroughs, defined as a rise in testosterone levels after reaching levels of 50 ng/dL. The safety profile is typical of LHRH agonists, with mild to moderately severe 'hot flushes' being the most common adverse event. The higher dose of 22.5 mg, with a volume of 0.375 mL is administered subcutaneously via a small 20G needle, causing little local discomfort.. Prostate cancer remains a major cause of morbidity and mortality in older men. In the majority of cases, suppression of serum testosterone levels is very effective. The level of testosterone suppression is currently under debate, with ideal suppression levels ranging from 20 to 50 ng/dL. Not all LHRH agonist therapy achieves the same degree of testosterone suppression as bilateral orchidectomy. The new leuprorelin acetate (Eligard) appears to achieve a testosterone suppression of 20 ng/dL in 98% of patients, while maintaining a side effect profile comparable to other products in its class.

Topics: Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Drug-Related Side Effects and Adverse Reactions; Humans; Leuprolide; Male; Prostatic Neoplasms; Testosterone

Topics: Androgen Antagonists; Biopsy, Needle; Castration; Diagnostic Imaging; Drug Therapy, Combination; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prognosis; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Radiotherapy; Testosterone

The development of resistance to anticancer therapies is a major hurdle in preventing long-lasting clinical responses to conventional therapies in hormone-refractory prostate cancer. Herein, the molecular evidence documenting that bone metastasis microenvironment survival factors (mainly the paracrine growth hormone-independent, urokinase-type plasminogen activator-mediated increase of IGF-1 and the endocrine production of growth hormone-dependent IGF-1, mainly liver-derived IGF-1 production) produce an epigenetic form of prostate cancer cells that are resistant to proapoptotic therapies is reviewed. Consequently, the authors present the conceptual framework of a novel antibone microenvironment survival factor, mainly an anti-IGF-1 hormonal manipulation for androgen ablation refractory prostate cancer (a combination of conventional androgen ablation therapy [luteinising hormone-releasing hormone agonist-A or orchiectomy]) with dexamethasone plus somatostatin analogue, which yielded durable objective responses and major improvement of bone pain and performance status in stage D3 prostate cancer patients.

Topics: Adenocarcinoma; Androgen Antagonists; Androgens; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bone Neoplasms; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Dexamethasone; Drug Resistance, Neoplasm; Estramustine; Etoposide; Gonadotropin-Releasing Hormone; Growth Substances; Humans; Leuprolide; Male; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Orchiectomy; Osteoblasts; Osteoclasts; Paracrine Communication; Peptides, Cyclic; Prospective Studies; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Receptors, Androgen; Salvage Therapy; Somatostatin; Survival Analysis; Triptorelin Pamoate

S.R., a 65-year-old male with a history of prostate cancer, went to a cancer center in 2003. He had developed symptoms of bladder outlet obstruction in 1999 and was seen by a urologist. His baseline prostate-specific antigen (PSA) was 44 ng/ml. On physical examination, his prostate was enlarged, and a biopsy in January 2000 revealed adenocarcinoma with a Gleason score of 8. A metastatic workup, including a bone scan and a computed tomography scan of the abdomen and pelvis (CT A/P), was negative for evidence of metastatic disease. S.R. received conformal external beam radiation, and the luteinizing hormone-releasing hormone agonist leuprolide acetate was initiated. Following treatment, his PSA nadired to 0.2 ng/ml, and he did well until 2002, when his PSA started to rise. A reevaluation CT A/P revealed enlarged retroperitoneal and pelvic lymph nodes, and a bone scan was positive for metastatic disease. He underwent a bilateral orchiectomy in November 2002.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Bone Density Conservation Agents; Combined Modality Therapy; Diphosphonates; Gonadotropin-Releasing Hormone; Humans; Imidazoles; Jaw Diseases; Leuprolide; Male; Orchiectomy; Osteonecrosis; Osteoporosis; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy, Conformal; Risk Factors; Tomography, X-Ray Computed; Zoledronic Acid

To evaluate the approach to management of localized prostate cancer (PCa) in patients with human immunodeficiency virus (HIV) in the highly active antiretroviral therapy era.. A retrospective analysis was performed on 10 HIV-positive patients who recently presented with elevated prostate-specific antigen levels and clinically localized PCa.. At the diagnosis of PCa, the average patient was 54.0 years old, had been HIV positive for 8.75 years, had a CD4 count of 417, a prostate-specific antigen level of 9.2 ng/mL, and a Gleason score of 6. Eight of the patients had risk factors for PCa--either African-American descent (n = 6) or a positive family history (n = 2). The treatment was laparoscopic radical prostatectomy in 1, potency-preserving androgen deprivation in 1, cryosurgery in 1, brachytherapy in 2, observation in 2, and external beam radiotherapy in 3.. Screening of all HIV-positive men should be initiated at age 40 if they have either a positive family history of prostate cancer or are of African-American descent. Asymptomatic HIV-positive patients should be offered all therapeutic PCa treatment options.

Topics: Adenocarcinoma; Adult; Aged; Anilides; Antineoplastic Agents, Hormonal; Antiretroviral Therapy, Highly Active; Biomarkers, Tumor; Brachytherapy; Case Management; Combined Modality Therapy; Cryosurgery; Finasteride; Follow-Up Studies; HIV Infections; Humans; Leuprolide; Life Expectancy; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Proteins; Nitriles; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Radiotherapy, High-Energy; Retrospective Studies; Tosyl Compounds

Leuprorelin acetate, an agonist of gonadotropin-releasing hormone (GnRH), is indicated in the treatment of prostate cancer. Recently, depot formulations of leuprorelin acetate have been widely used. We report three patients who showed a granulomatous reaction after treatment using a leuprorelin acetate 3-month depot formulation. These patients presented with 5-6-cm subcutaneous nodules at injection sites, which developed after the depot type was changed from a 1-month to a 3-month formulation. Skin biopsy showed epithelioid cells and foreign body giant cells containing round, translucent microspheres which formed sarcoidal granulomas. Changing to other GnRH agonists resulted in no further problems. We have reviewed the previous reports of leuprorelin acetate-induced granuloma formation. The formation of such granulomas may be related to the polymers that allow slow release after injection, or leuprorelin acetate itself may be responsible. The depot injection methods using leuprorelin also seem to have a causal effect in granuloma formation. Dermatologists need to know that depot leuprorelin acetate may cause a granulomatous reaction which produces a subcutaneous nodule that might be misdiagnosed as a malignant tumour.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Granuloma; Humans; Injections, Subcutaneous; Leuprolide; Male; Prostatic Neoplasms; Skin Diseases

Androgen deprivation therapy is a mainstay for the treatment of advanced prostate cancer. Hormonal therapy commonly consists of injection of gonadotropin hormone-releasing hormone agonists. Based on the need for improved convenience of administration, a novel formulation of leuprolide acetate (Eligard; Atrix Laboratories Inc. & Sanofi Aventis) which incorporates a mixture of selected polymers and solvents to achieve sustained drug delivery after subcutaneous injection, was developed. The US Food and Drug Administration has approved 1-, 3-, 4- and 6-month formulations of leuprolide acetate. In clinical trials, leuprolide acetate achieves sustained suppression of serum testosterone to castration levels (< or =50 ng/dl). The adverse-event profile is consistent with the effects of testosterone suppression. This novel delivery system in addition to the availability of a 6-month formulation of leuprolide acetate, offers patients the option of a convenient twice-yearly injection schedule.

Topics: Antineoplastic Agents, Hormonal; Clinical Trials as Topic; Delayed-Action Preparations; Drug Administration Schedule; Humans; Injections, Subcutaneous; Leuprolide; Male; Pain; Prostatic Neoplasms

Following Huggins' original observation of the dependence of the prostate on androgens, testosterone suppression by either orchiectomy or oestrogen compounds (e.g., diethylstilbesterol [DES]) became the standard palliative treatment for advanced prostate cancer. Early studies showed testosterone suppression improved symptoms and patient survival by several months but was not curative. In addition, DES treatment resulted in significant cardiovascular morbidity and mortality from increased thrombotic events. Thus, both orchiectomy and DES were indicated for palliation in late stage disease, but were considered too extreme for earlier stage disease. The discovery of the hypothalamic peptide, luteinising hormone releasing hormone (LHRH), and its stimulatory release of luteinising hormone (LH) from the pituitary gland led to the synthesis of LHRH analogues (i.e., hormone therapy). LHRH analogues (e.g., leuprolide acetate) desensitise and downregulate pituitary LHRH receptors, thus reducing LH synthesis and release. The reduced release, in turn, decreases testosterone levels to those observed in DES-treated and orchiectomised patients. In contrast, LHRH analogues do not increase cardiovascular events. Therefore, leuprolide acetate therapy has been adopted as a safer alternative to DES and is considered to be generally reversible. This increased safety has allowed LHRH therapy to be applied in earlier stage prostate cancer. Recent studies have shown decreased rates of biochemical failure and a potential for increased patient survival with hormone therapy in conjunction with radical prostatectomy or radiation therapy. This article will focus on the literature supporting early, adjuvant LHRH therapy and Eligard 7.5 mg, a new depot formulation of leuprolide acetate that uses the Atrigel drug delivery system, causing an increase in bioavailability and optimising testosterone suppression - two key features of depot hormone suppression.

Topics: Clinical Trials, Phase I as Topic; Delayed-Action Preparations; Drug Implants; Humans; Injections, Subcutaneous; Leuprolide; Male; Multicenter Studies as Topic; Prostatic Neoplasms

A 73-year-old man presented with an ulcer and a subcutaneous nodule where he was receiving leuprorelin acetate injections to treat his prostatic carcinoma. Pathological findings of a skin biopsy showed many epithelioid granulomas with multinuclear giant cells, which contained small vacuoles. Recently, these lesions have been suggested to be caused by a type IV allergic response to the copolymer of lactic and glycolic acids used as a vehicle for drug administration. When urologists treat a prostatic adenocarcinoma with subcutaneous infusion of leuprorelin acetate, they should be aware of this potential side effect of the drug because the resulting granulomar formation may interfere with the effect of the drug. If patients suffer from subcutaneous nodules, urologists should consider changing the drug to an other type of luteinizing hormone-releasing hormone analogues such as goserelin acetate. This reaction to leuprorelin acetate has been reported in only seven cases including our case.

Topics: Aged; Antineoplastic Agents, Hormonal; Granuloma; Humans; Injections, Subcutaneous; Leuprolide; Male; Prostatic Neoplasms; Skin Diseases

Our research into the pathophysiology of micrometastatic dissemination and cancer recurrence has resulted in the initiation of a clinical trial for men with clinically localized and locally advanced disease.. We describe the development of this trial, which exploits anti-angiogenesis therapy, and delineate how our understanding of prostate cancer metastasis influenced its design.. Prostate cancer is a heterogeneous disease. Although many men can be cured with local therapy, a large majority with clinically localized disease will experience a relapse usually at a distant site. This result is most likely due to micrometastatic dissemination early in the disease process. Therefore, successful contemporary treatment of many men with prostate cancer should include a combination of local and systemic therapies. Fortunately, cellular, molecular and genetic features that may predict which men are most in need of this therapeutic approach are being identified and characterized. This insight not only supports the rationale for a combination therapeutic approach to prostate cancer management, but will help identify the pathways and agents that provide the most promising targets for intervention.. Despite advances in prevention and early detection, refinements in surgical technique, and improvements in radiation and systemic therapies, the ability to cure all men with prostate cancer remains unattainable. The continuing challenge is the successful eradication of recurrent and metastatic disease.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Cholestanols; Disease Progression; Humans; Leuprolide; Male; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neovascularization, Pathologic; Orchiectomy; Prostatic Neoplasms

Prostate cancer is second only to lung and bronchial cancer as the leading cause of cancer death in men. Local treatment, surgery, and radiation remain the mainstay of treatment for early-stage disease. However, in locally advanced and advanced disease, there has been considerable evolution in the hormonal therapies. Suppression of testosterone production, the primary goal of hormonal therapy, may be accomplished with the use of estrogens, antiandrogens, and agonists and antagonists of luteinizing hormone-releasing hormone (LHRH). This article provides an overview of the primary hormonal therapies currently used in prostate cancer. Estrogen therapy was initially the predominant medical form of hormone manipulation and an alternative to orchiectomy. However, serious thrombogenic side effects were associated with its use, which decreased after the introduction of LHRH agonists in the 1980s. Many of the side effects occurring with oral estrogen therapy may be modulated by parenteral administration, and thus estrogen use is being revisited. LHRH agonists effectively reduce testosterone levels to castration levels (<50 ng/mL) within 2 to 4 weeks, although their use is associated with tumor flare. Antiandrogen monotherapy may offer quality-of-life benefits over treatment with androgen deprivation. The additive benefit of combined androgen blockade is yet to be determined. Recent evidence suggests that hormonal therapy may offer a survival benefit when initiated in earlier stages of prostate cancer. Future investigations will be directed to determining the most efficacious regimens.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Diethylstilbestrol; Drug Therapy, Combination; Estrogens; Forecasting; Gonadotropin-Releasing Hormone; History, 20th Century; Humans; Leuprolide; Male; Orchiectomy; Prostatic Neoplasms; Treatment Outcome

Leuprorelin is a luteinizing hormone-releasing hormone analogue, licensed in the UK for the treatment of advanced prostate cancer. This review highlights the efficacy and tolerance of this agent and the benefits provided for developing patient-centred therapy and optimizing patient quality of life.

Topics: Antineoplastic Agents, Hormonal; Forecasting; Humans; Leuprolide; Male; Microspheres; Prostatic Neoplasms; Treatment Outcome

Adjuvant hormone treatment with radiotherapy has been demonstrated in two studies (Bolla and RTOG 8531) to be beneficial in patients with locally advanced prostate cancer. However, the vast majority of patients with early prostate cancer can be cured with radiotherapy alone. Subset analysis combining RTOG 8610 and RTOG 8531 has demonstrated a survival benefit only for patients with a biopsy Gleason score < or =6 after short-term neoadjuvant hormonal therapy. The results of ongoing research will further clarify the use of hormone treatment with radiotherapy in patients with low and intermediate risk.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Retrospective Studies; Treatment Outcome

This article reviews the evidence underlying hormone treatment decisions for men with advanced prostate cancer. Luteinizing hormone-releasing hormone (LHRH) analogs are the mainstays of therapy, but 3 areas of LHRH use need clarification: (1) when to start therapy, (2) what alternatives are available, and (3) how to incorporate a long-term strategy for the individual patient. The Medical Research Council (MRC) study, a randomized clinical trial in 938 patients, shows that immediate hormone therapy in men presenting with advanced prostate cancer (stage > or =T3) imparts a survival advantage over a delayed-treatment approach (7.5 years vs 5.8 years, P = 0.0003). LHRH analogs are also widely used (1) along with definitive radiation therapy, (2) when positive lymph nodes are found after radical prostatectomy, and (3) when prostate-specific antigen increases after any primary treatment (biochemical failure). In these situations, timing of therapy is somewhat controversial. Several new developments in hormone therapy are noteworthy, including high-dose antiandrogen monotherapy, a LHRH antagonist (abarelix), transdermal estrogens, and a subcutaneous implant that releases leuprolide acetate at a constant rate for 1 year (Viadur; Bayer Corporation, West Haven, CT). With 4 years of clinical experience with Viadur now available, the long-term data indicate continued, uniform testosterone suppression into the castrate range and a high degree of patient satisfaction. Thus, a long-term strategy-permitting increased patient freedom and decreased dependence on a fixed injection schedule-has for the first time become possible with the Viadur implant in men requiring hormone therapy for prostate cancer.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Drug Implants; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Orchiectomy; Prostatectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Time Factors

With the increasing indications for the use of androgen-deprivation therapy in the treatment of men with prostate cancer, side effects of the therapy deserve greater attention. Side effects such as hot flashes, decreased libido, decreased sexual function, and fatigue primarily affect the patients quality of life. Other side effects such as osteoporosis and changes in lipid profiles may also affect the patients overall health. Treatments such as estrogen, megestrol acetate, antidepressants, and bisphosphonates are useful in the management of many of the deleterious side effects of androgen deprivation. In addition, alternative management strategies such as intermittent androgen ablation and antiandrogen monotherapy may be useful in minimizing side effects caused by androgen ablation. Patients and physicians should be well aware of the potential side effects of androgen-deprivation therapy as well as the preventive and treatment strategies for these side effects in order to improve patients quality of life and health.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Diphosphonates; Hot Flashes; Humans; Leuprolide; Male; Osteoporosis; Prostatic Neoplasms; Quality of Life

This review provides an update on leuprorelin acetate, the world's most widely prescribed depot luteinising hormone-releasing hormone analogue. Leuprorelin acetate has been in clinical use in the palliative treatment of prostate cancer for more than 20 years, but advances continue to be made in terms of convenience and flexibility of administration, and in the incorporation of leuprorelin acetate into novel treatment regimens. The drug is administered in the form of a depot injection containing leuprorelin acetate microspheres, and is at least as effective in suppressing testosterone secretion as orchiectomy. In patients with prostate cancer, serum testosterone levels are reduced to castrate levels (< or = 50 ng/dl) within 2-3 weeks of the first one-month depot injection of 3.75 mg or three-month depot injection of 11.25 mg. Both the one-month and three-month formulations are effective in delaying tumour progression and alleviating symptoms of locally advanced and metastatic prostate cancer. Tolerability is generally good, with side-effects reflecting effective testosterone suppression. Recent studies have investigated the place of leuprorelin acetate as part of continuous or intermittent maximal androgen blockade (MAB) and in neoadjuvant therapy (i.e. to reduce the size of the prostate and downsize the tumour before radiotherapy). Additional formulations and presentations are in development, including a six-month injection, with the aim of adding to the clinical flexibility and patient acceptability of this important palliative treatment for prostate cancer.

Topics: Antineoplastic Agents, Hormonal; Humans; Injections; Leuprolide; Male; Patient Satisfaction; Prostatic Neoplasms; Testosterone; Treatment Outcome

In the 60 years since Huggins first demonstrated the hormone dependency of prostate cancer, the introduction of various means of hormonal manipulation has resulted in modest achievements. Orchiectomy reduced testosterone but was irreversible and associated with reduced quality of life. Diethylstilbestrol (DES) represented the first alternative to surgical castration. However, cardiovascular adverse events severely limited its use. The luteinizing hormone-releasing hormone (LHRH) agonists offered true medical castration but suffered from problems of testosterone surge and tumor flare. The introduction of antiandrogens in combination with LHRH agonists appears on meta-analysis not to have improved survival and has implications for the cost and convenience of therapy, as well as added toxicity. Gonadotropin-releasing hormone (GnRH) antagonists offer for the first time a truly rapid medical means of reducing testosterone and also suppress follicle-stimulating hormone (FSH). However, the clinical benefit of this new class of drugs remains to be evaluated.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Diethylstilbestrol; Drug Therapy, Combination; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Oligopeptides; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

The use of the luteinising hormone releasing hormone (LHRH) analogues--goserelin (Zoladex, AstraZeneca) and leuprorelin (Prostap, Wyeth)--is well established and forms the backbone of the treatment of locally advanced and metastatic prostate cancer. Comparable efficacy with orchidectomy and, historically, diethylstilbestrol (DES) is accepted, with the advantages of reversibility and limited thromboembolic and cardiovascular toxicity, respectively. Side effects such as hot flushes, loss of libido, lethargy and decreased bone mineral density have recently stimulated more interest in the use of non-steroidal anti-androgens such as bicalutamide (Casodex, AstraZeneca) in locally advanced disease. Although better tolerated, bicalutamide has significant problems with gynaecomastia and breast pain. Maximal androgen blockade using LHRH analogues and their adjuvant use with radiotherapy are discussed, as well as their experimental application in intermittent androgen suppression therapy. Similar side effect profiles are reported for the LHRH analogues but injection tolerability differs with the smaller 23G needle for Prostap 3 compared to the 16G needle for Zoladex LA. There is no evidence to suggest a difference in the efficacy between the LHRH analogues goserelin and leuprorelin, although no direct comparison has yet been undertaken.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Clinical Trials as Topic; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms

Topics: Antineoplastic Agents, Hormonal; Clinical Trials as Topic; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms; Quality of Life

Topics: Antineoplastic Agents, Hormonal; Drug Administration Schedule; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Luteinizing Hormone; Male; Prostatic Neoplasms; Substance Withdrawal Syndrome; Testosterone; Time Factors

Topics: Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Castration; Chlormadinone Acetate; Drug Therapy, Combination; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Nitriles; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Tosyl Compounds

Topics: Adenoviridae; Androgen Antagonists; Antibodies, Monoclonal; Antineoplastic Agents; Aziridines; Cancer Vaccines; Drug Design; Flurbiprofen; Genetic Therapy; Genetic Vectors; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Oligonucleotides, Antisense; Panitumumab; Prostate-Specific Antigen; Prostatic Neoplasms

Standard therapies for locally advanced prostate cancer have resulted in suboptimal disease control rates. A Phase I/II trial was designed for patients with positive seminal vesicle biopsies, prostate-specific antigen (PSA) >15 ng/ml, Gleason score > or =8 or clinical classification T2c-T3 to improve local control and to test the tolerance of the prostate to high-dose radiation by using neoadjuvant hormonal therapy, 103Pd brachytherapy, and conformal three-dimensional external beam radiation therapy (EBRT). This article outlines treatment-related morbidity and PSA response to this regimen and analyzes the effect of escalating doses of brachytherapy.. Forth-three patients with T1c-T3 prostate cancer were enrolled in a Phase I/II trial from March 1994 through September 1997. Follow-up ranged from 12 to 64 months (median, 32 months). Pretreatment PSA ranged from 2.1 to 202 ng/ml (median, 16 ng/ml). Seventy-seven percent (33 of 43) of patients had high-grade tumors (score > or =7). Seventy-four percent (32 of 43) had stage > or =T2c. A total of 21 (49%) patients had positive seminal vesicle biopsies. Treatment consisted of hormonal therapy for 3 months with leuprolide and flutamide followed by a 103Pd implant and, 2 months later, 59.4 Gy of three-dimensional EBRT. Hormonal therapy was continued for 9 months. The planned 103Pd dose was escalated from 57 Gy (13 patients) to 77 Gy (13 patients) to 86 Gy (17 patients).. The actuarial freedom from PSA failure (PSA>0.5 ng/ml) at 4 years was 74%. There were no significant differences found when analyzing patients by presenting PSA or seminal vesicle status. There was a trend toward improved outcome with higher doses delivered to the prostate via the implant. Patients receiving doses > or =65 Gy (31 patients) had a freedom from PSA failure rate at 4 years of 89.5%, compared with 52.5% for those receiving doses <65 Gy (10 patients; p=0.08). The last PSA values for those patients free from PSA failure were < or =0.1 ng/ml in 25 (69%), >0.1-0.2 ng/ml in 5 (14%), and >0.2-0.5 ng/ml in 6 (17%). The actuarial freedom from developing Grade 2 proctitis was 75% at 4 years. There was a trend toward increased proctitis with increasing prostate implant doses. Patients with doses < or =70 Gy (n=12) had a 92% freedom from Grade 2 proctitis compared with 67.5% for those with doses delivered to 90% of the gland from a dose-volume histogram of >70 Gy (n=29) (p=0.15). There were no cases of Grade 3 or 4 proctitis. The 3-year actuarial preservation of sexual potency rate was 43%.. The preliminary results from this regimen show an improvement in PSA control for this group of locally advanced prostate cancer patients over more standard therapies. To maximize control while minimizing toxicity, doses of 65-70 Gy of 103Pd should be used when 59.4 Gy of three-dimensional EBRT is delivered. Longer follow-up will be needed to further substantiate these findings.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Brachytherapy; Chemotherapy, Adjuvant; Flutamide; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Palladium; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes; Radiotherapy Dosage; Radiotherapy, Conformal

Leuprorelin acetate is a synthetic agonist analogue of gonadotropin-releasing hormone. Continued leuprorelin administration results in suppression of gonadal steroid synthesis, resulting in pharmacological castration. Since leuprorelin is a peptide, it is orally inactive and generally given subcutaneously or intramuscularly. Sustained release parenteral depot formulations, in which the hydrophilic leuprorelin is entrapped in biodegradable highly lipophilic synthetic polymer microspheres, have been developed to avoid daily injections. The peptide drug is released from these depot formulations at a functionally constant daily rate for 1, 3 or 4 months, depending on the polymer type [polylactic/glycolic acid (PLGA) for a 1-month depot and polylactic acid (PLA) for depot of >2 months], with doses ranging between 3.75 and 30mg. Mean peak plasma leuprorelin concentrations (C(max)) of 13.1, 20.8 to 21.8, 47.4, 54.5 and 53 microg/L occur within 1 to 3 hours of depot subcutaneous administration of 3.75, 7.5, 11.25, 15 and 30 mg, respectively, compared with 32 to 35 microg/L at 36 to 60 min after a subcutaneous injection of 1mg of a non-depot formulation. Sustained drug release from the PLGA microspheres maintains plasma concentrations between 0.4 and 1.4 microg/L over 28 days after single 3.75, 7.5 or 15mg depot injections. Mean areas under the concentration-time curve (AUCs) are similar for subcutaneous or intravenous injection of short-acting leuprorelin 1mg; a significant dose-related increase in the AUC from 0 to 35 days is noted after depot injection of leuprorelin 3.75, 7.5 and 15mg. Mean volume of distribution of leuprorelin is 37L after a single subcutaneous injection of 1mg, and 36, 33 and 27L after depot administration of 3.75, 7.5 and 15mg, respectively. Total body clearance is 9.1 L/h and elimination half-life 3.6 hours after a subcutaneous 1mg injection; corresponding values after intravenous injection are 8.3 L/h and 2.9 hours. A 3-month depot PLA formulation of leuprorelin acetate 11.25mg ensures a C(max) of around 20 microg/L at 3 hours after subcutaneous injection, and continuous drug concentrations of 0.43 to 0.19 microg/L from day 7 until before the next injection. Recently, an implant that delivers leuprorelin for 1 year has been evaluated. Serum leuprorelin concentrations remained at a steady mean of 0.93 microg/L until week 52, suggesting zero-order drug release from the implant. In general, regular or depot leuprorelin treatment is well tole

Topics: Animals; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Half-Life; Humans; Leuprolide; Male; Microspheres; Prostatic Neoplasms; Randomized Controlled Trials as Topic

Viadur (leuprolide acetate implant), providing a sustained release of drug over a 12-month duration, decreases serum testosterone in advanced prostate cancer patients, providing long-term, palliative medical hormonal therapy. Clinical experience suggests Viadur implants are safe, effective, and generally well tolerated. The continuous drug delivery provided by Viadur ensures compliance. The Viadur implants was designed to be maintenance-free, thereby allowing nurses and other health professionals to focus on other patient needs, such as followup visits and diagnostic tests. Viadur is one aspect of a comprehensive approach to patient management, which also includes regular followup for prostate-specific antigen testing, digital rectal examination, and other tests throughout the 1-year therapy.

Topics: Antineoplastic Agents, Hormonal; Drug Implants; Humans; Leuprolide; Male; Palliative Care; Prostatic Neoplasms

Most cases of advanced carcinoma of the prostate are hormonosensitive. The use of combined androgen blockade (CAB) seems to improve survival and quality of life, but only when combined with chemical castration by luteinizing-hormone-releasing hormone analog and without the use of steroidal antiandrogens. After CAB, further hormonal treatments remain efficacious, such as antiandrogen withdrawal followed by estrogens, aromatase inhibitors, and hormone-refractory prostate cancer multiple cytotoxic agents. For painful bone lesions, external beam radiotherapy, biphosphonates, and strontium 89 or samarium 153 provide pain relief. The use of new methods for the evaluation of response and quality of life will allow the rapid identification of effective treatments and permit powered phase III trials.

Topics: Androgen Antagonists; Bone Neoplasms; Brachytherapy; Combined Modality Therapy; Estrogens; Humans; Leuprolide; Male; Pain; Patient Care Planning; Prostatic Neoplasms; Quality of Life; Radiotherapy; Strontium Radioisotopes

Topics: Animals; Drug Delivery Systems; Drug Design; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms

Prostate cancer has become the most common cancer among American men and is second only to lung cancer as a cause of male cancer-related death. Several treatment options exist for different stages of prostate cancer including observation, prostatectomy, radiation therapy, chemotherapy, and hormone therapy. Hormone therapy has evolved from the use of estrogens to gonadotropin-releasing hormone (GnRH) agonists and recently, investigational GnRH antagonists. GnRH receptor agonists such as leuprolide, bruserelin and goserelin have been used for the treatment of prostate cancer. These agonists eventually cause the inhibition of lutenizing hormone production, which in turn causes a suppression of testosterone and dihydrotestosterone, on which continued growth of prostate cancer cells depend. Several comparative studies of leuprorelin administered as daily injections or monthly depot injections have been reported. Disease progression was prevented in more than 72% of men administered daily leuprorelin, and in 82% to 89% of those receiving monthly depots. Another synthetic GnRH analog, goserelin, has been studied in a similar population of men with daily injections producing partial responses in 60% to 80% of men with previously untreated prostate cancer. Abarelix, a peptide antagonist of GnRH receptor, is also being studied for the treatment of prostate cancer. The discovery and development of GnRH antagonists may provide an important advance for patients with prostate cancer. Clearly the studies described herein, as well as many others, outline an exciting era of research to define the optimal use of hormonal therapy in prostate cancer.

Topics: Antineoplastic Agents, Hormonal; Buserelin; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms; Testosterone

An 88-year-old patient with a poorly differentiated adenocarcinoma of the prostate gland was found to have all cardinal findings of syndrome of inappropriate antidiuretic hormone secretion (SIADH). Elevated levels of antidiuretic hormone were found in the patient's serum and in the prostatic tumor and the cytoplasms of the tumor was positive for prostate specific antigen and was faintly positive for antidiuretic hormone (ADH). He responded well to combination therapy of androgen blockade with leuprorelin acetate and flutamide, and laboratory findings of SIADH and serum ADH level returned to normal. However, he died of sudden profuse bleeding caused by gastric ulcers 6 months after the therapy. Ten cases of SIADH caused by prostatic cancer have been reported including the present case.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Flutamide; Humans; Inappropriate ADH Syndrome; Leuprolide; Male; Paraneoplastic Endocrine Syndromes; Prostatic Neoplasms; Treatment Outcome; Vasopressins

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Goserelin; Humans; Leuprolide; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms

Topics: Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms

Topics: Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Libido; Male; Prostatic Neoplasms; Substance Withdrawal Syndrome

Topics: Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms

The Canadian Urologic Oncology Group has carried out three studies of neoadjuvant hormonal therapy (NHT) in prostate cancer. The first, a study of 3 months of cyproterone acetate (CPA) 100 mg TID in patients undergoing external-beam radiation therapy, showed a benefit with respect to time to biochemical progression. There are no survival or clinical progression data available from this study. The second study involved 3 months of CPA prior to radical prostatectomy compared with radical prostatectomy alone and enrolled 200 patients. The probability of biochemical progression at 36 months was similar in the two groups (CPA 40%; surgery alone 30%; P = 0.3233). More recently, we have carried out a randomized trial of 3 v 8 months of leuprolide plus flutamide prior to radical prostatectomy in 547 patients. Patients were stratified by clinical stage, Gleason grade, and serum prostate specific antigen (PSA) concentration. In the 3- and 8-month groups, presurgery PSA concentrations were <0.1 ng/mL in 35% v 73%, and >0.3 ng/mL in 37% v 10%, respectively. In the 3- and 8-month groups, the positive margin rates were 17% and 5% and the organ-confined rates 71% and 91% (P < 0.01). One-year follow-up is now available on the entire cohort. Data regarding time to biochemical and clinical progression and overall and disease-specific survival will be required to determine whether this change in the pathologic findings translates into a patient benefit.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Canada; Cyproterone Acetate; Disease Progression; Flutamide; Humans; Leuprolide; Male; Neoadjuvant Therapy; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Survival Rate

With 184,500 new cases and 39,200 deaths anticipated in 1998, prostate cancer is second only to lung cancer in cancer mortality for men. This report is a systematic review of the evidence from randomized controlled trials on the relative effectiveness of alternative strategies for androgen suppression as treatment of advanced prostate cancer. Three key issues are addressed: (1) the relative effectiveness of the available methods for monotherapy (orchiectomy, luteinizing hormone-releasing hormone [LHRH] agonists, and antiandrogens), (2) the effectiveness of combined androgen blockade compared to monotherapy, and (3) the effectiveness of immediate androgen suppression compared to androgen suppression deferred until clinical progression. Outcomes of interest are overall, cancer-specific, and progression-free survival; time to treatment failure; adverse effects; and quality of life. Two supplementary analyses were conducted for each key question: (1) meta-analysis of overall survival at 2 years (questions 1 and 2) and 5 years (questions 2 and 3), and (2) cost-effectiveness analysis.. The MEDLINE, CANCERLIT, and EMBASE databases were searched from 1966 to March 1998, and Current Contents to August 24, 1998, for the terms: leuprolide (Lupron); goserelin (Zoladex); buserelin (Suprefact); flutamide (Eulexin); nilutamide (Anandron, Nilandron); bicalutamide (Casodex); cyproterone acetate (Androcur); diethylstilbestrol (DES); and orchiectomy (castration, orchidectomy). The search was then limited to human studies indexed under the MeSH term "prostatic neoplasms" and by the UK Cochrane Center search strategy for randomized controlled trials. Total yield was 1,477 references.. We Reports of efficacy outcomes were limited to randomized controlled trials. Phase II studies that reported on withdrawals from therapy and all studies reporting on quality of life were also included.. The systematic review used a prospectively designed protocol conducted by two independent reviewers, with disagreements resolved by consensus. The meta-analysis combined data on overall survival using a random effects model. The cost-effectiveness analysis used a decision analysis model of advanced prostate cancer with health states and transitions derived from the literature and estimates of effectiveness derived from the meta-analysis. The cost-effectiveness analysis is conducted from a societal perspective, consistent with the guidelines of the U.S. Public Health Service Panel on Cost-Effectiveness in Health and Medicine.. Survival after treatment with an LHRH agonist is equivalent to survival after orchiectomy. The available LHRH agonists are equally effective, and no LHRH agonist is superior to the other when adverse effects are considered. Survival may be somewhat lower with use of a nonsteroidal antiandrogen. There is no statistically significant difference in survival at 2 years between patients treated with combined androgen blockade or monotherapy. Meta-analysis of the limited data available shows a statistically significant difference in survival at 5 years that favors combined androgen blockade. However, the magnitude of this difference is of questionable clinical significance. For the subgroup of patients with good prognosis, there is no statistically significant difference in survival. Adverse effects leading to withdrawal from therapy occurred more often with combined androgen blockade. No evidence is yet available from randomized controlled trials of androgen suppression initiated at prostate-specific antigen (PSA) rise after definitive therapy for clinically localized disease. For patients who are newly diagnosed with locally advanced or asymptomatic metastatic disease, the evidence is insufficient to determine whether primary androgen suppression initiated at diagnosis improves outcomes. (ABSTRACT TRUNCATED)

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Cost-Benefit Analysis; Evidence-Based Medicine; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Orchiectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Treatment Outcome

Endocrine therapy for prostate cancer has been changing rapidly. While LH-RH agonists have been popularly used in medication, their long-acting sustained release formulation is about to be introduced to clinics in Japan. LH-RH antagonists, which have not attracted much attention of clinicians because of adverse reactions, are also going to be put into practical use in the near future. Bicalutamide, which is considered to have greater usefulness than other anti-androgens, is now under regulatory review by the authorities for approval. In addition, a broader range of endocrine therapies is being studied for treatment of prostate cancer. In terms of treatment methods, a number of attempts are made in selection of subject patients, treatment timing, combination treatment and so on.

Topics: Adult; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Nitriles; Prostatic Neoplasms; Survival Rate; Testosterone; Tosyl Compounds

There can be seen many investigations to examine the effects and benefits of total androgen blockade (TAB), combining an antiandrogen with surgical castration or a LH-RH analogue, for advanced prostate cancer. This review summarizes the concept, theory, method and clinical application of TAB. The concept of TAB was supported by reports that show a survival advantage using the combined blockade over LH-RH analogue alone. The theory of TAB proposes that suppression of all androgen production, adrenal and testicular androgen, should result in a better response than standard hormonal management such as castration and/or estrogens. In Japan, Chlormadinone acetate (100 mg twice daily) or Flutamide (375 mg three times daily) is orally administered and Leuprorelin acetate (3.75 mg every 4 weeks) or Goserelin acetate (3.6 mg every 4 weeks) is administered by hypodermic injection. There have been unresolved controversies surrounding this therapeutic modality, therefore future studies should help to define the role of TAB.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Chlormadinone Acetate; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms

From what is known about the testicular and adrenal origins of testosterone, and the testosterone dependency of prostate cancer, treatment with combined androgen blockade (CAB) by castration plus an antiandrogen was expected to be beneficial to patients. A number of early studies verified this hypothesis, but the findings needed to be confirmed in large, randomized, prospective studies. Modest but significant benefits of CAB were seen when treatment with leuprorelin plus flutamide was compared with leuprorelin alone. Of note was the increased benefit from CAB seen in patients with minimal metastatic prostate cancer, a finding that needed to be confirmed. A study comparing orchidectomy plus nilutamide with orchidectomy alone showed significant benefits of CAB in terms of time to progression and overall survival. However, a recent major NCI study revealed no benefits for CAB with respect to survival, even for patients with minimal metastatic disease. Results from other clinical studies have been conflicting, perhaps because of the method of castration or differences in antiandrogen used. Before the question of whether CAB significantly benefits patients can be fully answered, a clearer understanding of the interactions between antiandrogens, luteinizing hormone-releasing hormone agonists and receptors, and of the response of prostate cancer to these, is needed.

Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Castration; Combined Modality Therapy; Flutamide; Humans; Leuprolide; Male; Prostatic Neoplasms; Randomized Controlled Trials as Topic

Indication and new agents for endocrine therapy in prostate cancer were outlined, and new development of endocrine therapy was reviewed in terms of total androgen blockade (TAB) for advanced disease and localized disease as neoadjuvant setting, and antiandrogen withdrawal syndrome. TAB is considered to be useful in the treatment of patients with advanced prostate cancer, particularly those with minimal disease and good performance status. Neoadjuvant TAB therapy before radical prostatectomy may decrease cancer positive surgical margins. However, long-term follow-up data are required to determine the impact on survival. Antiandrogen withdrawal seems to be therapeutically efficacious for patients with hormone-refractory prostate cancer, with a response rate of about 20%. Therefore, antiandrogen withdrawal should be tried before initiating therapy for hormone-refractory prostate cancer.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatectomy; Prostatic Neoplasms

A 72-year-old male treated with flutamide for metastatic prostate cancer developed lethargy and confusion. He was noted to be icteric and his liver enzymes were elevated. Within a week of discontinuing the medication, the patient's mental status and liver function returned to normal. Although flutamide-induced near fatal liver dysfunction has been described, progression to encephalopathy is a rare occurrence. Based on a review of the literature, management guidelines for the use of flutamide are suggested.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Drug Therapy, Combination; Flutamide; Hepatic Encephalopathy; Humans; Leuprolide; Male; Prostatic Neoplasms

Combined androgen blockade for metastatic prostate cancer has become the standard against which on-going clinical trials are measured. Benefit of combined androgen blockade with an LHRH agonist (leuprolide) and an antiandrogen (flutamide) has been noted, particularly for those with minimal disease. This has led to timely accrual of patients to a trial testing whether orchidectomy with flutamide is superior to orchidectomy alone. Positive findings with permanent and intermittent withdrawal of flutamide has prompted the design and implementation of additional trials. Suramin has been reintroduced in trials of chemohormonal intervention. Past success with combined androgen blockade in lengthening survival and improving quality of life for patients with metastatic prostate cancer has prompted enthusiasm for broadening the base of clinical studies for this disease.

Topics: Antineoplastic Agents, Hormonal; Combined Modality Therapy; Flutamide; Humans; Leuprolide; Male; Multicenter Studies as Topic; Neoplasm Staging; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Suramin; Survival Rate; Treatment Outcome

Topics: Aged; Androgen Antagonists; Androgens; Clinical Trials as Topic; Flutamide; Humans; Leuprolide; Male; Prostatectomy; Prostatic Neoplasms

Leuprorelin (leuprolide acetate) is a gonadotrophin-releasing hormone (GnRH) analogue used to treat a wide range of sex hormone-related disorders including advanced prostatic cancer, endometriosis and precocious puberty. It acts primarily on the anterior pituitary, inducing a transient early rise in gonadotrophin release. With continued use, leuprorelin causes pituitary desensitisation and/or down-regulation, leading to suppressed circulating levels of gonadotrophins and sex hormones. Clinical trials in men with advanced prostatic cancer demonstrate that leuprorelin (usually monthly depot injections of 3.75 or 7.5 mg) is less likely to cause serious adverse cardiovascular effects than diethylstilbestrol, and has comparable efficacy to bilateral orchiectomy or other GnRH analogues. Therefore, the choice between leuprorelin and orchiectomy may be made on the basis of the patient's treatment preference, along with specific patient characteristics and cost implications. Monthly intramuscular or subcutaneous administration of depot leuprorelin 3.75 mg was superior to placebo, and comparable to oral danazol 800 mg/day or intranasal buserelin 900 micrograms/day, in achieving objective and subjective responses in women with endometriosis. Thus, leuprorelin is an effective alternative to other treatments for women with endometriosis, but the recommended duration of its use in this clinical setting is limited to 6 months because it reduces bone mineral density. In children with central precocious puberty, leuprorelin (usually monthly intramuscular or subcutaneous injections of depot leuprorelin 3.75 to 15mg) decreases mean growth velocity and signs of sexual maturation and increases predicted adult height compared with baseline measurements. Although effects on final adult height are predicted from available data and require confirmation in long term follow-up studies, the absence of effective alternatives to GnRH analogues makes leuprorelin a first-line therapy for children with this rare disease. In women with uterine leiomyomata, monthly intramuscular administration of depot leuprorelin 3.75 mg for 6 months markedly reduces uterine volume and fibroid-related symptoms, but, as with other GnRH analogues, these effects dissipate following discontinuation of the drug. As adjuvant therapy in women undergoing in vitro fertilisation or gamete intrafallopian transfer, leuprorelin (usually 0.5 to 1 mg/day subcutaneously) reduces the risk of cancelled cycles for oocyte re

Topics: Amino Acid Sequence; Androgen Antagonists; Animals; Antineoplastic Combined Chemotherapy Protocols; Controlled Clinical Trials as Topic; Endometriosis; Female; Fertility; Gonadal Steroid Hormones; Half-Life; Humans; Leiomyoma; Leuprolide; Male; Metabolic Clearance Rate; Molecular Sequence Data; Prostatic Neoplasms; Puberty, Precocious; Uterine Neoplasms

We report a case of mucinous adenocarcinoma of the prostate treated successfully with androgen ablation followed by laparoscopic lymphadenectomy and total perineal prostatectomy. This case demonstrates that mucinous adenocarcinoma of the prostate may be hormonally sensitive.

Topics: Adenocarcinoma, Mucinous; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Remission Induction

We report the syndrome of inappropriate antidiuretic hormone secretion in a 59-year-old man with stage C adenocarcinoma of the prostate. Serum antidiuretic hormone levels returned to normal following treatment with a gonadotropin-releasing hormone analogue. To our knowledge this case represents the first in which resolution of this syndrome occurred with treatment of the carcinoma.

Topics: Adenocarcinoma; Humans; Inappropriate ADH Syndrome; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Remission Induction

Small cell carcinoma of the prostate is rare and associated with a rapidly fatal course. Since 1977, 47 cases have been reported in the world literature with data from 3 additional cases presented herein. The purpose of our review was to determine the effectiveness of hormonal versus chemotherapy. Thirty-four of the 50 cases have known clinical histories. Four patients were not treated, and all were dead of their disease within an average of 2.75 months. Six patients were eliminated from our review because small cell carcinoma was discovered at autopsy. Another 5 cases were omitted because hormonal +/- chemotherapy had already been given for a previous diagnosis of adenocarcinoma, but no specific therapy was given once the small cell carcinoma developed. Of the remaining 19 cases, only 2 have survived. One is still alive forty-three months after hormonal treatment, and another is alive with disease six months after the initiation of hormonal therapy and chemotherapy. Five patients were given hormonal therapy only, and none of them responded. In 4 patients chemotherapy was given after hormonal therapy had failed, and they too died of their disease within a short period of time. However, an additional 8 patients were treated with immediate chemotherapy +/- hormonal therapy and had substantially longer clinical remissions. Therefore, although small cell carcinoma is a uniformly fatal disease, immediate chemotherapy should be considered to promote better clinical remissions.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Chlorotrianisene; Cyclophosphamide; Diethylstilbestrol; Doxorubicin; Etoposide; Humans; Leuprolide; Male; Middle Aged; Prostatectomy; Prostatic Neoplasms

Endometrioid carcinoma of the prostate is an uncommon form of prostatic cancer. The authors present the case of a 77 year-old man and discuss the different particularities of this rare entity.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Flutamide; Humans; Leuprolide; Male; Prostatic Neoplasms

Topics: Androgen Antagonists; Clinical Trials as Topic; Drug Therapy, Combination; Flutamide; Humans; Leuprolide; Male; Prostatic Neoplasms

Leuprorelin (leuprolide, D-Leu6-(des-Gly10-NH2)-LH-RH ethylamide) acetate is a super-active agonist of luteinizing hormone-releasing hormone (LH-RH). We developed once-a-month injectable microcapsules of this agonist by our novel in-water drying method. This depot formulation can release the drug at an apparent zero-order rate over one month with bioerosion of copoly (lactic/glycolic acid) utilized as a wall material of the polycore microcapsules. A dramatic prolonged depression of pituitary-gonadal axis, chemical castration, was achieved by the once-a-month injection in experimental animals; it expects a reliable efficacy for treating hormone-dependent prostatic, breast cancers and endometriosis. Studies on the dosage design of this new delivery system of leuprorelin are summarized.

Topics: Amino Acid Sequence; Animals; Breast Neoplasms; Capsules; Delayed-Action Preparations; Drug Delivery Systems; Endometriosis; Glycolates; Humans; Injections; Lactates; Lactic Acid; Leuprolide; Male; Molecular Sequence Data; Polymers; Prostatic Neoplasms

Topics: Androgen Antagonists; Antineoplastic Agents; Buserelin; Delayed-Action Preparations; Estradiol Congeners; Goserelin; Humans; Leuprolide; Male; Orchiectomy; Prostatic Neoplasms

Advances in our understanding of hypothalamic-pituitary gonadal regulation have led to the development of pharmaceutical agents that produce a medically castrate state with minimal morbidity. The selection of the method for androgen ablation in a given patient with stage D adenocarcinoma of the prostate should be based on patient preference and on cost, because the therapeutic outcomes of medical castration and orchiectomy are equivalent. The addition of androgen receptor antagonists to a given patient's regimen should be made with the knowledge that the impact on the mortality rate is modest and the cost significant. Further manipulation of androgen production or action in patients with hormonally resistant cancer is unlikely to improve either the disease progression or the mortality rate. Research efforts should be focused on the development of effective chemotherapy for such disease.

Topics: Aminoglutethimide; Androgen Antagonists; Androgens; Estrogens; Gonadotropin-Releasing Hormone; Humans; Ketoconazole; Leuprolide; Male; Orchiectomy; Progestins; Prostatic Neoplasms

Luteinizing hormone-releasing hormone agonist therapy for prostate cancer is a new method of management for metastatic disease. During the initial 1 to 2-week period of administration an increase in serum testosterone concentration can lead to an exacerbation of clinical symptoms (flare phenomenon). Two patients are summarized who received luteinizing hormone-releasing hormone agonist therapy without flare blockade and died suddenly during month 1 of therapy. A review of 765 patients in 9 series found 10.9% who suffered disease flare and 15 who died during disease flare. Of these 17 patients 12 were similar to our 2. These data suggest that any patient placed on luteinizing hormone-releasing hormone agonist therapy for prostate cancer merits some form of flare blockade during the initial 1 or 2 months of therapy.

Topics: Adenocarcinoma; Antineoplastic Agents; Death, Sudden; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Testosterone; Time Factors

Leuprorelin acetate, a highly potent luteinizing hormone releasing hormone agonist, was originally launched in the USA to be administered once daily by self-injection for the treatment of metastatic prostatic cancer. A once-monthly intramuscularly or subcutaneously injectable depot form of leuprorelin acetate has, subsequently, been developed. Biodegradable copoly(DL-lactic acid/glycolic acid) was chosen as the release-controlling polymer and the microcapsules containing leuprorelin acetate were prepared by an in-water drying method. Results of studies in rats showed that a copolymer with a molecular weight of 14,000 and a lactic acid/glycolic acid ratio of 75/25 had the most satisfactory releasing properties. Microcapsules given once monthly reduced serum testosterone levels in rats, dogs and man. In clinical studies, the depot preparation effectively reduced the dose of leuprorelin acetate required to up to one-eighth of that needed when injected daily. A sophisticated manufacturing system has now been developed and a very reliable controlled-release product is now available that has many advantages.

Topics: Animals; Antineoplastic Agents; Delayed-Action Preparations; Drug Compounding; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Meta-Analysis as Topic; Polyglactin 910; Prostatic Neoplasms; Rats

Combined therapy, the treatment of advanced adenocarcinoma of the prostate by total androgen suppression, is still a controversial subject today. Some studies performed during the 1980s support the value of this therapeutic approach, while others have found it to be no more effective than surgical or chemical castration alone. Recently, the results of a randomized, controlled, multicenter intergroup study of combined therapy sponsored by the U.S. National Cancer Institute (NCI) became available. These results suggest that combined therapy offers some advantages over monotherapy in the treatment of advanced prostate cancer. A variety of drugs are available to suppress adrenal androgens. However, the value of these agents in prostate cancer therapy continues to be hotly debated.

Topics: Adenocarcinoma; Androgen Antagonists; Antineoplastic Agents; Combined Modality Therapy; Diethylstilbestrol; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Orchiectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic

The identification of the decapeptide luteinizing hormone-releasing hormone (LHRH) has led to the development of LHRH agonists, which are a new class of drugs for the treatment of advanced prostate cancer. These peptides have a modified amino acid structure that makes them more potent than LHRH. Prolonged administration of LHRH agonists results in down-regulation of the LHRH receptors in the pituitary and decreased secretion of luteinizing hormone. The result is decreased production of testosterone by Leydig cells, which is the basis for the use of LHRH agonists to treat prostate cancer. The effectiveness of LHRH agonists has been demonstrated in the United States in several randomized, controlled clinical trials. Daily administration of leuprolide produced equivalent results compared with diethylstilbestrol (DES). More recently, in two separate, randomized studies, the long-acting LHRH agonist Zoladex (ICI Pharma, Wilmington, Delaware) produced the same objective response rate as DES or bilateral orchiectomy. The equivalent response rates obtained with LHRH agonists indicate that these drugs can now be considered a reasonable treatment option for patients with metastatic prostatic cancer.

Topics: Antineoplastic Agents; Buserelin; Clinical Trials as Topic; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms

Analogs of GnRH constitute a new category of drugs available for the treatment of advanced prostatic cancer. The efficacy and safety of GnRH analogs in the treatment of this disease is now well established. These compounds represent an important alternative therapy for advanced prostatic cancer patients who do not wish to undergo orchiectomy or for whom DES is not tolerable because of the risk of cardiovascular complications. The advent of the monthly depot form of these drugs will make treatment more convenient and less invasive and will enhance patient compliance.

Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Buserelin; Clinical Trials as Topic; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms; Triptorelin Pamoate

Topics: Antineoplastic Agents; Breast Neoplasms; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Ovarian Neoplasms; Prostatic Neoplasms; Triptorelin Pamoate

The introduction of potent analogues of gonadotropin hormone-releasing hormone (GnRH) into clinical practice and their use in patients with metastatic prostatic carcinoma provides an effective alternative to the exogenous administration of pharmacologic doses of estrogens or surgical castration. Their advantages over estrogens are primarily related to a lower incidence of cardiovascular toxicity and gynecomastia. Their choice over orchiectomy is based on cosmetic and psychologic factors since their endocrine effects and clinical benefits are virtually the same. In this review, we describe the current experience with GnRH analogues in the treatment of prostatic carcinoma and discuss their use in the context of other endocrine manipulations. GnRH analogues act on the pituitary and indirectly affect gonadal function, and represent an opportunity for combination with other compounds capable of suppressing or interfering with the effects of circulating and androgens. The availability of several new compounds affecting different aspects of androgen metabolism provides promise for rational drug selection and testing.

Topics: Buserelin; Clinical Trials as Topic; Diethylstilbestrol; Gonadotropin-Releasing Hormone; Gonadotropins, Pituitary; Goserelin; Humans; Leuprolide; Male; Nafarelin; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Testosterone

Topics: Adenocarcinoma; Animals; Disease Models, Animal; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Prostatic Neoplasms; Rats; Rats, Inbred Strains; Testis; Testosterone

Metastatic prostatic cancer can be present in a variety of different ways. The authors describe the differences among stages D-0, D-1, and D-2 disease and present the treatment options for each of the substages. They summarize and integrate the clinical evidence that bears on the potential efficacy of each treatment.

Topics: Acid Phosphatase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Carcinoma; Castration; Clinical Trials as Topic; Combined Modality Therapy; Diethylstilbestrol; Estrogens; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Lymph Node Excision; Lymphatic Metastasis; Male; Neoplasm Staging; Prostatectomy; Prostatic Neoplasms; Radioisotope Teletherapy

To characterize the impact of concomitant prostate cancer treatments with the use of relugolix, the oral GnRH receptor antagonist, in advanced prostate cancer, a subgroup and pharmacokinetic/pharmacodynamic analyses of the HERO study was undertaken.. Overall, 934 patients were randomized 2:1 to receive relugolix 120 mg orally once daily or leuprolide injections every 12 weeks for 48 weeks. In the setting of rising PSA, patients could receive enzalutamide or docetaxel 2 months after study initiation. Assessments included sustained testosterone suppression to castrate levels (<50 ng/dL) through 48 weeks and safety parameters. Subgroups analyzed included patients with or without concomitant enzalutamide or docetaxel. A sensitivity analysis of the primary endpoint was performed excluding patients who received concomitant therapies that may affect testosterone. Pharmacokinetic/pharmacodynamic analyses of 20 participants in the relugolix treatment group assessed the net effect of enzalutamide on exposure to relugolix.. Overall, 125 patients (13.4%) took concomitant therapies that could impact testosterone levels. Enzalutamide (n = 23) was the most frequently used therapy in the relugolix (2.7%) and leuprolide groups (1.9%). Docetaxel (n = 13) was used by 1.3% and 1.6% of patients in the relugolix and leuprolide groups, respectively. All other relevant concomitant therapy were used in <1% of population. Sensitivity analysis showed concomitant therapy did not impact the testosterone levels. Castration rates were similar with and without concomitant use of enzalutamide or docetaxel. No clinically relevant differences in adverse events were observed between subgroups in either treatment group. No differences in relugolix C. Treatment with relugolix was associated with similar efficacy and safety profiles with and without concomitant enzalutamide or docetaxel. Standard-of-care use of relugolix in combination with these agents is supported by these data.

Topics: Antineoplastic Agents, Hormonal; Docetaxel; Humans; Leuprolide; Male; Prostatic Neoplasms; Testosterone

Volume 209, Supplement 4, Page e1190: The abstract text is as given below. This erratum also includes the additional disclosure, conflict of interest, and acknowledgments that were not included in the original publication. The online and PDF versions of the article have been updated.. Within 10 years following definitive therapy for prostate cancer, ∼20-50% of patients (pts) experience biochemical recurrence (BCR) characterized by rising prostate-specific antigen (PSA) levels. Pts with high-risk BCR have an increased risk of mortality and improved therapies are needed. The objective of EMBARK was to evaluate the efficacy and safety of enzalutamide (enza) + androgen deprivation therapy (ADT) and enza monotherapy (mono) in pts with high-risk BCR.. EMBARK is a randomized, phase 3 study of pts with BCR considered high-risk: PSA doubling time ≤9 months and PSA ≥2 ng/mL above nadir post-radiotherapy (RT) or ≥1 ng/mL after radical prostatectomy (RP) ± postoperative RT. Pts were randomized (1:1:1) to enza 160 mg/day + leuprolide acetate (LA) (double-blind), placebo (pbo) + LA (double-blind), or enza mono (open-label). LA 22.5 mg was administered every 12 weeks. If the PSA at week 36 was <0.2 ng/mL, therapy was stopped at week 37 and restarted when PSA was ≥2 ng/mL for pts with primary RP, and ≥5 ng/mL for pts without RP. The primary endpoint, determined by blinded, independent central review (BICR), was metastasis-free survival (MFS) with enza + LA vs pbo + LA. Key secondary endpoints were MFS of enza mono vs pbo + LA, time to PSA progression, time to antineoplastic therapy, and overall survival (OS) of enza + LA or enza mono vs pbo + LA.. 1068 pts were randomized into the study (enza + LA, n=355; pbo + LA, n=358; enza mono, n=355). After median follow-up of 60.7 months, per BICR, MFS for enza + LA (HR 0.42; 95% CI 0.30-0.61; p<0.0001) and enza mono (HR 0.63; 95% CI 0.46-0.87; p=0.0049) were statistically superior to pbo + LA. Statistically significant improvements were also observed in risk of PSA progression (enza + LA: HR 0.07; 95% CI, 0.03-0.14; enza mono: HR 0.33; 95% CI, 0.23-0.49; both p<0.0001) and time to first use of new antineoplastic therapy (enza + LA: HR 0.36; 95% CI, 0.26-0.49; enza mono: HR 0.54; 95% CI, 0.41-0.71; both p<0.0001). Interim OS data trended in favor enza + LA (HR 0.59; 95% CI, 0.38-0.91; p=0.0153, did not cross interim efficacy boundary) and enza mono (HR 0.78; 95% CI, 0.52-1.17; p=0.2304). Fatigue and hot flash were the most common adverse events; no new safety signals were observed.. In pts with high-risk BCR, enza + ADT and enza mono demonstrated a statistically significant and clinically meaningful improvement in MFS vs pbo + ADT. The safety profile of enza was consistent with results from previous clinical studies.. NCT02319837.. Pfizer Inc. and Astellas Pharma Inc.Conflict of Interest and Disclosure Statement:Neal D. Shore reports grant support and consulting fees from AbbVie, Amgen, Astellas Pharma Inc., AstraZeneca, Bayer, Clovis Oncology, Dendreon Pharmaceuticals LLC, Ferring Pharmaceuticals, GenesisCare, Janssen Oncology, Merck, Myovant Sciences, Pfizer Inc., Sanofi-Genzyme, and Tolmar Pharmaceuticals, Inc. Murilo de Almeida Luz reports receiving speaker honoraria from Astellas Pharma Inc., Bayer, Janssen, Merck Sharp & Dohme, and Pfizer Inc.; being an advisory board member for Astellas Pharma Inc., Bayer, and Janssen; sponsored research from Bayer, Bristol Myers Squibb, Ferring Pharmaceuticals, GlaxoSmithKline, Janssen, and Roche; receiving travel expenses from AstraZeneca, Bayer, Janssen, and Pfizer Inc. Ugo De Giorgi reports serving as a consultant for Janssen, Astellas Pharma Inc., Sanofi, Bayer, Pfizer Inc., Bristol Myers Squibb, Novartis, Ipsen, and Merck Sharp & Dohme. Martin Gleave reports stock or ownership interest in OncoGenex Technologies Inc., Sustained Therapeutics Inc., and Sikta Biopharma; is a consultant to Astellas Pharma Inc., AstraZeneca, Bayer, Genova Diagnostics (GDx), Janssen, Pfizer Inc., Roche, Sanofi, and TerSera Therapeutics LLC; and holds patents for OGX-011, OGX-427, ST-CP, and ST-POP. Geoffrey T. Gotto reports receiving honoraria from Amgen, Astellas Pharma Inc., Bayer, Ferring Pharmaceuticals, Janssen, and Merck; being a consultant or advisory board member for Amgen, Astellas Pharma Inc., Bayer, Janssen, and Merck; providing expert testimony for Janssen; and receiving support for travel, accommodation, and expenses from Janssen. Gabriel P. Haas reports being an employee of and shareholder in Astellas Pharma Inc. Miguel Ramirez-Backhaus reports serving as a consultant or advisory board member for Astellas Pharma Inc., Bayer, Janssen, and Karl Storz; receiving speaker honoraria from Astellas Pharma Inc., Bayer, Janssen, and GP Pharm. Antti Rannikko reports being a board member for the Ida Montin Foundation, and Orion Research Foundation; being an advisory board member for Bayer, Janssen, and Orion Pharma; being a stockholder and clinical advisor for Aqsens Health; being a clinical investigator for Astellas Pharma Inc., Bayer, Janssen, Orion Pharma, and RhoVac AB; and receiving competitive state research funding from HUS Helsinki University Hospital, Finnish Cancer Organizations, and the Jane and Aatos Erkko Foundation. Jamal Tazari, Yiyun Tang, an. The authors thank all the patients, their families, and the investigators and investigational site members involved in this study.Editorial Acknowledgement:Medical writing and editorial support was provided by Julie B. Stimmel, PhD, Sinead Stewart, and Rosie Henderson, of Onyx (a Prime Global Agency), funded by Pfizer, Inc. and Astellas Pharma Inc., the co-developers of enzalutamide.Submission Category:prostate cancer.Sub-category:Advanced (including drug therapy).

Topics: Androgen Antagonists; Antineoplastic Agents; Humans; Leuprolide; Male; Pharmaceutical Preparations; Prostate-Specific Antigen; Prostatic Neoplasms

Early treatment intensification with neoadjuvant therapy may improve outcomes in patients with high-risk, localized prostate cancer treated with radical prostatectomy. Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to radical prostatectomy in patients with localized, high-risk prostate cancer.. This open-label, multicenter, phase II trial randomized men with clinically localized, D'Amico high-risk prostate cancer to neoadjuvant abiraterone acetate (1,000 mg/day) and leuprolide acetate (22.5 mg every 3 months) with or without cabazitaxel (25 mg/m2) prior to radical prostatectomy. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile.. The per-protocol population consisted of 70 patients [cabazitaxel arm (Arm A): 37, no cabazitaxel arm (Arm B): 33]. Median patient age and prostate-specific antigen levels were 63.5 years [interquartile range (IQR), 58.0-68.0] and 21.9 ng/mL (IQR, 14.6-42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in arms A and B, respectively (P = 0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in arms A and B, respectively (P = 0.66). Patients with ≤ 25% total biopsy cores positive had increased odds of pCR/MRD (P = 0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% vs. 62.0%, P = 0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (P = 0.078).. Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to radical prostatectomy did not improve pCR/MRD in clinically localized, high-risk prostate cancer.

Topics: Abiraterone Acetate; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

Cardiovascular (CV) events are the leading cause of death in prostate cancer. Men with prostate cancer are likely to have CV risk factors and use CV-related concomitant medications. In the phase 3 HERO study, a 54% lower incidence of major adverse cardiac events was reported in men treated with the oral gonadotropin-releasing hormone (GnRH) receptor antagonist, relugolix, vs leuprolide. Herein, we characterize the impact of concomitant CV therapies on efficacy and safety in the HERO study.. In HERO, 930 men with advanced prostate cancer (APC) were randomized 2:1 and treated with relugolix (120 mg orally once daily; after single 360 mg loading dose) or leuprolide (injections every 3 months) for 48 weeks. Subgroups analyzed included men who received antihypertensives, antithrombotics, or lipid-modifying therapies (LMAs), as well as the most common drug classes (> 10%) and single most common agent within each class. Assessments included sustained testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks and safety.. Antihypertensives, antithrombotics, and LMAs were utilized by 52.7%, 39.1%, and 39.6% of men in HERO, respectively. In the main subgroups, point estimates for sustained castration rates were generally consistent with overall estimates of relugolix and leuprolide observed in the overall population. Sustained castration rates were also mostly consistent for men taking the most common drug classes and individual agents in each class (losartan [n = 103]: relugolix, 95.4% vs leuprolide, 80.6%; amlodipine [n = 229]: 97.2% vs 85.5%; metoprolol [n = 88]: 95.7% vs 86.9%; acetylsalicylic acid [n = 259]: 97.0% vs 92.1%; clopidogrel [n = 43]: 96.4% vs 86.7%; simvastatin [n = 78]: 98.0% vs 87.3%). Incidence and types of adverse events (AEs) among men who received these medications were mostly consistent with overall population results, with some increases in grade ≥ 3 and fatal AEs.. Relugolix suppressed testosterone and was generally well tolerated when given with concomitant CV agents.. Clinical Trial ID NCT03085095.. Data presented at 15th Annual Genitourinary Cancers Symposium; February 17-19, 2022, San Francisco, CA, USA [Abstract 101, Poster board E11]. The published abstract from this presentation can be found at https://ascopubs.org/doi/10.1200/JCO.2022.40.6_suppl.101 .

Topics: Antihypertensive Agents; Antineoplastic Agents, Hormonal; Fibrinolytic Agents; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms; Testosterone

Patients with prostate cancer who have high-risk biochemical recurrence have an increased risk of progression. The efficacy and safety of enzalutamide plus androgen-deprivation therapy and enzalutamide monotherapy, as compared with androgen-deprivation therapy alone, are unknown.. In this phase 3 trial, we enrolled patients with prostate cancer who had high-risk biochemical recurrence with a prostate-specific antigen doubling time of 9 months or less. Patients were randomly assigned, in a 1:1:1 ratio, to receive enzalutamide (160 mg) daily plus leuprolide every 12 weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or enzalutamide monotherapy (monotherapy group). The primary end point was metastasis-free survival, as assessed by blinded independent central review, in the combination group as compared with the leuprolide-alone group. A key secondary end point was metastasis-free survival in the monotherapy group as compared with the leuprolide-alone group. Other secondary end points were patient-reported outcomes and safety.. A total of 1068 patients underwent randomization: 355 were assigned to the combination group, 358 to the leuprolide-alone group, and 355 to the monotherapy group. The patients were followed for a median of 60.7 months. At 5 years, metastasis-free survival was 87.3% (95% confidence interval [CI], 83.0 to 90.6) in the combination group, 71.4% (95% CI, 65.7 to 76.3) in the leuprolide-alone group, and 80.0% (95% CI, 75.0 to 84.1) in the monotherapy group. With respect to metastasis-free survival, enzalutamide plus leuprolide was superior to leuprolide alone (hazard ratio for metastasis or death, 0.42; 95% CI, 0.30 to 0.61; P<0.001); enzalutamide monotherapy was also superior to leuprolide alone (hazard ratio for metastasis or death, 0.63; 95% CI, 0.46 to 0.87; P = 0.005). No new safety signals were observed, with no substantial between-group differences in quality-of-life measures.. In patients with prostate cancer with high-risk biochemical recurrence, enzalutamide plus leuprolide was superior to leuprolide alone with respect to metastasis-free survival; enzalutamide monotherapy was also superior to leuprolide alone. The safety profile of enzalutamide was consistent with that shown in previous clinical studies, with no apparent detrimental effect on quality of life. (Funded by Pfizer and Astellas Pharma; EMBARK ClinicalTrials.gov number, NCT02319837.).

Topics: Androgen Antagonists; Antineoplastic Agents; Drug Therapy, Combination; Humans; Leuprolide; Male; Neoplasm Recurrence, Local; Nitriles; Prostatic Neoplasms; Quality of Life

Pharmacobiological behavior differs between gonadotropin-releasing hormone (GnRH) antagonists and GnRH agonists. However, reliable evidence clarifying the difference between them is limited.. We aimed to elucidate the difference in recovery profile between GnRH antagonist (degarelix) and GnRH agonist (leuprorelin acetate or goserelin acetate) as short-term (12 weeks) neoadjuvant androgen deprivation therapy (ADT) prior to 125I-transperineal prostate brachytherapy (TPPB) for localized prostate cancer.. This study was initially designed as a single-center, prospective, open-label, randomized controlled trial. The primary endpoint was a serum testosterone level above the castration range (>50 ng/dl) after the cessation of 12-week neoadjuvant ADT (GnRH antagonist or GnRH agonists). All patients underwent 12 weeks of neoadjuvant ADT. The recovery profiles of hormones, prostate-specific antigen, total prostate volume (TPV), bone mineral density, and quality of life scores were investigated.. Testosterone recovery duration after the last injection was significantly longer in the GnRH antagonist arm than in the GnRH agonist arm (median, 27.3 vs. 4.8 weeks, p < 0.001). The serum levels of luteinizing hormone and follicle-stimulating hormone in the GnRH antagonist arm also remained significantly lower than those in the GnRH agonist arm between 16 and 24 weeks (p < 0.01). Meanwhile, reduction in TPV at the time of TPPB was comparable between both arms (p = 0.128). There were also no significant between-arm differences in the International Prostate Symptom Score and the International Index of Erectile Function scores.. The recovery patterns of hormonal profiles after short-term (12 weeks) neoadjuvant ADT differ between GnRH antagonists and GnRH agonists. The choice between these drugs matters and may have a clinical impact depending on the primary objective of ADT.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Brachytherapy; Gonadotropin-Releasing Hormone; Goserelin; Humans; Iodine Radioisotopes; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Oligopeptides; Orchiectomy; Organ Size; Prospective Studies; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Testosterone; Time Factors; Treatment Outcome; Withholding Treatment

The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains controversial.. In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomly assigned 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (composite of death, myocardial infarction, or stroke) through 12 months.. PRONOUNCE (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease) is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely because of the smaller than planned number of participants and events, and no difference in major adverse cardiovascular events at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02663908.

Topics: Aged; Humans; Leuprolide; Male; Oligopeptides; Prospective Studies; Prostatic Neoplasms

Intermittent androgen deprivation therapy with gonadotropin-releasing-hormone (GnRH) agonists can prevent or delay disease progression and development of castration resistant prostate cancer for subpopulations of prostate cancer patients. It may also reduce risk and severity of side effects associated with chemical castration in prostate cancer (PCa) patients. One of the earliest comprehensively documented clinical trials on this was reported in a Canadian patient population treated with leuprorelin preceded by a lead-in with cyproterone acetate. A systems-based mixed effect analysis of testosterone response in active and recovery phases allows inference of new information from this patient population. Efficacy of androgen deprivation therapy is presumed to depend on a treshold value for testosterone at the nadir, below which no additional beneficial effects on PSA reponse can be expected, and occurance of testosterone breakthroughs during active therapy. The present analysis results in a mixed effect model, incorporating GnRH receptor activation, testosterone turnover and feedback mechanisms, describing and predicting testosterone inhibition under intermittent androgen deprivation therapy on the individual and population level, during multiple years of therapy. Testosterone levels in these patients decline over time with an estimated first order rate constant of 0.083 year

Topics: Aged; Androgen Antagonists; Cyproterone Acetate; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Outcome

This multicenter randomized phase 2 trial investigates the impact of intense androgen deprivation on radical prostatectomy pathologic response and radiographic and tissue biomarkers in localized prostate cancer (NCT02903368).. Eligible patients had a Gleason score ≥4+3=7, prostate specific antigen >20 ng/mL or T3 disease and lymph nodes <20 mm. In Part 1, patients were randomized 1:1 to apalutamide, abiraterone acetate, prednisone and leuprolide (AAPL) or abiraterone, prednisone, leuprolide (APL) for 6 cycles (1 cycle=28 days) followed by radical prostatectomy. Surgical specimens underwent central review. The primary end point was the rate of pathologic complete response or minimum residual disease (minimum residual disease, tumor ≤5 mm). Secondary end points included prostate specific antigen response, positive margin rate and safety. Magnetic resonance imaging and tissue biomarkers of pathologic outcomes were explored.. The study enrolled 118 patients at 4 sites. Median age was 61 years and 94% of patients had high-risk disease. The combined pathologic complete response or minimum residual disease rate was 22% in the AAPL arm and 20% in the APL arm (difference: 1.5%; 1-sided 95% CI -11%, 14%; 1-sided p=0.4). No new safety signals were observed. There was low concordance and correlation between posttherapy magnetic resonance imaging assessed and pathologically assessed tumor volume. PTEN-loss, ERG positivity and presence of intraductal carcinoma were associated with extensive residual tumor.. Intense neoadjuvant hormone therapy in high-risk prostate cancer resulted in favorable pathologic responses (tumor

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Drug Therapy, Combination; Humans; Leuprolide; Male; Middle Aged; Prednisone; Preoperative Period; Prostatectomy; Prostatic Neoplasms; Risk Assessment; Thiohydantoins; Treatment Outcome

Limited data from controlled clinical trials are available for men who experience biochemical recurrence after definitive therapy for prostate cancer. In the absence of overt metastases, patients with non-metastatic castration-sensitive prostate cancer (nmCSPC) often receive androgen deprivation therapy (ADT). There is no standard-of-care consensus on optimal ADT timing, although most men are treated prior to metastases, especially those with high-risk features (Gleason score 8-10 or prostate-specific antigen doubling time (PSADT) <9-12 months). Given data that ADT plus novel hormonal agents improve survival in men with metastatic CSPC, there is a desire to evaluate these agents earlier in the disease course. The main objective of EMBARK is the comparative assessment of enzalutamide plus leuprolide (luteinising hormone-releasing hormone agonist (LHRHa)) or enzalutamide monotherapy versus monotherapy LHRHa to improve metastasis-free survival (MFS) in patients with high-risk nmCSPC PSA recurrence after definitive therapy.. EMBARK is a randomised, phase 3 study of high-risk patients with nmCSPC, a PSADT of ≤9 months and a screening PSA of ≥2 ng/mL above the nadir after radiotherapy (RT) or ≥1 ng/mL after radical prostatectomy (RP) with or without postoperative RT. Men (n=1050) are randomised 1:1:1 to enzalutamide 160 mg/day plus LHRHa or placebo plus LHRHa (double-blind arms) or enzalutamide monotherapy (open-label arm). Treatment is suspended at week 37 if PSA concentrations are <0.2 ng/mL and reinstated if levels rise to ≥2.0 ng/mL with RP or ≥5.0 ng/mL without RP. Patients with PSA ≥0.2 ng/mL at week 37 continue until treatment discontinuation criteria are met. The primary endpoint is MFS comparing enzalutamide plus LHRHa versus placebo plus LHRHa.. The study is conducted under the guiding principles of the World Medical Association Declaration of Helsinki. The results will be disseminated at research conferences and in peer-reviewed journals.. NCT02319837.

Topics: Androgen Antagonists; Benzamides; Humans; Leuprolide; Male; Neoplasm Recurrence, Local; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms

In a mouse model, degarelix generated the least metabolic consequences via low follicle-stimulating hormone (FSH) levels compared with orchiectomy and leuprolide after 4 months of androgen deprivation therapy (ADT). Here, we comparatively investigated the influence of ADT with degarelix or leuprolide on the development of metabolic syndrome in patients with prostate cancer (PCa).. Patients with hormone-naive PCa were recruited. Eligible patients were randomized (1:1) to monthly degarelix or monthly leuprolide for 6 months. Key trial variables were monitored monthly. The primary endpoint was changes in fasting blood sugar (FBS). Secondary endpoints were changes in body weight, abdominal circumference, lipid profiles, and hemoglobin A1c (HbA1c) and FSH levels. Computed tomography was performed to measure subcutaneous and visceral fat areas before and after 6 months of ADT. Data were analyzed using the χ. From the 100 patients registered, 85 completed the trial (degarelix: 40 patients; leuprolide: 45 patients). Mean increases in FBS did not differ between the two arms. Similarly, there were no differences between the arms in mean increases in body weight, abdominal circumference, lipid profiles, HbA1c, or subcutaneous and visceral fat areas. Follicle-stimulating hormone levels were significantly lower in the degarelix arm than in the leuprolide arm (p < 0.05).. Lipid and glucose metabolism did not differ significantly between the arms, while FSH levels were significantly lower in the degarelix arm.

Topics: Aged; Aged, 80 and over; Anilides; Antineoplastic Combined Chemotherapy Protocols; Humans; Leuprolide; Male; Metabolic Syndrome; Middle Aged; Nitriles; Oligopeptides; Prospective Studies; Prostatic Neoplasms; Tosyl Compounds

Immunosuppressive cytokines have the potential to promote prostate cancer progression. Assessing their longitudinal changes may implicate mechanisms of progression, treatment resistance, and suggest new therapeutic targets.. Thirty-seven men with biochemically recurrent (BCR) prostate cancer who received 6 months of androgen deprivation therapy (ADT) and were monitored until the time to prostate-specific antigen progression (TTPP) were identified from a completed phase III trial (NCT00020085). Serum samples were archived at baseline, 3 months after ADT, and at TTPP. Cytokine concentrations were quantified using a 36-parameter electrochemiluminescence assay. The Wilcoxon signed-rank sum test was used to compare observations between time points. Kaplan-Meier analysis was used to calculate TTPP dichotomized by cytokine values above or below the median. Pearson's rank correlation coefficient was used to compare continuous variables.. Median TTPP was 399 days (range, 114-1641). Median prostate-specific antigen (PSA) at baseline and progression were 8.5 and 5.3 ng/mL, respectively. Twenty-three patients (62%) achieved undetectable PSA with ADT. Castrate levels of testosterone (<50 ng/dL) after 3 months of ADT occurred in 35 patients (95%). TNF-α (P = .002), IL-23 (P = .002), and CXCL10 (P = .001) significantly increased from baseline to post ADT. Certain cytokines correlated longitudinally: TNF-α correlated with IL-23 (r = .72; P < .001) and IL-8 (r = .59; P < .001) from baseline to post ADT and to PSA progression. Neutrophil-to-lymphocyte ratio correlated with IL-27 (r = .57; P < .001) and MIP-3α (r = .56; P < .001). Patients with a detectable PSA after ADT had elevated levels of IL-6 (P = .049) and IL-8 (P = .013) at PSA progression as compared with those with an undetectable PSA. There was a trend toward shorter TTPP in patients with TNF-α levels above the median (P = .042).. Several innate cytokines were associated with biochemically recurrent prostate cancer.

Topics: Aged; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Cohort Studies; Cytokines; Disease Progression; Double-Blind Method; Goserelin; Humans; Immune Tolerance; Immunity, Innate; Immunosuppressive Agents; Kallikreins; Leuprolide; Longitudinal Studies; Male; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms; Thalidomide

Injectable luteinizing hormone-releasing hormone agonists (e.g., leuprolide) are the standard agents for achieving androgen deprivation for prostate cancer despite the initial testosterone surge and delay in therapeutic effect. The efficacy and safety of relugolix, an oral gonadotropin-releasing hormone antagonist, as compared with those of leuprolide are not known.. In this phase 3 trial, we randomly assigned patients with advanced prostate cancer, in a 2:1 ratio, to receive relugolix (120 mg orally once daily) or leuprolide (injections every 3 months) for 48 weeks. The primary end point was sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks. Secondary end points included noninferiority with respect to the primary end point, castrate levels of testosterone on day 4, and profound castrate levels (<20 ng per deciliter) on day 15. Testosterone recovery was evaluated in a subgroup of patients.. A total of 622 patients received relugolix and 308 received leuprolide. Of men who received relugolix, 96.7% (95% confidence interval [CI], 94.9 to 97.9) maintained castration through 48 weeks, as compared with 88.8% (95% CI, 84.6 to 91.8) of men receiving leuprolide. The difference of 7.9 percentage points (95% CI, 4.1 to 11.8) showed noninferiority and superiority of relugolix (P<0.001 for superiority). All other key secondary end points showed superiority of relugolix over leuprolide (P<0.001). The percentage of patients with castrate levels of testosterone on day 4 was 56.0% with relugolix and 0% with leuprolide. In the subgroup of 184 patients followed for testosterone recovery, the mean testosterone levels 90 days after treatment discontinuation were 288.4 ng per deciliter in the relugolix group and 58.6 ng per deciliter in the leuprolide group. Among all the patients, the incidence of major adverse cardiovascular events was 2.9% in the relugolix group and 6.2% in the leuprolide group (hazard ratio, 0.46; 95% CI, 0.24 to 0.88).. In this trial involving men with advanced prostate cancer, relugolix achieved rapid, sustained suppression of testosterone levels that was superior to that with leuprolide, with a 54% lower risk of major adverse cardiovascular events. (Funded by Myovant Sciences; HERO ClinicalTrials.gov number, NCT03085095.).

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Cardiovascular Diseases; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Testosterone

To determine the safety, efficacy and pharmacokinetic (PK) profile of a pre-mixed depot formulation of leuprolide mesylate subcutaneous injectable suspension (LMIS) 50 mg for up to 1 year of treatment for subjects with advanced prostate cancer.. In this open-label, multicenter study, prostate cancer patients with indication for androgen ablation therapy received two subcutaneous injection of LMIS 50 mg 6 months apart and were followed for an additional 6 months. Two efficacy primary end points were the percentage of subjects with a serum testosterone level ≤ 50 ng/dL by Day 28 as well as the percentage of subjects with similar testosterone suppression from Day 28 to Day 336.. Of the 137 enrolled subjects, 15 (10.9%) subjects did not complete the study, including 5 subjects who terminated early due to an adverse event. By Day 28, 98.5% (95% confidence interval 94.8-99.8) of the subjects achieved a castrate testosterone level. At the end of the study, 97% and 95.9% of the subjects had serum testosterone level ≤ 50 ng/dL and ≤ 20 ng/dL, respectively. LMIS 50 mg significantly reduced serum prostate-specific antigen levels after its first injection and this PSA declination effect remained until the end of the study. No statistically significant change was observed in worsening bone pain or urinary symptom assessments during the study. Hot flush (48.9%) and hypertension (14.6%) were the two most common adverse events reported.. LMIS 50 mg, administered at 6-month intervals, effectively suppressed serum testosterone level, and demonstrated a consistent safety profile.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Injections, Subcutaneous; Leuprolide; Male; Mesylates; Middle Aged; Neoplasm Staging; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Outcome

Patients with locally advanced prostate cancer have an increased risk of cancer recurrence and mortality. In this phase II trial, we evaluate neoadjuvant enzalutamide and leuprolide (EL) with or without abiraterone and prednisone (ELAP) before radical prostatectomy (RP) in men with locally advanced prostate cancer.. Eligible patients had a biopsy Gleason score of 4 + 3 = 7 or greater, prostate-specific antigen (PSA) greater than 20 ng/mL, or T3 disease (by prostate magnetic resonance imaging). Lymph nodes were required to be smaller than 20 mm. Patients were randomly assigned 2:1 to ELAP or EL for 24 weeks followed by RP. All specimens underwent central pathology review. The primary end point was pathologic complete response or minimal residual disease (residual tumor ≤ 5 mm). Secondary end points were PSA, surgical staging, positive margins, and safety. Biomarkers associated with pathologic outcomes were explored.. Seventy-five patients were enrolled at four centers. Most patients had high-risk disease by National Comprehensive Cancer Network criteria (n = 65; 87%). The pathologic complete response or minimal residual disease rate was 30% (n = 15 of 50) in ELAP-treated patients and 16% (n = four of 25) in EL-treated patients (two-sided P = .263). Rates of ypT3 disease, positive margins, and positive lymph nodes were similar between arms. Treatment was well-tolerated. Residual tumors in the two arms showed comparable levels of ERG, PTEN, androgen receptor PSA, and glucocorticoid receptor expression. Tumor ERG positivity and PTEN loss were associated with more extensive residual tumors at RP.. Neoadjuvant hormone therapy followed by RP in locally advanced prostate cancer resulted in favorable pathologic responses in some patients, with a trend toward improved pathologic outcomes with ELAP. Longer follow-up is necessary to evaluate the impact of therapy on recurrence rates. The potential association of ERG and PTEN alterations with worse outcomes warrants additional investigation.

Topics: Adenocarcinoma; Adult; Aged; Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Chemotherapy, Adjuvant; Humans; Kallikreins; Leuprolide; Magnetic Resonance Imaging; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Grading; Neoplasm, Residual; Nitriles; Phenylthiohydantoin; Prednisone; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Time Factors; Treatment Outcome; United States

This clinical trial investigated the effectiveness, pharmacokinetic properties, and safety profile of leuprolide acetate 22.5-mg depot, a new 3-month leuprolide depot formulation, as androgen deprivation therapy for patients with prostate cancer.. A Phase III, open-label, multicenter study design for patients with prostate cancer, with patient inclusion assessed by the investigative site as patient's appropriate for androgen deprivation therapy. Patients received 2 separate intramuscular injections of leuprolide acetate 22.5-mg depot for a 3-month depot interval of therapeutic effect. Plasma testosterone concentrations were determined throughout the study. The primary efficacy analysis was the percentage of patients who achieve and maintain castrate testosterone levels (≤50 ng/mL) from days 28-168. Secondary end points included luteinizing hormone, follicle-stimulating hormone, prostate-specific antigen, and safety assessments. A pharmacokinetic study was also conducted in a subset of 30 patients.. All 163 patients enrolled in the study received at least 1 dose of study drug; 162 of them were fully evaluable and 151 completed the study. Castrate levels of testosterone were achieved and maintained from days 28-168 in 96.8% (95% CI, 92.5%-98.7%) of patients. Five patients presented with sporadic testosterone levels >50 ng/dL. By day 28, of the 161 patients, 150 (99.4%) had achieved castrate levels, and 127 (78.9%) had achieved testosterone concentrations ≤20 ng/dL. At study end, 149 of 151 patients (98.7%) patients achieved castrate testosterone levels, with 142 of 151 (94.0%) having testosterone levels ≤20 ng/dL. At study end, mean luteinizing hormone and follicle-stimulating hormone concentrations had decreased from baseline to below the lower limit of quantitation and below baseline levels, respectively, whereas mean serum prostate-specific antigen was reduced by 94.7% from baseline. Most patients (>96%) had no change in their World Health Organization/Eastern Cooperative Oncology Group score, whereby 84.0% of patients had a baseline score of 0. Bone pain, urinary pain, and urinary symptoms were infrequent and remained so throughout the study. After administration, leuprolide concentrations increased rapidly. The peak was followed by a decline up to day 28, maintaining sustained drug levels until the following dose on day 84. The most common related treatment-emergent adverse events, detected in >5% of patients, were hot flushes, fatigue, and injection site pain reported by 77.3%, 9.8%, and 9.2% of patients, respectively.. Leuprolide acetate 22.5-mg depot was effective in achieving and maintaining testosterone suppression. Safety and tolerability profiles were consistent with established profiles of androgen deprivation therapy. Clinical Trials.gov identifier: NCT01415960.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Follicle Stimulating Hormone; Humans; Kallikreins; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

The treatment paradigm for metastatic hormone-sensitive prostate cancer (mHSPC) patients is evolving. PET/CT now offers improved sensitivity and accuracy in staging. Recent randomized trial data supports escalated hormone therapy, local primary tumor therapy, and metastasis-directed therapy. The impact of combining such therapies into a multimodal approach is unknown. This Phase II single-arm clinical trial sponsored and funded by Veterans Affairs combines local, metastasis-directed, and systemic therapies to durably render patients free of detectable disease off active therapy.. Patients with newly-diagnosed M1a/b prostate cancer (PSMA PET/CT staging is permitted) and 1-5 radiographically visible metastases (excluding pelvic lymph nodes) are undergoing local treatment with radical prostatectomy, limited duration systemic therapy for a total of six months (leuprolide, abiraterone acetate with prednisone, and apalutamide), metastasis-directed stereotactic body radiotherapy (SBRT), and post-operative fractionated radiotherapy if pT ≥ 3a, N1, or positive margins are present. The primary endpoint is the percent of patients achieving a serum PSA of < 0.05 ng/mL six months after recovery of serum testosterone ≥150 ng/dL. Secondary endpoints include time to biochemical progression, time to radiographic progression, time to initiation of alternative antineoplastic therapy, prostate cancer specific survival, health related quality-of-life, safety and tolerability.. To our knowledge, this is the first trial that tests a comprehensive systemic and tumor directed therapeutic strategy for patients with newly diagnosed oligometastatic prostate cancer. This trial, and others like it, represent the critical first step towards curative intent therapy for a patient population where palliation has been the norm.. Clinicaltrials.gov identifier: NCT03298087 (registration date: September 29, 2017).

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Combined Modality Therapy; Humans; Leuprolide; Male; Middle Aged; Neoplasm Micrometastasis; Prednisone; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Radiosurgery; Thiohydantoins; Treatment Outcome; Veterans; Young Adult

The NRG/RTOG 9413 study showed that whole pelvic radiotherapy (WPRT) plus neoadjuvant hormonal therapy (NHT) improved progression-free survival in patients with intermediate-risk or high-risk localised prostate cancer compared with prostate only radiotherapy (PORT) plus NHT, WPRT plus adjuvant hormonal therapy (AHT), and PORT plus AHT. We provide a long-term update after 10 years of follow-up of the primary endpoint (progression-free survival) and report on the late toxicities of treatment.. The trial was designed as a 2 × 2 factorial study with hormonal sequencing as one stratification factor and radiation field as the other factor and tested whether NHT improved progression-free survival versus AHT, and NHT plus WPRT versus NHT plus PORT. Eligible patients had histologically confirmed, clinically localised adenocarcinoma of the prostate, an estimated risk of lymph node involvement of more than 15% and a Karnofsky performance status of more than 70, with no age limitations. Patients were randomly assigned (1:1:1:1) by permuted block randomisation to receive either NHT 2 months before and during WPRT followed by a prostate boost to 70 Gy (NHT plus WPRT group), NHT 2 months before and during PORT to 70 Gy (NHT plus PORT group), WPRT followed by 4 months of AHT (WPRT plus AHT group), or PORT followed by 4 months of AHT (PORT plus AHT group). Hormonal therapy was combined androgen suppression, consisting of goserelin acetate 3·6 mg once a month subcutaneously or leuprolide acetate 7·5 mg once a month intramuscularly, and flutamide 250 mg twice a day orally for 4 months. Randomisation was stratified by T stage, Gleason Score, and prostate-specific antigen concentration. NHT was given 2 months before radiotherapy and was continued until radiotherapy completion; AHT was given at the completion of radiotherapy for 4 months. The primary endpoint progression-free survival was analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00769548. The trial has been terminated to additional follow-up collection and this is the final analysis for this trial.. Between April 1, 1995, and June 1, 1999, 1322 patients were enrolled from 53 centres and randomly assigned to the four treatment groups. With a median follow-up of 8·8 years (IQR 5·07-13·84) for all patients and 14·8 years (7·18-17·4) for living patients (n=346), progression-free survival across all timepoints continued to differ significantly across the four treatment groups (p=0·002). The 10-year estimates of progression-free survival were 28·4% (95% CI 23·3-33·6) in the NHT plus WPRT group, 23·5% (18·7-28·3) in the NHT plus PORT group, 19·4% (14·9-24·0) in the WPRT plus AHT group, and 30·2% (25·0-35·4) in the PORT plus AHT group. Bladder toxicity was the most common grade 3 or worse late toxicity, affecting 18 (6%) of 316 patients in the NHT plus WPRT group, 17 (5%) of 313 in the NHT plus PORT group, 22 (7%) of 317 in the WPRT plus AHT group, and 14 (4%) of 315 in the PORT plus AHT group. Late grade 3 or worse gastrointestinal adverse events occurred in 22 (7%) of 316 patients in the NHT plus WPRT group, five (2%) of 313 in the NHT plus PORT group, ten (3%) of 317 in the WPRT plus AHT group, and seven (2%) of 315 in the PORT plus AHT group.. In this cohort of patients with intermediate-risk and high-risk localised prostate cancer, NHT plus WPRT improved progression-free survival compared with NHT plus PORT and WPRT plus AHT at long-term follow-up albeit increased risk of grade 3 or worse intestinal toxicity. Interactions between radiotherapy and hormonal therapy suggests that WPRT should be avoided without NHT.. National Cancer Institute.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Canada; Chemoradiotherapy; Dose Fractionation, Radiation; Drug Administration Schedule; Flutamide; Goserelin; Humans; Kallikreins; Leuprolide; Male; Neoplasm Grading; Neoplasm Staging; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms; Time Factors; United States

Lower serum testosterone levels correlate with improved cause specific survival and longer time to progression in year 1 of continuous androgen deprivation in men with prostate cancer. ICELAND was a large European study demonstrating the efficacy of leuprorelin (Eligard®) during continuous androgen deprivation. In this post hoc analysis we investigated serum testosterone levels within year 1 of continuous androgen deprivation to determine survival and time to progression.. In ICELAND (ClinicalTrials.gov NCT00378690) patients with locally advanced or relapsing nonmetastatic prostate cancer and with prostate specific antigen 1 ng/ml or less following 6-month induction with leuprorelin 3-month depot 22.5 mg (plus bicalutamide 50 mg per day for 1 month) were randomized 1:1 to continuous androgen deprivation (361) or intermittent androgen deprivation (340) with leuprorelin for 36 months. Patients receiving continuous androgen deprivation were stratified by minimum, median and maximum testosterone levels during year 1 of therapy into 20 or less, greater than 20 to 50 and greater than 50 ng/dl subgroups. Cause specific survival and time to prostate specific antigen (castrate resistant prostate cancer) progression were analyzed.. A total of 90.1%, 83.5% and 74.5% of patients receiving continuous androgen deprivation achieved minimum, median and maximum serum testosterone levels of 20 ng/dl or less, respectively. Cause specific survival rates and time to prostate specific antigen progression did not differ among the testosterone subgroups.. In patients receiving continuous androgen deprivation cause specific survival and time to prostate specific antigen progression did not differ according to testosterone levels in year 1 of therapy. This finding may in part be due to the induction period and the effectiveness of leuprorelin in lowering testosterone.

Topics: Aged; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Leuprolide; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Tosyl Compounds; Treatment Outcome

Neoadjuvant androgen deprivation therapy (NADT) is one strategy for the treatment of early-stage prostate cancer; however, the long-term outcomes of NADT with radical prostatectomy including biochemical failure-free survival are not promising. One proposed mechanism is incomplete androgen ablation. In this study, we aimed to evaluate the efficiency of serum hydroxy-androgen suppression in patients with localized high-risk prostate cancer under NADT (leuprolide acetate plus abiraterone acetate and prednisone) and interrogate the primary sources of circulating hydroxy-androgens using our recently described stable isotope dilution liquid chromatography mass spectrometric method. For the first time, three androgen diols including 5-androstene-3β,17β-diol (5-adiol), 5α-androstane-3α,17β-diol (3α-adiol), 5α-androstane-3β,17β-diol (3β-adiol), the glucuronide or sulfate conjugate of 5-adiol and 3α-adiol were measured and observed to be dramatically reduced after NADT. By comparing patients that took leuprolide acetate alone vs leuprolide acetate plus abiraterone acetate and prednisone, we were able to distinguish the primary sources of these androgens and their conjugates as being of either testicular or adrenal in origin. We find that testosterone, 5α-dihydrotestosterone (DHT), 3α-adiol and 3β-adiol were predominately of testicular origin. By contrast, dehydroepiandrosterone (DHEA), epi-androsterone (epi-AST) and their conjugates, 5-adiol sulfate and glucuronide were predominately of adrenal origin. Our findings also show that NADT failed to completely suppress DHEA-sulfate levels and that two unappreciated sources of intratumoral androgens that were not suppressed by leuprolide acetate alone were 5-adiol-sulfate and epi-AST-sulfate of adrenal origin.

Topics: Abiraterone Acetate; Adrenal Glands; Androgens; Antineoplastic Agents, Hormonal; Glucuronides; Humans; Leuprolide; Male; Neoadjuvant Therapy; Prednisone; Prostatic Neoplasms; Sulfates; Testis; Testosterone; Testosterone Congeners

The optimal treatment for high-risk prostate cancer (PCa) remains to be established. We previously reported favorable, biochemical recurrence-free survival in high-risk PCa patients treated with a neoadjuvant gonadotropin-releasing hormone agonist or antagonist and estramustine phosphate (EMP) (chemohormonal therapy; CHT) followed by radical prostatectomy (RP). We conducted a retrospective study to elucidate the clinical benefit of neoadjuvant CHT for high-risk PCa patients.. We reviewed the clinical and pathological records of 1254 PCa patients who underwent RP and bilateral pelvic lymphadenectomy between July 1996 and April 2016 at Hirosaki University. According to the D'Amico risk classification, we focused on 613 patients in the high-risk group. The high-risk PCa patients were further divided into two groups based on whether the patients received neoadjuvant CHT before RP (EMP group) or not (non-EMP group). The endpoint was overall survival (OS) after surgery.. The 5- and 10-year OS rates were 98.5 and 92.6%, respectively. The 10-year OS rate in the EMP group was significantly higher compared to the non-EMP group (P = 0.021). In multivariate analysis, administration of neoadjuvant CHT, lymph node involvement, and castration-resistant PCa status were significantly associated with OS.. RP with neoadjuvant CHT using EMP for high-risk PCa patients provided excellent long-term OS.

Topics: Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Estramustine; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Lymph Node Excision; Male; Middle Aged; Multivariate Analysis; Neoadjuvant Therapy; Prostatectomy; Prostatic Neoplasms; Retrospective Studies; Survival Rate

To assess late toxicity and outcomes in high-risk prostate cancer patients treated with hypofractionated radiation treatment with androgen suppression therapy.. Sixty high-risk prostate cancer patients were enrolled. IMRT prescription was 68 Gy/25 fractions (2.7 Gy/fraction) to the prostate and proximal seminal vesicles (SV). The pelvic lymph nodes (PLN) and distal SV concurrently received 45 Gy/25 fractions (1.8 Gy/fraction). The patients were treated with helical TomoTherapy-based IMRT and underwent daily megavoltage CT image-guided verification before each treatment. RTOG Toxicity scores were recorded for a 5-year period.. Sixty patients completed RT with median follow-up of 63 months (range, 7 to 80 mo).At 5 years follow-up timepoint: Grade (G)2 and G3 late genitourinary toxicity was experienced in 7 (17.0%) and 1 (2.44%), respectively; gastrointestinal G2 as highest toxicity recorded in only 1 (2.44%) patient. There was no G3 gastrointestinal toxicity recorded at this timepoint.With 63-month median follow-up (mean of 65.41±1.72 mo), the 5-year overall survival was 86.67%; 5 years freedom from biochemical failure was 91.67% and freedom from clinical failure was 96.67%.. Dose escalation and hypofractionated radiation treatment with IMRT treating the prostate and proximal SV concurrently with the pelvic lymph nodes and distal SV and long-term androgen suppression therapy is well tolerated with respect to acute and late toxicity with 5-year actuarial overall survival 86.67%, freedom from biochemical failure 91.38%, and freedom from clinical failure 96.67%. Longer follow-up will provide more information on 10-year survival outcomes.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Humans; Leuprolide; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Radiation Dose Hypofractionation; Radiotherapy, Intensity-Modulated; Risk Assessment; Time Factors

A 3-month depot formulation of leuprolide acetate (Luphere 3M Depot) with a mean microsphere diameter of 22.3 μm was prepared aseptically by spray-drying glacial acetic acid solution of the drug and polylactic acid, and lyophilization in a d-mannitol solution. The encapsulation efficiency and loading content of the drug in the Luphere 3M Depot were 94.7% and 9.92% (w/w), respectively. The in vitro release of leuprolide from the depot was substantially delayed and the release profile was similar to that of Lucrin Depot (Abbott Korea, Korea). The safety and pharmacokinetics of leuprolide were investigated over a period of 42 days in 20 prostate cancer patients following a subcutaneous injection of Luphere 3M or Lucrin Depot suspensions (leuprolide acetate dose of 11.25 mg) in a multi-center, randomized, single dose, parallel study. Both formulations were well tolerated by the patients and no serious adverse effects were observed during and after the study. No significant differences were observed in the maximum serum concentration (C

Topics: Aged; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Drug Compounding; Humans; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Time Factors

Androgen deprivation therapy (ADT) is associated with coronary heart disease and diabetes in men with prostate cancer (PCa); however, controversy exists regarding ADT and cardiovascular mortality (CVM) with limited data for lower risk disease.. We conducted a hypothesis-generating retrospective analysis to evaluate the relationship between short-course ADT and CVM in patients with clinically localized PCa enrolled in a phase III trial.. A total of 1979 men with clinically localized (T1b-2b, prostate-specific antigen [PSA] <20 ng/ml) PCa enrolled in Radiation Therapy Oncology Group (RTOG) 94-08 from 1994 to 2001. Patients were randomized to radiation therapy (RT) with or without short-course ADT (4 mo of gonadotropin-releasing hormone (GnRH) agonist therapy and antiandrogen). Median follow-up was 9.1 yr for survivors.. The Cox proportional hazards model assessed overall survival. The Fine-Gray proportional hazards model assessed disease-specific survival (DSS) and CVM. Covariates included age, race, weight, baseline cardiovascular disease, baseline diabetes, baseline hypertension, Gleason score, T stage, and PSA.. Short-course ADT improved overall survival and DSS and was not associated with an increased risk of CVM. Overall, 191 cardiovascular-related deaths were observed. At 10 yr, 83 patients (cumulative incidence rate: 10%) receiving RT and ADT versus 95 patients (cumulative incidence rate: 11%) receiving RT alone experienced CVM. The treatment arm was not associated with increased CVM (unadjusted hazard ratio: 1.07; confidence interval, 0.81-1.42; p=0.62). Increased CVM was not observed in patients at low risk of PCa death or at high risk of cardiac-related death.. Data from patients enrolled in RTOG 94-08 support the hypothesis that ADT does not increase CVM risk in men with clinically localized PCa treated with short-course GnRH agonist therapy. These data support ADT use in settings with proven survival benefit.. We investigated the controversial relationship between hormone therapy and cardiovascular mortality in men with prostate cancer (PCa) treated with radiation in a large randomized trial. Our data suggest that hormone therapy does not increase the risk of cardiovascular death in patients with clinically localized PCa and support the use of such therapy in settings with proven survival benefit.

Topics: Aged; Antineoplastic Agents, Hormonal; Cardiovascular Diseases; Flutamide; Follow-Up Studies; Goserelin; Humans; Incidence; Leuprolide; Male; Middle Aged; Proportional Hazards Models; Prostatic Neoplasms; Retrospective Studies; Survival Rate; Time Factors

Intermittent androgen deprivation (IAD) has received increasing attention; however, the current literature is still limited, especially in nonmetastatic prostate cancer (PCa), and the relative efficacy and safety benefits of IAD versus continuous androgen deprivation (CAD) remain unclear.. To add to the knowledge base regarding efficacy and potential benefits, including reduced side effects and improved quality of life (QoL), of IAD versus CAD in patients with nonmetastatic relapsing or locally advanced PCa.. A 42-mo phase 3b open-label randomised study in 933 patients from 20 European countries.. Following a 6-mo induction with leuprorelin acetate (Eligard) 22.5mg 3-mo depot, patients were randomised to CAD or IAD with leuprorelin for 36 mo.. The primary end point was time to prostate-specific antigen (PSA) progression while receiving luteinising hormone-releasing hormone agonist, defined as three consecutive increasing PSA values ≥ 4 ng/ml ≥ 2 wk apart. Secondary end points included PSA progression-free survival (PFS), overall survival (OS), testosterone levels, performance status, and QoL.. A total of 933 patients entered the induction phase; 701 were randomised. The median number of injections administered after randomisation was 12 (range: 1-12) for the CAD group and 3 (range: 1-10) for the IAD group. There were no statistically significant or clinically relevant differences between the groups for time to PSA progression, PSA PFS, OS, mean PSA levels over time, or QoL. A similar number of adverse events was observed in each group; the most common were hot flushes and hypertension. Study limitations include the open-label design and absence of formal testosterone recovery assessment.. IAD and CAD demonstrated similar efficacy, tolerability, and QoL in men with nonmetastatic PCa. The principal benefit of IAD compared with CAD is a potential cost reduction with comparable OS rates. There are no apparent QoL benefits.. This randomised trial showed that both intermittent and continuous hormone therapy had similar efficacy, tolerability, and quality-of-life profiles in patients with relapsing M0 or locally advanced prostate cancer. Intermittent therapy may be a valid option for selected patients.. ClinicalTrials.gov identifier NCT00378690.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Europe; Health Status; Humans; Kallikreins; Kaplan-Meier Estimate; Leuprolide; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Surveys and Questionnaires; Testosterone; Time Factors; Treatment Outcome

Neoadjuvant androgen deprivation therapy (ADT) has been suggested to confer several clinical benefits in patients with prostate cancer (PCa) undergoing transperineal prostate brachytherapy (TPPB). Unlike gonadotropin-releasing hormone (GnRH) receptor agonists, a GnRH antagonist such as degarelix can achieve castrate levels of testosterone without testosterone flare. However, normalization of serum testosterone levels following completion of neoadjuvant ADT in either form of treatment has never been compared in clinical trials.. This is a single-center, open-label, randomized controlled study that will compare the efficacy and safety of degarelix with those of existing GnRH agonists combined with (125)I-TPPB. A total of 56 patients with low/intermediate-risk clinically localized PCa will be enrolled and randomized to one of two treatment groups: the GnRH agonist group and the degarelix group. Patients in the GnRH agonist group will receive leuprorelin acetate or goserelin acetate, and those in the degarelix group will receive the initial dose of 240 mg as 2 subcutaneous injections of 120 mg each, and then 80 mg of maintenance doses every 4 weeks for 12 weeks. Those randomly assigned to the 12-week intervention period will subsequently undergo 48-weeks of follow-up after (125)I-TPPB. The primary endpoint is defined as normalization of serum testosterone levels (>50 ng/dL) following completion of neoadjuvant ADT. All patients will be assessed every 4 weeks for the first 24 weeks, then every 12 weeks for the next 36 weeks after administrations of these drugs. Secondary endpoints are the proportion of normalized serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH), the percent reduction in prostate specific antigen (PSA) compared with pretreatment levels, the percent reduction in total prostate volume (TPV) during neoadjuvant ADT, the percent increase in TPV after (125)I-TPPB, the percent reduction in hemoglobin, serum alkaline phosphatase (ALP), changes in free testosterone and bone mineral content measurement, the proportion of patients who have serum testosterone levels over 50 ng/dL at 12 weeks following completion of neoadjuvant ADT, and the improvement of quality of life (QOL).. The present study will provide additional insight regarding the benefit and potency of degarelix and will examine its potential as a new option for administration in neoadjuvant ADT.. Identification number: UMIN000015519 . Registration date: October 24, 2014.

Topics: Adult; Aged; Androgen Antagonists; Brachytherapy; Chemoradiotherapy; Gonadotropin-Releasing Hormone; Goserelin; Humans; Iodine Radioisotopes; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Oligopeptides; Prostatic Neoplasms; Research Design

This study was conducted to determine the efficacy of switching therapy with a second-line luteinizing hormone-releasing hormone (LHRH) analogue after prostate-specific antigen (PSA) progression for advanced prostate cancer. We enrolled 200 patients, from December 2005 to September 2013, with nodal positive, metastatic prostate cancer or disease progression after definite treatment receiving continuous LHRH analogue therapy with monthly depot leuprorelin(sc) acetate 3.75 mg/vial (LA) or goserelin acetate(sc) 3.6 mg/vial (GA). If the patients had castration-resistant prostate cancer, the treatment choice of switching therapy (from LA to GA or from GA to LA) prior to starting chemotherapy was given. The LH, testosterone level, and PSA change were recorded. The records showed that there were 127 patients receiving LA as initial ADT therapy, whereas the other 73 patients were in GA therapy. A total of 92 patients received LHRH analogue switching therapy (54 patients switched from LA to GA and 38 switched from GA to LA). The effect of LH and testosterone reduction prior to and after switching therapy was comparable between the two groups, and increased PSA level after 3 months of treatment was seen in both groups (median PSA: 15.7-67.7 ng/mL in the LA to GA group; 15.2-71.4 ng/mL in the GA to LA group). This study concluded that switching therapy for patients with PSA progression after ADT has no efficacy of further PSA response.

Topics: Aged; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

A need remains for new therapeutic approaches for men with advanced prostate cancer, particularly earlier in the disease course.. To assess the ability of an oral selective estrogen receptor α agonist (GTx-758) to lower testosterone concentrations compared with leuprolide while minimizing estrogen deficiency-related side effects of androgen-deprivation therapy.. Hormone-naive advanced prostate cancer patients were randomized to oral GTx-758 1000 mg/d, 2000 mg/d, or leuprolide depot.. GTx-758 and leuprolide.. The primary end point was the proportion of patients achieving total testosterone ≤ 50 ng/dl by day 60. Secondary end points included serum free testosterone, prostate-specific antigen (PSA), sex hormone-binding globulin, hot flashes, bone turnover markers, and insulin-like growth factor (IGF)-1 levels.. Of 159 randomized patients, leuprolide reduced total testosterone to ≤ 50 ng/dl in a greater proportion of patients than GTx-758 by day 60 (43.4%, 63.6%, and 88.2% of subjects receiving GTx-758 1000 mg [p<0.001], GTx-758 2000 mg [p=0.004], and leuprolide, respectively). GTx-758 reduced free testosterone and PSA earlier and to a greater degree than leuprolide. GTx-758 led to fewer hot flashes, decreases in bone turnover markers, and alterations in IGF-1 compared with leuprolide. A higher incidence of venous thromboembolic events (VTEs) was seen with GTx-758 (4.1%) compared with leuprolide (0.0%).. Although leuprolide reduced total testosterone to ≤ 50 ng/dl in a greater proportion of patients compared with GTx-758, GTx-758 was superior in lowering free testosterone and PSA. GTx-758 reduced estrogen deficiency side effects of hot flashes, bone loss, and insulin resistance but with a higher incidence of VTEs.. This paper reports findings that leuprolide lowered total testosterone more than GTx-758 but that GTx-758 lowered free testosterone and prostate-specific antigen more than leuprolide. GTx-758 also reduced estrogen deficiency side effects, albeit at a higher rate of vascular events.. Clinicaltrials.gov identifier NCT01615120.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Benzamides; Biomarkers, Tumor; Delayed-Action Preparations; Down-Regulation; Humans; Leuprolide; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prospective Studies; Prostatic Neoplasms; Selective Estrogen Receptor Modulators; Testosterone; Treatment Outcome; United States

Intermittent androgen deprivation (IAD) represents an alternative to continuous AD with quality-of-life benefit and no evidence of inferior overall survival for nonmetastatic prostate cancer. Early markers of prognosis for men treated with IAD have not been described.. Men with nonmetastatic prostate cancer were treated with 9 months of leuprolide and flutamide followed by a variable off-treatment interval; AD was resumed when prostate specific antigen (PSA) reached a prespecified value (1 ng/mL, radical prostatectomy; 4 ng/mL, intact prostate). Cycles were repeated until castration resistance (marking the advent of castration-resistant prostate cancer [CRPC]), defined as 2 PSA rises with testosterone (T) ≤ 50 ng/dL. Kinetics and relationships of PSA and T levels were evaluated, with a focus on times to rise in each level, during the first off-treatment interval. Associations with CRPC and prostate cancer mortality were estimated using Cox proportional hazards models controlling for age and Gleason score.. Each 30-day increase in time to PSA rise was associated with a 21% reduction in the risk of developing CRPC (95% CI, 3%-36%; P = .02). Longer time (≥ 60 days) to PSA rise after rise to T > 50 ng/dL was associated with a 71% reduction in the risk of developing CRPC (95% CI, 92% reduction to 2% inflation; P = .05). Time to first T > 50 ng/dL and PSA doubling time were not prognostic for progression to CRPC. No time interval was prognostic for prostate cancer mortality.. During the first off-treatment interval of IAD, longer times to PSA rise overall and after T > 50 ng/dL were associated with reduced risk of developing CRPC.

Topics: Aged; Aged, 80 and over; Flutamide; Humans; Leuprolide; Male; Middle Aged; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Survival Analysis; Testosterone; Time Factors; Treatment Outcome

To assess total testosterone and prostatic-specific antigen (PSA) kinetics among diverse chemical castrations, advanced-stage prostate cancer patients were randomized into three groups of 20: Group 1, Leuprolide 3.75 mg; Group 2, Leuprolide 7.5 mg; and Group 3, Goserelin 3.6 mg. All groups were treated with monthly application of the respective drugs. The patients' levels of serum total testosterone and PSA were evaluated at two time periods: before the treatment and 3 months after the treatment. Spearman's rank correlation coefficient was utilized to verify the hypothesis of linear correlation between total testosterone and PSA levels. At the beginning the patients' age, stage, grade, PSA, and total testosterone were similar within the three groups, with median age 72, 70, and 70 years in Groups 1, 2, and 3, respectively. Three months after the treatment, patients who received Leuprolide 7.5 mg presented significantly lower median total testosterone levels compared with Goserelin 3.6 mg and Leuprolide 3.75 mg (9.5 ng/dL vs. 20.0 ng/dL vs. 30.0 ng/dL, respectively; p = .0072), while those who received Goserelin 3.6 mg presented significantly lower PSA levels compared with Leuprolide 7.5 mg and Leuprolide 3.75 mg (0.67 vs. 1.86 vs. 2.57, respectively; p = .0067). There was no linear correlation between total testosterone and PSA levels. Overall, regarding castration levels of total testosterone, 28.77% of patients did not obtain levels ≤50 ng/dL and 47.80% did not obtain levels ≤20 ng/dL. There was no correlation between total testosterone and PSA kinetics and no equivalence among different pharmacological castrations.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Dose-Response Relationship, Drug; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

Treatment of localized prostate cancer (PC) is controversial. This is the first randomized study comparing an open surgery procedure (radical prostatectomy) with a combination of high-dose rate brachytherapy (2×10 Gy) and external beam radiotherapy (25×2 Gy) in PC patients in Sweden 1996-2001. The two randomization arms were compared regarding differences in patients-reported outcomes, such as complications and health-related quality of life (HRQoL).. The patients had localized/locally advanced PC, clinical category T1b-T3a, N0, M0 and PSA≤50 ng/ml. All underwent total androgen blockade (six months). Self-reported HRQoL and symptoms including urinary, bowel, and sexual side effects were investigated prospectively before randomization and 12 and 24 months after randomization. A total of 89 patients were randomized and completed the EORTC QLQ C-33 and EORTC PR-25 questionnaires.. Over the study period, there were no discernible differences in HRQoL, or complications between the two groups. Emotional functioning, however, improved statistically significantly over time, whereas Social functioning decreased, and financial difficulties increased. No statistically significant differences in group-by-time interactions were found. The survival rate was 76%. Only eight patients (9%) died of PC.. Open radical prostatectomy and the combined high-dose rate brachytherapy with external beam radiation appeared to be comparable in the measured outcomes. It was not possible to draw any conclusion on the efficacy of the two treatments due to insufficient power of the study.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Cost of Illness; Emotions; Erectile Dysfunction; Fecal Incontinence; Flutamide; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Quality of Life; Radiotherapy Dosage; Social Participation; Surveys and Questionnaires; Survival Rate; Sweden; Urinary Incontinence

To determine whether prolonged androgen suppression (AS) duration before radiotherapy improves survival and disease control in prostate cancer.. One thousand five hundred seventy-nine men with intermediate-risk prostate cancer were randomly assigned to 8 weeks of AS followed by radiotherapy with an additional 8 weeks of concurrent AS (16 weeks total) or to 28 weeks of AS followed by radiotherapy with an additional 8 weeks of AS (36 weeks total). The trial sought primarily to detect a 33% reduction in the hazard of prostate cancer death in the 28-week assignment. Time-to-event end points are reported for up to 10 years of follow-up.. There were no between-group differences in baseline characteristics of 1,489 eligible patients with follow-up. For the 8- and 28-week assignments, 10-year disease-specific survival rates were 95% (95% CI, 93.3% to 97.0%) and 96% (95% CI, 94.6% to 98.0%; hazard ratio [HR], 0.81; P = .45), respectively, and 10-year overall survival rates were 66% (95% CI, 62.0% to 69.9%) and 67% (95% CI, 63.0% to 70.8%; HR, 0.95; P = .62), respectively. For the 8- and 28-week assignments, 10-year cumulative incidences of locoregional progression were 6% (95% CI, 4.3% to 8.0%) and 4% (95% CI, 2.5% to 5.7%; HR, 0.65; P = .07), respectively; 10-year distant metastasis cumulative incidences were 6% (95% CI, 4.0% to 7.7%) and 6% (95% CI, 4.0% to 7.6%; HR, 1.07; P = .80), respectively; and 10-year prostate-specific antigen-based recurrence cumulative incidences were 27% (95% CI, 23.1% to 29.8%) and 27% (95% CI, 23.4% to 30.3%; HR, 0.97; P = .77), respectively.. Extending AS duration from 8 weeks to 28 weeks before radiotherapy did not improve outcomes. A lower than expected prostate cancer death rate reduced ability to detect a between-group difference in disease-specific survival. The schedule of 8 weeks of AS before radiotherapy plus 8 weeks of AS during radiotherapy remains a standard of care in intermediate-risk prostate cancer.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Disease-Free Survival; Flutamide; Follow-Up Studies; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy; Time Factors; Tosyl Compounds; Treatment Outcome

Optimizing androgen suppression may provide better control of localized prostate cancer (PCa). Numerous trials have supported the benefit of combining androgen deprivation therapy with definitive radiation therapy in men with locally advanced or high-grade disease. Addition of abiraterone to luteinizing hormone-releasing hormone agonist (LHRHa) with radiation has not been reported. We examined the safety of this combination as well as its impact on androgen suppression.. A prospective, phase 2 study was conducted in men with localized PCa treated with 6 months of neoadjuvant and concurrent abiraterone with LHRHa and radiation. Duration of adjuvant LHRHa was at the discretion of the treating clinician. Prostate biopsy assays were obtained prior to the start of therapy and prior to radiation. Sera and tissue androgen levels were measured by liquid chromatography-tandem mass spectrometry.. A total of 22 men with intermediate- (n=3) and high-risk PCa (n=19) received study therapy. Sixteen men completed the intended course of abiraterone, and 19 men completed planned radiation to 77.4 to 81 Gy. Radiation to pelvic nodes was administered in 20 men. The following grade 3 toxicities were reported: lymphopenia (14 patients), fatigue (1 patient), transaminitis (2 patients), hypertension (2 patients), and hypokalemia (1 patient). There were no grade 4 toxicities. All 21 men who complied with at least 3 months of abiraterone therapy had a preradiation prostate-specific antigen (PSA) concentration nadir of <0.3 ng/mL. Median levels of tissue androgen downstream of CYP17A were significantly suppressed after treatment with abiraterone, and upstream steroids were increased. At median follow-up of 21 months (range: 3-37 months), only 1 patient (who had discontinued abiraterone at 3 months) had biochemical relapse.. Addition of abiraterone to LHRHa with radiation is safe and achieves effective prostatic androgen suppression. Preliminary analysis of the clinical data is also promising, with excellent PSA nadir and no relapse to date in this high-risk population.

Topics: Androgen Antagonists; Androgens; Androstenes; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Neoadjuvant Therapy; Prednisone; Prospective Studies; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy Dosage; Time Factors

Leuprolide is a gonadotropin-releasing hormone (GnRH) agonist, which inhibits gonadotropin secretion by down-regulating pituitary GnRH receptor when administered continuously at therapeutic doses. The objectives of this analysis were to develop a population model that can describe the pharmacokinetics of the 6-month depot formulation of leuprolide acetate in patients with prostate cancer and to characterize the relationship of leuprolide plasma concentrations and serum testosterone concentrations.. The pharmacokinetic and pharmacodynamic analyses were performed using a non-linear mixed-effect modeling approach. Observations were pooled from studies on healthy male volunteers and prostate cancer patients, who were administered a single 1 mg intravenous dose of immediate-release leuprolide acetate and two intramuscular doses of 45 mg of the depot formulation, respectively. The covariates that were screened for the pharmacokinetic model included body weight, creatinine clearance, liver function markers (total bilirubin, blood urea nitrogen, AST, alanine aminotransferase), age, and body mass index.. A two-compartment model with parallel first- and zero-order absorption processes and a delayed first-order process well-characterized the multi-phasic absorption profile of leuprolide acetate depot formulation. Typical population values of the absorption rate constant of the immediate and delayed processes were estimated to be 0.357 and 0.017 day(-1), respectively, with a mean transit time of 9.5 days. No covariates were significant in this analysis. A semi-mechanistic model, which accounts for down-regulation of the GnRH receptor via an inhibitory maximum effect (E max) model and the stimulatory effect of activated receptors on testosterone levels, adequately described serum testosterone profiles following dosing. The equilibrium dissociation constant of leuprolide and the typical leuprolide plasma concentration required to achieve a castration testosterone level of ≤0.5 ng/mL were 0.3 and 0.03 ng/mL, respectively.. Population pharmacokinetics and pharmacodynamics of the leuprolide depot formulation were characterized using an integrated semi-mechanistic model. The developed model adequately describes the leuprolide-testosterone relationship and can potentially be used to facilitate design of clinical studies for new formulations, to aid in the selection of candidate formulations, and for the optimization of doses and dosing schemes.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Patient-Specific Modeling; Prostatic Neoplasms; Testosterone; Young Adult

Leuprorelin acetate (TAP-144-SR) is commonly used worldwide in prostate cancer patients. This study was conducted to assess the non-inferiority of a 6-month depot formulation of TAP-144-SR (TAP-144-SR [6M]) 22.5 mg to a 3-month depot formulation of TAP-144-SR (TAP-144-SR [3M]) 11.25 mg in prostate cancer patients in Japan.. This was a 48-week Phase III, open-label, parallel-group comparative study. TAP-144-SR (6M) 22.5 mg (6M group) and TAP-144-SR (3M) 11.25 mg (3M group) were administered to 81 and 79 subjects, respectively. The primary endpoint was the rate of serum testosterone suppression to the castrate level (≤100 ng/dl).. Serum testosterone of all subjects excluding one subject in the 3M group was suppressed to the castrate level throughout 48 weeks. The estimated between-group difference (6M group - 3M group) in suppression rate was 1.3% (95% confidence interval: -3.4, 6.8), and its lower confidence interval was more than -10% of the pre-determined allowable limit value to judge the non-inferiority. The prostate-specific antigen concentrations were stable throughout the study in both groups. Progressive disease in the best overall response based on the Response Evaluation Criteria In Solid Tumors was 0.0% for the 6M group and 2.6% for the 3M group. Adverse events occurred in 92.6% in the 6M group and 89.9% in the 3M group. Adverse events leading to discontinuation were reported in 2.5% in the 6M group and 3.8% in the 3M group.. TAP-144-SR (6M) was not inferior to TAP-144-SR (3M) for the suppressive effect on serum testosterone level. TAP-144-SR (6M) was also as well tolerated as TAP-144-SR (3M).

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Delayed-Action Preparations; Humans; Japan; Leuprolide; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Research Design; Testosterone; Treatment Outcome

Androgen deprivation therapy (ADT) is an important component of modern prostate cancer treatment. Survival benefits from neo-adjuvant and adjuvant hormones may take years to manifest, and balancing this with potential morbidity of therapy can be challenging. This study aimed to assess whether education and short-term combined aerobic and resistance exercises could help to ameliorate the adverse side effects of ADT.. Eight hundred fifty-nine patients with relapsed or metastatic prostate cancer on leuprorelin acetate were allocated to three interventional streams based on patient preference and medical fitness: supervised group (Face-to-Face) exercise sessions, home-based (At Home) exercise or a support programme for those incapable of exercising (Support). Patients enrolled onto Face to Face underwent measurement of body composition and cardiorespiratory fitness variables at baseline and programme completion. Patients in the exercise streams were surveyed to determine the programme's impact on physical fitness and well-being.. Statistically significant improvements (p < 0.001) were seen in all measured cardiorespiratory fitness and strength variables. Programme attrition rates were low (75/859; 8.7%), the primary reason for withdrawal being discontinuation of hormones (70%). Programme satisfaction was high, with 98% of surveyed patients reporting a positive impact on fitness and 97% planning to continue exercising after programme completion. At 6 months, improved physical and emotional well-being was reported by 93 and 79% of patients, respectively.. A short-term structured exercise intervention results in high compliance and significant improvements in muscle strength and cardiorespiratory fitness in prostate cancer patients on ADT.

Topics: Aged; Androgen Antagonists; Australia; Cardiovascular Diseases; Causality; Combined Modality Therapy; Comorbidity; Exercise Therapy; Humans; Leuprolide; Male; Metabolic Diseases; Prevalence; Prospective Studies; Prostatic Neoplasms; Risk Factors; Treatment Outcome

To investigate the impact of 3-month androgen deprivation therapy (st-ADT) a secondary chemoprevention of indolent-localized prostate cancer (PCa).. A prospective phase II study enrolled men over 4 years with low-risk PCa and the following characteristics: PSA < 10 ng/mL, Gleason score of 6 (3 + 3) or less, three positive cores or less, and tumor stage T2a or less. Patients received a single sub-cutaneous injection of 22.5 mg of leuprolide acetate with Atrigel 3-month depot associated with a daily oral intake of bicalutamide 50 mg/day during 15 days around the injection. Follow-up included PSA and bioavailable testosterone blood tests every 3 months and yearly surveillance biopsies. Primary end point was the presence of PCa on biopsy at last follow-up. Secondary end points were detailed pathological features and adverse events.. Overall, 98 men were included and 45 of them (45.9 %) had a negative biopsy after a median follow-up of 13 months [11-19.5]. Of the 53 patients with positive biopsy, 17 had pathologic progression because of upgraded Gleason score (11 patients), four or more positive cores (three patients) or both (three patients). The only significant predictive factor biopsy outcome was the number of positive cores at diagnosis.. Secondary chemoprevention by st-ADT for localized PCa could be useful to pinpoint indolent tumors suitable for AS. Indeed, after st-ADT nearly one patient out of two had negative biopsies and 17 % had pathological progression. This is an innovative option to consider as an alternative to current AS protocols contingent upon confirmation in subsequent studies.

Topics: Aged; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Biopsy, Large-Core Needle; Chemoprevention; Delayed-Action Preparations; Humans; Kallikreins; Leuprolide; Male; Middle Aged; Nitriles; Pilot Projects; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Secondary Prevention; Tosyl Compounds; Treatment Outcome; Watchful Waiting

To evaluate for a possible testosterone surge during transition of therapy from degarelix to leuprolide.. We conducted an investigator-initiated, prospective, single-arm, open-label trial for evaluation of a potential testosterone surge during a transition of therapy from degarelix to leuprolide. Study patients were administered 3 monthly depot injections of degarelix, followed by one 3-month depot injection of leuprolide. A rise in serum testosterone was considered clinically relevant in previously castrate patients whose testosterone rose above 50 ng/dL.. Forty-five patients aged 59-86 years were included in the final analysis after completing the entire 6-month study. Nineteen percent of patients had received prior androgen deprivation therapy, and 10% had metastatic disease. Mean serum testosterone was reduced from a baseline of 374.6 ± 155.7 ng/dL to 16.5 ± 8.1 ng/dL, and prostate-specific antigen reduced from 23.8 ± 55.8 ng/mL to 1.6 ± 3.7 ng/mL after 3 months of treatment with degarelix. On transition from degarelix to leuprolide (day 90), there was a rise in testosterone from the nadir of 16.5 ng/dL to a peak of 25.8 ng/dL (P = .0005), occurring at day 93. Four patients (8.9%) experienced a testosterone surge with a mean peak serum testosterone of 80.7 ng/dL; all 4 returned to castrate levels within 7 days, and all remained asymptomatic throughout the testosterone fluctuation.. Fluctuations in serum testosterone after this transition of therapy were mild and short-lived with only 8.9% of men experiencing testosterone elevations to noncastrate levels.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

Procollagen 1 amino-terminal propeptide (P1NP) is a bone formation marker and has been shown to have a strong association with the extent of bone metastases (BM) in patients with advanced prostate cancer. More recently, its levels were found to be affected by androgen deprivation therapies and bisphosphonates. We investigated the role of P1NP as a surrogate marker of sub-radiological skeletal metastases in prostate cancer patients with biochemical failure (BF).. BePrepared is a prospective longitudinal substudy of RADAR trial in which serial P1NPs were collected at regular intervals for 123 patients who had completed RADAR protocol treatment.. There was no trend identified in P1NP levels prior to diagnosis of BM. We found that there was no difference in P1NP concentrations at the time of diagnosis of BM in the group that developed BM compared with P1NP levels in groups with only nodal metastases or BF. In the group of patients who did not experience BF, P1NP was affected by previous luteinizing hormone-releasing hormone-agonist and bisphosphonate therapy. Hence, patients who received an 18-month course of androgen deprivation without bisphosphonates had significantly higher P1NP values than patients with shorter androgen deprivation therapy (ADT) course combined with a course of bisphosphonates.. P1NP is not a sensitive serum marker of early BM in high-risk prostate cancer patients with BF and low prostate-specific antigen levels as its levels are affected by prior history of bone remodelling therapies such as ADT and bisphosphonates.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Bone Density Conservation Agents; Bone Neoplasms; Diphosphonates; Drug Therapy, Combination; Early Detection of Cancer; Humans; Imidazoles; Leuprolide; Male; Middle Aged; New South Wales; Peptide Fragments; Prevalence; Procollagen; Prostatic Neoplasms; Reproducibility of Results; Risk Factors; Sensitivity and Specificity; Survival Rate; Treatment Outcome; Zoledronic Acid

Leuprorelin is a well known luteinizing hormone releasing hormone agonist. However, there are insufficient data on the efficacy and safety of high dose leuprorelin acetate, especially in Asian patients with prostate cancer. We aimed to investigate the safety and efficacy of leuprorelin acetate 22.5 mg administered at three-month intervals in patients with prostate cancer.. In an open, prospective clinical trial enrolling 47 patients, we aimed to assess the efficacy and safety of leuprorelin acetate 22.5 mg in treating patients with histologically confirmed prostate cancer. The primary objective of this study was to evaluate the efficacy of the leuprorelin acetate 22.5 mg in producing and maintaining castration levels of testosterone over a 6-month follow-up period and to determine its safety profile.. All 42 patients achieved serum testosterone levels within the castration range by 4 weeks. A breakthrough response was observed in one of 36 patients by 8 weeks. However, this patient was medically castrated by 12 weeks. There were no significant prostate-specific antigen (PSA) or testosterone changes according to clinical stage or body mass index. Twenty adverse events (AEs) in 15 of 42 patients (35.7%) were observed during this study. The most common AEs were hot flushes (n=4, 20.0%) with mild intensity, pain (n=2, 10.0%), and infection (n=2, 10.0%). No patient withdrew from the study due to AEs.. Leuprorelin acetate 22.5 mg was shown to be effective and safe in Asian patients with prostate cancer, even though sexual function decreased.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Asian People; Drug Administration Schedule; Hot Flashes; Humans; Leuprolide; Male; Middle Aged; Penis; Prostate-Specific Antigen; Prostatic Neoplasms; Testis; Testosterone; Treatment Outcome

To demonstrate the safety and efficacy of up to 5 years of degarelix treatment and the effects of crossing over from leuprolide to degarelix in the extension phase of a phase III pivotal 1-year trial.. Patients receiving degarelix who completed the 1-year trial continued on 80 mg (n = 125) or 160 mg (n = 126) maintenance doses. Patients who received leuprolide were rerandomized to degarelix 240/80 mg (n = 69) or 240/160 mg (n = 65). Safety and tolerability were assessed (primary end point), as well as testosterone and prostate-specific antigen levels and prostate-specific antigen progression-free survival (secondary end points).. Adverse event frequency was similar between both the groups. Adverse events included initial injection site reactions, hot flushes, and increased weight. Testosterone and prostate-specific antigen values during the extension study were similar to those seen during the 1-year trial in patients who continued on degarelix or crossed over from leuprolide. The prostate-specific antigen progression-free survival hazard rate was decreased significantly after the crossover in the leuprolide to degarelix group (from 0.20 to 0.09; P = .002), whereas in patients who continued on degarelix, the rate did not change significantly. In patients with baseline prostate-specific antigen >20 ng/mL, the same hazard rate change pattern was observed on crossover (from 0.38 to 0.19; P = .019).. Degarelix was well tolerated; no safety concerns were identified. The significant prostate-specific antigen progression-free survival benefit established for degarelix over leuprolide during year 1 remained consistent at 5 years.

Topics: Cross-Over Studies; Disease-Free Survival; Humans; Leuprolide; Male; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Time Factors

To identify the factors underlying prostate cancer (PCa) patients' depression-anxiety, sexual problems, urinary dysfunction and androgen deprivation therapy (ADT)-linked breast changes and hot flushes, and test these as predictors of loss of masculinity (LoM) over 36 months following diagnosis.. One thousand seventy patients from the TROG 03.04 (RADAR) trial the EORTC QLQ C-30 and PR 25 questionnaires, and the International Prostate Cancer Symptom Score of the American Urological Association at baseline, 3, 7, 12, 18, 24 and 36 months. Selected items from these scales were factor-analysed to identify a four-component solution for responses at 18 and 36 months, and these components were regressed against a single-item measuring LoM.. Depression-anxiety factor was the most powerful predictor of LoM at both time points, followed by sexual problems of ADT side effects (breast changes and hot flushes). Urinary dysfunction was not a consistent predictor of LoM. Depression-anxiety was also the most significant factor distinguishing between those men who reported LoM and those who did not.. Although LoM is often reported as arising from ADT, the relative power of depression-anxiety in predicting LoM, both at the selected time points and using a time-lagged analysis, plus the finding that depression-anxiety was the most consistent difference between men who reported LoM and those who did not, argues for the presence of adverse mood states as being the key ingredient in deciding if PCa patients experience loss of their feelings of masculinity.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Anxiety; Depression; Hot Flashes; Humans; Leuprolide; Male; Masculinity; Middle Aged; Prostatic Neoplasms; Sexual Dysfunction, Physiological; Surveys and Questionnaires

The aim of this phase II study was to evaluate the pharmacokinetics, pharmacodynamics, efficacy, and safety of a 6- month depot formulation of a luteinizing hormone-releasing hormone (LH-RH) agonist, TAP-144-SR (6M), in Japanese treatment-naÏve patients with prostatic cancer. Each subject received a single subcutaneous or intramuscular injection of TAP- 144-SR (6M) and was monitored for 24 weeks. The primary endpoint was the change in serum testosterone levels. The serum testosterone level in six subjects who received 22.5 mg of TAP-144 (SR) subcutaneously decreased below the castrate level after 4 weeks and remained suppressed during the 24 weeks of follow-up. With regard to safety, TAP-144-SR (6M)was not associated with any additional concerns compared to those reported for the approved 1-month and 3-month depot formulations of TAP-144-SR. In addition, 30 mg of TAP-144-SR (6M) was administered subcutaneously to six subjects, and, on the basis of the results, the optimal clinical dosage of TAP-144-SR (6M) in Japan was considered to be 22.5 mg. Outcomes with 22.5mg TAP-144-SR (6M) administered intramuscularly were similar to those with TAP-144-SR (6M) administered subcutaneously.

Topics: Aged; Humans; Injections, Intramuscular; Injections, Subcutaneous; Leuprolide; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

Topics: Aged; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Germany; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Risk Assessment; Treatment Outcome; Ultrasound, High-Intensity Focused, Transrectal

Cure rates for localized high-risk prostate cancers (PCa) and some intermediate-risk PCa are frequently suboptimal with local therapy. Outcomes are improved by concomitant androgen-deprivation therapy (ADT) with radiation therapy, but not by concomitant ADT with surgery. Luteinizing hormone-releasing hormone agonist (LHRHa; leuprolide acetate) does not reduce serum androgens as effectively as abiraterone acetate (AA), a prodrug of abiraterone, a CYP17 inhibitor that lowers serum testosterone (< 1 ng/dL) and improves survival in metastatic PCa. The possibility that greater androgen suppression in patients with localized high-risk PCa will result in improved clinical outcomes makes paramount the reassessment of neoadjuvant ADT with more robust androgen suppression.. A neoadjuvant randomized phase II trial of LHRHa with AA was conducted in patients with localized high-risk PCa (N = 58). For the first 12 weeks, patients were randomly assigned to LHRHa versus LHRHa plus AA. After a research prostate biopsy, all patients received 12 additional weeks of LHRHa plus AA followed by prostatectomy.. The levels of intraprostatic androgens from 12-week prostate biopsies, including the primary end point (dihydrotestosterone/testosterone), were significantly lower (dehydroepiandrosterone, Δ(4)-androstene-3,17-dione, dihydrotestosterone, all P < .001; testosterone, P < .05) with LHRHa plus AA compared with LHRHa alone. Prostatectomy pathologic staging demonstrated a low incidence of complete responses and minimal residual disease, with residual T3- or lymph node-positive disease in the majority.. LHRHa plus AA treatment suppresses tissue androgens more effectively than LHRHa alone. Intensive intratumoral androgen suppression with LHRHa plus AA before prostatectomy for localized high-risk PCa may reduce tumor burden.

Topics: Abiraterone Acetate; Aged; Androgen Antagonists; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Receptors, Androgen; Testosterone

The pharmacokinetics (PK) and pharmacodynamics of two leuprolide acetate (LA) 45 mg 6-month depot formulations were characterized in prostate cancer patients. Subjects (planned N = 150 in each cohort) received two intramuscular injections of LA Formulation-A or Formulation-B administered 24 weeks apart. Samples were collected for the measurement of testosterone, LH (all subjects) and leuprolide (in a subset of subjects approximately N = 24 in each cohort) at the same time points. Leuprolide PK profile showed an initial peak followed by a rapid decline over the first week post-dose, with mean leuprolide concentrations staying relatively constant through the end of 24-week period. Mean testosterone and LH serum concentrations showed initial increases above baseline values after the first dose and then decreased to 16.0 ng/dL and 0.6 mIU/mL by Week 4 for Formulation-A and were maintained at ≤14.3 ng/dL and 0.4 mIU/mL, thereafter, with negligible mean increases after the second dose. Formulation-A showed a lower initial peak and higher leuprolide concentration during the sustained release phase which may explain higher testosterone suppression rates for Formulation-A compared to Formulation-B. Differences in PK between LA depot formulations were reflected in pharmacodynamic responses, with a higher rate of testosterone suppression and less escapes and acute-on-chronic responses for Formulation-A.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Drug Compounding; Humans; Injections, Intramuscular; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Prostatic Neoplasms; Testosterone; Treatment Outcome; United States

To evaluate the feasibility of administering sunitinib in combination with androgen deprivation therapy and external-beam intensity modulated radiation therapy (XRT) in patients with localized high-risk prostate cancer.. Seventeen men with localized adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or prostate-specific antigen >20 ng/mL received initial androgen deprivation (leuprolide 22.5 mg every 12 weeks plus oral bicalutamide 50 mg daily) for 4-8 weeks before oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks after XRT (75.6 Gy in 42 fractions to prostate and seminal vesicles). A 3+3 sequential dose-escalation design was used to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose of sunitinib.. Sunitinib at 12.5- and 25-mg dose levels was well tolerated. The first 4 patients enrolled at 37.5 mg experienced a DLT during lead-in, and a drug interaction between sunitinib and bicalutamide was suspected. The protocol was revised and concurrent bicalutamide omitted. Of the next 3 patients enrolled at 37.5 mg, 2 of 3 receiving concurrent therapy experienced DLTs during radiation: grade 3 diarrhea and grade 3 proctitis, respectively. Only 1 of 7 patients completed sunitinib at 37.5 mg daily, whereas 3 of 3 patients (25 mg as starting dose) and 3 of 4 patients (25 mg as reduced dose) completed therapy.. The feasibility of combined vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitor therapy, androgen deprivation, and radiation therapy for prostate cancer was established. Using a daily dosing regimen with lead-in, concurrent, and post-XRT therapy, the recommended phase 2 dose of sunitinib is 25 mg daily.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents; Combined Modality Therapy; Drug Interactions; Feasibility Studies; Goserelin; Humans; Indoles; Leuprolide; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Grading; Neoplasm Staging; Nitriles; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Pyrroles; Radiotherapy, Intensity-Modulated; Seminal Vesicles; Sunitinib; Tosyl Compounds

Degarelix, approved in the USA in 2008, is a gonadotropin-releasing hormone antagonist, representing one of the latest additions to androgen deprivation therapy (ADT). ADT is used as first-line therapy for locally advanced or metastatic prostate cancer with the aim to reduce testosterone to castrate levels. Like other gonadotropin-releasing hormone-antagonists, degarelix treatment results in rapid decrease in luteinizing hormone, follicle-stimulating hormone and testosterone levels without the associated risk of flare. Using one registration trial for degarelix with leuprolide as the active control, a cost-effectiveness analysis with a Markov model and a 20-year time horizon found the incremental cost-effectiveness ratio for degarelix to be US$245/quality-adjusted life years. Degarelix provides a cost-effective treatment for ADT among patients with locally advanced prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Cost-Benefit Analysis; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Markov Chains; Oligopeptides; Prostatic Neoplasms; Quality-Adjusted Life Years; Testosterone

Long-term hormonal ablation in prostate cancer is associated with decreased overall health and quality of life. Few reports emphasized the role of chemotherapy in the management of early stage prostate cancer. This study analyzed the safety and efficacy of androgen deprivation therapy (ADT) plus chemotherapy as initial treatment for patients identified as local failures or not eligible for prostatectomy or radiation therapy due to advanced disease presentation.. Enrolled patients received ADT in the form of leuprolide every 12 weeks for 24 months with bicalutamide initiating after the completion of chemotherapy. Chemotherapy consisted of ketoconazole and doxorubicin for weeks 1, 3, and 5 and estramustine and docetaxel and for weeks 2, 4 and 6. During weeks 7 and 8, no treatment was received.. Forty-six patients were enrolled, and forty-five patients were evaluable. Median progression-free survival (PFS) was 23.4 months. Median overall survival (OS) was 53.7 months. Out of 45 patients with measurable disease, 22 patients had an objective response: 9 patients achieved a complete response; 2 patients achieved a partial response; 10 patients achieved stable disease. Frequent grade 3 adverse events included elevated ALT (17 %), hypokalemia (13 %), and hypophosphatemia (13 %). Grade 4 adverse events were rare and included low bicarbonate (2 %), hypokalemia (2 %), leukocytopenia (2 %), and neutropenia (2 %).. The treatment demonstrated clinical benefit in all patient subsets with minimal reversible treatment-related adverse events. Subgroup analysis suggests that having prior local therapy resulted in greater PFS and OS.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Kallikreins; Leuprolide; Male; Middle Aged; Neoplasm Grading; Nitriles; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Radiotherapy; Tosyl Compounds; Treatment Failure

To assess the effects of timing and schedule of zoledronic acid (ZA) administration on bone mineral density (BMD) in patients beginning androgen deprivation therapy (ADT) for the treatment of recurrent prostate cancer.. In this randomized, 3-arm trial, we evaluated changes in BMD after 3 different ZA administration schedules in men with recurrent prostate cancer who were beginning ADT. Forty-four patients were enrolled and randomized to receive a single dose of ZA given 1 week before beginning ADT (arm 1), a single dose of ZA given 6 months after beginning ADT (arm 2), or monthly administration of ZA starting 6 months after beginning ADT, for a total of 6 doses (arm 3).. Patients who received ZA before ADT had a significant improvement in BMD at the total proximal femur and trochanter after 6 months compared with the other groups. In addition, only patients in the arm that received multiple doses improved lumbar spine BMD while on ADT, with these findings persisting to 24 months. However, this group also experienced more grade 1 adverse events.. Analysis of these data suggests that ZA administration before initiation of ADT was superior to treatment 6 months after starting ADT in maintaining BMD. In addition, monthly ZA administration can increase BMD above baseline but is associated with more adverse events. Further study is needed to examine whether the timing and frequency of ZA therapy in patients on ADT can reduce fracture risk.

Topics: Aged; Alkaline Phosphatase; Androgen Antagonists; Bone Density; Bone Density Conservation Agents; Cell Proliferation; Diphosphonates; Drug Administration Schedule; Goserelin; Humans; Imidazoles; Leuprolide; Lymphocyte Count; Male; Middle Aged; Osteoporosis; Prostate-Specific Antigen; Prostatic Neoplasms; T-Lymphocytes; Zoledronic Acid

The current trial evaluated 2 common therapies for patients with advanced prostate cancer, docetaxel and hormonal therapy (HT), in the surgical adjuvant setting.. TAX-3501 was a randomized, phase 3, adjuvant study post-radical prostatectomy (RP) in high-risk patients with prostate cancer (n=228) comparing 18 months of HT with (CHT) without docetaxel chemotherapy either immediately (I) or deferred (D). High-risk disease was defined as a 5-year freedom-from-disease-progression rate of ≤ 60% as predicted by a post-RP nomogram. Progression-free survival (PFS), including prostate-specific antigen disease recurrence, was the primary endpoint. The authors also assessed the accuracy of the nomogram and analyzed testosterone recovery in 108 patients treated with HT who had at least 1 posttreatment testosterone value.. Between December 2005 and September 2007, 228 patients were randomized between the treatment cohorts. TAX-3501 was terminated prematurely because of enrollment challenges, leaving it underpowered to detect differences in PFS. After a median follow-up of 3.4 years (interquartile range, 2.3-3.8 years), 39 of 228 patients (17%) demonstrated PSA disease progression, and metastatic disease progression occurred in 1 patient. The median time to baseline testosterone recovery after the completion of treatment was prolonged at 487 days (95% confidence interval, 457-546 days). The nomogram's predicted versus observed freedom from disease progression was significantly different for the combination D(HT) and D(CHT) group (P<.00001).. TAX-3501 illustrated several difficulties involved in conducting postoperative adjuvant systemic trials in men with high-risk prostate cancer: the lack of consensus regarding patient selection and treatment, the need for long follow-up time, nonvalidated intermediate endpoints, evolving standard approaches, and the need for long-term research support. Except for selected patients at very high-risk of disease recurrence and death, surgical adjuvant trials in patients with prostate cancer may not be feasible.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Disease Progression; Docetaxel; Follow-Up Studies; Humans; International Agencies; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prognosis; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Survival Rate; Taxoids

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.. 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.. 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.. 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.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms

To examine changes to whole body and regional lean mass (LM) and fat mass (FM) over 33 months of intermittent androgen suppression therapy (IAST).. Phase II cohort study of 72 prostate cancer patients without metastatic bone disease. Patients received flutamide 250 mg tid and leuprolide 22.5 mg three monthly depot for the 9-month initial treatment phase (iTREAT), at which point patients ceased therapy providing PSA <4 ng ml(-1) with continued monitoring for further 2 years (POST). AST was recommenced when PSA exceeded pretreatment level or ≥ 20 ng ml(-1). Body composition was assessed using dual energy X-ray absorptiometry at baseline, completion of treatment phase, and 1 and 2 years post treatment phase (months 21 and 33).. LM decreased by 1.3 kg and FM increased by 2.3 kg (P<0.001) following iTREAT. During the POST period, there were no further adverse effects on LM or FM, but also no recovery to pretreatment levels. Patients who failed to recover testosterone by month 33 experienced a significant increase in FM compared with those who recovered eugonadal levels of testosterone (10 nmol ml(-1); P = 0.019). Change in testosterone was moderately correlated to changes in % FM (r = -0.314, P<0.028) and LM (r = 0.300, P<0.036) during POST phase. Waist circumference progressively increased over time and by 2 years, POST had not recovered to baseline levels.. Loss of LM and gain in FM during the 9-month iTREAT was not reversed during 2-year POST, although further deterioration was not observed. Subgroup analysis identified those recovering testosterone showed some body composition improvements. These findings suggest potential benefits of IAST, where testosterone levels are able to recover, to reduce the ongoing adverse effects on body composition, such as the acceleration of sarcopenia and risks associated with metabolic disease.

Topics: Absorptiometry, Photon; Adipose Tissue; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Body Composition; Flutamide; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Time

Androgen-deprivation therapy (ADT) induces loss of bone mineral density (BMD) and increases the risk of fractures in patients with prostate cancer (PCa). We sought to determine whether a weekly dose of alendronate, an oral bisphosphonate, could reduce this unwanted side-effect.. To assess whether once-weekly oral alendronate therapy would maintain or improve BMD in men initiating ADT for localised PCa.. A multicentre, double-blind, randomised, placebo-controlled study, we included hormonally naïve PCa patients initiating ADT with leuprolide acetate 30 mg intramuscularly every 4 mo.. Patients were randomised to receive either oral alendronate 70 mg once weekly or placebo for 1 yr. Both groups received daily calcium 1g and vitamin D 400 international units.. Changes in BMD (at the lumbar spine [LS] and total hip [TH]) and bone markers.. One hundred ninety-one subjects were enrolled, and 186 were randomised between alendronate (n=84) and placebo (n=102). The alendronate group demonstrated a mean spine BMD increase of 1.7% compared with -1.9% in the placebo group (p<0.0001). Alendronate also increased the BMD at the hip (percent change: 0.7%) compared to placebo (-1.6%). Median urinary N-terminal crosslinking telopeptide of type I collagen (Ntx) values decreased by 3.5% in the alendronate group and increased by 16.5% in the placebo arm, even after adjusting for centre (p=0.510) and baseline urinary Ntx (p<0.0001). Bone-specific alkaline phosphatase (BSAP) decreased a median of 2.25% in the alendronate group and increased a median of 3.12% in the placebo arm, regardless of centre or baseline BSAP or other covariates (p<0.0001). The safety and tolerability profile was similar for the two treatment groups.. Although the study was closed early because of slow accrual, it showed that weekly oral alendronate prevented bone loss and increased bone mass in addition to decreasing bone turnover in patients initiating ADT for localised PCa, with few related side-effects.

Topics: Absorptiometry, Photon; Administration, Oral; Aged; Aged, 80 and over; Alendronate; Alkaline Phosphatase; Analysis of Variance; Androgen Antagonists; Antineoplastic Agents, Hormonal; Biomarkers; Bone Density; Bone Density Conservation Agents; Canada; Chi-Square Distribution; Collagen Type I; Double-Blind Method; Drug Administration Schedule; Hip Joint; Humans; Injections, Intramuscular; Leuprolide; Lumbar Vertebrae; Male; Middle Aged; Osteoporosis; Patient Selection; Peptides; Predictive Value of Tests; Prostatic Neoplasms; Time Factors; Treatment Outcome

To determine the time-dependent metabolic and angiogenic changes that occur in prostate cancer (CaP) during neoadjuvant hormone therapy (HT), using a combination of MRSI and DCEMR analysis.. This is a prospective study on a population of non-metastatic CaP submitted to neoadjuvant HT prior to radiation therapy. All cases homogeneously received a 6-month period of neoadjuvant HT using leuprorelin acetate 7.5 mg every 28 days. In all cases, a MRSI/DCEMR study was performed at baseline (pretreatment) and at regular intervals (4, 12, 24 weeks) during HT. Serum PSA was measured at baseline and at the same intervals (4, 12, 24 weeks). All MRI examinations were performed on a commercially available 3 T scanner.. There was a significant ( P < 0.01) time-dependent loss of all prostate metabolites during HT. In regions of CaP no significant variation in the absolute value of metabolites was reported at 1-month interval and a higher variation was observed at 24-week compared with 12-week interval. A complete metabolic atrophy was a common feature (30%) at a 24-week interval of HT, but not at short (4-week 0%), and lower at an intermediate interval (12-week 10%). At DCEMR, onset time and time to peak parameters significantly (P < 0.05) increased at 12- and 24-week intervals.. To individualize neoadjuvant HT courses prior to definitive treatment, the combination of MRSI and DCEMR may represent a valid noninvasive method, and the addition to PSA data could be used to better assess the time-dependent efficacy of HT in our patients.

Topics: Aged; Antineoplastic Agents, Hormonal; Humans; Image Enhancement; Leuprolide; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Neoadjuvant Therapy; Outcome Assessment, Health Care; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Reproducibility of Results; Sensitivity and Specificity; Time Factors

This open-label study evaluated the efficacy and safety of a new leuprolide acetate 45 mg 6-month depot formulation in 151 men with prostate cancer who received 2 intramuscular injections administered 24 weeks apart.. The primary efficacy measurement was the proportion of patients achieving suppression of serum testosterone to ≤ 50 ng dl(-1) from week 4 through week 48. Adverse events (AEs) and hormonal and safety laboratory values were monitored.. The primary efficacy end point was achieved in 93.4% of subjects (95% confidence interval (89.2%, 97.6%)). There were nine escapes from testosterone suppression during the study, none of which were accompanied by a rise in PSA. By week 4, mean testosterone concentration was suppressed below castrate levels to 15.9 ng dl(-1); suppression was maintained for the entire 24-week duration of each depot injection. No mean increase in testosterone was observed after the second injection. Mean PSA levels were maintained below 3 ng ml(-1) from week 14 through the 48-week treatment period. The most frequent AE was flushing (58.3%). Injection site reactions were reported in 24.5% of patients.. Leuprolide acetate 45 mg 6-month depot demonstrated rapid and sustained testosterone suppression through 12 months and was well tolerated. This 6-month leuprolide acetate depot will decrease the number of annual injections in the treatment of prostate cancer.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anemia; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Blood Glucose; Chemistry, Pharmaceutical; Hemoglobins; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Outcome

Study Type - Therapy (prospective cohort). Level of Evidence 2a. What's known on the subject? and What does the study add? The sequential administration of a GnRH antagonist followed by an LHRH agonist in the management of prostate cancer patients has not been studied, but such a program would provide a more physiologic method of achieving testosterone suppression and avoid the obligatory testosterone surge and need for concomitant antiandrogens that accompany LHRH agonist therapy. The current study which uses abarelix initiation therapy for 12 weeks followed by either leuprolide or goserelin demonstrates the ability to more rapidly achieve testosterone suppression, avoid the obligatory LHRH induced testosterone surge, avoid the necessity of antiandrogens, all of which were accomplished safely, without inducing either additional or novel safety issues.. • To demonstrate the safety and endocrinological and biochemical efficacy of initiating treatment with the gonadotropin-releasing hormone (GnRH) antagonist, abarelix, followed by administration of an luteinizing hormone-releasing hormone (LHRH) agonist in patients with advanced and metastatic prostate cancer.. • A multicentre, open-label design study was conducted at 22 centres in the US involving patients with: localized, locally advanced or metastatic disease; with a rising prostate-specific antigen (PSA) after definitive local treatment; patients undergoing neoadjuvant hormonal therapy before local therapy (radical prostatectomy, radiation therapy or cryosurgery); and patients in whom intermittent therapy was the planned treatment. • All patients received abarelix for 12 weeks followed by an LHRH agonist (either leuprolide or goserelin) for 8 weeks • The primary efficacy endpoint was achievement and maintenance of castration defined as testosterone <50 ng/dL from day 29 through to day 141 and whether abarelix initiation therapy could eliminate the testosterone surge after two consecutive doses of LHRH agonist therapy. • PSA, LH and follicle-stimulating hormone (FSH) levels were measured and adverse events were monitored.. • A total of 176 patients were enrolled into the present study, the majority of whom had localized prostate cancer (82%) and a PSA level <10 ng/mL (62%). • At the end of the abarelix treatment period (day 85), 93.8% of patients achieved castrate levels; during the first week of switch over to the LHRH agonist therapy (days 85-92) the rate was 86.5% and during the week after the second LHRH agonist injection (days 114-12) it was 93.3%. • A small, transient increase in testosterone occurred during the first injection of the LHRH agonist; mean (standard deviation [sd]) values increased from 17 (17.8) ng/dL at day 85 to 37.3 (51.07) ng/dL at day 86. • Mean (sd) PSA levels decreased from 20.5 (56.6) ng/mL at baseline to 3.7 (23.5) ng/mL on day 85 and remained stable throughout the LHRH agonist treatment phase. • Treatment-related adverse events occurred in 84% of patients overall; a similar incidence was reported during the two treatment phases.. • Abarelix initiation therapy results in the desired effect of achieving rapid testosterone suppression; testosterone surges after subsequent LHRH agonist therapy are greatly abrogated or completely eliminated. • This treatment paradigm (abarelix initiation followed by agonist maintenance) obviates the need for an antiandrogen. • Abarelix was well tolerated and no clinically meaningful or novel adverse events were observed during abarelix treatment or in the transition to LHRH agonist maintenance therapy.

Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Goserelin; Humans; Leuprolide; Male; Middle Aged; Oligopeptides; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; United States

To evaluate the relative efficiency of leuprolide 3.75 mg, leuprolide 7.5 mg, and goserelin 3.6 mg in relation to the reduction in serum testosterone, regarding the levels of castration.. We evaluated prospectively 60 randomized patients with advanced prostate carcinoma, with indication for hormone blockade. The patients were divided into 3 groups of 20: Group (1) received leuprolide 3.75 mg; Group (2) received leuprolide 7.5 mg; and Group (3) received goserelin 3.6 mg. All groups were treated with monthly application of the respective drugs. The patients' levels of serum testosterone were evaluated in two moments: before the treatment and 3 months after the treatment.. The patients' ages were similar within the three groups, with a median of 72, 70, and 70 in groups 1, 2, and 3, respectively. Of the patients that received leuprolide 3.75 mg, leuprolide 7.5 mg, and goserelin 3.6 mg, 26.3, 25, and 35%, respectively, did not reach castration levels, considering a testosterone cutoff ≤ 50 ng/dl. And 68.4, 30, and 45%, respectively, did not reach castration levels, considering a testosterone cutoff ≤ 20 ng/dl.. There were no statistically significant differences in the levels of castration when comparing leuprolide 3.75 mg, leuprolide 7.5 mg, and goserelin 3.6 mg, altogether. When compared in groups of two, there was a statistically significant difference between leuprolide 3.75 mg and leuprolide 7.5 mg, the latter presented better results in reaching castration levels, cutoff ≤ 20 ng/dl. The importance of this difference, however, must be measured with caution, since the comparison of the three groups simultaneously did not reach the established significance level, even though it came close.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Dose-Response Relationship, Drug; Follow-Up Studies; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

To investigate changes in bone mineral density (BMD) and fracture risk in men who received intermittent androgen deprivation (IAD) for nonmetastatic, hormone-sensitive prostate cancer.. Men with prostate cancer who lacked radiographically detectable metastases were treated in a prospective trial of IAD. After 9 months of treatment with leuprolide and flutamide, androgen deprivation therapy (ADT) was stopped until prostate-specific antigen reached a threshold (1 ng/mL for radical prostatectomy; 4 ng/mL for radiation or primary ADT) for a new cycle. Dual-energy x-ray absorptiometry (DXA) scans were performed before starting ADT and subsequently with each change in therapy. At least two consecutive DXA scans were required for this analysis. Computed tomography, bone scintigraphy, and lumbar spine x-rays were performed at the beginning and end of each treatment period.. Fifty-six of 100 patients met criteria for this analysis. The median age at study entry was 64.5 years (range, 49.8 to 80.9 years). The average percentage change in BMD during the first on-treatment period was -3.4% (P < .001) for the spine and -1.2% (P = .001) for the left hip. During the first off-treatment period (median, 37.4 weeks; range, 13.4 weeks to 8.7+ years), BMD recovery at the spine was significant, with an average percentage change of +1.4% (P = .002). Subsequent periods had heterogeneous changes of BMD without significant average changes. After a median of 5.5 years (range, 1.1 to 13.8+) years on trial, one patient (1.8%) had a compression fracture associated with trauma.. Patients experienced the greatest average change in BMD during early treatment periods of IAD with a smaller average change thereafter. Fractures were rare.

Topics: Absorptiometry, Photon; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Density; Bone Diseases, Metabolic; Drug Administration Schedule; Flutamide; Fractures, Bone; Humans; Leuprolide; Linear Models; Male; Middle Aged; Multivariate Analysis; Neoplasms, Hormone-Dependent; Osteoporosis; Prospective Studies; Prostatic Neoplasms; Risk Assessment; Risk Factors; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

Study Type - Therapy (RCT) Level of Evidence 1b. What's known on the subject? and What does the study add? Intermittent androgen deprivation therapy (ADT) involves cycling ADT, allowing hormonal recovery during off-treatment periods. This could lead to a better quality of life during off-treatment periods and could delay progression to castration resistance. Safety and feasibility of intermittent ADT have been shown but tolerability and health-related quality of life improvement have been suggested but questioned by others. Results from randomized trials, including relapsing or mixed populations, have suggested intermittent ADT to be as effective as continuous ADT. In this study of only metastatic patients, no statistical difference in either overall survival or progression-free survival was shown between intermittent and continuous ADT and suggests that intermittent might be as safe as continuous castration. It could be an option in highly responding and well-informed metastatic patients even if no clear benefit in health-related quality of life was shown. This intermittent modality could be of interest in metastatic patients with significant treatment-induced side-effects.. • To compare intermittent androgen deprivation therapy (ADT) and continuous ADT after 6 months of induction of ADT in patients with metastatic prostate cancer (PCa).. • This is an open-label randomized multi-centre study conducted in 58 centres in Europe. • Patients with metastatic PCa and prostate-specific antigen (PSA) level >20 ng/mL at selection were randomized after 6 months of induction of ADT (leuprorelin and flutamide) if PSA level had decreased below 4 ng/mL. • Patients received either continuous or intermittent ADT. All patients were treated until signs of disease progression under treatment or until study end with a monthly central PSA determination and follow-up visits were performed every 3 months. • The primary endpoint was overall survival. Secondary endpoints included progression-free survival, health-related quality of life (QLQ C30 questionnaire) and safety criteria.. • Of 383 selected patients, 173 had a PSA level below 4 ng/mL after 6 months of induction of ADT and were randomized. Median overall survival (52 vs 42 months, P= 0.75) and median progression-free survival (15.1 vs 20.7 months, P= 0.74) were not significantly different between continuous and intermittent ADT. • Although some differences in quality of life were observed, most of the functional and symptom scales showed no significant difference between the two groups. • Significantly fewer treatment-emergent adverse events occurred in the intermittent group (P= 0.042), with the incidence of headache and hot flushes also lower.. • This first randomized trial comparing continuous with intermittent ADT in metastatic PCa suggests that intermittent ADT might be as safe as continuous ADT. • It could be an option in highly responding and well-informed patients even if no clear benefit in health-related quality of life was shown.

Topics: Administration, Cutaneous; Administration, Oral; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Disease-Free Survival; Drug Administration Schedule; Flutamide; Humans; Kaplan-Meier Estimate; Leuprolide; Male; Prospective Studies; Prostatic Neoplasms; Tablets; Treatment Outcome

Radiotherapy combined with androgen-deprivation therapy (ADT) is superior to radiotherapy alone in localised prostate cancer; however, data comparing ADT alone are somewhat limited.. To compare 3-yr ADT plus radiotherapy with ADT alone in locally advanced prostate cancer patients.. A multicentre randomised open controlled phase 3 trial in 264 histologically confirmed T3-4 or pT3N0M0 prostate cancer patients randomised from March 2000 to December 2003.. ADT (11.25mg subcutaneous depot injection of leuprorelin every 3 mo for 3 yr) plus external-beam radiotherapy or ADT alone. Flutamide (750 g/d) was administered for 1 mo.. The primary objective was 5 yr progression-free survival (PFS) according to clinical or biologic criteria, using the American Society for Therapeutic Radiology and Oncology (ASTRO) and the newer (Phoenix) definition (nadir plus 2 ng/ml), by intention to treat. Secondary objectives included time to locoregional recurrence and distant metastases, and overall and disease-specific survival. Our Analyses: intent-to-treat analysis, multivariate analyses using a Cox model with a 5% threshold from univariate analysis, and Kaplan-Meier estimates.. ADT alone was administered to 130 patients and combined therapy to 133. With a median follow-up of 67 mo, 5-yr PFS was 60.9% for combined therapy versus 8.5% with ADT alone (ASTRO; p<0.0001), and 64.7% versus 15.4%, respectively, for Phoenix (p<0.0011). Locoregional progression was reported in 9.8% of combined-therapy patients versus 29.2% with ADT alone (p<0.0001) and metastatic progression in 3.0% versus 10.8%, respectively (p<0.018). Overall survival was 71.4% with combined therapy versus 71.5% with ADT alone; disease-specific survival was 93.2% versus 86.2%. Limitations included the relatively small population and a relatively short follow-up period.. Combined therapy strongly favoured improved PFS, locoregional control, and metastasis-free survival. Longer follow-up is needed to assess the potential survival impact.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Chemoradiotherapy; Disease-Free Survival; Drug Therapy, Combination; Flutamide; Humans; Leuprolide; Male; Middle Aged; Neoplasm Grading; Prostate-Specific Antigen; Prostatic Neoplasms

We investigated the effects of testosterone change on the sexual function of men with prostate cancer undergoing intermittent maximal androgen deprivation therapy.. We conducted a phase II cohort study of 250 patients with prostate cancer undergoing intermittent maximal androgen deprivation therapy. Flutamide (Eulexin®) 250 mg 3 times daily and leuprolide (Lucrin®) 22.5 mg were given during a 9-month treatment phase (ONPhase). Therapy was ceased provided that prostate specific antigen was 4 ng/ml or less. Monitoring continued every 3 months for a further 2 years (OFFPhase) unless re-treatment occurred. Sexual function was assessed with the QLQ-PR25 version 3.0 prostate module in conjunction with the QLQ-C30 questionnaire at baseline and every 3 months thereafter.. At baseline 46% of patients reported sexual activity with almost half (43%) reporting mild or no erectile problems. Of the men 63% reported an interest in sex (libido), with 28% reporting moderate to high libido. In addition, 26% felt less masculine as a result of illness or treatment. By 3 months of ONPhase all parameters deteriorated, worsening to a low at 9 months. Only 13% of the men reported sexual activity and 10% reported moderate to high libido. The proportion of men feeling less masculine increased to 50%. During the OFFPhase recovery was observed. Of those previously sexually active men 52% resumed sexual activity. Of these patients all reported erectile function returning to baseline. Levels of libido, masculinity and sexual activity recovered but not to baseline levels.. Libido, sexual activity and perceptions of masculinity deteriorate during ONPhase. Of the sexually active men at baseline half will resume sexual activity despite 9 months of androgen deprivation therapy.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Drug Administration Schedule; Flutamide; Humans; Leuprolide; Libido; Male; Masculinity; Penile Erection; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Recovery of Function; Sexuality; Surveys and Questionnaires; Testosterone

To investigate the effects of baseline testosterone on testosterone control and prostate-specific antigen (PSA) suppression using data from a phase III trial (CS21) comparing degarelix and leuprolide in prostate cancer.. In CS21, patients with histologically confirmed prostate cancer (all stages) were randomized to degarelix 240 mg for 1 month followed by monthly maintenance doses of 80 or 160 mg, or leuprolide 7.5 mg/month. Patients receiving leuprolide could receive antiandrogens for flare protection. Treatment effects on testosterone and PSA reduction, testosterone surge, and microsurges were investigated in 3 baseline testosterone subgroups: <3.5, 3.5-5.0, and >5.0 ng/mL. Data are presented for the groups receiving degarelix 240/80 mg (the approved dose) and leuprolide 7.5 mg.. Higher baseline testosterone delayed castration with both treatments. However, castrate testosterone levels and PSA suppression occurred more rapidly with degarelix irrespective of baseline testosterone. With leuprolide, the magnitude of testosterone surge and microsurges increased with increasing baseline testosterone. There was no overall correlation between baseline testosterone and initial PSA decrease in either treatment group, although PSA suppression tended to be slowest with leuprolide and fastest with degarelix in the high baseline testosterone subgroup.. Patients with high baseline testosterone may have greater risk of tumor stimulation (clinical flare) and mini-flares during gonadotrophin-releasing hormone agonist treatment and so the need for flare protection with antiandrogens in these patients is obvious, especially in metastatic disease. Although higher baseline testosterone delays castration, castrate testosterone and PSA suppression occur more rapidly with degarelix, irrespective of baseline testosterone, without the need for flare protection.

Topics: Aged; Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Oligopeptides; Prostatic Neoplasms; Testosterone

Adjuvant androgen suppression and bisphosphonates with escalating doses of radiotherapy might improve efficacy outcomes in men with locally advanced prostate cancer. In this study, we investigated whether these treatments had a detrimental effect on patient-reported-outcome (PRO) scores.. We undertook a phase 3 trial with a 2×2 factorial design in 23 centres in Australia and New Zealand in men with non-metastatic adenocarcinoma of the prostate (stage T2b-4 or T2a, Gleason score ≥7, and baseline prostate-specific antigen concentration [PSA] ≥10 μg/L), and without previous lymph node or systemic metastases or comorbidities that could reduce life expectancy to less than 5 years. The men were randomly assigned in a 1:1:1:1 ratio to 6 months of neoadjuvant (short-term) androgen suppression (STAS) with leuprorelin (22·5 mg every 3 months, intramuscularly) or an additional 12 months (intermediate-term androgen suppression [ITAS]) of leuprorelin with or without 18 months of zoledronic acid (4 mg every 3 months, intravenously). Study drug administration commenced at randomisation after which radiotherapy started within the fifth month in all groups. Treatment allocation was open-label, and computer-generated randomisation, stratified by centre, baseline concentrations of PSA, clinical stage of the tumour, Gleason score, and use of a brachytherapy boost, was done by use of the minimisation technique. PRO scores were calculated from European Organization for Research and Treatment of Cancer quality-of-life and prostate-specific quality-of-life module questionnaires and compared with multiple regression models at baseline, and end of radiotherapy, and 18 months and 36 months according to group and radiation dose. The trial is ongoing and the primary endpoint, prostate-cancer-specific mortality, will be reported in 2014. This study is the final report of PRO scores (a secondary endpoint). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00193856.. 1071 men were randomly assigned to STAS (n=268), STAS plus zoledronic acid (n=268), ITAS (n=268), and ITAS plus zoledronic acid (n=267). At the end of radiotherapy, significant detrimental changes in PRO scores (p<0·01) occurred in all groups. There were no significant differences in global health status between groups at any timepoint. At 18 months, PROs that were significantly worse in the ITAS groups when compared with STAS were hormone-treatment-related symptoms (HTRS; STAS, 10·20 [95% CI 8·66-11·75]; ITAS, 17·36 [13·63-21·08], p<0·01; and ITAS plus zoledronic acid, 19·14 [15·43-22·85], p<0·01), sexual activity (STAS, 26·38 [23·50-29·27]; ITAS, 14·40 [7·44-21·36], p<0·01; and ITAS plus zoledronic acid, 16·34 [9·39-23·28], p<0·01), social function (STAS, 90·31 [87·89-92·73]; ITAS, 87·35 [81·52-93·18], p=0·09; and ITAS plus zoledronic acid, 83·66 [77·85-89·48], p<0·01), fatigue (STAS, 17·05 [14·58-19·51]; ITAS 24·52 [18·58-30·46], p<0·01; and ITAS plus zoledronic acid, 24·26 [18·33-30·18], p<0·01), and financial problems (STAS, 3·39 [1·29-5·48]; ITAS, 8·97 [3·92-14·02], p<0·01; and ITAS plus zoledronic acid, 8·92 [3·89-13·96], p<0·01). With the exception of HTRS, in which marginal differences remained, persisting significant differences disappeared by 36 months. Other factors associated with significant detrimental changes in PRO scores were a brachytherapy boost, incomplete testosterone and haemoglobin recoveries, age, and smoking.. Compared with 6 months of androgen suppression, 18 months of androgen suppression causes additional detrimental changes at the 18 month follow-up in some PRO scores but not in global quality-of-life scores. However, with the exception of HTRS, these differences resolved by 36 months. The use of zoledronic acid every 3 months over 18 months does not result in additional detrimental changes, but the use of a brachytherapy boost to achieve radiation dose escalation in the prostate can adversely affect emotional function and financial problems.. National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, Abbott Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Radiation Oncology Fund, and Maitland Cancer Appeal.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Bone Density Conservation Agents; Brachytherapy; Diphosphonates; Humans; Imidazoles; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Prostatic Neoplasms; Quality of Life; Radiotherapy Dosage; Zoledronic Acid

The Scandinavian Prostate Cancer Group-7 randomized trial demonstrated a survival benefit of combined endocrine therapy and external-beam radiotherapy over endocrine therapy alone in patients with high-risk prostate cancer. In a subset of the study population, the incidence and clinical implications of residual prostate cancer in posttreatment prostate biopsy specimens was evaluated.. Biopsy specimens were obtained from 120 of 875 men in the Scandinavian Prostate Cancer Group-7 study.. Biopsies were performed at median of 45 months follow-up. In 63 patients receiving endocrine treatment only and 57 patients receiving combined treatment, residual cancer was found in 66% (n = 41) and 22% (n = 12), respectively (p < 0.0001). The vast majority of residual tumors were poorly differentiated (Gleason score ≥ 8). Endocrine therapy alone was predictive of residual prostate cancer: odds ratio 7.49 (3.18-17.7), p < 0.0001. In patients with positive vs. negative biopsy the incidences of clinical events were as follows: biochemical recurrence 74% vs. 27% (p < 0.0001), local progression 26% vs. 4.7% (p = 0.002), distant recurrence 17% vs. 9.4% (p = 0.27), clinical recurrence 36% vs. 13% (p = 0.006), cancer-specific death 19% vs. 9.7% (p = 0.025). In multivariable analysis, biochemical recurrence was significantly associated with residual cancer: hazard ratio 2.69 (1.45-4.99), p = 0.002, and endocrine therapy alone hazard ratio 3.45 (1.80-6.62), p < 0.0001.. Radiotherapy combined with hormones improved local tumor control in comparison with endocrine therapy alone. Residual prostate cancer was significantly associated with serum prostate-specific antigen recurrence, local tumor progression, clinical recurrence, and cancer-specific death in univariable analysis. Residual cancer was predictive of prostate-specific antigen recurrence in multivariable analysis.

Topics: Aged; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Biopsy; Combined Modality Therapy; Disease Progression; Flutamide; Follow-Up Studies; Humans; Leuprolide; Male; Neoplasm Recurrence, Local; Neoplasm, Residual; Nitriles; Odds Ratio; Prospective Studies; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Tosyl Compounds

To evaluate whether switching prostate cancer (PCa) patients from leuprolide to degarelix is associated with any change in the efficacy of testosterone suppression or safety profile during the first 3 months.. Participants were 134 patients with histologically confirmed PCa who had completed 1 year of treatment with leuprolide 7.5 mg monthly before being switched to degarelix. These patients were re-randomised for the extension trial to receive a starting dose of 240 mg degarelix followed by monthly maintenance doses of either 80 (n = 69) or 160 mg (n = 65). For efficacy assessment, serum testosterone, prostate-specific antigen (PSA), luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels measured at days 3, 7, 14, 28, 56 and 84 assessed whether treatment efficacy is sustained. Safety and tolerability assessments included adverse events (AEs), physical examinations, electrocardiograms and clinically significant changes in laboratory safety parameters.. Serum testosterone, LH, and PSA levels were all sustained in both treatment arms during the observation period. Interestingly, FSH levels were further decreased by 30% following the switch to degarelix. With the exception of injection site reactions, the overall prevalence and pattern of AEs during the first 3 months after the switch was comparable to that during the last 3 months leuprolide treatment in the main trial. There were five (4%) patients discontinued to treatment-related AEs including injection site pain (n = 3) and fatigue (n = 2).. This 3-month analysis indicates that patients with prostate cancer can be safely switched from leuprolide to degarelix treatment with sustained efficacy as measured by biochemical markers.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Drug Administration Schedule; Drug Substitution; Follicle Stimulating Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Outcome

The aim of the study was to compare the onset, incidence and frequency/intensity of hot flushes during androgen-deprivation therapy with a gonadotropin-releasing hormone antagonist (GnRH) blocker versus an agonist using data from a randomized Phase 3 clinical trial. In total, 610 prostate cancer patients received monthly degarelix (s.c., 240/80 mg, n=207, or 240/160 mg, n=202) or leuprolide (i.m., 7.5 mg, n=201) for 12 months. Data on hot flushes was collected as self-reported adverse events and in a subgroup of 254 patients with electronic diaries. The onset of hot flushes was faster on degarelix versus leuprolide, and was accompanied by higher median hot flush scores during the first 3 months. However, there were no significant differences in overall incidence rates and median hot flush scores over the entire 12 months. After the third month, incidence rates dropped below 6%, whereas prevalence rates remained constant in all the three treatment arms. In multivariate analysis, body weight and heart rate at baseline were independent predictors of hot flushes (P<0.05). Except for a more rapid onset with the GnRH antagonist, there were no major differences in the overall pattern of hot flushes between treatment options. Weight control may help to minimize the incidence of hot flushes.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Body Weight; Flushing; Follow-Up Studies; Gonadotropin-Releasing Hormone; Heart Rate; Humans; Leuprolide; Male; Middle Aged; Oligopeptides; Prostatic Neoplasms; Risk Factors; Self Report; Treatment Outcome

Post-treatment prostate biopsy side-effects were evaluated in patients with locally advanced prostate cancer on endocrine therapy alone or combined with radiotherapy in the Scandinavian Prostate Cancer Group-7 randomized trial.. One-hundred and twenty patients underwent transrectalultrasound-guided biopsy, and were requested to complete a questionnaire on side-effects occurring within 7 days' follow-up.. The questionnaire was returned by 109 patients (91%) (endocrine therapy only 52%, combined endocrine therapy and radiotherapy 48%). Previous therapy had no significant influence on pain, urinary flow, haematuria or haematospermia. Pain at biopsy was reported in 63% (mild, 57%; moderate, 5.6%; severe, one patient) and pain at follow-up in 31% (mild, 27%; moderate, four patients). Haematuria (mean duration 2.2 days) was reported in 41%, and reduced urinary flow in 20% (mild, 18%; severe: four patients; no patient had urinary retention). Haematospermia was scarce. No patient reported urinary tract infection. Rectal bleeding occurred in 18% in the endocrine and 35% in the combined therapy group (p = 0.047), with a mean duration of 1.6 and 2.2 days, respectively (p = 0.031). In logistic regression analysis, a trend towards increased rectal bleeding was found in patients on combined endocrine therapy and radiotherapy (odds ratio 2.4, p = 0.050).. Patient-reported post-treatment prostate biopsy side-effects were mild and self-limiting.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Biopsy; Combined Modality Therapy; Drug Therapy; Drug Therapy, Combination; Flutamide; Follow-Up Studies; Hematuria; Hemospermia; Humans; Incidence; Leuprolide; Logistic Models; Male; Middle Aged; Pain; Prostatic Neoplasms; Radiotherapy; Retrospective Studies; Surveys and Questionnaires

The adverse effects of long-term drug therapy for prostate cancer (PCa) can dramatically impact patient quality of life and are considered to be important factors when selecting treatment.. To assess stretched penile length before and after long-term androgen deprivation therapy (ADT) for treatment of PCa.. From January 2008 to June 2010 at a single institution, 39 consecutive patients without distant metastases who were elected to receive ADT as initial therapy for PCa were prospectively enrolled. Exclusion criteria were history of penile anomalies and/or trauma, and prior radical prostate surgery or radiation therapy. Erectile functions were evaluated at baseline according to the International Index of Erectile Function (IIEF). Vertically stretched penile length was measured every 3 months from the pubopenile junction to the meatus with a spring scale.. After ADT, significant 3-month interval changes in stretched penile length were noted for up to 15 months (P < 0.001). The relationship between potency and penile shortening was not significant (P = 0.45).. The mean patient age was 67.1 years. Before therapy, the mean stretched penile length was 10.76 cm. After 24 months of ADT, mean penile length had decreased to 8.05 cm. However, these changes plateaued after 15 months. Normal erectile function (EF) was reported by 41% of patients before therapy, while 10.5% reported normal EF at the 24-month follow-up. The relationship between potency and penile shortening was not significant. However, patients who preserved their potency tended to experience less penile shortening.. The administration of luteinizing hormone-releasing hormone (LHRH) agonists induced significant decreases in penile length for only up to 15 months in the absence of the confounding effects of surgery and radiation.

Topics: Aged; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Organ Size; Penile Erection; Penis; Prospective Studies; Prostatic Neoplasms; Testosterone

It is not known whether short-term androgen-deprivation therapy (ADT) before and during radiotherapy improves cancer control and overall survival among patients with early, localized prostate adenocarcinoma.. From 1994 through 2001, we randomly assigned 1979 eligible patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a prostate-specific antigen (PSA) level of 20 ng per milliliter or less to radiotherapy alone (992 patients) or radiotherapy with 4 months of total androgen suppression starting 2 months before radiotherapy (radiotherapy plus short-term ADT, 987 patients). The primary end point was overall survival. Secondary end points included disease-specific mortality, distant metastases, biochemical failure (an increasing level of PSA), and the rate of positive findings on repeat prostate biopsy at 2 years.. The median follow-up period was 9.1 years. The 10-year rate of overall survival was 62% among patients receiving radiotherapy plus short-term ADT (the combined-therapy group), as compared with 57% among patients receiving radiotherapy alone (hazard ratio for death with radiotherapy alone, 1.17; P=0.03). The addition of short-term ADT was associated with a decrease in the 10-year disease-specific mortality from 8% to 4% (hazard ratio for radiotherapy alone, 1.87; P=0.001). Biochemical failure, distant metastases, and the rate of positive findings on repeat prostate biopsy at 2 years were significantly improved with radiotherapy plus short-term ADT. Acute and late radiation-induced toxic effects were similar in the two groups. The incidence of grade 3 or higher hormone-related toxic effects was less than 5%. Reanalysis according to risk showed reductions in overall and disease-specific mortality primarily among intermediate-risk patients, with no significant reductions among low-risk patients.. Among patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a PSA level of 20 ng per milliliter or less, the use of short-term ADT for 4 months before and during radiotherapy was associated with significantly decreased disease-specific mortality and increased overall survival. According to post hoc risk analysis, the benefit was mainly seen in intermediate-risk, but not low-risk, men. (Funded by the National Cancer Institute; RTOG 94-08 ClinicalTrials.gov number, NCT00002597.).

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Erectile Dysfunction; Flutamide; Follow-Up Studies; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Multivariate Analysis; Prostate; Prostatic Neoplasms; Radiotherapy; Radiotherapy Dosage; Risk; Survival Rate

We investigated the efficacy and safety of degarelix treatment and the effects of switching from leuprolide to degarelix in an ongoing extension study with a median 27.5-month followup of a pivotal 1-year prostate cancer trial.. Patients who completed a 1-year pivotal phase III trial continued on the same monthly degarelix maintenance dose (160 or 80 mg in 125 each), or were re-randomized from leuprolide 7.5 mg to degarelix 240/80 mg (69) or 240/160 mg (65). Data are shown on the approved degarelix 240/80 mg dose. The primary end point was safety/tolerability and the secondary end points were testosterone, prostate specific antigen, luteinizing hormone and follicle-stimulating hormone responses, and prostate specific antigen failure and progression-free survival.. During followup testosterone and prostate specific antigen suppression were similar to those in the 1-year trial in patients who continued on degarelix or switched from leuprolide. The prostate specific antigen progression-free survival hazard rate was decreased significantly after the switch in the leuprolide/degarelix group while the rate in those who continued on degarelix was consistent with the rate in treatment year 1. The same hazard rate change pattern occurred in the group with baseline prostate specific antigen greater than 20 ng/ml. Adverse event frequency was similar between the groups and decreased with time.. Data support the statistically significant prostate specific antigen progression-free survival benefit for degarelix over leuprolide seen during year 1 and the use of degarelix as first line androgen deprivation therapy as an alternative to a gonadotropin-releasing hormone agonist.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Cross-Over Studies; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Oligopeptides; Prostatic Neoplasms

Testosterone stimulates growth in many prostate tumours. The established GnRH analogue leuprolide acetate is incorporated in a novel biodegradable polymer matrix (Atrigel® delivery system), that can be administered to reduce testosterone levels in men with advanced hormone-dependent prostate cancer. This novel formulation is available as a 1-, 3- and most recently 6-month depot (Eligard® 45 mg). The latter was shown to lower and maintain safe and effective serum testosterone suppression in a clinical study.. A non-interventional study to confirm the efficacy and safety of 6-monthly leuprolide acetate (Eligard® 45 mg) in routine urological practice was performed in Germany. Data were obtained from 1273 patients under the care of 634 urologists, and were analysed descriptively. Concentrations of PSA and serum testosterone were documented at the baseline visit and at 6 and 12 months following 6-monthly leuprolide acetate. The participating physicians were also asked to assess the efficacy, tolerability and handling of 6-monthly leuprolide acetate.. Serum concentrations of PSA and testosterone were decreased substantially within 6 months of initial 6-monthly leuprolide acetate administration. At 12 months, median reductions of 96% (to 0.5 ng/ml) in PSA, and 90% (to 8.9 ng/dl) in serum testosterone, were observed. Further PSA and serum testosterone decreases were also observed in a subpopulation of patients who switched to 6-monthly leuprolide acetate from other GnRH analogues. Physicians rated 6-monthly leuprolide acetate as easy to use, and patients reported good tolerability. Adverse events occurred in 9% of patients; the majority were not serious. In particular, low rates of hot flushes were reported.. This non-interventional study showed that the reliable reduction of PSA and testosterone levels demonstrated in previous clinical studies of twice-yearly leuprolide acetate can also be achieved in routine clinical practice. This study also confirmed good tolerability of 6-monthly leuprolide acetate in routine clinical use and received positive appraisal from physicians.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Time Factors

To report acute toxicity resulting from radiotherapy (RT) dose escalation and hypofractionation using intensity-modulated RT (IMRT) treatment combined with androgen suppression in high-risk prostate cancer patients.. Sixty patients with a histological diagnosis of high-risk prostatic adenocarcinoma (having either a clinical Stage of > or =T3a or an initial prostate-specific antigen [PSA] level of > or =20 ng/ml or a Gleason score of 8 to 10 or a combination of a PSA concentration of >15 ng/ml and a Gleason score of 7) were enrolled. RT prescription was 68 Gy in 25 fractions (2.72 Gy/fraction) over 5 weeks to the prostate and proximal seminal vesicles. The pelvic lymph nodes and distal seminal vesicles concurrently received 45 Gy in 25 fractions. The patients were treated with helical TomoTherapy-based IMRT and underwent daily megavoltage CT image-guided verification prior to each treatment. Acute toxicity scores were recorded weekly during RT and at 3 months post-RT, using Radiation Therapy Oncology Group acute toxicity scales.. All patients completed RT and follow up for 3 months. The maximum acute toxicity scores were as follows: 21 (35%) patients had Grade 2 gastrointestinal (GI) toxicity; 4 (6.67%) patients had Grade 3 genitourinary (GU) toxicity; and 30 (33.33%) patients had Grade 2 GU toxicity. These toxicity scores were reduced after RT; there were only 8 (13.6%) patients with Grade 1 GI toxicity, 11 (18.97%) with Grade 1 GU toxicity, and 5 (8.62%) with Grade 2 GU toxicity at 3 months follow up. Only the V60 to the rectum correlated with the GI toxicity.. Dose escalation using a hypofractionated schedule to the prostate with concurrent pelvic lymph node RT and long-term androgen suppression therapy is well tolerated acutely. Longer follow up for outcome and late toxicity is required.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Combined Modality Therapy; Dose Fractionation, Radiation; Gastrointestinal Tract; Humans; Leuprolide; Lymphatic Irradiation; Male; Middle Aged; Pelvis; Prospective Studies; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Radiation Injuries; Radiotherapy, Intensity-Modulated; Rectum; Seminal Vesicles; Urinary Bladder; Urogenital System

The effects of testosterone (T) and estradiol (E(2)) on cognition in men are confounded in extant studies. This randomized, placebo-controlled trial was undertaken to investigate the possible effects of E(2) on cognition in older men. Twenty-five men with prostate cancer (mean age: 71.0+/-8.8 years) who required combined androgen blockade treatment were enrolled. Performance on cognitive tests was evaluated at pre-treatment baseline and following 12 weeks of treatment with a gonadotropin-releasing hormone analog and the nonsteroidal antiandrogen bicalutamide to determine whether specific cognitive functions would decline when the production of both T and E(2) were suppressed. In the second phase of the study, either micronized E(2) 1mg/day or an oral daily placebo was randomly added to the combined androgen blockade for an additional 12 weeks to determine whether E(2) would enhance performance in specific cognitive domains (verbal memory, spatial ability, visuomotor abilities and working memory). Compared to pretreatment, no differences in scores occurred on any cognitive test following 12 weeks of combined androgen blockade. In the add-back phase of the study (Visit 3), the placebo-treated men, but not the E(2)-treated men, exhibited a trend towards improvement in their scores on both the immediate (p=.075) and delayed recall (p=.095) portions of a verbal memory task compared to baseline. Moreover, at Visit 3, placebo-treated men performed significantly better than the E(2)-treated men on both the immediate (p=.020) and delayed recall (p=.016) portions of the verbal memory task. Thus, combined androgen blockade plus add-back E(2) failed to improve short- or long-term verbal memory performance in this sample of older men being treated for prostate cancer.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cognition; Drug Administration Schedule; Estradiol; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Neuropsychological Tests; Nitriles; Placebos; Prostatic Neoplasms; Tosyl Compounds

Study Type - Therapy (RCT) Level of Evidence 1b OBJECTIVE To compare the activity of degarelix, a new gonadotrophin-releasing hormone (GnRH) blocker, with leuprolide depot 7.5 mg in the control of total serum alkaline phosphatase (S-ALP) levels in patients with prostate cancer. PATIENTS AND METHODS In the randomized, phase III trial (CS21), patients with histologically confirmed prostate cancer (all stages), were randomized to one of three regimens: degarelix subcutaneous 240 mg for 1 month followed by monthly maintenance doses of 80 mg or 160 mg, or intramuscular leuprolide 7.5 mg/month. Patients receiving leuprolide could also receive antiandrogens for flare protection. We report exploratory S-ALP analyses from CS21, focusing on the comparison of degarelix 240/80 mg with leuprolide 7.5 mg, in line with the recent approvals of this dose by the USA Food and Drug Administration and the European Medicines Agency. RESULTS Overall, 610 patients were included, with a median age of 73 years and median prostate-specific antigen (PSA) level of 19.0 ng/mL. Baseline S-ALP levels were high in metastatic patients and highest in patients with metastatic disease and a haemoglobin level of <13 g/dL. In metastatic disease, after initial peaks in both groups, S-ALP levels were suppressed below baseline with degarelix but were maintained around baseline with leuprolide. The late rise in S-ALP seen with leuprolide was not apparent with degarelix. The pattern of S-ALP response was similar in patients with a baseline PSA level of > or =50 ng/mL. Between-treatment differences in patients with metastatic disease and those with a PSA level of > or =50 ng/mL were significant at day 364 (P = 0.014 and 0.007, respectively). CONCLUSION Patients with metastatic disease or those with PSA levels of > or =50 ng/mL at baseline had greater reductions in S-ALP levels with degarelix than with leuprolide. Patients in the degarelix group maintained S-ALP suppression throughout the study, in contrast to those in the leuprolide group. This suggests that degarelix might offer better S-ALP control than leuprolide and might prolong control of skeletal metastases, compared with GnRH agonists, over a 1-year treatment period.

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Antineoplastic Agents; Epidemiologic Methods; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

Recent data suggest prostate-specific antigen (PSA) progression may predict overall survival in prostate cancer patients.. To compare the activity of degarelix and leuprolide regarding PSA recurrence-free survival.. Phase 3, 1-yr, multicentre, randomised, open-label trial comparing the efficacy and safety of degarelix at 240 mg for 1 mo, and then 80 mg monthly (240/80 mg); degarelix at 240 mg for 1 mo, and then 160 mg monthly; and leuprolide at 7.5 mg/mo. Overall, 610 patients with histologically confirmed prostate cancer (all stages), for whom androgen deprivation therapy was indicated, were included. The primary end point of this trial has been reported previously; the protocolled and exploratory subgroup analyses reported in this paper focus on degarelix at 240/80 mg (dose approved by the US Food and Drug Administration and the European Medicine Evaluation Association for the treatment of patients with hormone-naive advanced prostate cancer).. PSA progression-free survival (two consecutive increases in PSA of 50% compared with nadir and ≥ 5 ng/ml on two consecutive measurements at least 2 wk apart or death) and change in PSA were reviewed. Effects of baseline disease stage (localised, locally advanced, and metastatic) and PSA level (<10, 10-20, >20-50, and >50 ng/ml) were analysed.. Patients receiving degarelix showed a significantly lower risk of PSA progression or death compared with leuprolide (p=0.05). PSA recurrences occurred mainly in patients with advanced disease and exclusively in those with baseline PSA >20 ng/ml. Patients with PSA >20 ng/ml had a significantly longer time to PSA recurrence with degarelix (p=0.04). The relatively low number of patients in each subgroup is a limitation of this study.. These results generate the hypothesis that degarelix at 240/80 mg offers improved PSA control compared with leuprolide. PSA recurrences occurred almost exclusively in patients with metastatic prostate cancer or high baseline PSA during this 1-yr study. Further studies are warranted to confirm these findings.

Topics: Aged; Antineoplastic Agents, Hormonal; Disease-Free Survival; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Neoplasm Recurrence, Local; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms

This was an exploratory analysis of a trial of intermittent androgen deprivation (IAD) in men with biochemical relapse (BR) to establish first cycle characteristics prognostic for progression to castration-resistant prostate cancer (CRPC) and death.. Men with BR of prostate cancer after radical prostatectomy (RP) or radiation (RT) were treated with androgen deprivation therapy (ADT) comprised of leuprolide and flutamide. After 9 months on treatment, ADT was stopped, and monthly prostate-specific antigen (PSA) levels were observed during the off-treatment interval. When the PSA reached a threshold value (1 ng/mL for RP, 4 ng/mL for RT), ADT was resumed in a new cycle. Patients were treated intermittently in this manner until CRPC, which was defined as > or = two consecutive increasing PSA values while on ADT with castrate testosterone levels.. Seventy-two of 100 patients enrolled onto the study met criteria for this analysis. The duration of the first off-treatment interval (< or = v > 40 weeks) was associated with shorter time to CRPC (hazard ratio = 2.9; 95% CI, 1.1 to 7.7; P = .03) and death (hazard ratio = 3.8; 95% CI, 1.1 to 13.6; P = .04) after adjusting for age, stage, grade, and PSA at diagnosis.. In patients who completed the first cycle of IAD, a duration of the first off-treatment interval of < or = 40 weeks defines a subset of patients at higher risk of CRPC and death. Conversely, patients with an off-treatment interval of more than 40 weeks have a significantly better long-term prognosis.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Androgen Antagonists; Antineoplastic Agents, Hormonal; Brachytherapy; Castration; Cause of Death; Chemotherapy, Adjuvant; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Flutamide; Follow-Up Studies; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Leuprolide; Male; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Neoplasm Staging; Probability; Prospective Studies; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Risk Assessment; Salvage Therapy; Survival Analysis; Time Factors; Treatment Outcome

A microencapsulated, sustained-release formulation of leuprolide acetate 3.75 mg has been developed.. This study investigated the effectiveness, pharmacokinetics, and safety profile of a 1-month leuprolide acetate 3.75-mg depot formulation for suppressing testosterone concentrations in patients with prostate cancer.. This was a Phase III, open-label, international multicenter clinical trial. Patients with prostate cancer who, in the judgment of the investigators, could benefit from androgen deprivation therapy received 6 monthly intramuscular injections of leuprolide acetate 3.75-mg depot. Plasma testosterone concentrations were determined at specific times throughout the study. The primary end point was the proportion of successful patients over the total number of evaluable patients (ie, patients with evaluable testosterone concentrations at all monthly assessments and no missing values due to treatment-related adverse events). Treatment success was defined as testosterone suppression below the clinical castration level (ie,

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Area Under Curve; Delayed-Action Preparations; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Testosterone

To investigate the impacts of leuprolide acetate on the quality of life (QoL) of patients with prostate cancer.. A total of 104 patients was enrolled in this prospective multicenter study. All patients received subcutaneous injections of 3.75 mg leuprolide acetate at 4 week intervals for a total of 12 weeks. QoL was assessed before treatment and at 12 weeks using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and an accompanying prostate cancer-specific module (QLQ-PR25).. Eighty-nine of 104 patients (85.6%) completed the 12 week study. Eighty-six of 89 patients (96.6%) achieved and maintained medical castration. The results of the EORTC QLQ-C30 indicated that patients experienced an improvement in global health status/QoL (p < 0.001), despite a deterioration in physical and role functioning (p = 0.012 and p = 0.007, respectively). The symptom scales indicated a statistically significant improvement in appetite (p = 0.003). The results of the QLQ-PR25 revealed that patients experienced an increase in hot flushes (p < 0.001) and erection problems and uncomfortable sexual intimacy among the sexual functioning items (p = 0.030 and p = 0.023, respectively), but day-time urinary frequency was improved (p = 0.004).. The results of this prospective study indicate that leuprolide acetate treatment was accompanied by improvements in global health status/QoL, despite a deterioration in physical, role and sexual function.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Castration; Chemotherapy, Adjuvant; Hot Flashes; Humans; Leuprolide; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Quality of Life; Republic of Korea; Sexual Dysfunction, Physiological; Sexual Dysfunctions, Psychological; Statistics, Nonparametric; Surveys and Questionnaires; Urination Disorders

We assessed the cardiovascular safety profile of degarelix, a new gonadotropin-releasing hormone antagonist.. This is the first report to our knowledge on cardiovascular safety data from a completed 1-year randomized controlled trial of leuprolide acetate vs degarelix. Outcomes considered in these analyses included the QT interval by central reading and analysis, and cardiovascular adverse events. On multivariate analyses relationships between selected baseline factors and cardiovascular events were evaluated.. There were no significant differences between treatment groups for mean change in Fridericia's correction of QT during the trial. Markedly abnormal Fridericia's correction of QT values (500 milliseconds or greater) were observed in only a small number of subjects by treatment group, that is 2 (less than 1%) in the pooled degarelix group and 2 (1%) in the leuprolide group. Supraventricular arrhythmias were the most common type of arrhythmias, affecting 2% of subjects in the pooled degarelix group and 4% in the leuprolide group. Other arrhythmias occurred in 1% or less of subjects by treatment group. The most frequently reported cardiac disorder was ischemic heart disease, which occurred in 4% of subjects treated with degarelix and 10% of those on leuprolide. Cox proportional hazard ratio estimates for selected baseline covariates showed a significantly increased risk of cardiovascular events by age (p=0.0459) and systolic blood pressure (p=0.0061).. In men with prostate cancer degarelix and leuprolide have similar cardiovascular safety profiles. These observations suggest that the cardiovascular events associated with both agents result from hypogonadism rather than a direct drug effect.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Cardiovascular Diseases; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Oligopeptides; Prostatic Neoplasms; Time Factors

This multicentre European study compared the safety and tolerability of the existing 11.25 mg 3-month depot of leuprorelin acetate with a new 30 mg 6-month depot in men with newly diagnosed prostate cancer or prostate-specific antigen relapse after radiotherapy or prostatectomy. The primary end points were safety and tolerability and secondary end points were clinical response based on European Organization for Research and Treatment of Cancer (EORTC) criteria and response rate by time point for testosterone suppression (castrate level

Topics: Aged; Antineoplastic Agents; Delayed-Action Preparations; Europe; Follicle Stimulating Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

To investigate hot flashes and quality of life during combined androgen blockade (CAB) therapy using steroidal or nonsteroidal antiandrogens.. A total of 151 patients with prostate cancer, who were enrolled into this study from May 2001 to June 2003, were randomized to receive CAB therapy using a luteinizing hormone-releasing hormone agonist (leuprorelin) combined with a steroidal antiandrogen (chlormadinone) or a nonsteroidal antiandrogen (bicalutamide). The incidence of, frequency of, and distress due to hot flashes were evaluated with a self-administered questionnaire during a 2-year period. The general and disease-specific quality-of-life outcomes were also measured using the Functional Assessment of Cancer Therapy-Prostate questionnaire.. Data were available for analysis from 124 patients. Although the incidence of hot flashes largely tended to be greater in the bicalutamide group than in the chlormadinone group, no significant difference was noted in the cumulative incidence of hot flashes at 2 years. The median frequency of hot flashes daily was 1.3 and 2.2 for warmth/flushing (P = .16) and 1.0 and 3.6 for sweating (P = .021) in the chlormadinone and bicalutamide groups, respectively. Patients in the chlormadinone group were significantly less likely to be distressed by warmth/flushing (odds ratio 0.47, P < .001) and sweating (odds ratio 0.61, P = .01) than were those in the bicalutamide group. The Functional Assessment of Cancer Therapy-Prostate scores over time showed no intergroup differences.. Our results suggest that CAB using a steroidal antiandrogen such as chlormadinone might induce fewer and less-distressing hot flashes than CAB with bicalutamide.

Topics: Aged; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Chlormadinone Acetate; Drug Therapy, Combination; Gonadotropin-Releasing Hormone; Hot Flashes; Humans; Leuprolide; Male; Nitriles; Prospective Studies; Prostatic Neoplasms; Quality of Life; Steroids; Tosyl Compounds

We determined whether thalidomide can prolong progression-free survival in men with biochemically recurrent prostate cancer treated with limited androgen deprivation therapy.. A total of 159 patients were enrolled in a double-blind randomized trial to determine if thalidomide can improve the efficacy of a gonadotropin-releasing hormone agonist in hormone responsive patients with an increasing prostate specific antigen after primary definitive therapy for prostate cancer. Patients were randomized to 6 months of gonadotropin-releasing hormone agonist followed by 200 mg per day oral thalidomide or placebo (oral phase A). At the time of prostate specific antigen progression gonadotropin-releasing hormone agonist was restarted for 6 additional months. Patients were then crossed over to the opposite drug and were treated until prostate specific antigen progression (oral phase B). Testosterone and dihydroxytestosterone were likewise monitored throughout the study.. During oral phase A the median time to prostate specific antigen progression was 15 months for the thalidomide group compared to 9.6 months on placebo (p = 0.21). The median time to prostate specific antigen progression during oral phase B for the thalidomide group was 17.1 vs 6.6 months on placebo (p = 0.0002). No differences in time to serum testosterone normalization between the thalidomide and placebo arms were documented during oral phase A and oral phase B. Thalidomide was tolerable although dose reductions occurred in 47% (58 of 124) of patients.. Despite thalidomide having no effect on testosterone normalization, there was a clear effect on prostate specific antigen progression during oral phase B. This is the first study to our knowledge to demonstrate the effects of thalidomide using intermittent hormonal therapy.

Topics: Administration, Oral; Aged; Aged, 80 and over; Androgens; Angiogenesis Inhibitors; Antineoplastic Agents, Hormonal; Cross-Over Studies; Double-Blind Method; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Thalidomide

To investigate changes in bone mineral density (BMD) and osteoporosis, over 3 years of intermittent androgen-suppression therapy (IAST).. This was a Phase II individual cohort study of 72 patients with prostate cancer without metastatic bone disease, enrolled between 1999 and 2002. Patients had 9 months flutamide (250 mg, three times daily) and leuprolide (22.5 mg, 3-monthly depot) after which, patients ceased therapy providing that their PSA levels were <4 ng/mL. AST re-commenced when the PSA level exceeded the pretreatment level or was >20 ng/mL. BMD for hip and spine was the primary endpoint; assessed at baseline; completion of initial treatment period; and at 1 and 2 years after initial treatment (POST period).. Osteoporosis increased from 7% at baseline to 10% at 3 years. The BMD declined after 9 months treatment, at -1.9% and -3.3% at hip and spine, respectively (P < 0.001). Subsequent BMD decline in the POST period was attenuated; at 1 years and 2 years later, hip -0.6% (not significant), and -0.8% (P < 0.014), and spine +1.0% and +0.2% (not significant). The BMD change in those remaining 'off' therapy for 2 years (n = 20) was strongly associated with the level of testosterone recovery; a peak testosterone level of <5 nmol/L associated with a greater then normal physiological loss. Testosterone recovery was less likely in older men.. The attenuation of spine and hip BMD decline after 3-year IAST compared with those reported for continuous AST appears to be due to testosterone driven BMD recovery in the POST period. Failure of testosterone recovery was associated with worse final BMD. By reducing the potential risk for adverse bone complications, intermittent therapy may become an important consideration when the therapeutic ratio is narrow.

Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Bone Density; Cohort Studies; Flutamide; Hip; Humans; Leuprolide; Male; Middle Aged; Osteoporosis; Prostatic Neoplasms; Quality of Health Care; Spine; Testosterone; Time Factors

We evaluated rapid androgen cycling in combination with docetaxel for men with progressive noncastrate prostate cancers.. Noncastrate patients with 150 ng/dL) and an undetectable prostate-specific antigen (PSA;

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Docetaxel; Humans; Leuprolide; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Testosterone

We determined the risk of recurrence in men enrolled on a randomized trial for prostate cancer who were treated with radiation therapy (RT) alone or in conjunction with combined or less than combined androgen suppression therapy (AST).. Between 1995 and 2001, 206 men with localized but unfavorable-risk adenocarcinoma of the prostate were randomly assigned to receive RT or RT and AST, which was defined as 6 months of both a luteinizing hormone-releasing hormone agonist and an antiandrogen. A post-random assignment hypothesis that was generated by multivariable Cox regression analyses was used to evaluate whether the risk of prostate-specific antigen (PSA) recurrence was significantly associated with months of antiandrogen use; regression analysis adjusted for known prognostic factors, comorbidity score, and medications that can elevate liver function tests sufficiently to necessitate discontinuation of the antiandrogen.. After a median follow-up of 8.2 years (interquartile range,7.0 to 9.5 years), 81 men sustained PSA recurrence. An increasing PSA level (P < .001); Gleason score of 8, 9, or 10 (P < .001); and clinical category T2 disease (P = .005) were significantly associated with an increased risk of recurrence. However, recurrence risk was significantly decreased (adjusted hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = .001) with each additional month of antiandrogen use after analysis was adjusted for these known prognostic factors.. Men with localized but unfavorable-risk prostate cancer who were treated with RT and 6 months of planned combined AST appear to have an increased risk of recurrence when treated with less than as compared with 6 months of the antiandrogen.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Factors

To determine optimal predictors with which to select the crucial patients enrolled in delayed-combined androgen blockade (CAB) trials, based on risk factors.. From January 2001 to December 2004, 92 prostate cancer patients with T1c, T2 and T3aN0M0 were enrolled in a clinical trial. Medical castration and anti-androgen treatment were used sequentially as delayed-CAB. The prostate specific antigen (PSA) nadir was determined following medical castration only. Anti-androgen treatment was administered if a PSA progression was observed and the subsequent PSA response was evaluated. Time to PSA biochemical failure, induced by medical castration or with anti-androgen treatment, was estimated. Risk factors of PSA failure were evaluated by multivariate analysis.. During luteinizing hormone-releasing hormone (LH-RH) monotherapy, a Kaplan-Meier analysis estimated that the proportion of patients without PSA progression was 64.8% at 5 years. In the multivariate analysis of the prediction of PSA progression with LH-RH monotherapy, a Gleason score over 8, initial PSA >20 ng/ml and PSA nadir >0.2 ng/ml were significant independent risk factors that affected PSA biochemical failure. The PSA progression-free rate in the lower PSA nadir group was significantly lower than that in the other. The 25 patients in the higher PSA nadir group were treated with anti-androgen therapy. Under anti-androgen therapy, the PSA progression-free rate was 62.6% at 5 years. Only PSA nadir >0.2 ng/ml was a significant independent risk factor. The PSA progression-free rate in the lower PSA nadir group was significantly lower than the other.. PSA nadir was the optimal predictive for low stage, non-metastatic population during delayed-CAB.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Monitoring; Gonadotropin-Releasing Hormone; Goserelin; Humans; Kaplan-Meier Estimate; Leuprolide; Male; Middle Aged; Multivariate Analysis; Nitriles; Patient Selection; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Factors; Tosyl Compounds; Treatment Failure

Groups have investigated time to testosterone recovery in patients who have undergone androgen deprivation therapy, usually by measuring androgen every 3 months, with varying results. To our knowledge this represents the largest study using monthly testosterone and dihydroxytestosterone measurement to evaluate the kinetics of androgen recovery following limited androgen deprivation therapy.. Monthly serum androgen levels were analyzed following 2, 6-month cycles of gonadotropin-releasing hormone agonist therapy as part of a randomized, placebo controlled study of the role of thalidomide in delaying time to prostate specific androgen progression.. By the Kaplan-Meier method the median time to testosterone normalization in cycles 1 vs 2 was 15.4 vs 18.3 weeks with similar dihydroxytestosterone recovery times. Neither on-study prostate specific antigen, Gleason score nor thalidomide treatment had a significant impact on time to testosterone normalization. However, in cycle 1 men with low baseline dihydroxytestosterone and those who were more than 67 years old had significantly longer time to T normalization on Cox model analysis. Additionally, in cycle 2 patients with prior local radiation therapy had longer time to testosterone normalization, although this was no longer significant on Cox model analysis. Cox model analysis in cycle 2 showed that low baseline dihydroxytestosterone and testosterone, low testosterone nadir and white race were associated with longer time to testosterone normalization.. Findings of delayed testosterone recovery may be useful for designing and analyzing clinical trials of limited androgen deprivation therapy and for estimating the duration of treatment associated side effects in patients undergoing limited androgen deprivation therapy.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Androgens; Antineoplastic Agents, Hormonal; Biopsy, Needle; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Goserelin; Humans; Immunohistochemistry; Leuprolide; Male; Middle Aged; Neoplasm Staging; Probability; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Recovery of Function; Reference Values; Risk Assessment; Testosterone; Thalidomide; Treatment Outcome

To evaluate the efficacy and safety of degarelix, a new gonadotrophin-releasing hormone (GnRH) antagonist (blocker), vs leuprolide for achieving and maintaining testosterone suppression in a 1-year phase III trial involving patients with prostate cancer.. In all, 610 patients with adenocarcinoma of the prostate (any stage; median age 72 years; median testosterone 3.93 ng/mL, median prostate-specific antigen, PSA, level 19.0 ng/mL) were randomized and received study treatment. Androgen-deprivation therapy was indicated (neoadjuvant hormonal treatment was excluded) according to the investigator's assessment. Three dosing regimens were evaluated: a starting dose of 240 mg of degarelix subcutaneous (s.c.) for 1 month, followed by s.c. maintenance doses of 80 mg or 160 mg monthly, or intramuscular (i.m.) leuprolide doses of 7.5 mg monthly. Therapy was maintained for the 12-month study. Both the intent-to-treat (ITT) and per protocol populations were analysed.. The primary endpoint of the trial was suppression of testosterone to

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Oligopeptides; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Outcome

We prospectively examined the development of depressive symptoms and fatigue among men with locally advanced prostate cancer receiving hormone therapy.. Fifty-two men with advanced or recurrent prostate cancer were randomly assigned to receive either parenteral leuprolide or oral bicalutamide. Patients completed the Beck Depression Inventory (BDI) and Fatigue Severity Scale (FSS) at pretreatment baseline, 6 months, and 12 months.. Rates of at least mild depression ranged from 10.4 to 16.3% over the 12 months and were not significantly different at each time point. Mean change in BDI scores from baseline to 6 months for the entire sample was 0.91 (SE = 0.73), and from baseline to 12 months was 0.35 (SE = 0.67). Mean FSS scores increased significantly from baseline (M = 24.43, SD = 11.75) to 6 months (M = 27.93, SD = 13.52) and remained steady at 12 months (M = 27.80, SD = 14.44). There were no significant differences in depression between the two types of hormone therapy.. Hormone therapy does not appear to cause clinically significant changes in depression among men with locally advanced prostate cancer. However, fatigue increased significantly over the study period.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Depression; Fatigue; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Nitriles; Prospective Studies; Prostatic Neoplasms; Severity of Illness Index; Surveys and Questionnaires; Tosyl Compounds

Testosterone administration can lead to increased antipyrine clearance in humans. Medical or surgical castration is a standard treatment of progressive prostate carcinoma, but the effect of the subsequent fall of testosterone concentrations upon drug metabolism has not been reported.. Eleven men with a biopsy-proven diagnosis of progressive prostate cancer were enrolled after providing informed consent. CYP3A4 activity was determined using the erythromycin breath test (EBT) in each patient prior to their beginning with an LHRH-agonist (leuprolide or goserelin). No patients had elected to undergo orchiectomy during the period of subject accrual. Each subject underwent a second EBT 2 months after beginning LHRH suppression. Blood samples were collected at these time points to determine changes in testosterone and leutinizing hormone.. All subjects had a predictable drop in serum testosterone concentrations over the 8-week course of the study, but concentrations in three did not fall below castrate levels (<50 ng/dl). There was no statistically significant change in CYP3A4 activity using the EBT method (p = 0.88). The extent and direction of changes in CYP3A4 activity was highly variable, with three subjects experiencing an increase in activity, and five demonstrating a decrease in activity.. There is no clinically significant change in CYP3A4 activity after medical castration. No changes in the clearance of docetaxel or other CYP3A4 substrates are likely during and after medical castration. Although similar findings are expected after orchiectomy, we were not able to test this presumption because of patient preference for medical castration.

Topics: Aged; Antineoplastic Agents, Hormonal; Breath Tests; Cytochrome P-450 CYP3A; Erythromycin; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Orchiectomy; Prostatic Neoplasms; Testosterone

Because of the low alpha/beta value of prostate cancer, a therapeutic gain may be possible with a hypofractionated radiation scheme, and this gain may be further increased with the adjunct of hormone therapy. A Phase II study was undertaken to study the toxicity of such a treatment.. Forty-two patients with intermediate-risk prostate cancer were recruited for this study. Neoadjuvant and concomitant hormone therapy consisted of one injection of leuprolide acetate (4-month preparation) and 1 month of oral nonsteroidal, anti-androgen medication starting on the day of the injection. Radiation treatment was started 8 weeks after the injection and patients received 57 Gy in 19 fractions.. Median follow-up was 46 months. The treatment was well tolerated and no interruptions occurred. The majority (59%) had Grade 0 or 1 acute genitourinary (GU) toxicity, whereas 36% had Grade 2 and 5% had Grade 3 acute GU toxicity. Only Grade 1 or 2 gastrointestinal toxicity was seen. All chronic toxicity was of Grade 1 or 2 except for 3 patients (8%) with Grade 3 toxicity. Sixty-eight percent (68%) of patients had no long-term side effects from the treatment. At time of analysis, 79% showed no sign of treatment failure.. Hypofractionated radiation with neoadjuvant and concomitant hormone therapy is well tolerated with no significant short- or long-term morbidity. Control for this risk group is good, and comparative Phase III studies should be undertaken to determine whether this treatment is superior to new evolving treatments.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Combined Modality Therapy; Dose Fractionation, Radiation; Follow-Up Studies; Gastrointestinal Tract; Humans; Leuprolide; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Radiation Injuries; Urogenital System

To evaluate the toxicity and efficacy of individualized neoadjuvant androgen deprivation (AD) to maximal response followed by external beam radiotherapy (RT) with continued AD for a total of 9 months in a prospective phase II trial.. One hundred twenty-three patients received a total of 9 months of flutamide and luprolide combined with RT. RT initiation was individualized to begin after maximum response to AD as assessed by monthly digital rectal examination and prostate-specific antigen (PSA). The neoadjuvant phase was restricted to no more than 6 months.. Median time to initiation of RT was 4.7 months. Indications to begin RT (and their rates) were undetectable PSA (28%), PSA unchanged from one month to the next (46%), PSA rising from one month to the next (10%), 6 months of AD (14%), and other (2%). Five-year outcomes were biochemical disease-free survival, (DFS) 63% +/- 7%; clinical DFS, 75% +/- 5%; cancer-specific survival, 99% +/- 1%; and overall survival, 89% +/- 3%. Patients initiating RT after 6 months of AD had significantly lower biochemical and clinical DFS. Those patients whose testosterone recovered to normal after completion of AD had a significantly superior survival rate. Of those patients potent before treatment, 65% remained so at last follow-up.. The combination of 9 months of AD and RT, with initiation of RT individualized on the basis of maximum response to AD, achieves disease control rates comparable with past studies, while preserving potency in many patients. Further studies are warranted to determine the optimal combination of AD and RT in this patient population.

Topics: Adenocarcinoma; Androgen Antagonists; Antineoplastic Agents, Hormonal; Disease-Free Survival; Flutamide; Humans; Leuprolide; Male; Neoadjuvant Therapy; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy; Risk; Time Factors; Treatment Outcome

To compare combination therapy with bicalutamide 80 mg and a luteinizing hormone-releasing hormone agonist (LHRH-A) versus LHRH-A alone in Japanese men with untreated advanced prostate cancer. A total of 205 patients with stage C/D prostate cancer were randomized to either LHRH-A+once-daily oral bicalutamide 80 mg or placebo. Primary study variables have been reported previously. Secondary variables included: time to achieve prostate-specific antigen < or = 4 ng/ml, time-to-treatment failure (TTTF), time-to-disease progression (TTP), overall survival (OS), adverse events and adverse drug reactions. Following combination therapy with bicalutamide 80 mg, there were significant (P<0.001) advantages over LHRH-A alone in terms of TTTF and TTP, but the difference in the interim OS was not statistically significant. First-line combination therapy with bicalutamide 80 mg in Japanese patients with advanced prostate cancer offers significant benefits over LHRH-A alone, with respect to TTTF and TTP. Follow-up for OS continues.

Topics: Aged; Anilides; Double-Blind Method; Drug Therapy, Combination; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Nitriles; Prostatic Neoplasms; Tosyl Compounds; Treatment Outcome

To assess the early histological effects of pharmacological androgen deprivation (AD), which have been assessed only over longer periods, as surgical castration leads rapidly to diminished cell proliferation and enhanced cell death within the prostate.. With Institutional Review Board approval, 35 patients were randomly assigned (seven in each group) to receive 0, 7, 14, 21 and 28 days of AD (flutamide, 250 mg orally three times/day, and one injection with leuprolide acetate 7.5 mg) before radical prostatectomy. The surgical specimens were assessed by conventional histology and immunohistochemistry, while macroarray analysis and quantitative real-time polymerase chain reaction (QRT-PCR) were used to examine gene expression.. There were morphological changes within the prostatic tissues as early as 7 days after initiating AD, similar to the response to castration. There was tumour cell vacuolization indicating cellular injury, glandular atrophy and mononuclear cell infiltration as prominent and progressive effects but, by contrast with castration studies, there were no changes in epithelial proliferation or apoptosis. Macroarray analysis, validated by QRT-PCR and immunohistochemistry, showed up-regulation of numerous and potentially counter-effective genes involved in the cell cycle and apoptosis.. Pharmacological AD induces significant involution within prostatic tissues over 7-28 days, but allows the persistence of some viable tumour cells capable of proliferation.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Flutamide; Humans; Leuprolide; Male; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

Biochemical results from a prospective Phase II trial of intermittent androgen suppression for recurrent prostate cancer after radiotherapy were analyzed for correlations to the onset of hormone-refractory disease.. Patients with histologically confirmed adenocarcinoma of the prostate and a rising serum prostate-specific antigen (PSA) level after external beam irradiation of the prostate were treated intermittently with a 36-week course of cyproterone acetate and leuprolide acetate. Then, patients were stratified according to their serum PSA range at the start of each cycle and were followed with further biochemical testing until disease progression was evident.. The mean PSA reduction was 95.2% irrespective of stratification group. A baseline serum PSA level <10 microg/L and a serum PSA nadir or=7.5 nmol/L was observed in 75%, 50%, 40%, and 30% of men in Cycles 1 to 4, respectively, and was sufficient to normalize the level of hemoglobin in each cycle, which dropped by an average of 10.8 g/L during treatment (P < .0001).. The length of the off-treatment interval during cyclic androgen withdrawal therapy was related inversely to baseline and nadir levels of serum PSA. Nadir PSA was a powerful predictor of early progression to androgen independence.

Topics: Adenocarcinoma; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cyproterone Acetate; Humans; Leuprolide; Male; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy; Testosterone

To evaluate the long-term effectiveness, side effects and compliance rates of two types of drugs (luteinizing hormone-releasing hormone [LHRH] agonist and antiandrogen) that were used individually to treat patients with localized prostate cancer (T1-2) at our institution.. Ninety-seven patients who were diagnosed in the period from April 1997 to January 2000 as having clinically localized prostate cancer (T1-2) received either LHRH agonist (leuprolide acetate 7.5 mg/month) monotherapy (group 1, n = 62) or antiandrogen monotherapy (group 2, n = 35; 18 received bicalutamide 50 mg q.d., 13 received nilutamide 150 mg t.i.d. and 4 received flutamide 250 mg t.i.d.). The mean age in both groups was 76 years.. The mean follow-up time was (50.8 +/- 8.5) months in group 1 and (43.1 +/- 2.2) months in group 2. Prostate-specific antigen (PSA) levels rose in only 1 of the 62 patients (1.6%) in group 1, and in 20 of the 35 patients (57.1%) in group 2. In group 2, 10 of the 20 patients (50%) with increasing PSA levels were treated with LHRH salvage therapy, and eight (80%) responded. Hot flashes (54.8%) and lethargy (41.9%) were the most common side effects in group 1. In contrast, nipple-tenderness (40%) and light-dark adaptation (17.1%) were more often seen in group 2. Only 1 of the 62 patients (1.6%) in group 1 switched to another medication because of adverse side effects; whereas 8 of the 35 patients (22.9%) in group 2 did so.. Unlike antiandrogen monotherapy, LHRH agonist monotherapy provided long-term durable control of localized prostate cancer (T1-2). It can also be an effective treatment option for patients whose disease failed to respond to antiandrogen monotherapy. The limitations of our study are the lack of health outcomes analysis and a small sample size.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Flutamide; Gonadotropin-Releasing Hormone; Humans; Imidazolidines; Leuprolide; Male; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Tosyl Compounds

Long acting luteinizing hormone releasing hormone agonists are the predominant form of androgen suppression in the treatment of prostate cancer with the goal of maintaining castrate levels of testosterone. Current dosing of luteinizing hormone releasing hormone agonists does not include monitoring the end organ response of serum testosterone. Recent evidence suggests standard dosing regimens fail to achieve castrate levels of testosterone in some patients while in other patients testosterone can remain at castrate levels longer than the manufacturer recommended dosing interval. We prospectively evaluated patients with prostate cancer receiving luteinizing hormone releasing hormone agonist hormonal therapy to determine the length of time that serum testosterone remains at or below castrate levels.. A 3-month dose of 22.5 mg leuprolide was administered to all patients as a first dose followed by a second dose 3 months later. Serum testosterone and prostate specific antigen were measured prospectively before starting hormonal therapy, after the first dose (12 weeks) and again following the second dose (24 weeks) to assess if castrate levels of testosterone (50 ng/dl or less) had been reached. At 24 weeks if patient serum testosterone was 50 ng/dl or less, then 22.5 mg leuprolide were not administered, and serum testosterone and prostate specific antigen were checked monthly. When serum testosterone was greater than 50 ng/dl a subsequent dose of 22.5 mg leuprolide was given. Serum testosterone and prostate specific antigen were then checked 3 months later and monthly thereafter until testosterone was greater than 50 ng/dl. Thus, the time that testosterone remained at castrate levels could be accurately established.. From February 2003 to August 2005, 42 patients were treated in this manner with a median followup of 18 months (range 10 to 30). Average patient age was 77 years. Median Gleason grade was 7 (range 6 to 9). Median pretreatment prostate specific antigen was 15.1 ng/ml (range 0.6 to 433) and median posttreatment prostate specific antigen was 0.74 (less than 0.1 to 120). The median dosing interval was 6 months (range 5 to 12). Three patients had an increase in prostate specific antigen while receiving treatment despite castrate levels of testosterone. No patient required more frequent dosing than every 5 months.. Testosterone based luteinizing hormone releasing hormone agonist therapy makes empirical sense. It represents continuous androgen ablation based on the patient physiological end point, namely testosterone. Early data suggest that using serum testosterone to guide luteinizing hormone releasing hormone dosing is safe, efficacious and cost-effective. By following end organ response, patients receive individualized care and more accurate androgen suppression therapy.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Drug Administration Schedule; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

The safety, efficacy and pharmacokinetics of LA-2585, a new 6-month subcutaneous depot of leuprolide acetate (Atrix Laboratories, Fort Collins, Colorado) were investigated in patients with prostate cancer.. In this 12-month, open label, multicenter study 111 patients with adenocarcinoma of the prostate were administered 45.0 mg LA-2585 subcutaneously once every 6 months. The primary efficacy parameter was serum testosterone 50 ng/dl or less. Leuprolide acetate pharmacokinetics were analyzed in a subset of 28 patients.. Of the 111 enrolled patients 103 (93%) completed the 12-month study. Eight patients withdrew due to nonmedical reasons in 1, disease progression in 5 and cardiovascular disease in 2. By day 28, 108 of the 109 remaining patients (99%) achieved testosterone suppression, while 1 who never attained suppression was withdrawn at day 85. Mean time to castrate suppression was 21.2 days (median 21). At study completion 102 of 103 patients (99%) were below medical castrate testosterone levels of 50 ng/dl (mean +/- SE 12.3 +/- 2.1 ng/dl) with 91 of 103 (88%) at less than 20 ng/dl. Mean luteinizing hormone decreased from 6.98 +/- 0.48 mIU/ml at baseline to 0.23 +/- 0.14 mIU/ml at month 12. Luteinizing hormone was consistently below 1 mIU/ml. Mean prostate specific antigen decreased 97% from 39.8 +/- 21.5 ng/ml at baseline to 1.2 +/- 0.3 ng/ml at 12 months. No clinically significant flare reactions were observed. The most common treatment related adverse event was mild to moderate hot flashes.. LA-2585 (45.0 mg depot) consistently produced and maintained safe and effective serum testosterone suppression with total serum testosterone well below the medical castrate level of less than 50 ng/dl.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Drug Delivery Systems; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Subcutaneous Tissue; Time Factors

This prospective Phase II study was undertaken to evaluate intermittent androgen suppression as a form of therapy in men with localized prostate cancer who failed after they received external beam irradiation.. Patients who demonstrated a rising serum prostate-specific antigen (PSA) level after they received radiotherapy and who were without evidence of distant metastasis were accepted into the study. Treatment in each cycle consisted of cyproterone acetate given as lead-in therapy for 4 weeks, followed by a combination of leuprolide acetate and cyproterone acetate, which ended after a total of 36 weeks.. Of 109 patients registered, 103 patients were eligible for interruption of treatment, yielding a PSA response rate of 95%. The study continued for 6 years with a mean follow-up of 3.7 years (median follow-up, 4.2 years). The time off treatment averaged 53% of the total cycle time but, in absolute terms, decreased with each succeeding cycle, ranging from 63.7 weeks in Cycle 1 to 25.6 weeks in Cycle 5. Prostate volume was reduced by 40% in Cycle 1 and by 34% in Cycle 2, and there were no decreases in Cycle 3 or Cycle 4. At the end of the trial, 38.5% of patients still were receiving treatment, 23.9% of patients had failed, and 15.6% of patients had died. Only 2% of deaths were cancer-specific.. Biochemical recurrence after irradiation for localized prostate cancer was amenable to cyclic androgen withdrawal therapy and showed a high response rate. Despite progressively shorter treatment cycles, the off-treatment interval remained appreciable, ranging from 65% in Cycle 1 to 46% in Cycle 5.

Topics: Aged; Androgen Antagonists; Androgens; Antineoplastic Agents, Hormonal; Canada; Cyproterone Acetate; Humans; Leuprolide; Male; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

To evaluate the clinicopathological outcomes of 8 months of neoadjuvant hormonal therapy (NHT) prior to radical prostatectomy for high-risk prostate cancer.. A multi-institutional prospective trial was performed between July 2000 and May 2003 involving high-risk prostate cancer patients without metastasis, including 21 who received 8 months of NHT before radical prostatectomy. High-risk group was defined as clinical stage > or =T2c and/or prostate-specific antigen (PSA) >20 ng/ml and/or Gleason score > or =8. PSA values were considered elevated (biochemical failure) if values of 0.1 ng/ml or greater were obtained.. Median of initial PSA levels before prostate biopsy was 27.6 ng/ml (8.5-80.7 ng/ml), and median of pre-operative PSA levels after NHT was 0.28 ng/ml (0.02-4.2 ng/ml). There were 5 patients (23.8%) with lower limit of PSA detection (less than 0.02 ng/ml) in 8 months after NHT. The clinical T stage was T1c in 9 patients (42.9%), T2a-b in 8 patients (38.1%), T2c in 3 patients (14.3%), and T3a in 1 patient (4.8%). The median follow-up was 25 months (range 4 to 37). There were 2 patients (9.5%) in pT0, 5 patients (23.8%) with positive surgical margin, 5 patients (23.8%) with extracapsular extension (ECE) and 3 patients (14.3%) with seminal vesicle involvement (SVI). Biochemical failure was occurred in 9 of 21 (42.9%) including of one pT0. Range of time to postoperative biochemical failure was 2 to 25 months (median 6 months) and most of biochemical failure was found within 12 months after surgery. Biochemical failure rate was significantly higher in patient with positive SVI (p = 0.0308) and higher in patients with pre-operative PSA levels of more than 0.1 ng/ml (p = 0.0836), positive ECE (p = 0.0545) and positive surgical margin (p = 0.0545).. Biochemical failure was frequent after this combined treatment, even in a pT0 case. Long-term follow-up of patients is needed to assess the impact of this therapy on mortality.

Topics: Aged; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Chemotherapy, Adjuvant; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Nitriles; Prospective Studies; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Risk; Time Factors; Tosyl Compounds; Treatment Failure

To clarify the optimal duration and methods for adjuvant endocrine therapy after external beam radiation therapy (EBRT) in patients with locally advanced prostate cancer.. Between 2001 and 2003, 215 patients with locally advanced prostate cancer were enrolled in the study. Patients were registered as primary candidates of the study and were treated with 6 months of LHRH agonist, with short-term of antiandrogen treatment for flare-up prevention. Patients with PSA levels below 10 ng/ml after the 6-month endocrine treatment were randomly divided into two arms. Then, a total dose of 72 Gy was given to the prostate. After 14 months of the protocol treatment, patients were treated with continuous androgen ablation (arm 1) or intermittent androgen ablation (arm 2).. A total of 188 cases (87%) remained in the protocol. The median PSA level at entry was 25.3 ng/ml. The Gleason score was 2-6 in 32 cases (16%), 7 in 94 cases (48%), and 8-10 in 68 cases (35%). The median PSA level showed a remarkable decrease to 1.1, 0.2, and 0.1 ng/ml, after 6, 8, and 14 months of the protocol treatment, respectively. Of the 157 cases treated with EBRT, 153 cases (97.5%) had no biochemical failure in the mean follow-up of 17.3 months.. The present study may reveal the possibilities of intermittent endocrine therapy after EBRT. However, the follow-up interval is short and little can be said about the results observed so far, exception of acute tolerance and patient acceptance of the protocol.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Brachytherapy; Chlormadinone Acetate; Combined Modality Therapy; Disease-Free Survival; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Treatment Outcome

To determine whether needle size influences a patient's perception of pain, 50 patients requiring hormonal manipulation for prostate cancer were blindfolded and randomised to receive two goserelin ('Zoladex') or two leuprorelin ('Prostap') injections, using 16- or 23-gauge needles, respectively. Median visual analogue scale pain scores for the first injections of goserelin and leuprorelin were below the level of clinical significance and were not statistically different. Mean administration time for goserelin was significantly shorter than for leuprorelin. In conclusion, there was no statistically significant difference in pain experienced on injection of goserelin and leuprorelin when patients were unaware of needle size.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Goserelin; Humans; Leuprolide; Male; Middle Aged; Needles; Pain; Pain Measurement; Patient Satisfaction; Prostatic Neoplasms; Single-Blind Method

Patients with prostate cancer are treated with neoadjuvant, adjuvant and intermittent therapy with gonadotropin-releasing hormone agonists (GnRH-A). While these are largely successful in decreasing testosterone (T) and dihydroxytestosterone (DHT) to castrate levels, discontinuation of such therapy often results in continued suppression of androgens for variable periods of time. We present the largest published series of patients evaluating the timing of T and DHT increase after cessation of GnRH therapy.. Serial T and DHT measurements were prospectively obtained every 3 months while on GnRH-A then monthly upon discontinuation of GnRH-A. Analysis of time from the second 3-month GnRH-A administration to T and DHT increase was undertaken.. A total of 80 evaluable patients had a median time to T 50 ng/dl or greater of 12.9 weeks and a median time to T normalization (212 ng/dl or greater) of 16.6 weeks. Low baseline T was associated with a prolonged time to T 212 ng/dl or greater (p = 0.0086) and a similar trend was seen in patients older than 66 years (p = 0.08). There were 62 evaluable patients with a median of 14.9 weeks to DHT 150 pg/ml or greater. There was no association with Gleason score at diagnosis, on study prostate specific antigen, type of prior definitive therapy, or any prior hormonal therapy and time to increase in circulating androgens.. After 6 months of GnRH-A therapy in these patients, DHT and T levels did not return to normal for a median of 14.9 and 16.6 weeks, respectively.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Testosterone; Time Factors

Prostatectomy or radiation for localized prostate cancer (PC) can fail in up to 15% to 30% of patients. The purpose of this study was to determine feasibility, tolerability, and outcome of docetaxel followed by hormone therapy in men experiencing an increasing prostate-specific antigen (PSA) after their primary local treatments for PC.. Men with increasing serum PSA after prostatectomy or/and radiation were eligible. Serum PSA had to be > or = 4 ng/mL and serum testosterone had to be in the noncastrate range. Treatment included docetaxel 70 mg/m2 every 3 weeks for up to six cycles, followed by total androgen suppression (luteinizing hormone-releasing hormone agonist plus bicalutamide) and peripheral androgen blockade (finasteride plus bicalutamide) for 12 to 20 months.. Thirty-nine men were enrolled; 32 had PSA-only failure, seven also had clinical metastasis. Baseline median PSA was 13.7 ng/mL. Serum PSA decreased > or = 50% in 17 of 35 patients (48.5%) and > or = 75% in seven of 35 patients (20%) with docetaxel. The PSA decreased to a median of 0.1 ng/mL with subsequent hormone therapy. In 28 of 33 patients the PSA increased (median, 0.41 ng/mL) at a median follow-up of 2.3 months after treatment. In contrast, in five of 33 men the PSA remains at 0.1 ng/mL at a median of 18.9 months after therapy; three of these five men had soft tissue metastasis at entry but remain in complete remission. The most common grade 3 to 4 toxicity was neutropenia (61.5%).. Docetaxel followed by hormone therapy of limited duration may provide disease control in subgroups of men experiencing failure after local treatments for PC.

Topics: Aged; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Docetaxel; Goserelin; Humans; Infusions, Intravenous; Injections, Intramuscular; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Taxoids; Treatment Outcome

To our knowledge this study represents the first analysis monitoring the efficacy of cyproterone acetate (CPA) monotherapy for achieving castrate testosterone levels prior to administering a luteinizing hormone-releasing analogue (LHRHA) for treating prostate cancer in the prostate specific antigen (PSA) era.. Patients with untreated locally advanced or metastatic prostate cancer were recruited prospectively. Treatment involved a 28-day course of oral cyproterone acetate and LHRHA depot injection on day 14. Patients had serum PSA, luteinizing hormone and testosterone monitored at intervals during a 56-day period.. A total of 15 patients with a mean age of 74 years completed the study. Near castrate serum testosterone was achieved on day 7 (mean +/- 95% CI 83.38 +/- 17.87 ng/dl). There was a significant testosterone increase after LHRHA administration on day 14 compared with the level of 160.23 +/- 36.60 ng/dl on day 16 (p <0.01). Serum luteinizing hormone mirrored testosterone, increasing from a mean of 4.93 +/- 0.61 to 15.4 +/- 6.12 nmol/l after LHRHA administration (p <0.01). Mean serum PSA demonstrated a decrease from 199.25 +/- 6.12 microg/l at day 0 to 43.77 +/- 33.08 microg/l by day 56. There was no increase in serum PSA after LHRHA administration.. Two weeks of priming with CPA does not eliminate the surge in serum testosterone (testosterone flare) upon LHRHA administration but the testosterone increase does not exceed pretreatment levels. Furthermore, 2 weeks of CPA may not offer a benefit over 1 week in lowering serum testosterone. Finally, there is no increase in serum PSA when LHRHA is administered after priming with CPA.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Castration; Cyproterone Acetate; Humans; Leuprolide; Male; Middle Aged; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

There is no standard therapeutic strategy for advanced hormone refractory prostate cancer after the initial hormonal therapy fails. The objective of this study was to retrospectively evaluate the clinical outcome of the oral anticancer agent, uracil/tegafur (UFT) for patients with hormone refractory prostate cancer. This study included 68 patients with hormone refractory prostate cancer treated by oral administration of UFT (300-600 mg/day). All patients had previously received maximum androgen blockade (MAB) which failed. In this series, response was defined as more than 50% decrease from the baseline prostate specific antigen (PSA) value at the start of second line therapy. Upon initiating administration of UFT, a reduction in PSA value was observed in 41 of the 68 patients (60.3%), among whom 13 (19.1%) were regarded as responders; however, PSA value continued to increase in the remaining 27 (39.7%). Median duration of PSA response was 7 months (range 1-22 months). During the observation period, there were no severe side effects due to UFT administration, but 7 patients transiently presented appetite loss. Patients without bone metastasis at the initial diagnosis or whose serum PSA value at the start of UFT therapy was less than 2.0 ng/ml showed a significantly higher incidence of PSA response to UFT; however, other factors examined had no significant impact on PSA response to UFT. Furthermore, cause-specific survival in responders to UFT therapy was significantly better than that in non-responders. These findings suggest that administration of UFT after the failure of initial MAB therapy can achieve a comparatively favorable PSA response without severe side effects; therefore, it may be worthy to consider administering UFT to patients with hormone refractory prostate cancer.

Topics: Administration, Oral; Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antimetabolites, Antineoplastic; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Middle Aged; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Tegafur; Tosyl Compounds; Treatment Failure; Treatment Outcome

To assess the feasibility and tolerability of intermittent androgen suppression therapy (IAS) in prostate cancer.. Patients with recurrent or metastic prostate cancer received cyclical periods of treatment with leuprolide acetate and nilutamide for 8 months, and rest periods. Cycles were repeated at progression until the treatment failed to achieve normal prostate-specific antigen (PSA) levels. Patients were followed with PSA level, testosterone level, haemoglobin level, weight and bone mineral density evaluations. The median time to treatment failure, recovery from anaemia, or normalization of testosterone level was estimated by the Kaplan-Meier method.. In all, 95 patients received 245 cycles; the median duration of rest periods was 8 months and median time to treatment failure 47 months. Testosterone recovery during rest periods was documented in 117 (61%) of cycles. Anaemia was mild and reported in 33%, 44% and 67% of cycles 1, 2 and 3, respectively. Sexual function recovered during the rest periods in 47% of cycles. There was no significant overall change in body mass index at the end of the treatment period. Osteoporosis was documented in at least one site evaluated in 41 patients (37%).. IAS has the potential to reduce side-effects, including recovery of haemoglobin level, return of sexual function and absence of weight gain at the end of the study period.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents; Disease-Free Survival; Follow-Up Studies; Humans; Imidazolidines; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Osteoporosis; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Outcome

To assess the effects of intermittent maximal androgen blockade (IMAB) on testosterone (T) levels during on- and off-treatment periods.. A total of 51 patients with metastatic prostate cancer underwent a 6-months period of continuous maximal androgen blockade (MAB) consisting of leuprorelin (3.75 mg at monthly intervals) plus flutamide (250 mg t.i.d.) followed by IMAB. During each cycle, the cut-off prostate-specific antigen (PSA) levels to stop and resume treatment were 4 and 10 ng/ml, respectively. IMAB continued until progression under treatment occurred. Monthly PSA and T measurements were performed in central laboratories.. From the 51 patients included (mean age 67.6 years), 27, 16, 12, 8 and 5 underwent a second, third, fourth, fifth and sixth cycle, respectively (mean follow up: 17 months). Before treatment, 4 patients had a T lower than normal laboratory value but these recovered all to a normal T value at the end of the first cycle. During the 6 cycles, only 8 patients did not recover a normal T at least once during the off-treatment periods (OTP). The mean T values at the end of each OTP did not change during these 6 cycles (Anova test, p=0.621) with a mean stable recovery delay of 32-43 days (Anova test, p=0.722).. IMAB protocol with an initial 6-month treatment period can result in an intermittent castration with the recovery of normal T levels in most patients during six consecutive cycles of treatment.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Drug Administration Schedule; Flutamide; Follow-Up Studies; Humans; Leuprolide; Male; Neoplasm Metastasis; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Outcome

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Drug Administration Schedule; Goserelin; Humans; Injections, Intramuscular; Injections, Subcutaneous; Leuprolide; Male; Prospective Studies; Prostatic Neoplasms; Radiotherapy, Conformal; Treatment Outcome

The aim of this study was to compare the speed of administration (preparation and delivery) and nurses' perceived ease of use and relative safety of two injection systems used to administer luteinising hormone-releasing hormone agonists: a depot system used to administer goserelin acetate ('Zoladex', AstraZeneca) and a vial system used to administer leuprorelin acetate ('Prostap', Wyeth). This was a randomised, crossover study with 82 volunteer nurses (50 pre-registration and 32 post-registration). All nurses were timed in the administration of both systems and all were required to assess the two systems by completing a questionnaire. Results indicate that both pre- and post-registration nurses administered the depot system in less time than the vial system. Overall mean times for administration of the depot system and the vial system were 1.70 and 3.34min, respectively. In questionnaire responses, significantly more nurses thought that the depot system had 'good safety precautions' compared with the vial system (85% versus 40%; P<0.001) and significantly more nurses also expressed a preference for the depot system (58% versus 42%; P=0.036). In conclusion, this study demonstrates that nurses prefer the one-step depot system used to administer goserelin acetate over the vial system used to administer leuprorelin acetate.

Topics: Antineoplastic Agents, Hormonal; Attitude of Health Personnel; Cross-Over Studies; Delayed-Action Preparations; Drug Delivery Systems; England; Goserelin; Humans; Injections; Leuprolide; Male; Prostatic Neoplasms; Time Factors

To evaluate bicalutamide (Casodex) 80 mg as a component of maximum androgen blockade (MAB) in Japanese patients with previously untreated advanced prostate cancer.. 205 patients with previously untreated stage C/D prostate cancer were randomized (1:1) to receive once-daily bicalutamide 80 mg or placebo, each combined with a luteinizing hormone-releasing hormone (LHRH) agonist. Primary study variables were the 12 week prostate-specific antigen (PSA) normalization (i.e. PSA level

Topics: Aged; Anilides; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease-Free Survival; Double-Blind Method; Goserelin; Humans; Japan; Leuprolide; Lymphatic Metastasis; Male; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Tosyl Compounds; Treatment Outcome

We retrospectively compared the 5-year survival rates of T1b-T3N0M0 prostate cancer patients treated either by endocrine therapy plus radical prostatectomy or endocrine therapy alone.. Clinical T1b-T3N0M0 prostate cancer patients were enrolled at 104 institutions in Japan. They were assigned to study 1 (n = 176), if they were indicated to prostatectomy, if not indicated, they were assigned to study 2 (n = 151). The indication of prostatectomy was based on the clinical judgement of physicians and/or patients. Those assigned to study 1 underwent prostatectomy and adjuvant endocrine therapy with or without preoperative androgen deprivation. Those assigned to study 2 were treated with leuprorelin acetate with or without chlormadinone acetate. They were followed-up every 3 months until death or for 5 years and over.. Those assigned to study 1 were younger (mean age 67.2 vs 75.7 years), less advanced in clinical stage, and had lower prostate specific antigen levels (mean 43.8 vs 103.6 ng/mL). Death for any reason was observed less frequently in study 1 (n = 29, 16%) than study 2 (n = 50, 33%), and the 5-year overall survival rate was higher in study 1 (87 vs. 68%). However, prostate cancer deaths were comparatively seldom (9% in study 1 and 7% in study 2), resulting in the identical 5-year cause specific survival rate in both study groups (91%). In both study groups the overall survival was almost equal to the natural survival of age-matched men.. Endocrine therapy offers a reasonable survival rate in T1b-T3 prostate cancer patients within a 5-year follow-up. Observation will be extended to determine 10-year outcomes.

Topics: Age Factors; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Chlormadinone Acetate; Humans; Leuprolide; Male; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Retrospective Studies; Survival Rate

There is an evolving role for combining radiotherapy (RT) with gene therapy in the management of prostate cancer. However, the clinical results of this combined approach are much needed. The preliminary results addressing the safety of this Phase I-II study combining RT and gene therapy (adenovirus/herpes simplex virus-thymidine kinase gene/valacyclovir with or without hormonal therapy) in the treatment of prostate cancer have been previously reported. We now report the prostate-specific antigen (PSA) response and biopsy data.. This trial was composed of three separate arms. Arm A consisted of low-risk patients (Stage T1-T2a, Gleason score <7, pretreatment PSA <10 ng/mL) treated with combined RT-gene therapy. A mean dose of 76 Gy was delivered to the prostate with intensity-modulated RT. They also received adenovirus/herpes simplex virus-thymidine kinase/valacyclovir gene therapy. Arm B consisted of high-risk patients (Stage T2b-T3, Gleason score >6, pretreatment PSA level >10 ng/mL) treated with combined RT-gene therapy and hormonal therapy (luteinizing hormone-releasing hormone agonist [30-mg Lupron, 4-month depot] and an antiandrogen [flutamide, 250 mg t.i.d. for 14 days]). Arm C consisted of patients with Stage D1 (positive pelvic lymph nodes) who received the same regimen as Arm B with the addition of 45 Gy to the pelvic lymphatics. PSA determination and biopsy were performed before, during, and after treatment. The American Society for Therapeutic Radiology and Oncology consensus definition (three consecutive rises in PSA level) was used to denote PSA failure.. Fifty-nine patients (29 in Arm A, 26 in Arm B, and 4 in Arm C) completed the trial. The median age was 68 years (range, 39-85 years). The median follow-up for the entire group was 13.5 months (range, 1.4-27.8 months). Only Arm A patients were observed to have an increase in PSA on Day 14. The PSA then declined appropriately. All patients in Arm A (median follow-up, 13.4 months) and Arm B (median follow-up, 13.9 months) had biochemical control at last follow-up. Three patients in Arm C (with pretreatment PSA of 335, 19.6, and 2.5 ng/mL and a combined Gleason score of 8, 9, and 9 involving all biopsy cores) had biochemical failure at 3, 3, and 7.7 months. Two patients had distant failure in bone and 1 patient in the para-aortic lymph nodes outside the RT portal. Six to twelve prostate biopsies performed in these 3 patients revealed no evidence of residual carcinoma. In Arm A, biopsy showed no evidence of carcinoma in 66.7% (18 of 27), 92.3% (24 of 26), 91.7% (11 of 12), 100% (8 of 8), and 100% (6 of 6) at 6 weeks, 4 months, 12 months, 18 months, and 24 months after treatment, respectively. In Arm B, no evidence of carcinoma on biopsy was noted in 96% (24 of 25), 90.5% (19 of 21), 100% (14 of 14), 100% (7 of 7), and 100% (2 of 2), respectively, in the same interval after treatment.. This is the first reported trial of its kind in the field of prostate cancer that aims to expand the therapeutic index of RT by combining it with in situ gene therapy. The initial transient PSA rise in the Arm A patients may have been a result of local immunologic response or inflammation elicited by in situ gene therapy. Additional investigation to elucidate the mechanisms is needed. Hormonal therapy may have obliterated this rise in Arm B and C patients. The biopsy data were encouraging and appeared to show no evidence of malignancy earlier than historical data. Combined RT, short-course hormonal therapy, and in situ therapy appeared to provide good locoregional control but inadequate systemic control in patients with positive pelvic lymph nodes. Longer term use of hormonal therapy in addition to gene therapy and RT has been adopted for this group of patients to maximize both locoregional and systemic control.

Topics: Acyclovir; Adenoviridae; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antiviral Agents; Biopsy; Combined Modality Therapy; Flutamide; Follow-Up Studies; Genetic Therapy; Genetic Vectors; Humans; Leuprolide; Male; Middle Aged; Prodrugs; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy Dosage; Radiotherapy, Conformal; Thymidine Kinase; Valacyclovir; Valine

To assess the effect of neoadjuvant hormone treatment before radical prostatectomy on: tumor/prostate volume, prostate-specific antigen (PSA) and testosterone levels, surgical margin status and tumor stage, and the ease of surgery following treatment.. Patients with clinically localized prostatic carcinoma were randomized to receive leuprolide acetate depot 3.75 mg once a month for 3 months and cyproterone acetate 300 mg once a week for 3 weeks prior to surgery (group A). A control group of patients had surgery without any pretreatment (group B).. 167 patients were evaluated for the efficacy parameters. In group A, 31% of patients had a reduction in tumor/prostate volume following hormone therapy. PSA and testosterone levels were significantly reduced (p = 0.0001) in patients in group A compared to basal values. Centralized histopathological data evaluated in 145 patients (group A and 75 group B) showed that more patients in group B had tumors at stages T3A and T3B than in group A; this difference was close to significance (p = 0.057). Positive surgical margins were more common in group B (60% of patients) compared to group A (39% of patients). Similarly lymph node involvement was more common in group B compared to group A (11 versus 3%). There was little difference between the 2 study groups for the other surgical parameters assessed (ease of dissection, duration of surgery, blood loss).. Neoadjuvant hormone therapy before radical prostatectomy has some effects in the treatment of prostate cancer. However, long-term follow-up of patients is needed to assess the impact of this therapy on morbidity and mortality.

Topics: Adenocarcinoma; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Cyproterone Acetate; Delayed-Action Preparations; Humans; Leuprolide; Male; Middle Aged; Preoperative Care; Prostatectomy; Prostatic Neoplasms

To investigate the effects of different management strategies for non-localized prostate cancer on men's quality of life and cognitive functioning.. Men with prostate cancer were randomly assigned to one of four treatment arms: leuprorelin, goserelin, cyproterone acetate (CPA), or close clinical monitoring. In a repeated-measures design, men were assessed before treatment (baseline) and after 6 and 12 months of treatment. A community comparison group of men of the same age with no prostate cancer participated for the same length of time. The men were recruited from public and private urology departments from university teaching hospitals. All those with prostate cancer who were eligible for hormonal therapy had no symptoms requiring immediate therapy. In all, 82 patients were randomized and 62 completed the 1-year study, and of the 20 community participants, 15 completed the study. The main outcome measures were obtained from questionnaires on emotional distress, existential satisfaction, physical function and symptoms, social and role function, subjective cognitive function, and sexual function, combined with standard neuropsychological tests of memory, attention, and executive functions.. Sexual dysfunction increased for patients on androgen-suppressing therapies, and emotional distress increased in those assigned to CPA or close clinical monitoring. Compared with before treatment there was evidence of an adverse effect of leuprorelin, goserelin, and CPA on cognitive function.. In deciding the timing of androgen suppression therapy for prostate cancer, consideration should be given to potential adverse effects on quality of life and cognitive function.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Cognition Disorders; Cyproterone Acetate; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms; Quality of Life; Sexual Dysfunction, Physiological; Stress, Psychological

The effects of preoperative androgen deprivation on the outcomes of prostate cancer patients who received radical prostatectomy and subsequent adjuvant endocrine therapy have not yet been fully evaluated.. Patients with stage A(2), B or C prostate cancers were randomized to one of two groups: group I (n = 90), who received androgen deprivation (leuprolide and chlormadinone acetate) for 3 months followed by radical prostatectomy and subsequent adjuvant endocrine therapy (leuprolide alone), and group II (n = 86), who underwent the surgery followed by 3-month androgen deprivation (leuprolide and chlormadinone acetate) and subsequent adjuvant endocrine therapy (leuprolide alone). The effects of preoperative androgen deprivation on survival, clinical relapse (serum prostate specific antigen, PSA, above the normal level, local recurrence, or distant metastases), and PSA relapse (PSA above the detectable level) were evaluated at 5 years or later after treatment.. There were no significant differences in overall, cause-specific, clinical relapse-free, or PSA relapse-free survival rates between the two groups. In a subanalysis, no prostate cancer deaths or clinical relapses were noted in 29 patients with organ-confined disease (OCD: negativity of capsular invasion, seminal vesicle invasion, surgical margins or nodal involvement). The odds ratio for OCD depending on group assignment was 2.44 (95% confidence interval, CI 1.04-5.72), for group I, demonstrating a higher probability of having OCD. This ratio was increased to 4.00 (95% CI 1.06-15.16) if the analysis was conducted in a subpopulation with prostate specific antigen levels less than 35.6 ng/mL and with clinical stage B or C cancers.. Preoperative androgen deprivation has no demonstrable benefit in 5-year outcomes for patients undergoing radical prostatectomy and adjuvant endocrine therapy. However, it did increase the probability of OCD, which was associated with no clinical relapse during the follow-up. A longer observation is needed to clarify the exact extent of the benefits in terms of survival.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Chlormadinone Acetate; Disease-Free Survival; Drug Therapy, Combination; Humans; Leuprolide; Male; Middle Aged; Neoplasm Recurrence, Local; Preoperative Care; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Treatment Outcome

The results of several recent studies suggest that estrogen and testosterone play an important role in the modulation of mood and cognitive function in women, and preliminary evidence indicates that these hormones may also modulate the levels of beta-amyloid (Abeta), a 4 Kilo Dalton peptide that is likely to be involved in the pathogenesis of Alzheimer's disease. However, the physiological and clinical effects of reversible castration remain unclear and no systematic data is currently available for men. We designed the present study to investigate the effects of reversible chemical castration on the mood and cognitive performance of men treated for prostate cancer, as well as its impact on the levels of plasma Abeta. Forty men with prostate cancer were clinically treated with androgen blockade therapy (flutamide and leuprolide) for 36 weeks and subsequently followed up for another 18 weeks after treatment was discontinued. All subjects received a comprehensive clinical, neuropsychological and biochemical evaluation that included the use of the Beck Depression (BDI) and Anxiety Inventories (BAI), several subtests of the Wechsler Memory and Intelligence Scales (Word Lists-WL, Verbal Paired Associates-VPA, Visual Reproduction-VR and Block Design-BD), and biochemical monitoring of changes in estrogen, testosterone and Abeta levels. Chemical castration was associated with a rapid and marked decline in the levels of testosterone and estradiol, and significant increase in plasma Abeta levels. Treatment was associated with increased BDI (p = 0.004) and BAI scores (p < 0.001), although such changes were of questionable clinical significance (i.e., few subjects had scores > or = 13). CAMCOG (p = 0.046) and WL recall total scores (p < 0.001) improved significantly after androgen blockade treatment was discontinued, but visuospatial abilities, as assessed by BD, was not influenced by the introduction or discontinuation of treatment. There was a significant negative correlation between changes in Abeta levels and subjects' WL total score change between weeks 36 and 54 (r = -0.452, p = 0.012). The results of this naturalistic study indicate that chemical castration is associated with a significant rise in the plasma levels of Abeta and, clinically, with increased depression and anxiety scores. The discontinuation of treatment is associated with better cognitive performance, most noticeably of verbal memory. The performance of subjects on the WL test was negatively corr

Topics: Adult; Affect; Aged; Aged, 80 and over; Amyloid beta-Peptides; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Anxiety Disorders; Cognition; Depressive Disorder; Estradiol; Flutamide; Follow-Up Studies; Humans; Hypogonadism; Leuprolide; Male; Memory; Middle Aged; Multivariate Analysis; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

Gonadotropin-releasing hormone agonists decrease bone mineral density, lean mass, and muscle size and increase fat mass in men with prostate cancer. Less is known about the effects of bicalutamide monotherapy on bone mineral density and body composition.. In a 12-month, open-label study, we randomly assigned 52 men with prostate cancer and no bone metastases to receive either leuprolide or bicalutamide (150 mg by mouth daily). Bone mineral density and body composition were measured by dual energy x-ray absorptiometry and quantitative computed tomography.. Mean (+/- standard error) bone mineral density of the posterior-anterior lumbar spine decreased by 2.5% +/- 0.5% in the leuprolide group and increased by 2.5 +/- 0.5 in the bicalutamide group from baseline to 12 months (P <.001). Mean changes in bone mineral density of the total body, total hip, femoral neck, and trabecular bone of the lumbar spine also differed significantly between groups (P < or =.003 for each comparison). Fat mass increased by 11.1% +/- 1.3% in the leuprolide group and by 6.4% +/- 1.1% in the bicalutamide group (P =.01). Changes in lean mass, muscle size, and muscle strength were similar between the groups. Breast tenderness and enlargement were more common in the bicalutamide group than in the leuprolide group. Fatigue, loss of sexual interest, and vasomotor flushing were less common in the bicalutamide group than in the leuprolide group.. In men with prostate cancer, bicalutamide monotherapy increases bone mineral density, lessens fat accumulation, and has fewer bothersome side effects than treatment with a gonadotropin-releasing hormone agonist.

Topics: Aged; Anilides; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Body Composition; Bone Density; Humans; Leuprolide; Male; Middle Aged; Nitriles; Prostatic Neoplasms; Tosyl Compounds; Treatment Outcome

This study was designed to determine whether androgen ablation (AA) affects expression of alpha1A-adrenergic receptors (AR) in the human prostate.. Concentrations of alpha1A-AR mRNA were determined in benign prostatic tissue from patients undergoing surgery after a 3-month course of combined androgen ablation (CAD) therapy with leuprolide and flutamide, and a matched group of untreated patients with clinical BPH.. Mean concentration of alpha1A-AR in the AA group was 0.53 +/- 0.53 SD (range 0.026-1.55) attomol/mg. Control mean was 0.29 +/- 0.22 SD (range 0.02-0.69; P = 0.3, two tailed t-test). Tissue composition did not statistically differ between the two groups. Expression of alpha1A-AR correlated with concentration of smooth muscle myosin heavy chain (SMMHC) (r = 0.84, P = 0.001). No significant differences were observed after adjusting for SMMHC content.. A 3-month course of CAD does not appear to have a significant effect on alpha1A-AR mRNA expression in the human prostate.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Flutamide; Humans; Leuprolide; Male; Middle Aged; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Adrenergic, alpha-1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

To clarify the effect of intermittent androgen suppression on the time to androgen-independent progression and changes in quality of life (QOL).. Patients with locally advanced or metastatic prostate cancer were treated with a combination of leuprolide acetate and flutamide for 36 weeks. When the serum prostate-specific antigen (PSA) levels at 24 and 32 weeks were less than 4.0 ng/mL, treatment was withheld until the PSA level reached 15 ng/mL or the pretreatment level. This cycle of on-treatment and off-treatment was repeated until PSA failure (three consecutive increases in PSA level greater than 4.0 ng/mL during the on-treatment period) or symptomatic progression was observed. Changes in QOL were assessed by a self-assessment questionnaire.. Forty-nine patients (26 with T3N0M0, 8 with T2-T3N1M0, 2 with T4N0M0, and 13 with T2-T3N0M1) were enrolled. The mean follow-up period was 136.5 weeks. Thirty-one patients finished cycle 1, six finished cycle 2, and three finished cycle 3. The mean off-treatment duration in cycles 1, 2, and 3 was 46.1, 36.9, and 23.3 weeks, respectively. In the off-treatment period, statistically significant improvements in the QOL score were observed in the categories of potency (11.4 versus 2.4) and social/family well-being (20.3 versus 16.1) compared with those in the on-treatment period. PSA failure occurred in 6 patients (3 with T3N0M0 and 3 with T2-T3N1M0), and all patients were alive at last follow-up.. Our interim analysis indicated that QOL is remarkably improved during the off-treatment period. Intermittent androgen suppression would be a viable option for treatment of advanced prostate cancer, although a randomized controlled study is required to determine whether intermittent androgen suppression prolongs the time to androgen-independent cancer. We will continue follow-up in this study to a minimum of 3 years.

Topics: Adenocarcinoma; Aged; Androgens; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Disease Progression; Drug Administration Schedule; Flutamide; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Pilot Projects; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Surveys and Questionnaires; Testosterone; Treatment Failure

Survival benefit in the management of high-grade clinically localized prostate cancer has been shown for 70 Gy radiation therapy combined with 3 years of androgen suppression therapy (AST), but long-term AST is associated with many adverse events.. To assess the survival benefit of 3-dimensional conformal radiation therapy (3D-CRT) alone or in combination with 6 months of AST in patients with clinically localized prostate cancer.. A prospective randomized controlled trial of 206 patients with clinically localized prostate cancer who were randomized to receive 70 Gy 3D-CRT alone (n = 104) or in combination with 6 months of AST (n = 102) from December 1, 1995, to April 15, 2001. Eligible patients included those with a prostate-specific antigen (PSA) of at least 10 ng/mL, a Gleason score of at least 7, or radiographic evidence of extraprostatic disease.. Time to PSA failure (PSA >1.0 ng/mL and increasing >0.2 ng/mL on 2 consecutive visits) and overall survival.. After a median follow-up of 4.52 years, patients randomized to receive 3D-CRT plus AST had a significantly higher survival (P =.04), lower prostate cancer-specific mortality (P =.02), and higher survival free of salvage AST (P =.002). Kaplan-Meier estimates of 5-year survival rates were 88% (95% confidence interval [CI], 80%-95%) in the 3D-CRT plus AST group vs 78% (95% CI, 68%-88%) in the 3D-CRT group. Rates of survival free of salvage AST at 5 years were 82% (95% CI, 73%-90%) in the 3D-CRT plus AST group vs 57% (95% CI, 46%-69%) in the 3D-CRT group.. The addition of 6 months of AST to 70 Gy 3D-CRT confers an overall survival benefit for patients with clinically localized prostate cancer.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Flutamide; Goserelin; Humans; Leuprolide; Male; Middle Aged; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy, Conformal; Survival Analysis

Patients with clinical T3 or T4 prostate cancer or with elevated serum prostate-specific antigen (PSA) levels greater than 40 ng/ml are at high risk of failure with primary treatment. Chemotherapy administered at the time of diagnosis may decrease the risk of recurrence. Patients with high risk localized prostate cancer were treated with two cycles of liposomal doxorubicin (Doxil) at 50 mg/m2 every 28 days. Patients were assessed for response by digital rectal examination (DRE), PSA, and endorectal magnetic resonance imaging (MRI) (erMRI). Patients were then treated with androgen ablative therapy and prostate radiotherapy. Seven patients were treated. Three patients had T3 disease, and 4 patients had T2b disease with either PSA greater than 40 ng/ml or erMRI evidence of seminal vesicle involvement or extracapsular disease. Median PSA was 29.4 ng/ml. None of the seven patients experienced a significant response, as measured by changes in DRE, PSA, or erMRI. Toxicity was significant, with 4 of 7 patients developing skin toxicity. All seven patients responded to androgen ablative therapy and prostate irradiation. Neoadjuvant liposomal doxorubicin demonstrates no apparent activity and significant toxicity. New strategies are needed to improve outcomes in high-risk prostate cancer.

Topics: Adenocarcinoma; Androgen Antagonists; Anilides; Antibiotics, Antineoplastic; Antineoplastic Agents, Hormonal; Doxorubicin; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Middle Aged; Neoadjuvant Therapy; Nitriles; Pilot Projects; Prostate-Specific Antigen; Prostatic Neoplasms; Tosyl Compounds

Luteinising hormone releasing hormone (LHRH) analogues are routinely used in the treatment of patients with advanced prostate cancer. This randomised crossover trial was conducted to compare patient comfort and tolerability between two commonly used LHRH analogues: goserelin acetate and leuprorelin acetate. A total of 50 patients were randomised into two groups, each receiving 6-monthly injections of leuprorelin acetate (a liquid presentation) and goserelin acetate (a depot pellet) and crossing over between treatments. Patients completed a simple visual analogue score for the discomfort felt from the injections. An analysis of variance model was used, and the results found that patients do tolerate leuprorelin acetate (0.589) better than goserelin acetate (1.343) (P < 0.001, CI = 95%).

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Cross-Over Studies; Delayed-Action Preparations; Goserelin; Humans; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Pain; Prostatic Neoplasms

To compare the efficacy of monthly administrations of the luteinizing hormone-releasing hormone agonists triptorelin pamoate and leuprolide acetate to induce and maintain castrate levels of serum testosterone in men with advanced prostate cancer.. Men with advanced prostate cancer were randomly assigned to receive triptorelin 3.75 mg or leuprolide 7.5 mg. The agent was injected intramuscularly every 28 days for nine injections. Primary endpoints were the percentages of men whose serum testosterone concentrations declined to and were maintained at or below castrate levels (

Topics: Aged; Aged, 80 and over; Analgesics; Antineoplastic Agents, Hormonal; Castration; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Survival Analysis; Testosterone; Treatment Outcome; Triptorelin Pamoate

To investigate the safety, efficacy, and pharmacokinetics of a new 4-month subcutaneous depot of leuprolide acetate in patients with prostate cancer.. Ninety patients diagnosed with adenocarcinoma of the prostate were enrolled in an open-label, multicenter study. LA-2575 30.0 mg was administered subcutaneously once every 4 months for 8 months. The primary efficacy parameter was a serum testosterone level of 50 ng/dL or less. The pharmacokinetics of leuprolide acetate were analyzed in the first 24 enrolled patients. The values are reported as the mean +/- standard error.. Of 90 enrolled patients, 82 (91%) completed the 8-month study. Eight patients voluntarily withdrew from the study for the following reasons: nonmedical reasons (n = 3), treatment-related adverse events (n = 3), disease progression (n = 1), and cardiovascular disease (n = 1). By day 28, 85 (94%) of the 90 patients had achieved a serum testosterone level less than 50 ng/dL. At study completion, 88 (98%) of the 90 patients had a testosterone value less than the castrate level (mean 12.4 +/- 0.8 ng/dL), with 81 (90%) at less than 20 ng/dL. From baseline to month 6, the mean luteinizing hormone level had decreased from 7.51 +/- 0.69 mIU/mL to 0.12 +/- 0.02 mIU/mL. The mean prostate-specific antigen level had decreased 90% from 13.2 +/- 2.0 ng/mL at baseline to 1.3 +/- 0.3 ng/mL at 8 months. No clinically significant flare reactions were observed. The most common treatment-related adverse event was mild hot flashes.. LA-2575 30.0-mg depot consistently produced and maintained safe and effective suppression of serum testosterone, with total serum testosterone concentrations well below the medical castrate level of less than 50 ng/dL.

Topics: Aged; Delayed-Action Preparations; Drug Delivery Systems; Humans; Injections, Subcutaneous; Lactic Acid; Leuprolide; Male; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Prostatic Neoplasms; Pyrrolidinones; Testosterone

Men with prostate specific antigen (PSA) only relapse of prostate cancer after primary therapy are generally fully functional and asymptomatic with a life expectancy of up to 10 or more years. These patients are often treated with androgen suppression. We evaluate the effects of androgen suppression on cognitive function.. Hormone naïve patients without evidence of metastases with an increasing PSA were treated with intermittent androgen suppression consisting of 9 months of leuprolide and flutamide followed by an off treatment period determined by the increase in PSA. Cognitive function tests were administered at baseline, after 9 months of androgen suppression and after 3 months off treatment. Cognitive tests measured spatial abilities, spatial memory, verbal fluency, verbal memory and selective attention. A total of 19 patients 52 to 76 years old completed the intermittent androgen suppression study along with 15 healthy community dwelling control participants.. Combined androgen blockade reduced PSA and testosterone in all patients compared to baseline. Patients did not significantly change on measures of verbal and spatial memory, executive functions or language. Patients declined on a measure of spatial rotation and improved on a measure of verbal memory during treatment which continued during the off treatment period.. Although preliminary, these findings demonstrate that 9 months of combined androgen blockade resulted in a beneficial effect on verbal memory but adversely affected a measure of spatial ability. Intermittent androgen suppression for a period of 9 months in otherwise healthy men with prostate cancer may have beneficial and adverse effects on cognition that are selective.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Attention; Biomarkers, Tumor; Chemotherapy, Adjuvant; Drug Administration Schedule; Drug Therapy, Combination; Flutamide; Humans; Leuprolide; Male; Mental Recall; Middle Aged; Neoplasm Staging; Neuropsychological Tests; Problem Solving; Prostate-Specific Antigen; Prostatic Neoplasms; Space Perception; Testosterone

To report the first systematic investigation of the cognitive effects of luteinizing hormone-releasing hormone (LHRH) analogues in male patients, as LHRH analogues have been associated with memory impairments in women using these drugs for gynaecological conditions.. Eighty-two men with extraprostatic prostate cancer were randomly assigned to receive either continuous leuprorelin, goserelin (both LHRH analogues), cyproterone acetate (a steroidal antiandrogen) or close clinical monitoring. These patients underwent cognitive assessments at baseline and before starting treatment (77), and then 6 months later (65).. Compared with the baseline assessments, men receiving androgen suppression monotherapy performed worse in two of 12 tests of attention and memory; 24 of 50 men randomized to active treatment and assessed 6 months later had a clinically significant decline in one or more cognitive tests but not one patient randomized to close monitoring showed a decline in any test performance.. Pharmacological androgen suppression monotherapy for prostate cancer may be associated with impaired memory, attention and executive functions.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Androgen Antagonists; Antineoplastic Agents, Hormonal; Cognition Disorders; Cyproterone Acetate; Drug Combinations; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms

The pattern of serum testosterone suppression as well as the potential for agonistic stimulation of serum testosterone during chronic treatment was compared in patients with prostate cancer randomized to receive 4 depot injections of either the monthly or 3-month depot formulations of leuprolide acetate in an open label study.. A total of 71 patients were enrolled in a randomized prospective study comparing the pattern of serum testosterone suppression and the potential for agonistic stimulation of serum testosterone following reinjection ("acute-on-chronic" effect) during treatment of advanced stage prostate cancer with monthly (7.5 mg.) and 3-month (22.5 mg.) depot formulations of leuprolide acetate.. The 2 formulations produced nearly identical patterns of testosterone suppression which included uniform suppression throughout the duration of the dosing intervals. A transient minor "escape" from suppression (defined as a single testosterone value greater than 50 ng./dl. once suppression was achieved) occurred in 1 patient receiving each formulation. Assessment of agonistic stimulation ("acute-on-chronic" response) following the second depot injection as well as the depot injection following 3 months of treatment for each formulation revealed no pattern of stimulation.. We conclude that monthly and 3-month sustained release (depot) formulations of leuprolide acetate provide consistent, uniform suppression of serum testosterone throughout the respective dosing intervals, and that the initial depot injection of each formulation provides sufficient pituitary desensitization to prevent agnostic stimulation of serum testosterone during chronic treatment.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Drug Administration Schedule; Humans; Injections, Intramuscular; Leuprolide; Male; Prospective Studies; Prostatic Neoplasms; Testosterone

The safety, efficacy and pharmacokinetics of a unique 3-month subcutaneous depot of leuprolide acetate were investigated in patients with prostate cancer.. This open label, noncomparative, 6-month multicenter study enrolled 117 patients diagnosed with adenocarcinoma of the prostate. LA-2550 (22.5 mg. depot) (Atrix Laboratories, Fort Collins, Colorado) was administered subcutaneously once every 3 months. The primary efficacy parameter was serum testosterone 50 ng./dl. or less. Pharmacokinetics were analyzed in a subset of 22 patients.. Of the 117 enrolled patients 111 (98%) completed the 6-month study. Five patients withdrew for nontreatment related events and 1 was withdrawn because he received less than a full dose of the study drug. By day 28, 98% of patients had serum testosterone 50 ng./dl. or less and 84% had achieved 20 ng./dl. or less. By day 35 all patients had 50 ng./dl. or less testosterone. A patient with a breakthrough response after testosterone suppression on day 49 (112 ng./dl.) regained suppression (27 ng./dl.) 14 days after the second injection (day 98). At study completion all patients had 50 ng./dl. or less testosterone (mean plus or minus standard error of mean 10.1 +/- 0.07) and 104 of the 111 (94%) had 20 ng./dl. or less. From baseline to month 6 mean luteinizing hormone decreased from 9.2 +/- 1.1 to 0.08 +/- 0.01 mIU/ml. and mean prostate specific antigen decreased more than 98%. No flare reactions were observed and patient assessments of bone pain and urinary symptoms were unchanged. The most common treatment related adverse event was hot flashes, which were mild in 57% of cases, moderate in 12% and severe in 0%.. LA-2550 (22.5 mg. depot) produced and maintained safe and effective suppression of serum testosterone to well below the medical castrate level of 50 ng./dl. or less.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Humans; Injections, Subcutaneous; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

It is unclear whether positive interactions between radiation and androgen withdrawal for patients with locally advanced prostate cancer is synergistic or additive. The present study aimed to clarify the significance of neoadjuvant androgen ablation prior to external radiotherapy in a human prostate LNCaP tumor model and in patients with locally advanced prostate cancer.. Comparisons were made between the effect of castration prior to radiation on the growth of subcutaneous LNCaP tumors implanted into male nude mice and their serum prostate-specific antigen (PSA) levels, and the results of castration or radiation alone. Twenty-nine patients with histologically proven and locally advanced adenocarcinoma of the prostate were treated with luteinizing hormone-releasing hormone analog at least 3 months before, during, and after external radiation therapy with a total dose of 70 Gy. The toxicity and response to this therapy were evaluated.. Treatment combining castration and radiation resulted in synergistic inhibition of LNCaP tumor growth and a significant delay in the emergence of androgen-independent recurrence as opposed to either treatment alone. The external radiotherapy was completed in 28 patients (96.6%), resulting in a reduction of serum PSA levels in all 28 patients to below 1.0 ng/mL. All patients were alive after a mean follow-up period of 34 months (range 11-53) with a 3-year PSA relapse-free survival rate of 83.7%. Among several factors examined, only the Gleason score was significantly associated with PSA relapse-free survival in univariate analysis, but not in multivariate analysis. Thirteen of 28 patients (46%) and 7 of 28 (25%) also showed at least one form of gastrointestinal or genitourinary toxicity, respectively. Of these patients, 8 with gastrointestinal toxicities, and 1 with genitourinary toxicity, experienced acute complications higher than grade 3.. The experimental findings objectively suggested the use of neoadjuvant androgen withdrawal prior to radiation therapy. Although our clinical experience is preliminary, combined androgen ablation and radiation therapy may also be effective in controlling locally advanced prostate cancer, with tolerable side-effects.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Animals; Antineoplastic Agents, Hormonal; Disease Models, Animal; Goserelin; Humans; In Vitro Techniques; Leuprolide; Male; Mice; Mice, Inbred BALB C; Middle Aged; Neoadjuvant Therapy; Orchiectomy; Prostatic Neoplasms; Tumor Cells, Cultured

The safety, efficacy, and pharmacokinetics of monthly subcutaneous injections of a new leuprolide acetate (LA) depot formulation were investigated in patients with advanced prostate cancer.. The 2-part, 6-month (168-day), open-label, multicenter study enrolled male patients diagnosed with adenocarcinoma of the prostate (Jewett stage C or D). LA-2500 7.5-mg (a new subcutaneous depot formulation containing 7.5 mg of LA) injections were administered at monthly (28-day) intervals. The primary efficacy parameter was total serum testosterone level. A breakthrough response was defined as a single testosterone measurement > 50 ng/dL after achieving castration testosterone levels. Testosterone was isolated from sera by alumina column chromatography and measured by radioimmunoassay (RIA). LA was purified by solid-phase extraction and high-performance liquid chromatography and was then quantitated by RIA.. One hundred seventeen of the 120 enrolled patients completed the 6-month study. Three patients withdrew for reasons not related to treatment. LA had a mean (SD) maximal concentration of 26.3 (12.6) ng/mL at 4.66 (1.44) hours and was detected for a mean of 37 days (range, 28-49 days). By day 28, 94.1% (112/119) of the patients achieved medical castration (serum testosterone < or = 50 ng/dL). By day 42, 100.0% (118/118) of the patients remaining in the study had serum testosterone levels < or = 50 ng/dL and 97.5% (115/118) had levels < or = 20 ng/dL. At study completion, the mean (SD) serum testosterone level was 6.12 (4.3) ng/dL (range, 3.0-27.0 ng/dL). No breakthrough or acute-on-chronic responses were reported throughout the study. From baseline to month 6, mean (SD) luteinizing hormone level decreased from 8.0 (7.3) mIU/mL to 0.09(0.1) mIU/mL, and mean (SD) prostate-specific antigen level decreased from 32.9 (86.3) ng/mL to 3.2 (12.0) ng/mL. Treatment-related adverse events were reported by 74.2% (89/120) of patients, the most common being hot flashes (56.7%).. This 6-month, open-label, noncontrolled study showed LA-2500 7.5-mg depot was well tolerated and maintained testosterone suppression (< or = 50 ng/dL) in the patients completing the study without any testosterone breakthrough responses.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Humans; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; United States

TAP-144-SR (3M) is a 3-month sustained releasing injection of a super-active agonist of luteinizing hormone releasing hormone (LH-RH), leuprorelin acetate. At the Department of Urology of Gunma University Hospital, TAP-144-SR (3M) was injected once subcutaneously into 10 prostatic cancer patients who had had no treatment in the past to investigate safety, serum testosterone levels, drug concentrations and efficacy. In safety, no problematic adverse reactions occurred, and the drug was well tolerated. Serum testosterone levels elevated temporarily up to 2 days after injection and then were reduced rapidly. The levels were reduced below the castration level (100 ng/dl) after 3 weeks and then remained reduced up to 12 weeks. Serum TAP-144 levels including metabolite M-I, elevated to maximal plasma concentration up to 3 hours after injection and then were maintained at about 0.2 ng/ml between 1 week and 12 weeks after injection. With respect to the anti-tumor effects, the response rate according to "criteria of prostate cancer" at 12 weeks after injection was 100% (stable response cases) and the ratio of PSA normalization at 12 weeks was 90%. These results showed that an injection of TAP-144-SR (3M) was well tolerated in prostate cancer patients having no prior treatment and inhibited serum testosterone persisting for at least 12 weeks so that TAP-144-SR (3M) was concluded to be safe and clinically effective for prostate cancer patients.

Topics: Aged; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Testosterone; Time Factors; Treatment Outcome

A randomized, multicenter, double-blind, parallel-group study was conducted in order to evaluate the hormonal kinetics, pharmacokinetics, efficacy and safety of TAP-144-SR (3M) a three-month sustained-release injectable preparation of leuprorelin acetate, a highly active luteinizing hormone-releasing hormone (LH-RH) derivative by comparing the treatment with two subcutaneous doses of the test medication TAP-144-SR (3M) and the treatment with six subcutaneous doses of the reference medication TAP-144-SR (1M), a 1-month sustained-release injectable preparation. Study participants were 103 patients with prostate cancer in whom a stable anti-tumor effect had been obtained with Leuplin Injection 3.75. The hormonal kinetics revealed that the proportion of the patients "maintaining the castration level of serum testosterone (maximum serum testosterone level during treatment below the castration level [100 ng/dl])" was 100% in both treatment groups. With regard to the efficacy, the proportions of the patients in whom the anti-tumor effects (> or = Stable) of the baseline treatment prior to the initiation of the treatment with the study medication were maintained during the study treatment period (6 months) were comparable; 84.0% with TAP-144-SR (1M) and 80.4% with TAP-144-SR (3M). On evaluation of the pharmacokinetics, the mean value of AUC1-12w of the serum TAP-144 concentration (including the metabolite M-I) for the treatment with TAP-144-SR (3M) was 77.0% that of the treatment with TAP-144-SR (1M). Adverse events were similar in the subjects on TAP-144-SR (3M) and in those on TAP-144-SR (1M). There existed no big differences in kind, incidence or time of occurrence of adverse events between two groups. TAP-144-SR (3M) showed no clinically relevant findings in particular. These results indicate that one dose of TAP-144-SR (3M) is comparable to three doses of the already approved Leuplin injection 3.75 in serum testosterone level-inhibitory effect, efficacy and safety. Hence, it is considered that TAP-144-SR (3M) is a drug suitable for treatment of prostate cancer over a prolonged period of time.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Double-Blind Method; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Testosterone; Time Factors; Treatment Outcome

Low androgen levels in men are associated with increased cardiovascular risk, through unclear mechanisms. We measured arterial stiffness ('compliance') in 21 men receiving complete testosterone suppression therapy for prostate cancer, and in 25 controls. Systemic arterial compliance (SAC), which assesses proximal aortic stiffness, was calculated by simultaneous recording of aortic flow and carotid artery pressure (the 'area method'). Aorto-femoral (A-F), aorto-radial (A-R) and femoral-dorsalis pedis (F-DP) pulse-wave velocities (PWVs) were recorded using the 'Complior' system. SAC was significantly lower in the androgen-depleted men compared to controls (0.81 +/- 0.53 vs. 1.18 +/- 0.43 arbitrary compliance units, p = 0.01, mean +/- SD). Correspondingly, their A-F PWV was higher (14.1 (10.1-21.8) vs. 12.4 (9.6-17.4) m/s, p = 0.03, median (range)). Cases tended to be older (75 +/- 7 vs. 71 +/- 6 years, p = 0.07), and to have higher systolic blood pressure (148 +/- 22 vs. 143 +/- 17 mmHg, p = 0.40); however, SAC was still significantly lower (p = 0.03) after adjustment for age and stratification for central systolic pressure (< or = or > the median). Adjustment of A-F PWV for age and central systolic pressure reduced significance to p = 0.07. There was no significant difference in peripheral PWVs between groups. In conclusion, testosterone suppression is associated with increased aortic stiffness, only partly explained by age and blood pressure. Loss of androgens in men might therefore adversely affect cardiovascular risk.

Topics: Age Factors; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Arteries; Cardiovascular Diseases; Flutamide; Goserelin; Hemodynamics; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Vascular Patency

Standard therapies for locally advanced prostate cancer have resulted in suboptimal disease control rates. A Phase I/II trial was designed for patients with positive seminal vesicle biopsies, prostate-specific antigen (PSA) >15 ng/ml, Gleason score > or =8 or clinical classification T2c-T3 to improve local control and to test the tolerance of the prostate to high-dose radiation by using neoadjuvant hormonal therapy, 103Pd brachytherapy, and conformal three-dimensional external beam radiation therapy (EBRT). This article outlines treatment-related morbidity and PSA response to this regimen and analyzes the effect of escalating doses of brachytherapy.. Forth-three patients with T1c-T3 prostate cancer were enrolled in a Phase I/II trial from March 1994 through September 1997. Follow-up ranged from 12 to 64 months (median, 32 months). Pretreatment PSA ranged from 2.1 to 202 ng/ml (median, 16 ng/ml). Seventy-seven percent (33 of 43) of patients had high-grade tumors (score > or =7). Seventy-four percent (32 of 43) had stage > or =T2c. A total of 21 (49%) patients had positive seminal vesicle biopsies. Treatment consisted of hormonal therapy for 3 months with leuprolide and flutamide followed by a 103Pd implant and, 2 months later, 59.4 Gy of three-dimensional EBRT. Hormonal therapy was continued for 9 months. The planned 103Pd dose was escalated from 57 Gy (13 patients) to 77 Gy (13 patients) to 86 Gy (17 patients).. The actuarial freedom from PSA failure (PSA>0.5 ng/ml) at 4 years was 74%. There were no significant differences found when analyzing patients by presenting PSA or seminal vesicle status. There was a trend toward improved outcome with higher doses delivered to the prostate via the implant. Patients receiving doses > or =65 Gy (31 patients) had a freedom from PSA failure rate at 4 years of 89.5%, compared with 52.5% for those receiving doses <65 Gy (10 patients; p=0.08). The last PSA values for those patients free from PSA failure were < or =0.1 ng/ml in 25 (69%), >0.1-0.2 ng/ml in 5 (14%), and >0.2-0.5 ng/ml in 6 (17%). The actuarial freedom from developing Grade 2 proctitis was 75% at 4 years. There was a trend toward increased proctitis with increasing prostate implant doses. Patients with doses < or =70 Gy (n=12) had a 92% freedom from Grade 2 proctitis compared with 67.5% for those with doses delivered to 90% of the gland from a dose-volume histogram of >70 Gy (n=29) (p=0.15). There were no cases of Grade 3 or 4 proctitis. The 3-year actuarial preservation of sexual potency rate was 43%.. The preliminary results from this regimen show an improvement in PSA control for this group of locally advanced prostate cancer patients over more standard therapies. To maximize control while minimizing toxicity, doses of 65-70 Gy of 103Pd should be used when 59.4 Gy of three-dimensional EBRT is delivered. Longer follow-up will be needed to further substantiate these findings.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Brachytherapy; Chemotherapy, Adjuvant; Flutamide; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Palladium; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes; Radiotherapy Dosage; Radiotherapy, Conformal

In the initial report of the Lupron Depot Neoadjuvant Prostate Cancer Study Group patients who received 3 months of androgen deprivation had a significant decrease in the positive margin rate. We monitored these patients for 5 years and to our knowledge present the longest followup of any neoadjuvant trial.. A multi-institutional prospective randomized trial was performed between February 1992 and April 1994 involving patients with stage cT2b prostate cancer, including 138 who received 3 months of leuprolide plus flutamide before radical prostatectomy and 144 who underwent radical prostatectomy only. Patients were followed every 6 months with serum prostate specific antigen (PSA) testing for 5 years. Biochemical recurrence was defined as PSA greater than 0.4 ng./ml.. At 5 years there was no difference in the biochemical recurrence rate. PSA was less than 0.4 ng./ml. in 64.8% of the patients in the neoadjuvant androgen ablation plus prostatectomy and 67.6% in the prostatectomy only group (p = 0.663).. Although 3 months of androgen deprivation before radical prostatectomy resulted in an apparently significant decrease in positive surgical margins, a 5-year followup does not indicate any difference in the recurrence rate. Until studies document improvement in biochemical or clinical recurrence with longer periods of treatment, induction androgen deprivation before radical prostatectomy is not indicated.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Flutamide; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

The aim of this study was to determine the effects of initial treatment with a GnRH agonist on body composition in asymptomatic men with nonmetastatic prostate cancer. Forty men with locally advanced, node-positive or biochemically recurrent prostate cancer, no radiographic evidence of metastases, and no prior androgen deprivation therapy were treated with leuprolide 3-month depot 22.5 mg im every 12 wk for 48 wk. The main outcome measures were percentage changes in weight, percentage fat body mass, percentage lean body mass, fat distribution, and muscle size after 48 wk. Thirty-two subjects were evaluable. Serum T concentrations decreased by 96.3% plus or minus 0.4% (P < 0.001). Weight increased by 2.4% plus or minus 0.8% (P = 0.005). Percentage fat body mass increased by 9.4% plus or minus 1.7% (P < 0.001), and percentage lean body mass decreased by 2.7% plus or minus 0.5% (P < 0.001). Cross-sectional areas of the abdomen and abdominal sc fat increased by 3.9% plus or minus 1.2% (P = 0.003) and 11.1% plus or minus 3.4% (P = 0.003), respectively. In contrast, the cross-sectional area of intraabdominal fat did not change significantly (P = 0.94). Cross-sectional paraspinal muscle area decreased by 3.2% plus or minus 1.3% (P = 0.02). GnRH agonists increase weight and percentage fat body mass and decrease percentage lean body mass and muscle size in men with nonmetastatic prostate cancer. Increased fatness resulted primarily from accumulation of sc rather than intraabdominal adipose tissue.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Body Composition; Delayed-Action Preparations; Diphosphonates; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Hemoglobins; Humans; Leuprolide; Lipoproteins; Male; Middle Aged; Pamidronate; Prostate-Specific Antigen; Prostatic Neoplasms

Phase III studies have demonstrated the clinical benefit of adding neo-adjuvant androgen deprivation to radical radiotherapy for clinically localised prostate cancer. We have developed a nomogram to describe the probability of PSA control for patients treated in this way. Five hundred and seventeen men with clinically localised prostate cancer were treated with 3-6 months of neo-adjuvant androgen deprivation and radical radiotherapy (64Gy in 32#) between 1988 and 1998. Median presenting PSA was 20 ng x ml(-1), and 56% of patients had T3/4 disease. Multivariate analysis of pre-treatment factors was performed, and a nomogram developed to describe PSA-failure-free survival probability. At a median follow-up of 44 months, 233 men had developed PSA failure. Presenting PSA, histological grade and clinical T stage were all highly predictive of PSA failure on multivariate analysis. The nomogram score for an individual patient is given by the summation of PSA (<10=0, 10-19=16, 20-49=44, > or =50=100), grade (Gleason 2-4=0, 5-7=44, 8-10=81) and T stage (T1/2=0, T3/4=35). For a nomogram score of 0, 50, 100 and 150 points the 2 year PSA control rate was 93, 87, 75 and 54%, and the 5 year PSA control rate was 82, 67, 44 and 18%. These results are comparable to those using surgery or higher doses of radical radiotherapy alone. The nomogram illustrates the results of multivariate analysis in a visually-striking way, and facilitates comparisons with other treatment methods.

Topics: Administration, Oral; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Cyproterone Acetate; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Patient Care Planning; Predictive Value of Tests; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Treatment Outcome

We compared the endocrinological and biochemical efficacy of abarelix depot, a gonadotropin-releasing hormone antagonist, with that of a widely used combination of luteinizing hormone releasing hormone agonist and a nonsteroidal antiandrogen.. A total of 255 patients were randomized to receive open label 100 mg. abarelix depot or 7.5 mg. leuprolide acetate intramuscularly injection on days 1, 29, 57, 85, 113 and 141 for 24 weeks. Patients in the abarelix group received an additional injection on day 15 and those in the leuprolide acetate group received 50 mg. bicalutamide daily. Patients could continue treatment with study drug for an additional 28 weeks. The efficacy end points were the comparative rates of avoidance of testosterone surge (greater than 10% increase) within 7 days of the first injection and the rapidity of achieving reduction of serum testosterone to castrate levels (50 ng./dl. or less) on day 8. Patients were monitored for adverse events and laboratory abnormalities.. Abarelix was more effective in avoidance of testosterone surge (p <0.001) and the rapidity of reduction of testosterone to castrate levels on day 8 (p <0.001) than combination therapy. No significant difference was seen between the groups in the initial rate of decline of serum prostate specific antigen or the ability to achieve and maintain castrate levels of testosterone. No unusual or unexpected adverse events were reported.. Abarelix as monotherapy achieves medical castration significantly more rapidly than combination therapy and avoids the testosterone surge characteristic of agonist therapy. Both treatments were equally effective in reducing serum prostate specific antigen, and achieving and maintaining castrate levels of testosterone.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Humans; Leuprolide; Male; Middle Aged; Nitriles; Oligopeptides; Prostatic Neoplasms; Tosyl Compounds

To investigate the possibility that more complete blockade of androgens or combined androgen blockade (CAB) could lead to even longer term control of localized prostate cancer. A series of recent studies have shown important benefits on survival using medical or surgical castration in localized or locally advanced prostate cancer.. The effect of CAB on long-term control or possible cure of prostate cancer was evaluated by the absence of biochemical failure or prostate-specific antigen (PSA) rise for at least 5 years after cessation of continuous treatment. A total of 57 patients with localized or locally advanced disease received CAB for periods ranging from 1 to 11 years. Twenty patients with Stage B2/T2 prostate cancer who were treated for a median duration of 7.2 years (range 2.8 to 11.7) with CAB stopped treatment and were followed up for a median of 4.9 years. Eleven patients with Stage B2/T2 also received CAB but for only 1 year. Twenty-six patients with Stage C/T3 treated with continuous CAB for a median of 9.9 years (range 3.8 to 11.3) with undetectable PSA levels stopped treatment and were followed up for a median of 5.6 years. The median follow-up since diagnosis was 14.6 years for patients with Stage B2/T2 and 16.4 years for patients with Stage C/T3 disease.. With a minimum of 5 years of follow-up after cessation of long-term CAB, two PSA rises occurred among 20 patients with Stage T2-T3 cancer who stopped treatment after continuous CAB for more than 6.5 years, for a nonfailure rate of 90%. For the 11 patients who had received CAB for 3.5 to 6.5 years, the nonfailure rate was only 36%. The serum PSA increased within 1 year in all 11 patients with Stage B2/T2 treated with CAB for only 1 year, thus indicating that active cancer remained present after short-term androgen blockade despite undetectable PSA levels. In all patients who had biochemical failure after stopping CAB, the serum PSA level rapidly decreased again to undetectable levels when CAB was restarted and remained at such low levels afterward. Of these patients, only 1 patient had died of prostate cancer at last follow-up.. The present data suggest that long-term and continuous CAB offers the possibility of long-term control or possible cure of localized prostate cancer.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Therapy, Combination; Flutamide; Follow-Up Studies; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Longitudinal Studies; Male; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome; Triptorelin Pamoate

Hypogonadism is associated with osteoporosis in men. GnRH- agonist-induced hypogonadism increases bone turnover and bone loss in men, but the mechanism underlying these changes is unknown. To determine whether gonadal steroid deprivation increases the skeletal sensitivity to PTH or blunts the ability of PTH to promote 1,25-dihydroxyvitamin D formation, we infused human PTH-(1-34) at a dose of 0.55 U/kg.h for 24 h, in 11 men (ages, 50-82 yr) with locally advanced, node-positive, or biochemically recurrent prostate cancer but no evidence of bone metastases. PTH infusions were performed before initiation of GnRH agonist therapy (leuprolide acetate, 22.5 mg im, every 3 months) and again after 6 months of confirmed GnRH agonist-induced hypogonadism. Serum osteocalcin (OC), bone- specific alkaline phosphatase (BSAP), N-telopeptide (NTX), whole-blood ionized calcium, and 1,25-dihydroxyvitamin D were measured at baseline and every 6 h during each PTH infusion. Urinary NTX and free deoxypyridinoline (DPD) were assessed on spot morning samples before PTH infusion and on 24-h samples collected during the PTH infusions. Sex steroid levels were lowered to the castrate range in all subjects. Baseline serum NTX levels (drawn before PTH infusion) increased from 9.1 +/- 3.7 before leuprolide therapy to 13.9 +/- 5.0 nmol bone collagen equivalents (BCE)/L after leuprolide therapy (P = 0.003). Spot urine NTX collected before PTH infusion increased from 28 +/- 8 before leuprolide therapy to 49 +/- 17 nmol BCE/mmol creatinine after leuprolide therapy (P < 0.001), and urinary DPD increased from 4.7 +/- 1.1 to 7.4 +/- 1.8 nmol BCE/mmol creatinine (P < 0.001). Baseline serum OC and BSAP levels drawn before each PTH infusion did not change before vs. after leuprolide therapy. Serum NTX levels increased significantly during PTH infusion pre-GnRH agonist therapy (P < 0.001), and the rate of increase was greater after 6 months of GnRH agonist-induced hypogonadism (P < 0.01 for the difference in rates of change before and after GnRH agonist administration). Serum OC and BSAP levels decreased during PTH infusion (P < 0.001 for OC and P = 0.002 for BSAP), but the rates of decrease did not differ before or after leuprolide therapy (P = 0.45 for OC and P: = 0.19 for BSAP). Whole-blood ionized calcium levels increased during PTH infusion (P < 0.001), and the rate of increase was greater after GnRH agonist-induced hypogonadism (P = 0.068). Serum 1,25-dihydroxyvitamin D levels increased in r

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Amino Acids; Antineoplastic Agents, Hormonal; Biomarkers; Bone and Bones; Calcitriol; Calcium; Collagen; Collagen Type I; Diphosphonates; Humans; Hypogonadism; Leuprolide; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Osteocalcin; Pamidronate; Peptides; Prostatic Neoplasms; Teriparatide; Time Factors

We investigated the influence of flutamide on plasma adrenal androgens in advanced prostate cancer patients treated with dietylstilbestrol diphosphate (DES-DP) followed by luteinizing hormone-releasing hormone agonist (LH-RH agonist). Nine patients were enrolled in this study and they were divided into the following two treatment groups; group A: LHRH agonist mono-therapy (n = 4) and group B: LHRH agonist with flutamide (n = 5). For prevention of flare up, all patients were treated with DES-DP.. Two-week DES-DP administration led to reduction of plasma adrenal androgen levels. These levels were kept lower for 16 weeks in group B in contrast with group A in which the levels returned to the pretreatment levels. Basal ACTH levels in group B were significantly lower than those in group A.. From our observations, we found that flutamide reduced adrenal androgen levels in prostate cancer patients treated with LH-RH agonist. ACTH suppression might be related to this phenomenon.

Topics: Adrenocorticotropic Hormone; Aged; Androgens; Depression, Chemical; Diethylstilbestrol; Drug Therapy, Combination; Flutamide; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms

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.. 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.. Patients were treated for a median of 13 months with triple androgen blockade. At baseline, mean PSA level was 13.2 +/- 1.2 ng/ml (range, 0.39-100 ng/ml), and mean Gleason score was 6.6 +/- 0.1 (range, 4-10). During treatment, PSA levels declined to < or =0.1 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 (95.5%). 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 1.88 +/- 0.1 (range, 0-11.0 ng/ml). Only 9 of 110 (8.1%) patients have a PSA level > or =4.0 ng/ml. To date, no patient has received a second cycle of hormone blockade.. 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.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Finasteride; Flutamide; Follow-Up Studies; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Tosyl Compounds; Treatment Outcome

Flare-up phenomena, such as an increase in prostate-specific antigen (PSA) and/or deterioration of symptoms, are observed in some patients undergoing gonadotropin-releasing hormone (GnRH) agonist therapy. This study was carried out to determine the optimal time for starting the administration of flutamide to prevent flare-up phenomena.. Twenty-six patients with prostate cancer and elevated serum levels of PSA were randomly assigned to 5 groups. Group A patients (n = 6) were treated with a subcutaneous injection of 3.75 mg leuprorelin acetate depot alone. Group B, C, D and E patients (5 patients in each group) were treated with 375 mg/day of orally administered flutamide combined with leuprorelin. Flutamide was initiated on the day of leuprorelin injection in group B, and at 1, 2 and 4 weeks before leuprorelin injection in groups C, D and E, respectively. Serum PSA and testosterone levels were measured in each patient.. Pretreatment with flutamide increased the serum testosterone level, but the testosterone surge after leuprorelin administration was almost the same in all 5 treatment groups. In patients who had been treated with flutamide in combination with leuprorelin, the mean PSA level did not exceed the pretreatment levels after leuprorelin administration. The rate of decrease in PSA in the group receiving simultaneous administration of flutamide with leuprorelin showed a decline comparable to that during the period before leuprorelin administration in the flutamide pretreatment groups.. Simultaneous administration of flutamide with a GnRH agonist is sufficient to prevent flare-up phenomena.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Flutamide; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Time Factors

We contrasted the endocrinological and biochemical efficacies of abarelix depot, a pure gonadotropin-releasing hormone antagonist, with a prospective concurrent control cohort receiving luteinizing hormone releasing hormone (LH-RH) agonists with or without antiandrogen for treatment of patients with prostate cancer receiving initial hormonal therapy.. In this phase 2 open label study 242 patients with prostate cancer requiring initial hormonal treatment received abarelix depot (209) or LH-RH agonists (33) with or without antiandrogen. A total of 100 mg. abarelix depot was delivered intramuscularly every 28 days with an additional injection on day 15. LH-RH agonists with or without antiandrogen were administered according to the depot formulation used. Endocrine efficacy was measured by the absence of testosterone surge and rapidity of castration onset. The rate of prostate specific antigen decrease was assessed.. No patient treated with abarelix depot had testosterone surge during week 1 compared with 82% of those treated with LH-RH agonists. The concomitant administration of antiandrogen had no effect. During the first week of drug administration, in 75% of patients treated with abarelix depot and in 0% of those treated with LH-RH agonist medical castration was achieved. Prostate specific antigen decrease was faster, with no flare or surge in patients treated with abarelix depot. Abarelix depot was well tolerated.. Abarelix depot represents a new class of hormonal therapy, gonadotropin releasing hormone antagonists, that has rapid medical castration and avoids the testosterone surge characteristic of LH-RH agonists.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Dihydrotestosterone; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Goserelin; Humans; Injections, Intramuscular; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Oligopeptides; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testis; Testosterone

A prospective phase 3 trial was initiated to determine whether 8 compared with 3-month neoadjuvant hormonal therapy reduces prostate specific antigen (PSA) recurrence rates after radical prostatectomy. Our interim analysis includes secondary end points of differences in biochemistry, pathology and adverse events between the 2 groups.. Men with clinically confined prostate cancer were randomized to receive 7.5 mg. leuprolide intramuscularly monthly and 250 mg. flutamide orally 3 times daily for 3 or 8 months before radical prostatectomy. Our study was powered to detect a 35% decrease in PSA recurrence, assuming a 30% recurrence rate in the 3-month arm after 3 years.. A total of 547 men were randomized between August 1995 and April 1998. Men in the 8 and 3-month groups were equally stratified for T stage (29% T1c, 70% T2), Gleason grade (68% less than 4, 32% 4 or greater) and pretreatment PSA (63% less than 10, 27% 10 to 20 and 10% greater than 20 microg./l.). Mean pretreatment PSA was slightly higher in the 8-month compared with the 3-month group (11.64 versus 9.95 microg./l., respectively, p = 0.0539). A total of 44 men withdrew from study before surgery and, therefore, were nonevaluable. Preoperative PSA nadir was less than 0.1 microg./l. in 43.3% versus 75.1% (p <0.0001), and 0.3 microg./l. or greater in 21% versus 9.2% after 3 versus 8 months, respectively (p <0.0006). Mean serum PSA decreased 98% to 0.12 microg./l. after 3 months, with a further 57% to 0.052 microg./l. from 3 to 8 months. Transrectal ultrasound determined that prostatic volume decreased 37% from a mean of 40.6 to 25.4 cc after 3-month neoadjuvant hormonal therapy (p = 0.0001) and a further 13% to 22.2 cc after 8 months (p = 0.03). Mean hemoglobin decreased 15% (148.2 to 125.4 gm./dl.) after 3-month neoadjuvant hormonal therapy but stabilized thereafter. Radical prostatectomy was completed in 500 men, while surgery was aborted intraoperatively in 3. Positive margin rates were significantly lower in the 8 than 3-month group (12% versus 23%, respectively, p = 0.0106). There were no fatal adverse events and no differences between the 2 groups in the severity or causality (p = 0.287, 0.0564) of adverse events, or incidence of increased liver enzymes or diarrhea (p = 0.691, 0.288, respectively). However, men in the 8-month group noticed a higher number of newly reported adverse events (4.5 versus 2.9, p <0.0001) and higher incidence of hot flushes than the 3-month group (87% versus 72%, respectively, p <0.0001).. Ongoing biochemical and pathological regression of prostate tumors occurs between 3 and 8 months of neoadjuvant hormonal therapy, suggesting that the optimal duration of neoadjuvant hormonal therapy is longer than 3 months. Longer followup is needed to determine whether longer therapy alters PSA recurrence rates.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Flutamide; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Prospective Studies; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

To assess patient-reported general satisfaction, effect on daily activities, and effect on health-related quality of life of a 12-month leuprolide implant for prostate cancer.. A total of 80 men with prostate cancer participated in an open-label Phase III study of the Viadur leuprolide implant. One implant was inserted in each patient at enrollment and was removed after 52 weeks. At 24 and 52 weeks after implantation, patients were asked to complete a questionnaire about their experience with the implant, and at 0, 12, 24, 36, and 52 weeks after implantation, the patients were asked to complete the Medical Outcome Study Short Form-36 health-related quality-of-life instrument.. The surveys about the patients' experience with the implant were completed by 70 subjects, and two or more SF-36 questionnaires were completed by 72 patients. At weeks 24 and 52 after implantation, greater than 90% of patients were extremely satisfied or satisfied with the overall treatment, found the implant convenient, forgot about the implant most of the time or were occasionally aware of the implant, and found the implant very comfortable or somewhat comfortable. No meaningful change was found in the summary scores of the mental and physical aspects of the SF-36 assessments during treatment. Of 73 men who were eligible for reimplantation after the 12-month study period, 70 (96%) elected to undergo reimplantation.. In this study, patients found the Viadur 12-month leuprolide implant convenient, and the implant did not affect their health-related quality of life.

Topics: Aged; Antineoplastic Agents, Hormonal; Attitude to Health; Drug Implants; Health Status; Humans; Leuprolide; Male; Patient Acceptance of Health Care; Patient Satisfaction; Prostatic Neoplasms; Quality of Life; Sickness Impact Profile; Treatment Outcome

Treatment with a gonadotropin-releasing hormone agonist decreases bone mineral density and increases the risk of fracture in men with prostate cancer. We conducted a controlled study of the prevention of osteoporosis in men undergoing treatment with a gonadotropin-releasing hormone agonist.. In a 48-week, open-label study, we randomly assigned 47 men with advanced or recurrent prostate cancer and no bone metastases to receive either leuprolide alone or leuprolide and pamidronate (60 mg intravenously every 12 weeks). Bone mineral density of the lumbar spine and the proximal femur was measured by dual-energy x-ray absorptiometry. Trabecular bone mineral density of the lumbar spine was measured by quantitative computed tomography. Forty-one men completed the study.. In men treated with leuprolide alone, the mean (+/-SE) bone mineral density decreased by 3.3+/-0.7 percent in the lumbar spine, 2.1+/-0.6 percent in the trochanter, and 1.8+/-0.4 percent in the total hip, and the mean trabecular bone mineral density of the lumbar spine decreased by 8.5+/-1.8 percent (P<0.001 for each comparison with the base-line value). In contrast, the mean bone mineral density did not change significantly at any skeletal site in men treated with both leuprolide and pamidronate. There were significant differences between the two groups in the mean changes in bone mineral density at 48 weeks in the lumbar spine (P<0.001), trochanter (P = 0.003), total hip (P=0.005), and trabecular bone of the lumbar spine (P=0.02).. Pamidronate prevents bone loss in the hip and lumbar spine in men receiving treatment for prostate cancer with a gonadotropin-releasing hormone agonist.

Topics: Aged; Antineoplastic Agents, Hormonal; Bone Density; Bone Resorption; Diphosphonates; Femur; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Lumbar Vertebrae; Male; Osteocalcin; Osteoporosis; Pamidronate; Pelvic Bones; Prostatic Neoplasms

To report the preliminary results of a Phase I/II study combining radiotherapy and in situ gene therapy (adenovirus/herpes simplex virus thymidine kinase gene/valacyclovir) with or without hormonal therapy in the treatment of prostate cancer.. Arm A: low-risk patients (T1-T2a, Gleason score <7, pretreatment PSA <10) were treated with combined radio-gene therapy. A mean dose of 76 Gy was delivered to the prostate with intensity-modulated radiotherapy. Arm B: high-risk patients (T2b-T3, Gleason score >or=7, pretreatment PSA >or=10) were treated with combined radio-gene therapy and hormonal therapy. Hormonal therapy was comprised of a 4-month leuprolide injection and 2-week use of flutamide. Arm C: Stage D1 (positive pelvic lymph node) patients received the same regimen as Arm B, with the additional 45 Gy to the pelvic lymphatics. Treatment-related toxicity was assessed using Cancer Therapy Evaluation Program common toxicity score and Radiation Therapy Oncology Group (RTOG) toxicity score.. Thirty patients (13 in Arm A, 14 in Arm B, and 3 in Arm C) completed the trial. Median follow-up was 5.5 months. Eleven patients (37%) developed flu-like symptoms (Cancer Therapy Evaluation Program Grade 1) of fatigue and chills/rigors after gene therapy injection but recovered within 24 h. Four patients (13%) and 2 patients (7%) developed Grade 1 and 2 fever, respectively. There was no patient with weight loss. One patient in Arm B developed Grade 3 elevation in liver enzyme, whereas 11 and 2 patients developed Grade 1 and 2 abnormal liver function tests. There was no Grade 2 or above hematologic toxicity. Three patients had transient rise in creatinine. There was no RTOG Grade 3 or above lower gastrointestinal toxicity. Toxicity levels were as follows: 4 patients (13%), Grade 2; 6 patients (20%), Grade 1; and 20 patients (67%), no toxicity. There was 1 patient with RTOG Grade 3 genitourinary toxicity, 12 patients (40%) with Grade 2, 8 patients (27%) with Grade 1, and 9 patients (30%) with no toxicity. No patient dropped out from the trial or had to withhold treatment because of severe toxicity.. This is the first trial of its kind in the field of prostate cancer that aims to expand the therapeutic index of radiotherapy by combining in situ gene therapy. Initial experience has demonstrated the safety of this approach. There is no added toxicity to each therapy used alone. Long-term follow-up and larger cohort studies are warranted to evaluate long-term toxicity and efficacy.

Topics: Adenoviridae; Adult; Aged; Aged, 80 and over; Combined Modality Therapy; Flutamide; Genetic Therapy; Genetic Vectors; Humans; Leuprolide; Lymphatic Irradiation; Male; Middle Aged; Prostatic Neoplasms; Simplexvirus; Thymidine Kinase

An increasingly important issue in the management of prostate cancer is the occurrence of biochemical failure (ie, increasing serum prostate-specific antigen [PSA] levels) in patients with clinically localized prostate cancer who initially underwent definitive treatments with curative intent (prostatectomy and/or radiation therapy). This pilot trial evaluated chemotherapy followed by hormone therapy for a defined period in patients with biochemical (and possibly clinical) recurrence after initial local therapies for localized/locally advanced prostate cancer. Patients who developed increasing PSA > 4 ng/mL after initial prostatectomy and/or radiation therapy received docetaxel, 70 mg/m(2) every 3 weeks for up to 6 courses, followed by 4 months of total androgen suppression (using a luteinizing hormone-releasing hormone agonist plus bicalutamide, 50 mg/d) and 8 months of peripheral androgen blockade (using finasteride, 5 mg/d, plus bicalutamide, 50 mg/d). Twenty-seven patients have enrolled to date, 23 of whom received four or six cycles of docetaxel before hormonal therapies. Seventeen (74%) of 23 patients who completed four to six cycles of chemotherapy had a > or =40% decrease in PSA, and 16 (89%) of 18 patients who completed 4 months of total androgen suppression achieved PSA values of < or =0.1. The most common hematologic toxicity was grade (3/4) neutropenia; grade 3 nonhematologic toxicities were rare, and no grade 4 nonhematologic toxicities were reported. Thus, the preliminary results suggest that docetaxel before hormonal therapy includes a PSA response in many prostate cancer patients with biochemical failure after definitive local therapies.

Topics: Adenocarcinoma; Aged; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Docetaxel; Finasteride; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoplasm Recurrence, Local; Nitriles; Paclitaxel; Pilot Projects; Prostate-Specific Antigen; Prostatic Neoplasms; Salvage Therapy; Taxoids; Tosyl Compounds

A prospective randomized study was designed to determine whether flutamide (FLU) administered before treatment with a luteinizing hormone-releasing hormone agonist (LH-RHa) prevented prostate-specific antigen (PSA) flare in prostate cancer patients.. Prostate cancer patients were randomized into two groups and received either FLU (n = 11) or no pretreatment (n = 13) for 2 weeks before the initial injection of LH-RHa. LH-RHa (every 4 weeks) and FLU (every day) were administered throughout the period of this study. Blood samples, for the determination of PSA, testosterone (T), and luteinizing hormone levels, were collected before FLU administration, and before and 2, 7, 14, 28, 56, and 84 days after the first administration of LH-RHa.. Treatment with FLU prior to LH-RHa induced an early decline in PSA level. The mean PSA level showed no significant secondary rise after LH-RHa administration in those patients with FLU pretreatment. Patients in both groups showed T flare after the first LH-RHa administration. However, the number of patients with PSA flare was significantly lower in patients with prior FLU administration than in those with LH-RHa alone.. These results clearly demonstrate that, in patients with prostatic cancer, the administration of FLU for 2 weeks prior to the first LH-RHa administration is effective in preventing PSA flare, as well as in inducing an early decline in PSA levels.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Drug Administration Schedule; Flutamide; Goserelin; Humans; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms

To evaluate the levels of testosterone and other hormones in men with prostate cancer treated with abarelix versus leuprolide acetate.. Patients (n = 269) were randomized to receive open-label abarelix 100 mg or leuprolide acetate 7.5 mg by intramuscular injection. The results of the first 84 days of the study are reported. The primary efficacy endpoints included avoidance of testosterone surge, castration on day 8, and achievement and maintenance of castration from days 29 through 85. The secondary endpoints included castration on days 2, 4, and 15; a reduction in prostate-specific antigen level; and measurements of other hormones. Patients were monitored for clinical adverse events and laboratory abnormalities.. No men in the abarelix group and 82% of men in the leuprolide acetate group experienced a testosterone surge (P <0.001). Abarelix caused rapid medical castration: 24% of men 1 day after treatment and 78% after 7 days compared with 0% of men treated with leuprolide acetate on either day. A comparable percentage of men achieved and maintained castration between days 29 and 85 in each group. Prostate-specific antigen had a statistically significant decrease for the first month in patients treated with abarelix. Dihydrotestosterone, luteinizing hormone, prostate-specific antigen, and follicle-stimulating hormone showed similar rapid reductions without an initial increase. The overall occurrence of adverse events was similar across the treatment groups, and most were sequelae of comorbid disorders.. Treatment with abarelix produced a higher percentage of patients who avoided a testosterone surge and had a more rapid time to testosterone suppression with a higher rate of medical castration 1 day after treatment and greater reductions in testosterone, luteinizing hormone, follicle-stimulating hormone, and dihydrotestosterone during the first 2 weeks of treatment compared with leuprolide acetate. The achievement and maintenance of castration was comparable between the two groups.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers; Castration; Follicle Stimulating Hormone; Humans; Injections, Intramuscular; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Time Factors

Twenty-two institutes have organized Keio University Prostate Cancer Study Group to study clinical efficacy and safety of Leuprolide acetate (Leuplin) for the treatment of advanced prostate cancer (clinical stage D1 and D2). Cotreatment of Leuplin and Estramustine phosphate disodium (Estracyt) has been performed to investigate its clinical efficacy.. One hundred and two cases of advanced prostate cancer were treated either with Leuplin alone (group I), Leuplin and Estracyt (group II) or Estracyt alone (group III). After 12 weeks treatment, clinical effects against subjective symptoms (pain, voiding difficulty, performance status and body weight), serum testosterone level, tumor size and serum PSA level were examined to investigate short-term effect of each treatment. The treatment had been continued for 24 months and the treatment effects including progression free survival and overall survival were analyzed.. Clinical efficacy after 12 weeks treatment were examined among 97 cases (group I; 35 cases, group II; 36 cases, group III; 26 cases). The background of those patients in each group was statistically equal. Treatment effects against subjective symptoms and serum testosterone level statistically revealed no significant difference among 3 groups. Treatment effects against primary tumor, bone metastatic lesion, lymphnode metastatic lesion and serum PSA level were investigated and anti-tumor effect was characterized by total efficacy rate (complete remission rate plus partial remission rate) of each treatment group. Treatment efficacy rates for each lesion and PSA demonstrated no statistical difference among 3 treatment groups. Total efficacy rate of group I, II and III were 88.2%, 84.0% and 78.3%, respectively, which statistically revealed no significant difference. Total efficacy rate of each group after completing 24 months treatment was; group I 80.0%, group II 55.6% and group III 83.3%, which statistically showed no significant difference among 3 treatment groups. The median day for progression free survival of group I, II and III were 661, 731 and 517, respectively. The overall survival rate of group I, II and III after completing 24 months treatment were 77.5%, 83.0% and 72.4%, respectively. Both progression free survival rates and overall survival rates revealed no significant difference among 3 groups. Side effects during 24 months treatment were seen in 8.6% of group I, 47.2% of group II and 26.9% of group III, and these occurrence rates were significantly different among the groups (p = 0.0013).. Although number of the cases had not been able to continue the treatment for their side effects, the statistical characterization demonstrated that cotreatment of Leuplin and Estracyt had no greater treatment effect than monotreatment of each drug.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Estramustine; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Survival Rate

To assess the effectiveness and tolerability of transdermal estrogen in men with hot flushes after hormonal therapy for prostate cancer.. Twelve men with moderate to severe hot flushes were randomized to receive either low-dose (0.05 mg) or high-dose (0.10 mg) estrogen patches applied twice weekly for 4 weeks. After a 4-week washout period in which no treatment was given, each patient received the alternative dose for 4 weeks. Treatment response was assessed by daily logs and questionnaires completed every 4 weeks that included a visual analog assessment. Serum luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol levels were also measured every 4 weeks during the study.. There was a significant reduction in the overall severity of the hot flushes seen in patients with both the low and high-dose estrogen patch. A significant reduction in the daily frequency of the hot flushes was seen with the high-dose patch only. Overall, 10 (83%) of 12 men reported either mild, moderate, or major improvement in symptoms with either the low or high-dose patch. Mild, painless breast swelling or nipple tenderness was noted in 2 (17%) and 5 (42%) of 12 men treated with the low and high-dose estrogen patch, respectively. FSH levels decreased significantly with both the low and high-dose patch. Estradiol levels increased from 12.1 to 16.4 pg/mL and 26.9 pg/mL with the low and high-dose patch, respectively. There was no significant change in serum testosterone or luteinizing hormone levels.. Transdermal estrogen appears to be a promising, well-tolerated therapy for men with hot flushes after endocrine treatment for prostate cancer. Further study in larger groups of patients is necessary to assess the relative effectiveness and morbidity of this treatment.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Estrogens; Hot Flashes; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms

To assess the feasibility of administering a combination of suramin and hydrocortisone in addition to androgen deprivation in a cooperative group setting; to assess the feasibility of treatment with multiple courses of suramin; and to assess progression-free and overall survival in patients with newly diagnosed metastatic prostate cancer who underwent such treatment.. Patients with newly diagnosed metastatic prostate cancer who had adequate hematologic, hepatic, renal, neurologic, and coagulation parameters were treated by combined androgen deprivation and suramin plus hydrocortisone. Suramin was administered on a 78-day fixed dosing schedule (one cycle), and suramin treatment cycles were repeated every 6 months for a total of four cycles. The statistical design was developed on the basis of the feasibility of administering suramin, as judged by the number of patients who developed neurotoxicity of grade 3 or higher or by treatment interruption of 4 weeks or longer due to any persistent suramin-related toxicity.. Of the 62 patients enrolled onto the study between August 1994 and January 1997, 59 were eligible and assessable for toxicity on the first cycle. Thirty-two (54%) of 59 patients received a second cycle, 13 (22%) of 59 patients received a third cycle, and only five patients (8%) received a fourth cycle. During the first cycle, 27 patients were removed from the study: 17 because of toxicity, five because of disease progression, two who had died, and three because of other reasons. There was one therapy-related death. Grade 4 toxicities were noted in 11 and three patients during first and second courses, respectively. Neurotoxicity of grade 3 or higher was observed in nine and seven patients during the first and second cycles, respectively. Fifteen patients had treatment interruptions of 4 weeks or longer. Overall, only 54% (95% confidence interval, 41% to 67%) of the patients demonstrated acceptable limits of toxicity.. Suramin plus hydrocortisone and androgen deprivation has limited applicability in the treatment of patients with newly diagnosed metastatic prostate cancer.

Topics: Adult; Aged; Androgens; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Drug Administration Schedule; Feasibility Studies; Goserelin; Humans; Hydrocortisone; Leuprolide; Male; Middle Aged; Orchiectomy; Prostatic Neoplasms; Suramin; Treatment Outcome

To explore whether less than 120 days of an antiandrogen plus a luteinizing hormone-releasing hormone agonist resulted in a different survival outcome than 120 days or more of combined treatment in patients with Stage D2 prostate cancer.. Survival data were available from a previously published controlled trial that had evaluated the efficacy and tolerability of two antiandrogens, bicalutamide and flutamide, each combined with a monthly depot preparation of leuprolide or goserelin, in 813 patients with Stage D2 prostate cancer. Cox's proportional hazards regression model assessed the relative effects of the length of combined androgen blockade (CAB) therapy on survival. This analysis was repeated in the subset of patients who lived at least 2 years beyond the date of randomization. Data were obtained at a median follow-up of 160 weeks.. A survival benefit was demonstrated for patients receiving prolonged CAB therapy, with a hazard ratio of 0.275 (95% confidence interval 0.213 to 0.355, P = 0.0001) in favor of patients who received 120 days or more of CAB therapy (median survival 1035 days versus 302 days for less than 120 days of therapy). This result was confirmed in the patients who lived at least 2 years, in whom the median survival time was increased by 35%. The hazard ratio for 120 days or more of CAB therapy versus less than 120 days was 0.415 (95% confidence interval 0.246 to 0.702, P = 0.001).. The results of the present exploratory analysis suggest that prolonged (120 days or more) antiandrogen treatment as part of CAB therapy may result in a better survival outcome.

Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Drug Administration Schedule; Drug Therapy, Combination; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Nitriles; Prostatic Neoplasms; Survival Rate; Tosyl Compounds

To evaluate the Viadur implant, which delivers leuprolide acetate for the palliative treatment of advanced prostate cancer.. Inserted subcutaneously, the 4 x 45-mm implant uses osmotic pressure to deliver leuprolide continuously at a controlled rate for 1 year. This 19-center open-label study enrolled patients with prostate cancer who had had no prior therapy or showed biochemical evidence of treatment failure after prostatectomy or radiotherapy. Each patient received one implant. After 1 year, that implant was removed, another was inserted, and patients were followed up for 2 additional months. The primary efficacy measure was suppression of testosterone to less than the castrate threshold (50 ng/dL).. Eighty patients were enrolled. The implant effectively suppressed testosterone in 79 patients (99%) within 2 to 4 weeks and maintained that suppression through the study period. In 1 patient, the testosterone was suppressed to less than 100 ng/dL within 4 weeks but was not less than 50 ng/dL until week 24. Prostate-specific antigen levels normalized (4 ng/mL or less) or a clinically significant decrease occurred in all patients. Leuprolide was rapidly absorbed, resulting in mean serum concentrations of 16.8 ng/mL 4 hours after implant insertion and 2.4 ng/mL at 24 hours; steady mean serum leuprolide concentrations were then maintained throughout the year, at approximately 0.9 ng/mL. Investigators were satisfied with the insertion and removal procedures. All patients reported satisfaction after 1 year of treatment. The safety profile of the implant was consistent with androgen ablation therapy. Most adverse events were mild, and the most common event was hot flashes.. The leuprolide implant effectively suppressed testosterone concentrations to less than the castrate threshold and maintained that suppression throughout the study period.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Drug Implants; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Palliative Care; Prostatic Neoplasms; Testosterone; Time Factors

The majority of patients with localized and some cases of locally advanced prostate cancer undergo radical prostatectomy. However, radical prostatectomy cannot always be selected for those patients. In this situation, primary hormone therapy is an alternative treatment option. We have designed a prospective randomized study of the effects of primary hormone therapy for such patients.. A total of 151 patients with T1b, T1c, T2a, T2b or T3a prostate cancer who were not scheduled for radical prostatectomy were enrolled into this study. Patients were randomly allocated into two groups; Group I received luteinizing hormone-releasing hormone (LH-RH) agonist monotherapy (leuprorelin acetate depot, 3.75 mg monthly) and Group II received LH-RH agonist in combination with chlormadinone acetate (100 mg/day). Effects on serum prostate-specific antigen level, progression-free survival and survival were observed for 2 years.. The reasons why radical prostatectomy was not scheduled were poor risk for surgery (38%), patient's wish (32%) and physician's recommendation (30%). After 12 weeks of treatment, 49% of the patients in both groups showed a complete response (CR). Of the patients showing a partial response (PR) after 12 weeks of treatment, 25% in Group I and 52% in Group II improved to CR 1 year later (p<0.05). Group II showed a longer progression-free survival (p <0.05). Progression-free survival rates were 62% (Group I) and 91% (Group II) in T2b patients and 43% (Group I) and 73% (Group II) in T3 patients. Only one patient in each group died from prostate cancer.. Early primary hormone therapy is a reasonable treatment option for localized or locally advanced prostate cancer patients if radical prostatectomy was not scheduled. Chlormadinone acetate showed an additive effect with LH-RH agonist, at least in 2 years' observation.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Chlormadinone Acetate; Disease-Free Survival; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prospective Studies; Prostatic Neoplasms

We evaluated the pharmacokinetics, safety and efficacy of the implantable Viadur++ leuprolide delivery system during 12 months in patients with advanced prostate cancer.. Our open label, multicenter, dose ranging study was done in 2 phases. The treatment phase was a stratified, randomized, parallel evaluation of the safety and efficacy of 1 or 2 implants. The safety extension phase assessed the long-term safety and efficacy of 1 implant. Implant insertion and removal, pharmacokinetic profile and patient satisfaction were also evaluated. The primary efficacy parameter was testosterone suppression for 12 months but luteinizing hormone and prostate specific antigen were also evaluated.. Of the 51 patients 27 received 1 and 24 received 2 implants, of whom 49 completed the 12-month treatment phase. Steady serum leuprolide concentration was maintained from day 3 through the remainder of the 12-month treatment phase and for 2 months after reimplantation. Implantation and reimplantation were well tolerated and acceptable to physicians and patients. Testosterone suppression to the castrate range was 100% in each group. At 12 months mean prostate specific antigen decreased from a baseline of approximately 84% and 91% in groups 1 and 2, respectively. Serious adverse events during the study period in 15 patients were not attributable to treatment.. The implantable leuprolide delivery system provides effective suppression of testosterone in patients with advanced prostate cancer.

Topics: Aged; Antineoplastic Agents, Hormonal; Confidence Intervals; Drug Delivery Systems; Drug Implants; Follow-Up Studies; Humans; Leuprolide; Longitudinal Studies; Luteinizing Hormone; Male; Neoplasm Staging; Patient Satisfaction; Prostate-Specific Antigen; Prostatic Neoplasms; Safety; Testosterone; Treatment Outcome

To determine whether administration of estrogen or gestagen prior to luteinizing hormone-releasing hormone (LH-RH) agonist prevents disease flare in prostate cancer patients, we pretreated the patients with either diethylstilbestrol diphosphate (DES-P) 300 mg daily (N = 17) or chlormadinone acetate (CMA) 100 mg daily (N = 16) or none (N = 16) for two weeks before the initial injection of leuprolide acetate (L). Blood samples for prostatic specific antigen (PSA), testosterone (T), and luteinizing hormone were collected before CMA and DES-P administration, before and at 2, 7, 14, 28, 56, and 84 days after the first administration of leuprolide. The treatment with DES-P and CMA prior to LH-RH agonist induced an early decline of PSA. The mean PSA level showed no significant secondary rise in those patients with pretreatment after L administration. In the patients pretreated with DES-P or CMA, the mean serum T level never exceeded the pretreatment baseline after L administration. On the other hand, in the patients without DES-P or CMA, both serum T and PSA levels increased after the first administration of L. These results clearly demonstrate that pretreatment with DES-P 300 mg daily or CMA 100 mg daily for 2 weeks is quite effective to prevent disease flare after the first administration of L in patients with prostatic cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Autacoids; Chlormadinone Acetate; Diethylstilbestrol; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Neoplasm Recurrence, Local; Premedication; Progesterone Congeners; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

This prospective, randomized, multicenter comparative trial studied the effect of neoadjuvant hormonal treatment (NHT) prior to radical, prostatectomy.. Histopathologic tissue specimens were obtained from 91 consecutive patients (aged 60-70 years) who underwent a radical prostatectomy for stage B prostate adenocarcinoma. The patients had received NHT for three months. Specimens were compared with those from 48 age-matched control patients who underwent similar surgery for stage B disease without receiving preoperative therapy.. Treated tumors with an acinar pattern were distinguishable from the untreated tumors by neoplastic acini that appeared shrunken and areas of individual infiltrating tumor cells separated by an abundant interglandular connective tissue. The epithelial tumor cells had inconspicuous nucleoli, nuclear shrinkage, chromatin condensation and pyknosis, cytoplasmic clearing, and enlargement by coalescence of vacuoles and rupture of cell membranes. No mitotic figures were seen in any treated tumors.. Preliminary results show a benefit for patients receiving NHT in regard to the histologic indicators that we evaluated.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Cyproterone Acetate; Diagnosis, Differential; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Prospective Studies; Prostatectomy; Prostatic Hyperplasia; Prostatic Neoplasms

In most clinical trials that have investigated the potential beneficial effects of neoadjuvant combined androgen blockade (CAB) in clinically localized prostate cancer, CAB has been given for 3 months, but no data are available on the influence of a longer duration of neoadjuvant CAB on the pathologic features of prostate cancer.. Prostatectomy specimens of 40 patients, randomized to 3 (n = 18) or 6 (n = 22) months of neoadjuvant CAB, were blindly evaluated with regard to tumor volume, pathologic stage, and surgical margins. The morphologically most vital tumor areas were investigated for nucleolar size and MIB-1 defined proliferative activity.. The patients treated for 6 months had a median tumor volume 60% lower than the 3-month treatment group (P = 0.005). In the 6-month treatment group, no residual tumor could be found in 2 cases, but the proportion of prostatectomy specimens with seminal vesical invasion and positive surgical margins was not statistically different from that after 3 months. Compared with untreated controls, tumor proliferative activity assessed by MIB-1 immunoreactivity was significantly lower at 3 and 6 months of neoadjuvant CAB (P = 0.01). However, in 2 of 1 7 examined tumors that had been treated for 6 months, high MIB-1 scores suggested a development toward therapy-resistant cancer.. Prolonged neoadjuvant CAB for 6 months leads to a further decrease in prostatic tumor volume compared with the findings after 3 months. In a few instances, residual tumor areas with substantial MIB-1 defined proliferative activity persist at 6 months, thus indicating that in at least some cases, despite the overall decrease in tumor size, cancer cells can continue the cell cycle under CAB.

Topics: Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Time Factors; Triptorelin Pamoate

Intermittent androgen suppression (IAS) has been suggested as a means of attenuating the androgen deprivation syndrome in men with incurable prostate cancer. Laboratory data suggest that intermittent therapy may prolong the duration of androgen dependence.. Since October 1993, 54 patients have entered a Phase II protocol consisting of 8 months of total androgen blockade (TAB) using leuprolide (Lupron) depot and nilutamide (Anandron) followed by an off-treatment interval of variable length. Eleven patients had biopsy-proven local failure after radiotherapy, 4 had biochemical failure, 24 had distant metastases (fewer than six axial sites on bone scan), 11 had combined local and distant failure, and 4 were treated as primary management for nodal disease. Mean prostate-specific antigen (PSA) at entry was 37 ng/mL (range 3.8 to 196). After 8 months of TAB, hormonal therapy was discontinued for those patients whose PSA was less than 4.0 ng/mL and stable or decreasing and was resumed (cycle 2) when PSA increased to greater than 10 ng/mL.. As of April 1 998, mean follow-up was 33 months (range 14 to 53). Patients have completed at least one, and up to five treatment cycles. The mean time to nadir PSA in cycle 1 was 20 weeks, and the mean time off was 35 weeks (31 weeks for those with metastatic disease versus 39 for local or biochemical failure). In cycle 2, the mean time to PSA nadir was 17 weeks, and the mean time off was 30 weeks (28 weeks for metastatic disease and 38 weeks for local or biochemical failure). In cycle 3, the time to PSA nadir was 19 weeks. Full testosterone data are available for 40 patients in cycle 1. Normal levels were achieved during the off-treatment interval in 73% by a mean of 18 weeks (median 9). Testosterone normalization in cycle 2 was achieved in 71% at a mean time of 17 weeks (median 14).. TAB can be used intermittently, and appears to be more appropriate for patients with local or biochemical failure. Testosterone recovery is not universal in the off-treatment intervals. IAS needs to be investigated in a randomized trial to determine the effect on overall survival and quality of life.

Topics: Adenocarcinoma; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Follow-Up Studies; Humans; Imidazoles; Imidazolidines; Leuprolide; Male; Prostatic Neoplasms

To determine the hormonal (luteinizing hormone [LH] and testosterone) and biochemical (serum prostate-specific antigen [PSA]) response to withdrawal of luteinizing hormone-releasing hormone (LHRH) agonists in patients who received more than 2 years of LHRH therapy for advanced prostate cancer.. Fourteen patients with clinical Stage T3 or higher prostate cancer and no evidence of clinical or biochemical progression, who had received 2 years or more of LHRH therapy, were enrolled at the time of their scheduled 3-month depot injection. Patients underwent history, physical examination, and measurement of serum PSA, LH, and testosterone at baseline, monthly for 3 months, and then every 3 months for 1 year following LHRH withdrawal.. The mean age of patients was 70.3 years (range 56 to 84). Patients previously received LHRH agonist for a mean of 38.6 months (range 25 to 82). All patients had castrate levels of testosterone (median 10.0 ng/dL) and suppressed LH levels (median 0.1 mIU/mL) at baseline. Median baseline PSA was 0.15 ng/mL. On multiple groupwise comparison, there was no significant change (compared with baseline) in LH or testosterone until 6 months after withdrawal and no change in PSA throughout the duration of the study (median PSA at 1 2 months 0.30 ng/mL). Despite significant increases in LH and testosterone when compared with baseline beginning at 6 months, both LH and testosterone remained markedly suppressed, with median testosterone remaining in the castrate range at both 6 and 9 months and significantly below the lower limit of normal at 12 months (median 111.0 ng/dL). Despite no statistically significant change for the entire cohort in serum PSA, a rising PSA was noted in 4 patients between 3 and 9 months, and LHRH therapy was reinitiated. The remaining patients continued to have suppressed LH and testosterone, with 4 patients remaining in the castrate range at 12 months.. The recovery of function of the hypothalamic-pituitary-testicular axis after prolonged LHRH administration is variable. Castrate levels of testosterone and suppressed LH may persist even up to 1 year after discontinuing LHRH. These results have significant implications regarding the interpretation of clinical trials incorporating neoadjuvant and adjuvant hormonal therapy. Further studies are needed to expand on these preliminary observations and should also address the feasibility of incorporating LHRH withdrawal into clinical practice.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Pilot Projects; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

The effects of preoperative androgen deprivation were explored in the patients who received radical prostatectomy and subsequent adjuvant endocrine therapy for prostate cancer.. Stage A2, B or C prostate cancers were randomized to one of two groups: (i) group I (n=90), who received androgen deprivation (leuploride and chlormadinone acetate) for 3 months preoperatively followed by radical prostatectomy and adjuvant endocrine therapy (leuploride only); and (ii) group II (n=86), who underwent the surgery followed by 3 month androgen deprivation and subsequent adjuvant endocrine therapy. The effects of preoperative androgen deprivation on clinical relapse (serum prostate specific antigen (PSA) > 1.98 ng/mL, local recurrence or distant metastasis) and PSA relapse (PSA >0.2ng/mL) were evaluated at 2 years after randomization.. There was no significant difference in clinical or PSA relapse-free survival and quality of life measures between the two groups, although relapses occurred significantly more frequently in patients who had more advanced stages, higher pretreatment PSA values or lower histologic differentiation in either group. Subgroup analysis indicated that clinical relapse-free survival in stage C cancer tended to be better in patients with preoperative androgen deprivation than in those patients without it (P< 0.1).. Preoperative androgen deprivation may be beneficial for stage C prostate cancer patients receiving radical prostatectomy and adjuvant endocrine therapy over the 2 year observation period. A longer follow up is needed to clarify the exact extent of benefit in terms of survival and quality of life.

Topics: Aged; Aged, 80 and over; Androgens; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Chlormadinone Acetate; Disease-Free Survival; Drug Therapy, Combination; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Neoplasm Recurrence, Local; Preoperative Care; Progesterone Congeners; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Retrospective Studies; Treatment Outcome

Black race has been associated with a significantly increased risk of prostate cancer mortality. This exploratory analysis investigated the effect of race on the clinical outcome of combined androgen blockade (CAB).. Data for analysis were obtained from a double-blind, randomized, multicenter trial comparing CAB in the form of bicalutamide (50 mg once daily) or flutamide (250 mg three times daily) plus luteinizing hormone-releasing hormone analogs (LHRHa; goserelin acetate 3.6 mg, or leuprolide acetate 7.5 mg) in 813 patients with stage D(2) prostate cancer (median follow-up, 160 weeks). Patients were analyzed according to race (African American [AA], white, or other). The primary clinical events were disease progression and survival.. Four hundred and four patients received bicalutamide/LHRHa and 409 received flutamide/LHRHa. Although treatment with bicalutamide/LHRHa resulted in slightly longer time to progression and survival time in white and AA males than treatment with flutamide/LHRHa, the differences between the treatment groups were not statistically significant.. No marked effect of race on clinical outcome was observed regardless of antiandrogen, suggesting that similar treatment benefits are to be expected in either race.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Black People; Bone Neoplasms; Cohort Studies; Disease Progression; Disease-Free Survival; Double-Blind Method; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Nitriles; Prostatic Neoplasms; Tosyl Compounds; White People

To evaluate the efficacy of chemoendocrine therapy for the initial treatment of stage D2 prostate cancer, we conducted a prospective randomized study which compared combined androgen blockade alone to that combined with UFT. Twenty-one patients received LH-RH agonist and flutamide (Group-A), and 23 patients received LH-RH agonist, flutamide and UFT (Group-B). The overall response rate and the PSA response rate of Group-A was 71.4% and 100% respectively, against 65.2% and 90%, respectively in Group-B. The median follow-up period was 24 months. The 2-year progression-free survival rate of Group-A was 7.4% and that of Group-B was 15.9%. The response rate and progression-free survival rate did not differ significantly between the 2 groups. Liver dysfunction due to flutamide was common in both groups, and a total of 4 patients did not continue the treatment because of this adverse effect. We conclude that in patients with stage D2 prostate cancer, treatment with combined androgen blockade and UFT is not superior to treatment with combined androgen blockade alone.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Antimetabolites, Antineoplastic; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Flutamide; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Prostatic Neoplasms; Tegafur; Treatment Outcome; Uracil

We studied the effect of neoadjuvant hormonal therapy on prostatic intraepithelial neoplasia in patients undergoing radical prostatectomy and assessed the effect of prostatic intraepithelial neoplasia on disease recurrence as measured by serum prostate specific antigen (PSA).. A total of 278 patients with clinically localized prostate cancer were included in phase II and III studies evaluating radical prostatectomy alone versus radical prostatectomy following neoadjuvant hormonal therapy at Memorial Sloan-Kettering Cancer Center between October 1991 and August 1996. Patient data related to prostatic intraepithelial neoplasia were analyzed.. Of 275 evaluable patients 145 (52.7%) had prostatic intraepithelial neoplasia. Of 50 patients treated with neoadjuvant hormonal therapy (hormone group) 22 (44%) had a lower incidence of prostatic intraepithelial neoplasia compared to 69 of 80 controls (86.3%) (chi-square test p<0.0001). Of 262 patients (95.3%) with followup PSA 44 (16.8%) had PSA recurrence at a median followup of 32 months, with a median time to recurrence of 30 months. PSA recurrence was noted in 23 of 145 patients with compared to 21 of 130 without prostatic intraepithelial neoplasia (chi-square test p = 0.95), and did not significantly differ between the hormone group (25 of 142, 17.6%) and controls (19 of 130, 14.6%) (chi-square test p = 0.45).. While patients treated with neoadjuvant hormonal therapy had significantly lower incidence of prostatic intraepithelial neoplasia, neither prostatic intraepithelial neoplasia nor neoadjuvant hormonal therapy significantly affected PSA recurrence at a median followup of 32 months.

Topics: Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Flutamide; Follow-Up Studies; Humans; Leuprolide; Male; Multivariate Analysis; Neoplasm Recurrence, Local; Prognosis; Prostate-Specific Antigen; Prostatectomy; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms

Collagen cross-link molecules such as pyridinoline (PYD), deoxypyridinoline (DPD), and N-terminal cross-linked peptides (NTX) have been measured in urine as indices of bone resorption. However, very little is known regarding the excretion of pyridinolines into other biological fluids. We report a collection device, normalizing analyte, and high-sensitivity immunoassay for quantitative analysis of free pyridinoline cross-links in sweat.. Flame atomic emission and ion-selective electrode techniques were used to measure potassium as a sweat volume marker. The Pyrilinks immunoassay for urine free pyridinolines was optimized to increase sensitivity for measurements in sweat. The precision, accuracy, and detection limit of this assay were characterized. To assess values and variability of sweat pyridinolines in human subjects, a nonocclusive skin patch was used to collect sweat samples from a reference group and from a mixed group experiencing accelerated bone resorption, postmenopausal women and men receiving gonadotropin-releasing hormone for prostate cancer.. The immunoassay intra- and interassay variations were

Topics: Amino Acids; Antineoplastic Agents, Hormonal; Biomarkers; Bone Resorption; Collagen; Cross-Linking Reagents; Female; Humans; Immunoenzyme Techniques; Leuprolide; Male; Postmenopause; Potassium; Prostatic Neoplasms; Reference Values; Spectrophotometry, Atomic; Sweat

To assess the potential for using the serum testosterone level as the guide for redosing depot luteinizing hormone-releasing hormone (LHRH) agonist and to characterize the duration of castrate level testosterone after the last 22.5-mg leuprolide injection repeatedly administered for the control of prostate cancer.. Informed consent was obtained from 32 men with prostate cancer (Stage T3N+/- M+/- or greater) treated with 3-month (22.5-mg) leuprolide acetate injection. Serum testosterone and prostate-specific antigen levels were obtained every 28 days beginning on the 90th day after the last 22.5-mg leuprolide injection. The duration of action was the calculated interval, in months, between the last injection and the first noncastrate serum testosterone (greater than 0.2 ng/mL) value.. The median duration of castrate level testosterone was 6.0 months (SE +/- 0.15; upper and lower quartile 5.3 and 7.0, respectively). Prostate cancer biochemical (prostate-specific antigen) activity at enrollment and when the castrate testosterone threshold of 0.2 ng/mL was exceeded remained stable, with no significant change observed during this interval (P = 0.52). A significant association was observed between an increasing duration of castration after LHRH agonist injection and advancing patient age (P = 0.03) and increasing duration of hormonal therapy (P = 0.05).. These results suggest that using the serum testosterone level to guide in redosing of long-acting LHRH agonist may provide a novel, effective, and economical method to administer hormonal ablative therapy in patients with prostate cancer. These observations have important implications for product dosing and the design and interpretation of neoadjuvant and intermittent androgen ablative trials.

Topics: Aged; Drug Administration Schedule; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Patient Satisfaction; Prostatic Neoplasms; Testosterone; Time Factors

The presence and morphology of high-grade prostatic intraepithelial neoplasia (H-PIN) was blindly evaluated in 40 totally embedded radical prostatectomy specimens of patients with prostate cancer randomized to either a 3 (n = 18) or 6 months (n = 22) combined androgen blockade regimen before surgery. In 5 cases, neo-adjuvant therapy was abrogated some time before surgery. In the remaining cases, foci of H-PIN were identified in 72% and 59% of prostates from patients treated for 3 and 6 months, respectively. Cellular features used to distinguish H-PIN from normal glands were increased nuclear size, nuclear crowding, anisonucleosis, and disordered nuclear arrangement. In some cases, density of cytoplasm was an additional feature. Unfortunately, the molecular marker erbB2 proved unhelpful for identification of H-PIN. The median number of prostatic glands involved by H-PIN was 19 +/- 21 (SD) glands in 3 months treated prostatectomies (n = 18) and 7 +/- 12 (SD) glands in 6 months treated prostatectomies (n = 17), a nonsignificant difference (P = .17). H-PIN was localized within areas of residual carcinoma in 62% and 20%, respectively of prostatectomies of patients treated for 3 and 6 months, respectively. Architectural patterns of H-PIN differed at 3 and 6 months of endocrine pretreatment: The predominant tufted pattern at 3 months was replaced by flat H-PIN at 6 months. The continued expression of androgen receptors and the cell cycle marker MIB-1 in persistent H-PIN suggests that recovery of androgen levels after cessation of androgen blockade therapy will lead to its further expansion.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Cell Nucleus; Cohort Studies; Cytoplasm; Flutamide; Humans; Immunohistochemistry; Leuprolide; Male; Neoadjuvant Therapy; Prostatectomy; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Receptors, Androgen

An unblinded, multicenter study to evaluate the efficacy and safety of a long-acting depot formulation of leuprolide (30 mg injected intramuscularly every 16 weeks) was carried out in 49 patients with Stage D2 prostate cancer.. Clinical evaluations were performed every 16 weeks, and serum testosterone levels were monitored biweekly or weekly for 32 weeks.. The mean serum testosterone level for the 45 evaluable patients fell to the castrate range (50 ng/dL or less) by week 3 after the initial depot injection and remained at that level throughout the initial 32-week treatment period. The median time to the onset of castrate levels was 22 days (range 9 to 43). Onset of castrate levels of testosterone was achieved within 4 weeks of the initial depot injection in 96% of patients. One patient (2%) experienced a transient "escape" (testosterone levels greater than 50 ng/dL on two consecutive determinations). Delay of an injection by up to 3 weeks did not have an effect on testosterone suppression. Objective tumor response (no progression) occurred in 90% of patients at week 16 and in 80% at week 32. Prostate-specific antigen and prostatic acid phosphatase decreased by 50% or more at week 32 in 97% and 76% of patients, respectively. Assessment of local disease status and overall performance status showed improvement or stability in most patients. The most common adverse events were hot flashes (45%), back pain (16%), and arthralgia (14%).. The 30-mg depot formulation of leuprolide, which acts in a manner similar to the 7.5- and 22.5-mg depot formulations (given monthly and every 3 months, respectively) is effective in lowering serum testosterone to castrate levels in all patients and demonstrates a favorable response in 80% of the patients with advanced prostate cancer for the 32-week observation period. The drug was well tolerated in all patients.

Topics: Acid Phosphatase; Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Disease Progression; Drug Administration Schedule; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

The investigational objectives of this open, noncomparative phase I study were to determine the pharmacokinetic profile of a single dose of 11.25 mg leuprorelin acetate, the effective duration of the chemical castration (serum testosterone < or = 1.73 nmol/l) and safety in patients with locally advanced and/or metastatic carcinoma of the prostate foreseen for chemical castration, in the hope that such a dose of leuprorelin acetate may be suitable as a depot formulation to be administered 3-monthly to these patients.. A total of 24 males up to 85 years old with histologically proven advanced carcinoma of the prostate were enrolled in the study to obtain 18 eligible patients. Each patient was given 11.25 mg of leuprorelin acetate in a depot formulation subcutaneously after reconstitution in 2 ml of a special suspension vehicle. The study period lasted 24 weeks. Patients whose serum testosterone levels reincreased prior to the end of the observation period of 24 weeks were withdrawn from the study and received the monthly depot formulation of 3.75 mg of leuprorelin acetate.. The 3M-depot formulation of leuprorelin acetate ensured continuous and constant drug release and effective suppression of testosterone serum levels to castration range for at least 13 weeks. After an initial rise, 5 alpha-dihydrotestosterone as well as the gonadotropin serum levels of luteinizing hormone and follicular stimulating hormone reflected the testosterone serum pattern.. The results of this study show that the 3M-depot preparation of leuprorelin acetate is effective in suppressing the serum testosterone levels to the castration range for a targeted period of at least 13 weeks.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Carcinoma; Delayed-Action Preparations; Dihydrotestosterone; Evaluation Studies as Topic; Follicle Stimulating Hormone; Humans; Injections, Subcutaneous; Leuprolide; Linear Models; Luteinizing Hormone; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Severity of Illness Index; Statistics, Nonparametric; Testosterone; Treatment Outcome

In an open, randomized phase II pharmacokinetic study conducted in Germany and Italy, a total of 42 patients with advanced or metastatic prostate cancer (PCa) were treated for 9 months with the luteinizing hormone-releasing hormone analogue (LH-RH-a) leuprorelin acetate depot in two different formulations. Fifteen patients received the 1-month depot and 27 patients received the newly developed 3-month depot, containing 3.75 mg and 11.25 mg, respectively. In both groups, subcutaneous injections of leuprorelin acetate injected monthly or at 3-month intervals produced a complete down-regulation of the pituitary and led to persistent suppression of testosterone and dihydrotestosterone to the castrate range (< or = 50 ng/dl for testosterone) within the first month of treatment, which thereafter could be maintained over the entire observation period of 9 months. In 10 patients, pretreatment with an antiandrogen for the prevention of clinical flare-up resulted in a slightly more profound and earlier drop in serum testosterone. The 3-month depot showed a higher median peak serum concentration (Cmax) of leuprorelin at 20.8 ng/ml than the 1-month depot at 10.7 ng/ml but, conversely, this did not influence the rise in serum testosterone levels. Cmax occurred at 3 h for the 3-month and at 1 h for the 1-month depot formulation. During the steady state, constant release could be detected, starting on day 3 and day 7 for the 1-month and 3-month depot, respectively. A marked decrease in median prostate-specific antigen levels of 97.8% (1-month depot) and 96.6% (3-month depot) compared with baseline was observed, indicating an objective clinical response for more than 80% of all patients in both arms. Based on European Organization for Research and Treatment of Cancer criteria, the best response in terms of complete/partial remissions and stabilization was comparable in the two arms at 86.7% (1-month depot) and 85.2% (3-month depot). 6.7% in the 1-month group and 3% in the 3-month depot group showed progression of the disease. The most common side effects in both treatment groups were related to hormone deprivation. Both formulations of the potent LH-RH-a leuprorelin acetate were highly effective in the treatment of advanced PCa and led to comparable endocrine and clinical effects.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Dihydrotestosterone; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Time Factors

In spite of a great amount of data, the hormonal treatment of advanced prostatic carcinoma (CaP) still remains controversial. As a relevant amount of dihydrotestosterone is present within the prostate tissue after castration, complete androgen blockade (CAB), with inhibition of the activity of both testicular and adrenal androgens, has been advocated as up-front treatment of advanced CaP. However, many controlled studies have failed to demonstrate a benefit for CAB in comparison with simple surgical or chemical castration. The present study was performed to bring additional data for a worldwide meta-analysis of all phase III trials comparing castration and CAB.. This is a centrally controlled phase III study in which chemical castration with leuprorelin acetate depot was compared with leuprorelin plus flutamide in stage C and D CaP. Two hundred and forty-one eligible and evaluable patients with histologically proven CaP were recruited for the study (120 treated with castration and 121 with CAB). The diagnostic and staging workup consisted of blood chemistry, general condition assessment, prostate-specific antigen (PSA), abdominal sonography and computed tomography scan, and whole-body isotopic bone scan. End points of the study were survival, time to treatment failure, and time to progression. The patients were followed every 6 months with PSA and sonography.. At a cut-off analysis performed in December 1996, when the mean follow-up period was 43.7 +/- (SD) 24.1 months, no statistical differences in terms of time to treatment failure, time to progression, and death rate could be detected. Also considering the common risk factors, such as basal PSA, haemoglobin, alkaline phosphatase, and Gleason score, the outcome did not show any clear advantage for CAB.. This study appears to confirm that the advantages of first-line CAB in CaP are at best marginal. The final analysis will be performed when the follow-up period has reached 5-years, but it seems unlikely that the present results will change.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Disease Progression; Drug Administration Schedule; Flutamide; Humans; Leuprolide; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate

In the last few years, the role of neoadjuvant hormonal treatment (NHT) prior to radical prostatectomy has been largely debated and investigated in randomized multicenter trials as well as in large single-institution studies. We have initiated a prospective randomized comparative trial with parallel groups in patients with clinically limited disease to contribute to the clarification of the possible role of NHT; to evaluate the efficacy of NHT with leuprolide plus cyproterone acetate in 'maintaining' the stage of the disease; to reduce the percentage of pathological overstaging, and mainly to accurately assess the pathological modifications induced by NHT. The present paper is an interim report of the results.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Carcinoma in Situ; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cyproterone Acetate; Delayed-Action Preparations; Diagnosis, Differential; Disease-Free Survival; Drug Administration Schedule; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Prostatectomy; Prostatic Diseases; Prostatic Hyperplasia; Prostatic Neoplasms

To determine median survival time, median time to tumor progression and maintenance of testosterone suppression (i.e. < or = 50 ng/dl) during long-term treatment with subcutaneous injections of leuprorelin acetate 3-month depot (LAD-3M). In Germany 62 patients with advanced prostate cancer participated in a prospective, randomized, multicenter phase II trial as part of a European study. Of these, 37 patients entered the follow-up study.. Standard clinical investigations and methods were employed in the study.. Twenty-five of the 62 (40.3%) patients died during the course of the study. No death had a causal relationship with the study drug. Median survival time, median time to tumor progression and median period of progression-free survival were 1,149 (3.1 years), 1,015 (2.8 years) and 680 days (1.9 years), respectively. Adequate suppression of testosterone serum levels to the castration range was confirmed. Objective and subjective response as well as the safety profile were comparable to previously published results with LAD-3M, LAD-1 M and other LHRH analogues.. The results of this follow-up study confirm long-term efficacy and safety of LAD-3M for treatment in advanced prostate cancer. LAD-3M is a suitable alternative to the established shorter-acting LHRH-a depot formulations.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Bone Neoplasms; Carcinoma; Delayed-Action Preparations; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Europe; Follow-Up Studies; Germany; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Testosterone; Time Factors

At our institution, a Phase II trial using androgen suppression followed by surgery was completed for men with Stage T3 disease and negative laparoscopic nodal dissection. We recently reported the unfavorable biochemical outcome of that experience. Because that analysis did not include a control group of irradiated patients, the current project was undertaken to compare that Phase II experience with clinical Stage T3 patients treated at our institution with definitive irradiation during an overlapping period of time.. The Phase II trial included 21 patients with T3 tumors and negative laparoscopic nodal dissections treated by 4 months of neoadjuvant hormonal treatment (leuprolide +/- flutamide) prior to radical prostatectomy. Patients who declined to participate in the study or those judged ineligible by virtue of poor surgical risk were treated with definitive irradiation (n = 29). Although the radiation portals were shaped with multileaf collimation, no attempt was made to design "conformal fields." The median dose was 68 Gy (range 66 to 72) delivered in conventional fractionation. Biochemical failure after prostatectomy was defined as prostate-specific antigen (PSA) levels exceeding 0.2 ng/mL. Biochemical failure after irradiation was defined as a rise in absolute level of PSA greater than 1.5 ng/mL, or two consecutive elevations of PSA on sequential measurements, even if the absolute level was less than 1.5 ng/mL.. In univariate comparison, the freedom from biochemical relapse rate at 3 years was 41% for irradiated patients and 23% for those treated by hormones combined with surgery (P <0.05). In a multivariate regression model controlling for the prognostic factors of baseline PSA, age, clinical substage, Gleason score, and treatment modality (induction androgen suppression + prostatectomy versus radiotherapy), only low baseline PSA independently predicted improved freedom from biochemical recurrence (P = 0.04).. The combination of induction hormonal treatment followed by radical prostatectomy offered no advantage over irradiation alone in this single institutional experience. Notwithstanding, the majority of men treated by definitive radiotherapy manifested biochemical failure. More innovative strategies such as conformal irradiation (either alone or combined with androgen ablation) and radiation dose escalation should be pursued to optimize outcome for this unfavorable group of patients.

Topics: Age Factors; Aged; Aged, 80 and over; Analysis of Variance; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Disease-Free Survival; Dose Fractionation, Radiation; Flutamide; Forecasting; Humans; Leuprolide; Lymph Node Excision; Male; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Radiotherapy Dosage; Treatment Outcome

To perform exploratory analyses of data from a controlled trial that assessed the efficacy and tolerability of two antiandrogens, bicalutamide and flutamide, each combined with monthly depot preparations of leuprolide or goserelin, in patients with Stage D2 prostate cancer. One analysis compared goserelin plus antiandrogen therapy with leuprolide plus antiandrogen therapy; a second analysis compared the four combined androgen blockade (CAB) regimens.. This was a randomized, multicenter trial, open-label for luteinizing hormone releasing hormone analogue (LHRH-A) therapy, double-blind for antiandrogen therapy, with a two-by-two factorial design. Eight-hundred thirteen patients were allocated in a ratio of 2:1 to goserelin therapy (3.6 mg every 28 days) or leuprolide therapy (7.5 mg every 28 days) and 1:1 to bicalutamide therapy (50 mg once a day) or flutamide therapy (250 mg three times a day). The end points of time to progression and survival were assessed with a median of 160 weeks of follow-up.. The percentages of progression events (70.9% versus 73.3%) and deaths (54.3% versus 56.8%) were similar for goserelin plus antiandrogen and leuprolide plus antiandrogen therapies. The hazard ratios for goserelin plus antiandrogen therapy to leuprolide plus antiandrogen therapy were 0.99 (95% confidence interval [CI] 0.84 to 1.18; P = 0.92) and 0.91 (95% CI 0.75 to 1.11; P = 0.34) for time to progression and survival, respectively. Goserelin plus antiandrogen and leuprolide plus antiandrogen therapies were generally well tolerated, and the side effects associated with depot administration occurred with a low frequency in the two groups. There were no significant differences among the goserelin plus bicalutamide, goserelin plus flutamide, or leuprolide plus bicalutamide therapy groups, but leuprolide plus flutamide therapy had a significantly poorer outcome than the other three therapies. The side-effect profiles for the four CAB groups were generally similar; diarrhea was more common among patients treated with flutamide and hematuria was more common among patients treated with bicalutamide.. Although the results of these exploratory analyses should be interpreted with caution, they indicate that goserelin plus antiandrogen and leuprolide plus antiandrogen therapies are similarly well tolerated and have equivalent time to progression and survival, and that leuprolide plus flutamide therapy appears to be the least effective of the four CAB regimens.

Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Double-Blind Method; Flutamide; Goserelin; Humans; Leuprolide; Male; Middle Aged; Nitriles; Prostatic Neoplasms; Survival Rate; Tosyl Compounds

Twenty-four previously untreated patients with a diagnosis of prostatic cancer were treated with chlormadinone acetate (CMA) alone (100 mg/day) for 4 weeks, and luteinizing hormone-releasing hormone analogue (LH-RHa) was added for the next 24 weeks. Marked decreases in blood LH, testosterone (T), prostate specific antigen (PSA), gamma-seminoprotein (gamma-Sm), and prostatic acid phosphatase (PAP) were observed after a single dose of CMA. T levels were significantly increased 3 days after the initial dose of LH-RHa, and did not return to the pretreatment level. There were no significant increases in any of the markers, nor were there any flare-up cases. Triglyceride levels, which were slightly elevated before the start of treatment, were significantly decreased 24 weeks after the completion of combined therapy. PSA was evaluated as partial response (PR) or better in 86.7% of the patients. Overall evaluation showed PR or better in 75.0% of the patients. These findings suggest that prior administration of CMA followed by combined administration with LH-RHa is useful in the treatment of prostatic cancer. No negative effects on lipid metabolism were observed at any time during the treatment period.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Apolipoproteins; Chlormadinone Acetate; Cholesterol; Drug Administration Schedule; Drug Therapy, Combination; Humans; Leuprolide; Lipid Metabolism; Male; Middle Aged; Progesterone Congeners; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Triglycerides

The aim of the present study is to investigate whether combined androgen blockade associated with radiation therapy for localized prostate cancer decreases at 12 and 24 months the rate of positive follow-up biopsies and serum PSA compared to radiation therapy alone. This is the report of an interim analysis.. One hundred and twenty patients with clinical Stage B1-T2a, B2-T2b/T2c, and C-T3/T4, adenocarcinoma of the prostate were entered in a prospective randomized study. After written informed consent, the subjects were randomly allocated between external beam radiation therapy (EBRT) alone (group 1), 3 months of neoadjuvant combination therapy (LHRH-agonist + Flutamide) prior to EBRT (group 2), and a third group receiving combination therapy 3 months before, during, and 6 months after EBRT. There is no significant difference between the three groups concerning age, stage of disease, grade of tumor, and pretreatment PSA levels. Control transrectal ultrasound (TRUS)-guided needle biopsies (one core was taken from the initial cancer site regardless of the presence or absence of TRUS abnormalities) were done 12 and 24 months after the end of EBRT. Serum PSA measurements were done on schedule visits.. Ninety-two and 68 patients underwent biopsies at 12 and 24 months, respectively, after the end of radiation therapy. While 62% of control patients at 12 months in Group 1 disclosed residual neoplasm, only 30% and 4% showed residual disease in groups 2 and 3, respectively (p = 0.00005). When looking at 24 months, 65, 28, and 5% showed residual cancer for groups 1, 2, and 3, respectively (p = 0.00001). The PSA measurements indicate also at 12 months a difference between the three groups (p < 0.0001), except at 24 months, the difference between the group 2 and 3 is no longer significant.. The preliminary analysis of this clinical trial indicates that patients treated with radiation therapy alone show a significantly higher rate of positive biopsies at 12 and 24 months after the end of radiation therapy as compared with those treated with total antiandrogen blockade (TAB) and radiation therapy. When analyzing the median PSA serum levels, we found the same advantage at 12 months, but, at the time of the analysis at 24 months, the PSA levels are not different between groups 2 and 3.

Topics: Aged; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Biopsy; Combined Modality Therapy; Flutamide; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms

To evaluate and compare the effects of medical or surgical castration combined with either nilutamide (Anandron) or placebo on symptoms of local tumour progression in men with carcinoma of the prostate.. The results from twin, randomised, prospective, placebo-controlled trials were analysed. 434 patients received nilutamide 300 mg/day for 1 month and 150 mg thereafter, and 434 received a matched placebo from either the day of orchidectomy or the first leuprolide injection. Before treatment, and at months 1, 3, 6 and every 6 months thereafter, urinary obstruction and tumour volume were evaluated. Data on adverse or intercurrent events affecting the urological system were documented.. Before treatment, urinary obstructive symptoms and tumour volume were similar in both treatment groups. After treatment, improvement in urinary obstructive symptoms accompanied a decrease in prostate volume. The majority of men in both treatment groups reported an improvement in obstructive voiding symptoms. However, total adverse events secondary to local symptoms were significantly less frequent in the nilutamide-treated patients (20%) compared with the placebo-treated patients (35%). Only a small percentage of men in both treatment groups had disabling local symptoms and only 2% experienced problems with incontinence.. Local symptoms from primary tumour growth are relatively common in patients with metastatic carcinoma of the prostate and are favourably influenced by hormonal therapy. In these trials, the problems resulting from local tumour progression were significantly fewer in the group treated with castration plus nilutamide compared with the group treated with castration plus placebo.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Castration; Humans; Hydronephrosis; Imidazoles; Imidazolidines; Leuprolide; Male; Prospective Studies; Prostatic Neoplasms; Urination Disorders

Prostate specific antigen (PSA), prostatic acid phosphatase and alkaline phosphatase were analyzed in 2 large prospective multicenter and multinational trials to assess their correlation with time to progression and overall survival after hormonal therapy for metastatic carcinoma of the prostate.. A total of 868 patients who underwent medical or surgical castration was randomized to receive an oral antiandrogen (nilutamide) or placebo. The serum markers under study were measured at baseline and at 1, 3, 6 and every 6 months thereafter.. At baseline the strongest predictive factor was serum alkaline phosphatase. Patients with an alkaline phosphatase of 2 or less times normal lived almost twice as long as those with a level of more than 2 times normal (p < 0.0001). The longer survival was observed in patients whose PSA became normal 3 months after initiation of hormonal therapy compared to those whose PSA never reached normal (p < 0.0001).. Serum markers at baseline and during the few months after initiation of hormonal therapy can provide prognostic information for the clinical treatment of patients with metastatic carcinoma of the prostate. In addition, the PSA level at month 3 can serve as a surrogate end point in clinical trials.

Topics: Acid Phosphatase; Alkaline Phosphatase; Androgen Antagonists; Antineoplastic Agents, Hormonal; Bone Neoplasms; Disease Progression; Disease-Free Survival; Humans; Imidazoles; Imidazolidines; Leuprolide; Male; Multivariate Analysis; Orchiectomy; Prognosis; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Time Factors

To determine the impact of neoadjuvant hormonal therapy (NHT) prior to conformal radiotherapy on the reduction of volume of normal tissue structures exposed to high doses of radiation therapy and to evaluate the overall late toxicity and response to treatment among patients treated with this approach.. Among 214 patients treated with neoadjuvant leuprolide acetate and flutamide for 3 months prior to three-dimensional conformal radiotherapy (3D-CRT), 45 patients were prospectively evaluated with detailed dose-volume histogram (DVH) analyses to determine the extent of improvement of the geometry of the target volume after NHT. All patients underwent simulation and conformal treatment planning before and after NHT, and the pre- and posthormone DVH calculations for all normal tissue structures were compared for each patient. In addition, toxicity and response to therapy were evaluated in the 214 patients treated with this combined approach.. In the 45 patients evaluated, the median reduction of the rectal and bladder volumes receiving 95% of the prescription dose (D95) were 18% and 46%, respectively, while 91% showed a reduction of small bowel volume in a range of 27% to 100% of the prehormonal values. Among the entire group of 214 patients treated with NHT and 3D-CRT, no grade 3 or 4 toxicity was observed with a median follow-up of 15 months after 3D-CRT. The 3-year actuarial grade 2 late gastrointestinal and genitourinary toxicity rates were 6% and 18%, respectively.. Neoadjuvant hormonal therapy effectively reduces the volume of normal tissue exposed to high radiation doses in the majority of treated patients and decreases the potential morbidity of therapy.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Drug Therapy, Combination; Flutamide; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms

Neoadjuvant hormonal therapy reduces positive margins in patients undergoing radical prostatectomy. All patients experience a decrease in serum prostate specific antigen (PSA), but not always to a level that is nondetectable. The results of several prospective, randomized trials indicate that the incidence of positive margins decreases with the use of androgen deprivation prior to radical prostatectomy. It has been suggested that a greater decline in PSA levels would result in fewer positive margins. In a recent US trial of patients with T2bNxMO prostate cancer, we reported that 18% of patients randomized to receive 3 months of leuprolide acetate and flutamide had positive margins, compared to 48% of those who had radical prostatectomy alone (P < 0.001). We correlated the PSA levels prior to and following androgen deprivation and the presence of a positive margin following radical prostatectomy (RP).. One hundred and thirty-seven of 149 patients randomized to receive presurgery androgen deprivation (AD) underwent radical prostatectomy. Of these, 135 had a PSA level obtained both prior to androgen deprivation and prior to surgery. We analyzed the percent positive margins in patients whose PSA values became undetectable and in those whose values remained above 0.1 ng/mL despite androgen deprivation.. Eight of 43 patients (19%) with a nadir PSA < or = 0.1 ng/mL had a positive surgical margin and 16/92 (17%) with a nadir PSA > 0.1 ng/mL had tumor at the margin. There were no statistical differences in these two groups (P = 1.0 by Fisher's Exact Test [two-tailed], and the Pearson correlation was -0.015).. There was no correlation between an undetectable PSA and a PSA > 0.1 ng/mL and the presence of tumor at the margin when 3 months of AD was given prior to RP. It is possible that longer periods of AD prior to RP will reduce PSA to an undetectable level in a higher percent of patients. However, these data suggest that an undetectable level will not result in less positive margins.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Drug Therapy, Combination; Flutamide; Humans; Incidence; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prognosis; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

Preoperative endocrine therapy has been suggested to improve surgical radicality and/or patient prognosis in prostate cancer.. Patients with clinical stage A2, B, and C prostate cancer were randomized to either group I (n = 113) or group II (n = 111). Group I patients were to receive preoperative endocrine therapy consisting of leuprolide and chlormadinone for 3 months, followed by radical prostatectomy with lymph node dissection. Group II patients were to undergo the surgery before endocrine therapy.. Group I patients showed a remarkable decrease in prostate-specific antigen (PSA) (mean +/- SE: 41.8 +/- 8.6 ng/mL to 2.7 +/- 0.7 ng/mL) and prostate volume (29.8 +/- 1.7 mL to 21.2 +/- 1.6 mL) during the preoperative therapy. Histopathologic analysis showed a significant difference in the rates of down-staging (19.1% in group I versus 3.3% in group II), positive surgical margins (63.8% versus 81.3%) and positive lymph node metastasis (20.7% versus 36.5%). No significant difference was detected in operating features. Subgroup analyses indicated that beneficial effects were correlated positively with degree of histologic differentiation and negatively with the basal PSA level.. Preoperative endocrine therapy reduced local extension of prostate cancer, and the effects depended on histologic differentiation and PSA level. Long-term follow-up data are needed to determine the effects on the patient prognosis.

Topics: Aged; Antineoplastic Agents, Hormonal; Chlormadinone Acetate; Humans; Leuprolide; Lymph Node Excision; Male; Multivariate Analysis; Neoplasm Staging; Preoperative Care; Progesterone Congeners; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Time Factors; Treatment Outcome

To assess the efficacy and toxicity of suramin, hydrocortisone, leuprolide, and flutamide in previously untreated metastatic prostate cancer.. Patients with stage D2 and poor-prognosis stage D1 prostate cancer were given suramin on a pharmacokinetically derived dosing schedule to maintain suramin concentrations between 175 and 300 micrograms/mL. Additionally, all patients received flutamide 250 mg orally three times daily, initiated on day 1 and continued until disease progression; depot leuprolide 7.5 mg intramuscularly begun on day 5 and repeated every 4 weeks indefinitely; and replacement doses of hydrocortisone.. Fifty patients were entered onto the study: 48 with stage D2 and two with stage D1 disease. The median age was 59 years (range, 42 to 79) and 31 patients had a Karnofsky performance status (KPS) of 100%. Forty-five patients had bone metastases and 25 had measurable soft tissue disease. Forty-one (82%) had severe disease. The overall response rate in 49 assessable patients was three complete responses (CRs) and 30 partial responses (PRs) for an overall response rate of 67%. Eighteen patients have died. The median survival time has not been reached, with a median potential follow-up duration of 44 months. Grade 3 to 4 toxicity was seen in 38% of patients and was predominantly hematologic and reversible.. The high response rate and prolonged survival in a poor-prognosis group of patients with metastatic prostate cancer warrant a phase III randomized comparison of this regimen versus hormonal therapy alone. Toxicity was moderate and reversible.

Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Drug Administration Schedule; Flutamide; Humans; Leuprolide; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Suramin; Survival Analysis; Treatment Outcome

To establish the pharmacodynamic and safety equivalence between 2 sustained-release forms of leuprorelin 11.25 mg and 3.75 mg, in the treatment of metastatic prostatic carcinoma.. 44 patients received subcutaneous injections of leuprorelin for 9 months (randomization: 2/l): either 11.25 mg every three months (n = 29) or 3.75 mg monthly (n = 15). Main criterion: centralized monthly assay of plasma testosterone (T).. The equivalence of the 2 forms in terms of mean plasma testosterone was demonstrated (p = 0.002): 1 month: T = 0.19 +/- 0.03 ng/ml; 3 months: T = 0.27 +/- 0.04 ng/ml. Exploratory analysis did not reveal any significant difference between the groups for the number of patients castrated at each visit or for the number of patients with all T values < or = 0.5 ng/ml, or for clinical responses or safety.. The 2 forms have a comparable efficacy and safety.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Chemistry, Pharmaceutical; Delayed-Action Preparations; Humans; Leuprolide; Male; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Therapeutic Equivalency; Treatment Outcome

To compare the efficacy and tolerability of bicalutamide and flutamide, each combined with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy, in patients with metastatic (Stage D2) prostate cancer.. This was a randomized, double-blind (for antiandrogen therapy), multicenter study with a two-by-two factorial design. Eight hundred thirteen patients were allocated 1:1 to bicalutamide (50 mg once daily) and flutamide (250 mg three times daily) and 2:1 to goserelin acetate (3.6 mg every 28 days) and leuprolide acetate (7.5 mg every 28 days).. The median times to progression and death were 97 and 180 weeks for the bicalutamide plus LHRH-A group compared with 77 and 148 weeks for the flutamide plus LHRH-A group. The hazard ratio for time to progression for bicalutamide plus LHRH-A to flutamide plus LHRH-A was 0.93 (95% confidence interval [CI] 0.79 to 1.10, P = 0.41) and that for survival time was 0.87 (95% CI 0.72 to 1.05, P = 0.15). The therapies were generally well tolerated. The most common adverse event in the two groups was hot flashes. The incidence of hematuria was significantly higher for the bicalutamide plus LHRH-A group than for the flutamide plus LHRH-A group (12% versus 6%, P = 0.007), but no patient withdrew from therapy because of hematuria. There was a significantly (26% versus 12%, P < 0.001) higher incidence of diarrhea and more withdrawals for diarrhea (25 patients versus 2) for the flutamide plus LHRH-A group relative to the bicalutamide plus LHRH-A group.. With a median follow-up time of 160 weeks, the combination of bicalutamide plus LHRH-A was well tolerated and had equivalent time to progression and survival compared with flutamide plus LHRH-A. Treatment with bicalutamide plus LHRH-A resulted in longer median survival than treatment with flutamide plus LHRH-A.

Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Flutamide; Follow-Up Studies; Goserelin; Humans; Leuprolide; Male; Middle Aged; Nitriles; Prostatic Neoplasms; Survival Rate; Tosyl Compounds

The aims of the study were (i) to compared the efficacy of the two long-acting GnRH agonists (GnRHa) triptorelin (Trp) and leuprolide (Leu) in men with prostate cancer and (ii) to assess the pattern of plasma testosterone levels following each injection of GnRHa.. 67 patients referred for prostate cancer not suitable for surgery were randomly allocated to two treatment regimens: 33 patients received 3.75 mg Trp i.m. at 4-week intervals for 3 months and 34 patients were treated with 3.75 mg Leu s.c. at the same rhythm of administration for 3 months.. Clinical data at entry and assessed monthly during follow-up did not differ between the two groups. Plasma prostate-specific antigen (PSA) and testosterone were measured before, 24 and 72 h after each injection of GnRHa. During treatment, PSA dropped similarly in both groups. By month 2, testosterone was < 1.0 nmol/l in 77 and 48% of patients treated with Trp and Leu, respectively (p = 0.02). 24 and 72 h after GnRHa injection, 77 (Trp) and 56% (Leu) of patients had testosterone < 1.0 nmol/l (p < 0.05).. The second and third injections of GnRHa were not followed by a significant increase in testosterone. Trp induced a higher decrease in testosterone than did Leu. The implications in terms of survival should, however, be studied in a larger and longer study.

Topics: Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Triptorelin Pamoate; Ultrasonography

Serum levels of LH, FSH and testosterone (T) were measured by radioimmunoassays in 36 patients with advanced prostate cancer before and during androgen ablation therapies. Both leuprolide acetate (LH-RH agonist: LHRH-A) and diethylstilbestrol diphosphate (DES-DP) administration decreased serum LH significantly to an undetectable level (LHRH-A: P < 0.01, DES-DP: P < 0.05). LHRH-A and DES-DP diminished serum FSH to 20% of the pre-treatment level (P < 0.005) and to an undetectable level (P < 0.001), respectively. LHRH-A and DES-DP decreased serum T to the castration level and an undetectable level, respectively (P < 0.001). Serum levels of the same 3 hormones before and after DES-DP administration were measured in 8 patients who received DES-DP after LHRH-A treatment or castration because of relapse of the disease. DES-DP lowered serum FSH further than LHRH-A to an undetectable level (P < 0.005) and diminished T further than previous treatments to an undetectable level (P < 0.05 vs. LHRH-A, P < 0.01 vs. castration). These results suggest that 1) DES-DP is able to reduce T production from extra-testicular site(s), and achieve the minimal serum T level, and 2) this DES-DP action appears to be one of the mechanisms of the effectiveness of the estrogen on refractory prostate cancer after castration or LHRH-A. In addition, basal (independent of LH-RH) FSH secretion in elderly men is about 20% of total FSH secretion and DES-DP inhibits the basal FSH secretion at the level of the pituitary.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Diethylstilbestrol; Follicle Stimulating Hormone; Humans; Leuprolide; Male; Orchiectomy; Prostatic Neoplasms; Receptors, LHRH; Retrospective Studies; Testosterone

Comparative efficacy and safety of 2 LHRH analogues in metastatic prostatic carcinoma.. 68 patients received monthly injections for 6 months (randomization): either subcutaneous leuprolide 3.75 mg LP (n = 36), or intramuscular triptorelin 3.75 mg LP (n = 32). (Flare-up prevention: nilutamide). Parameters re-evaluated at 1.3 and 6 months: centralized assays of plasma testosterone (T), LH and serum PSA; clinical symptoms. Main criterion: proportion of patients with T < or = 0.5 ng/mL.. The percentages of patients with T < or = 0.50 ng/mL was not significantly different between the two groups and were equal to 100 and 90%, 97 and 100%, and 100 and 96% at the 3 study times, for leuprolide or triptorelin, respectively. The difference was significant at 1 month on complementary analysis at the limit of T < 0.30 ng/mL: 86% with leuprolide versus 60% with triptorelin (p = 0.02) and for mean plasma testosterone: 0.16 +/- 0.10 ng/mL versus 0.33 +/- 0.44 ng/mL, respectively (p = 0.02). The clinical subjective efficacy was not significantly different.. Both treatments were effective, although plasma testosterone fell more rapidly with leuprolide. No conclusion about the possible clinical or survival benefits can be formulated. Overall safety was satisfactory.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Data Interpretation, Statistical; Drug Tolerance; Humans; Imidazoles; Imidazolidines; Injections, Intramuscular; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Time Factors; Triptorelin Pamoate

To review the outcome of therapy with maximal androgen blockade and compare the efficacy and safety of bicalutamide and flutamide, each used in combination with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy, in patients with untreated metastatic (Stage D2) prostate cancer.. Randomized, double-blind (for antiandrogen therapy), multicenter study with a 2 x 2 factorial design. A total of 813 patients were allocated 1:1 to bicalutamide (50 mg once daily) or flutamide (250 mg three times daily), plus 2:1 to goserelin acetate (3.6 mg every 28 days) or leuprolide acetate (7.5 mg every 28 days).. At the time of analysis (median follow-up, 49 weeks), bicalutamide plus LHRH-A was associated with a statistically significant improvement in time-to-treatment failure, the primary endpoint, when compared with flutamide plus LHRH-A. The results with longer follow-up (median, 95 weeks) support previous findings of an improved time-to-treatment failure with bicalutamide plus LHRH-A; however, the difference between groups was not statistically significant. A treatment failure endpoint was reached by 68% of patients in the bicalutamide plus LHRH-A group, compared with 72% of patients in the flutamide plus LHRH-A group. The hazard ratio of bicalutamide plus LHRH-A to flutamide plus LHRH-A was 0.87 (95% confidence interval [CI], 0.74-1.03; P = 0.10). The upper one-sided 95% confidence limit for survival was 1.00, meeting the definition for equivalence (< 1.25). With longer follow-up, overall mortality was 34%, with equivalent survival between groups: 32% of patients in the bicalutamide plus LHRH-A group died, compared with 35% in the flutamide plus LHRH-A group. The hazard ratio of bicalutamide plus LHRH-A to flutamide plus LHRH-A was 0.88 (95% CI, 0.69-1.11; P = 0.29). The upper one-sided 95% confidence limit for survival was 1.07, meeting the definition for equivalence (< 1.25). Diarrhea occurred in 24% of patients in the flutamide plus LHRH-A group compared with 10% of patients in the bicalutamide plus LHRH-A group (P < 0.001).. In patients with metastatic prostate cancer, bicalutamide plus LHRH-A is effective and well tolerated. Because of its efficacy and tolerability profile, together with its convenient once-daily dosing formulation, bicalutamide represents a prime candidate for antiandrogen of first choice in combination with LHRH-A therapy in the treatment of men with metastatic prostate cancer.

Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Flutamide; Follow-Up Studies; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Prostatic Neoplasms; Tosyl Compounds

The results of therapy in 288 men with pathologic Stage C prostate cancer who underwent radical retropubic prostatectomy (RRP) were analyzed to determine the effects of adjuvant therapy.. Twenty-seven of the 288 patients received preoperative neoadjuvant hormonal therapy (leuprolide acetate). Postoperatively, 60 patients received adjuvant radiotherapy (RT) to the prostate bed. Follow-up ranged from 3 to 83 months (median = 32 months). Freedom from failure (FFF) was defined as maintaining a serum PSA level of < or = 0.3 ng/ml.. The FFF was 61% at 3 years and 45% at 5 years for the entire group. The FFF following RRP plus RT was 75% at 3 years and 57% at 5 years as compared to 56% at 3 years and 40% at 5 years for RRP without RT (p=0.049). The FFF following RRP plus neoadjuvant hormonal therapy was 58% at 3 years and 40% at 5 years as compared to 60% at 3 years and 45% at 5 years following RRP without hormonal therapy (p=0.3). In patients without seminal vesicle (SV) invasion, the FFF was 81% at 3 years and 5 years for RRP plus RT as compared to 61% at 3 years and 50% at 5 years for RRP without RT (p=0.01). In patients with SV invasion, the FFF was 61% at 3 years and 36% at 5 years for RRP plus RT as compared to 44% at 3 years and 23% at 5 years for RRP without RT (p=0.23). The projected local control rate was 83% at 5 years for those with RRP alone as compared to 100% for RRP plus RT (p=0.02). Survival at 5 years was projected to be 92% and was not significantly altered by the administration of adjuvant therapies.. Postoperative RT was associated with significantly improved local control and FFF rates, especially in patients with tumors which did not involve the seminal vesicles.

Topics: Aged; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Combined Modality Therapy; Humans; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prostatectomy; Prostatic Neoplasms; Radiotherapy, Adjuvant; Treatment Failure

There is interest in treating prostate cancer with induction androgen deprivation prior to radical prostatectomy. Data on long-term prostate-specific antigen (PSA)-based survival analyses among patients treated with neoadjuvant hormonal therapy (NHT) and prostatectomy are limited. In 1991 we instituted a pilot study for T3 disease based on endorectal coil magnetic resonance imaging (eMRI), mandatory negative laparoscopic nodal dissection prior to hormonal manipulation, and prostatectomy followed by pathologic and PSA-based outcome determinations.. Of 26 patients, 21 had negative laparoscopic lymphadenectomy followed by 4 months of NHT (leuprolide +/- flutamide) prior to radical prostatectomy. eMRI was performed at the time of diagnosis and following hormonal treatment. Serum PSA was determined at 3-month intervals. Prostatectomy specimens were evaluated by 3-mm whole-mount step sections.. Prior to prostatectomy, biochemical response was documented in all patients and downsizing was observed by eMRI in 57%. Pathologic downstaging to a lower stage (T2c or lower) was achieved in 48%. However, the actuarial 3-year freedom from biochemical relapse rate was only 24%.. Using laparoscopy to exclude node-positive patients and 4 months of NHT appears to result in pathologic and initial biochemical evidence of regression. These factors have not translated into improved freedom from biochemical relapse among patients with Stage T3 disease treated with NHT and prostatectomy. Recent data strongly suggest a beneficial effect in patients with clinical T2 disease treated with NHT and radical prostatectomy. The NGT and radical prostatectomy approach appeared to offer no clear advantage when compared with PSA-based benchmarks achieved with conformal irradiation or NHT followed by external beam treatment among patients with clinical T3 disease.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Flutamide; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Preoperative Care; Prospective Studies; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

Thanks to earlier detection of clinically significant prostatic adenocarcinoma by measurement of serum prostate-specific antigen (PSA) levels, increasing numbers of patients are undergoing radical prostatectomy. However, the curative potential of this procedure is seriously limited by clinical understaging, which results in positive surgical margins and a marked increase in disease progression. In a multicenter study, histopathologic evaluation of radical prostatectomy specimens showed that presurgical androgen deprivation with leuprolide plus flutamide reduced the incidence of surgical margin involvement by 62%. In patients who received androgen deprivation therapy, characteristic and recognizable histopathologic changes in nontumor glands included atrophy, basal cell prominence, vacuolated luminal cell layers, and squamous and transitional cell metaplasia. Androgen deprivation markedly reduced the incidence of prostatic intraepithelial neoplasia (PIN) to 35%. The effects of androgen deprivation on prostatic carcinoma included smaller tumor glands, pyknosis and empty glandular spaces, and vacuolization and degeneration of tumor cells with an inflammatory response. Similar but less pronounced changes with no decrease in PIN were observed in finasteride-treated patients. It is important for pathologists to be aware of these histological changes and process tissue appropriately, because the changes affect the recognition and histological grading of tumors in radical prostatectomy specimens.

Topics: Adenocarcinoma; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Flutamide; Humans; Leuprolide; Male; Neoplasm Staging; Premedication; Prostatectomy; Prostatic Neoplasms

The effects of pharmacotherapeutic complete androgen deprivation treatment for 2 months before radical retropubic prostatectomy (RRP) were investigated in an open study in 375 patients. Prostate volume, tumor staging and prostatespecific antigen (PSA) were investigated as clinical parameters. The RRP specimens were analyzed particularly in terms of tumor cell regressions, pathological tumor staging and grading. Before neoadjuvant therapy (NAT) the 375 patients were classified according to stage: 36 (9.6%) were T1B; 137 (46.1%) were T2, and 166 (44.3%) were T3 stage. After NAT, the clinical investigation (digital rectal examination + transrectal ultrasonography) gave an impression of a T0 stage in 11% of the T2 patients, and a T2 tumor stage in 39% of the T3 patients. The histopathological analysis of the initial T1B and T2 cases did not reveal any tumor in the RRP specimen in 11 (3.8%) cases, a pT2 tumor in 153 (73%) cases, and a pT3 tumor in 48 (23.5%) cases. In the patients initially classified as T3, a tumor was no longer found in 1 (0.6%) case, and a pT2 tumor was found in 48 (29.3%) cases and a pT3 tumor in 113 (67.7%) cases. Under NAT, the prostate volume fell by 34% in T3 tumors and by 24% in T2 tumors. The fall in PSA averaged 85% without significant differences in the individual tumor stages. A statistically significant correlation could not be demonstrated between the fall of PSA and the definitive pathological tumor stage. Tumor cell regressions were found in all preparations. The degree of regression was predominantly RII. These results document the direct effect on tumor cells of an inductive androgen-ablative pharmacotherapy. Regression and volume reduction of the tumor might lead to an improvement of the local surgical control. A final clinical evaluation of NAT will only be possible after long-term analysis of ongoing prospective, randomized studies.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Cyproterone Acetate; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prostate; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Time Factors

Androgen deprivation based on hormone manipulation is the treatment of choice in advanced prostatic cancer. The unequivocal role of adrenal androgens in the growth of prostatic cancer after medical or surgical castration requires a new logical approach (complete androgen blockade) in the treatment of advanced prostate cancer. One hundred and fifty patients with biopsy-proven advanced prostatic cancer were randomized into two groups. One group (74 patients) received leuprolide + flutamide (complete androgen blockade); the second group (76 patients) received only leuprolide and, during the first 3 weeks of treatment, cyproterone acetate (150 mg/day) to prevent flare-up phenomena. The aim of the study was to evaluate the differences between the two groups on overall survival and time to progression (log-rank test). One hundred and twenty-five patients were evaluable, 62 in the leuprolide-only group and 63 in the leuprolide + flutamide group. Median duration of follow-up was 102 weeks. No statistical difference between the two groups was observed in overall survival, in time to disease progression, and in time to treatment failure. In the combination (leuprolide + flutamide) treatment group, a positive trend for overall survival and in time to progression was observed in a subgroup of patients with good performance status and no bone metastases. We observed mild gastrointestinal toxicity (diarrhea, nausea) in the group treated with leuprolide + flutamide. The aim of this study was to compare the effectiveness of total androgen withdrawal with medical testicular suppression in advanced prostatic cancer. No significant statistical difference was observed between the two groups in overall survival and in time to progression, but probably too few patients were enrolled in each treatment arm to give a statistical interpretation of our results. We conclude that there is a positive trend in the combination treatment arm in patients with good prognostic factors.

Topics: Age Distribution; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cyproterone Acetate; Flutamide; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Survival Rate

Androgen suppression, using gonadotrophin-releasing hormone analogues (leuprorelin), is being developed as an effective treatment of advanced prostate carcinoma. Treatment with leuprorelin acetate 1-month depot is already well established all over the world. In order to increase patients' acceptability of this treatment, by reducing frequency of administration, a 3-month depot formulation has been developed in Takeda's research laboratories. A single-shot pharmacokinetic study was conducted to confirm efficacy in terms of hormone suppression and safety of the 3-month depot formulation. Thereafter, a parallel-group, open-labelled, randomized trial was performed to compare clinical efficacy and safety profiles of the 1- and 3-month depot formulations. Patients with a histologically and/or cytologically confirmed advanced prostate carcinoma, without prior hormonal or surgical androgen deprivation, are included. According to 1:2 randomization, patients are treated with either the 1- or 3-month depot for 9 months. To prevent initial flare-up, a concomitant antiandrogen therapy might be administered within 2 weeks prior to first injection and continued for up to 3 weeks. The clinical efficacy of the formulations is assessed by both objective response, EORTC and NPCTG response criteria, and subjective response by using WHO performance status. In addition, the level of prostate-specific antigen is determined every 3 months. The efficacy of the two formulations is also evaluated by determination of serum testosterone, dihydrotestosterone, luteinizing hormone and follicle stimulating hormone. To date, 106 patients have been treated with the 3-month depot and 53 patients with the 1-month depot. Preliminary evaluation shows a satisfying level of testosterone suppression with both the 3- and 1-month depot formulations. Therapeutic equivalence was assumed. The 3-month depot is tolerated as well as the 1-month depot.

Topics: Aged; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Humans; Leuprolide; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Time Factors

In an open, prospective clinical trial enrolling 205 patients, efficacy and safety of the gonadotropin-releasing hormone agonist leuprorelin acetate depot (LAD) in the treatment of patients with advanced prostatic carcinoma were assessed. 3.75 mg of the LAD formulation was injected subcutaneously in monthly intervals. The primary objective of this study was to evaluate the efficacy of the analogue in producing and maintaining castration levels of testosterone over a > 3-year follow-up period and to determine its safety profile. Median pretreatment serum testosterone levels fell from 350 to 21 ng/dl after 4 weeks and 20 ng/dl after 45 months. The long-term clinical efficacy of the LAD formulation can be expressed by best treatment response over time. These respective figures read as follows: 10.7% complete response; 49.8% partial response; 34.1% no change; 1.5% progression, and 3.9% no data available. The median time to progression was 12 (15 +/- 11) months. Median survival time calculated by Kaplan-Meier exceeded 42.5 months for patients on monotherapy and 30.9 months for those on combination therapy. Hot flushes which were related to androgen deprivation were the most common side effects. Patients and treating physicians judged tolerability of LAD in more than 90% as good. Androgen deprivation remains the mainstay of hormone-dependent advanced carcinoma of the prostate. Up to now, surgical castration has been considered the standard method. LAD is an advantage in the endocrine treatment of advanced prostatic carcinoma and is a good alternative to castration.

Topics: Aged; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Follow-Up Studies; Humans; Leuprolide; Male; Prospective Studies; Prostatic Neoplasms; Survival Rate; Testosterone; Time Factors

To affirm the feasibility of using intermittent androgen suppression in patients with hormone-naive prostate cancer.. Leuprolide and flutamide were administered for 9 to 12 months and then discontinued until prostate-specific antigen (PSA) levels reached a threshold value determined by the baseline PSA value. This constituted one cycle of treatment. Androgen suppression was then administered intermittently as described until there was evidence of androgen independence.. Twenty-two patients with PSA failure after primary therapy with surgery and/or radiation and untreated early or Stage D2 disease were treated. Twenty-one patients completed androgen suppression during cycle 1, with a median time to PSA nadir of 3.5 months (range, 2 to 12). Fifteen patients completed cycle 1 with a median time off treatment of 6 months (range, 2 to 19) or 38% (range, 17% to 64%) of a treatment cycle. Six patients continued off treatment during cycle 1 for 1+ to 31+ months. During cycle 2, 12 patients achieved a PSA nadir in a median time of 3.5 months. Two patients completed cycle 2 with a median time off treatment of 10 months (51%). Median follow-up for all patients is 26 months (range, 10 to 51). While off treatment, all patients reported a reduction of symptoms associated with androgen suppression.. Intermittent androgen suppression is a feasible alternative to continuous androgen suppression for treatment of prostate cancer, and quality of life is improved while off treatment.

Topics: Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Flutamide; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Pilot Projects; Prostatic Neoplasms

A randomized, multicenter trial, double-blind for antiandrogen therapy, compared the antiandrogens bicalutamide and flutamide, each combined with luteinizing hormone-releasing hormone analogue therapy (LHRH-A) in 813 patients with Stage D2 prostate carcinoma. An analysis of time to progression (median follow-up, 95 weeks) was performed to augment previous analyses of time to treatment failure and time to death.. Patients were randomly assigned 1:1 to double-blind antiandrogen therapy, receiving either bicalutamide (50 mg once daily) or flutamide (250 mg three times daily), and were assigned 2:1 to LHRH-A with goserelin acetate (3.6 mg every 28 days) or leuprolide acetate (7.5 mg every 28 days). The primary endpoint of the trial was time to treatment failure, defined as an adverse event leading to withdrawal of randomized therapy, objective progression, death, or withdrawal from study therapy for any reason. Secondary endpoints were time to death, quality of life, and subjective response. The current analysis of time to progression included progression data collected prospectively for 561 patients (69%) and retrospectively for 252 patients (31%).. Disease progression occurred for 223 of 404 patients (55%) in the bicalutamide plus LHRH-A group and for 235 of 409 patients (58%) in the flutamide plus LHRH-A group. The hazard ratio for time to progression of bicalutamide plus LHRH-A to that of flutamide plus LHRH-A was 0.9 (two-sided 95% confidence interval [CI], 0.75 to 1.08; P = 0.26). The upper one-sided 95% CI was 1.05, which met the definition of equivalence (< 1.25).. At a median follow-up time of 95 weeks, bicalutamide plus LHRH-A and flutamide plus LHRH-A had equivalent time to progression.

Topics: Adenocarcinoma; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Double-Blind Method; Flutamide; Goserelin; Humans; Leuprolide; Male; Nitriles; Prostatic Neoplasms; Tosyl Compounds

In a European, prospective, 1:2 randomized phase II multicentre study, 237 patients with advanced or metastatic prostate cancer were treated with either the 1M- (80 patients) or 3M-depot formulation (157 patients) of leuprorelin acetate for 9 months to compare efficacy and safety.. Standard clinical investigations and methods were employed in the study. Leuprorelin levels were determined using a specially modified RIA.. The two formulations produced virtually identical effects with a pronounced fall in testosterone and gonadotropin serum levels and a marked reduction in PSA levels. After 9 months' treatment, PSA was normalized (< or = 4 ng/ml) in 65.2 and 66.1% of the 1M and 3M depot patients, respectively. The best response to 1M vs. 3M depot during the study was as follows: complete remission in 5 vs. 5.7%, partial remission in 36.3 vs. 33.8% and stabilization in 40.0 vs. 40.8%. The main side effects of both formulations were related to androgen deprivation.. Comparable results were recorded for the two formulations of leuprorelin acetate in terms of clinical response, endocrine effects and tolerability. The newly developed leuprorelin acetate 3M depot, as a refinement of the established 1M depot, offers an opportunity to improve patient compliance and provides individualized and optimized, patient-orientated treatment by reducing the number of injections to four per year.

Topics: Aged; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Gonadotropins; Humans; Leuprolide; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Time Factors

In a recent study by the Casodex Combination Study Group, USA, patients in a flutamide (750 mg/day) plus LH-RH agonist group showed a high treatment failure rate, mainly due to flutamide-induced diarrhea and hepatotoxicity. Our current study was conducted to determine the optimal dose of flutamide for use in this type of combination therapy.. In a randomized, multicenter study, 30 patients (hormone untreated; stage C or D) were divided into 2 groups: flutamide 250 mg (125 mg x 2; 14 patients) and flutamide 375 mg (125 mg x 3; 16 patients, and each dose combined with either goserelin acetate (3.6 mg every 4 weeks) or leuprolide acetate (3.75 mg every 4 weeks). Goserelin and leuprolide were administered to patients in a 1:1 ratio. Flutamide monotherapy at a daily dose of 375 mg was determined to be the optimal dose in Japan in our previous phase II study. The endpoints of this pilot study were the objective response and adverse events during the 12-week treatment.. The objective response rate was 83.3% in the flutamide 250 mg group and 85.7% in the flutamide 175 mg group according to the Japanese response criteria for prostate cancer. Elevated PSA levels fell to within the normal range in 83.3% of the patients in the former group and in 93.3% of the patients in the latter group. One patient administered 250 mg of flutamide experienced diarrhea, while the serum GOT and/or GPT were elevated in 3 patients administered 250 mg of flutamide and 4 patients administered 375 mg of flutamide.. Based on the findings of this pilot study of maximal androgen-depletion therapy for advanced prostate cancer, 375 mg/day of flutamide is recommended in combination with an LH-RH agonist. Assessment of the effects of our recommended regimen on longer term survival, quality of life and antiandrogen withdrawal syndrome of patients treated requires additional patients and time for follow-up.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Chemical and Drug Induced Liver Injury; Diarrhea; Dose-Response Relationship, Drug; Flutamide; Follow-Up Studies; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms

To compare the efficacy and safety of bicalutamide and flutamide, each used in combination with luteinizing hormone-releasing analogue (LHRH-A) therapy, in patients with untreated metastatic (Stage D2) prostate cancer.. Randomized, double-blind (for antiandrogen therapy), multicenter study with a 2 x 2 factorial design. Eight hundred thirteen patients were allocated 1:1 to bicalutamide (50 mg once daily) and flutamide (250 mg three times daily) and 2:1 to goserelin acetate (3.6 mg every 28 days) and leuprolide acetate (7.5 mg every 28 days).. With a median duration of follow-up of 49 weeks, time to treatment failure, the primary endpoint, was significantly (P = 0.005) better for the bicalutamide plus LHRH-A group than for the flutamide plus LHRH-A group. Patients in the flutamide plus LHRH-A group were 34% more likely to fail treatment over the given time period, as indicated by the hazard ratio of 0.749 (95% confidence interval, 0.61 to 0.92) for bicalutamide plus LHRH-A to flutamide plus LHRH-A. Results for secondary endpoints (survival, quality of life, and subjective response) were similar between groups. Diarrhea occurred in 24% of patients in the flutamide plus LHRH-A group, compared with 10% of patients in the bicalutamide plus LHRH-A group (P < 0.001).. In patients with metastatic prostate cancer, bicalutamide plus LHRH-A is well tolerated and provides superior efficacy to flutamide plus LHRH-A with respect to time to treatment failure. Assessment of the effects of these regimens on longer term survival requires additional time for follow-up.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Confidence Intervals; Double-Blind Method; Flutamide; Follow-Up Studies; Goserelin; Humans; Leuprolide; Male; Middle Aged; Nitriles; Proportional Hazards Models; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Regression Analysis; Survival Rate; Tosyl Compounds; Treatment Failure

To test the feasibility of using intermittent androgen suppression in the treatment of prostate cancer by taking advantage of the reversible action of medical castration.. Observations were made on a group of 47 patients (clinical Stage D2, 14; D1, 10; C, 19; B2, 2; and A2, 2) with a mean follow-up time of 125 weeks. Treatment was initiated with combined androgen blockade and continued for at least 6 months until a serum prostate-specific antigen (PSA) nadir was observed. Medication was then withheld until the serum PSA increased to a mean value between 10 and 20 ng/mL. This cycle of treatment and no treatment was repeated until the regulation of serum PSA became androgen independent.. The first two treatment cycles lasted 73 and 75 weeks, with a mean time off therapy of 30 and 33 weeks and an overall mean percentage time off therapy of 41% and 45%, respectively. The mean time to achieve a nadir level of serum PSA was 20 weeks in cycle 1 and 18 weeks in cycle 2. Serum testosterone returned to the normal range within 8 weeks (range, 1 to 26) of stopping treatment. The off-treatment period in both cycles was associated with an improvement in sense of well-being and the recovery of libido and potency in the men who reported normal or near-normal sexual function before the start of therapy. In 7 patients with Stage D2 disease, the cancer progressed to an androgen-independent state. The mean and median times to progression were 128 weeks and 108 weeks, respectively. Seven patients have died, 1 from a noncancer-related illness, with mean and median overall survival times of 210 weeks and 166 weeks, respectively.. Prostate cancer is amenable to control by intermittent androgen suppression. This approach affords an improved quality of life when the patient is off therapy. It also results in reduced toxicity and cost of treatment and possibly delays tumor progression. Whether survival is affected in a beneficial or adverse way remains to be studied in a randomized, prospective study.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Cyproterone Acetate; Diethylstilbestrol; Drug Therapy, Combination; Follow-Up Studies; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Time Factors

Nonrandomized clinical trials have suggested that preoperative androgen deprivation can decrease the likelihood of positive surgical margins in patients with clinically localized prostate cancer. A multicenter prospective randomized trial compared radical prostatectomy alone to radical prostatectomy after 3 months of leuprolide acetate depot and flutamide in patients with stage cT2bNxM0 prostate cancer and a serum prostate specific antigen level less than 50 ng./ml.. We randomized 149 patients to undergo androgen deprivation and 138 to undergo lymphadenectomy with (137) or without (1) prostatectomy. Of the 154 patients randomized to the surgery alone group 144 underwent pelvic node dissection with (138) or without (6) prostatectomy.. There was no statistically significant difference between the 2 groups in operating time, blood loss, need for transfusion, postoperative morbidity or length of hospital stay. There were 4 rectal and 2 ureteral injuries in the surgery alone group and none in the pretreatment group (p < 0.05). Patients who received androgen deprivation preoperatively had a significantly lower rate of capsule penetration (47% versus 78%, p < 0.001), positive surgical margins (18% versus 48%, p < 0.001) and tumor at the urethral margin (6% versus 17%, p < 0.01).. Long-term followup data will be needed to determine whether there will be a lower incidence of biochemical relapse as determined by prostate specific antigen, local recurrence or metastasis, with an improvement in patient survival.

Topics: Aged; Combined Modality Therapy; Flutamide; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Preoperative Care; Prospective Studies; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

A total of 161 patients diagnosed as having stage B (134 patients) or C (27 patients) prostate cancer were randomly assigned to radical prostatectomy alone or to 3 months of neoadjuvant combination therapy with the anti-androgen flutamide and an LHRH agonist before radical prostatectomy. Neoadjuvant combination therapy before radical prostatectomy decreased cancer positive surgical margins from 33.8% in the control group to only 7.8%, thus leaving 92.2% of patients with negative margins at surgery for a 39.2% increase in specimen confined disease. Although on average the final stage determined at histopathological examination of the surgical specimen was more advanced than predicted at initial diagnosis in 33.8% of control patients, an opposite observation was made in the group of men who received the 3 month neoadjuvant combination therapy where the final stage, instead of being more advanced, was less advanced than at diagnosis in an average of 21.1% of men for a net 54.9% improvement of staging in favour of combination therapy. On the other hand, organ confined disease increased from 49.3% to 77.8% of patients after 3 months of combination therapy, for a 57.9% increase in the incidence of organ confined disease. Although long term follow up of these patients is required to determine the impact on survival, the marked influence of neoadjuvant combination therapy on the stage of the disease suggests the possibility of a major improvement in the morbidity and mortality from prostate cancer.

Topics: Aged; Combined Modality Therapy; Drug Therapy, Combination; Flutamide; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prostatectomy; Prostatic Neoplasms

A prospective evaluation of neoadjuvant hormonal downsizing in patients with localized carcinoma of the prostate was undertaken to assess its effect on normal tissue irradiation. Twenty patients with stage T1 or T2 (A, B) carcinoma of the prostate received 3 months of Lupron prior to definitive radiotherapy. The volumes of the prostate, seminal vesicles, bladder, and rectum from both the pre- and posthormone treatment planning CT were entered onto a 3-D treatment-planning system. The treatment planning parameters were standardized to facilitate comparison of the pre- and posthormonal volumes. Following the three monthly injections of Lupron, the average volume of the prostate was reduced by 37%. As a consequence, the volume of the bladder receiving at least 40, 52, and 64 Gy was reduced by an average of 15, 18, and 20%, respectively. In addition, the volume of the rectum receiving at least 40, 52, and 64 Gy was reduced by an average of 13, 20, and 34%, respectively. In conclusion, in patients with localized prostate cancer, downsizing of the prostate resulted in a reduction in the volume of bladder and rectum receiving high radiation doses. This approach may result in an improvement in the therapeutic ratio by reducing the morbidity of treatment.

Topics: Adenocarcinoma; Chemotherapy, Adjuvant; Humans; Leuprolide; Male; Neoplasm Staging; Prospective Studies; Prostate; Prostatic Neoplasms; Rectum; Tomography, X-Ray Computed; Urinary Bladder

Evaluation of the prognostic value of prostatic markers with regard to disease progression after endocrine therapy in patients with prostate carcinoma. A total of 51 patients (21 stage C, 5 stage D1 and 25 stage D2). Endocrine therapy consisted in complete hormonal blockade with flutamide and an LH-RH analog depot (leuprolide). PSA-PAP levels were determined both pre-treatment and during follow-up of patients using radioimmunometric techniques. Follow-up extended for 13 to 62 months (mean 30 months). Death due to progression happened in 24 of 51 patients. Previous PSA levels did not correlate to progression. Changes in PSA levels during treatment and time scope when they occurred were associated to subsequent evolution. Patients with PAP higher than 10 ng/ml at the beginning of therapy experienced higher progression rates (p < 0.05). Decrease of PSA levels by a percentage greater than 80% during the first quarter of treatment relative to initial figures was related to lower progression rates (p < 0.01). Maintenance of high levels in the first six months of treatment predicted a higher progression rate (p < 0.001). The study suggests a better prognosis for patients wit decreased serum PSA rates by a percentage of around 80% after one to three months treatment.

Topics: Acid Phosphatase; Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Flutamide; Follow-Up Studies; Humans; Leuprolide; Male; Prognosis; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms

Leuprolide, an agonist of luteinizing hormone-releasing hormone (LH-RH), and flutamide, an antiandrogen, increasingly are being used in the treatment of clinically localized prostate cancer. Only two small series (of 23 and 12 patients) have been published on the distinctive pathologic changes induced in the prostate by androgen deprivation therapy with discrepancies on the presence of squamous metaplasia, necrosis, and possible tumor destruction by combined androgen deprivation therapy.. One hundred and thirteen radical prostatectomy specimens obtained after at least 3 months of leuprolide-flutamide androgen inhibition therapy and 60 nonhormonally treated prostates in randomly selected clinical Stage T2 prostate adenocarcinoma patients were entirely sectioned. Distinctive histologic findings were tabulated and their statistical value determined.. Resection margins of excision were involved by tumor in 43% of untreated and in 19% of androgen-deprived patients. Characteristic changes in androgen-inhibited nontumor glands included atrophy, basal cell prominence, vacuolated luminal cell layer, and squamous and transitional cell metaplasia. Prostatic intraepithelial neoplasia (PIN) was observed in 35% of treated patients. The presence of small tumor glands separated by stroma was the most frequently noted effect of androgen deprivation on prostate adenocarcinoma; pyknosis and branching empty spaces were less frequent. Large clear tumor cells within an inflammatory response was a third histologic pattern. Apparently unaltered tumor areas were observed in 43% of prostates exposed to androgen deprivation therapy.. Androgen deprivation therapy results in histologically distinctive changes that can be recognized in both nonneoplastic and neoplastic prostate tissue. Residual tumor was present in all 113 treated radical prostatectomy specimens. In addition to glandular shrinkage, therapy was associated with statistically significant reductions in the frequency of high grade PIN and extension of cancer to prostate specimen margins of excisions.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Flutamide; Humans; Leuprolide; Male; Prospective Studies; Prostatic Neoplasms

Seventy-two patients were admitted in a multicentre trial with the purpose of assessing the clinical efficacy and safety of the hormonal control and tolerance of leuprolide acetate in a once-a-month depot injection formulation for the treatment of disseminated prostate cancer. During a 1-year follow-up, there were ten withdrawals for different reasons. At baseline and at 6 months of treatment the following parameters were evaluated: clinical examination, routine blood analysis, PAP, PSA, LH and testosterone, as well as bone scan. LH and testosterone determinations were repeated at 2, 4, 8, 12, 16, 20 and 24 weeks. Testosterone reached castration levels within the second week and was maintained until the end of the study. In agreement with the NPCP criteria, 65 patients were assessed as: complete response 3%, partial response 40%, disease stabilization 36%, and progression 21%. In summary, a once-a-month injection of leuprolide acetate offers a safe and effective alternative to surgical castration.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Delayed-Action Preparations; Drug Administration Schedule; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms

To determine the extent of reduction of volume of normal tissue structures exposed to high doses of radiation therapy (RT) after administration of neoadjuvant hormonal therapy (NHT) in patients with bulky, geometrically unfavorable prostatic cancers.. Twenty-two patients with bulky prostatic cancers were treated with a 3 month course of neoadjuvant leuprolide acetate and eulexin prior to three-dimensional (3-D) conformal radiotherapy. Patients were included if 3-D treatment planning revealed that either > 30% of the rectal wall would receive 95% of the prescription dose (D95) (n = 13); > or = 50% of the bladder wall would receive D95 (n = 10); or that any volume of small bowel would receive > or = 65% of the prescription dose (n = 16). All patients underwent simulation and conformal treatment planning before and after NHT. Pre and posthormone cumulative dose volume histogram (DVH) calculations for all normal tissue structures were analyzed and compared for each patient.. The median percentage of target volume reduction after NHT was 25% (range: 3-52%). Ten of 13 patients (78%) whose prehormone rectal DVH demonstrated > 30% of the rectal wall receiving D95 responded to NHT with a median 25% (range: 16-48%) reduction of rectal volume receiving the D95. A median reduction of 50% (range: 6-64%) of the bladder volume receiving D95 was observed in nine of ten patients (90%), while 13 of 16 (81%) showed a reduction of small bowel volume to a median percentage of 88% (range: 67-100%) of the prehormonal values.. Neoadjuvant hormonal therapy is an effective method for decreasing the size of bulky prostatic tumors as well as for optimizing the geometry of the target volume in relation to the adjacent normal tissue structures prior to radiation therapy. Such an approach allows for reduction of the volume of normal tissues exposed to high doses in the majority of treated patients. Currently, studies are underway to determine whether NHT will lead to a decreased likelihood of long-term complications associated with radiotherapy of bulky, geometrically unfavorable prostatic tumors, and permit the safe delivery of escalated dose levels using conformal treatment techniques.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Combined Modality Therapy; Flutamide; Humans; Leuprolide; Male; Middle Aged; Pilot Projects; Prospective Studies; Prostatic Neoplasms; Radiotherapy Dosage; Radiotherapy, High-Energy; Rectum; Urinary Bladder

Prostatic intraepithelial neoplasia (PIN) is considered the most likely precursor of prostatic adenocarcinoma. The effect of androgen deprivation therapy on the prevalence of PIN is unknown.. We undertook a case-control study of radical retropubic prostatectomies from 24 treated patients and a control group of 24 untreated patients matched for age and clinical stage (all T3). Androgen deprivation therapy included LHRH agonist leuprolide and flutamide (18 patients), diethylstilbestrol (DES) (2 patients), DES with leuprolide and flutamide (1 patients), and orchiectomy (3 patients). Prostatectomy specimens were evaluated for the presence and extent of high-grade PIN according to the number of high-power microscopic fields, and nuclear tumor grade (1 to 4 scale) and Gleason score were also determined.. The prevalence of high-grade PIN in pretreatment transrectal needle biopsies was similar in the treated and untreated groups. The prevalence and extent of high-grade PIN were lower in cases treated with androgen deprivation therapy than controls. Nuclear tumor grade was also lower in treated patients, but there was a paradoxical increase in the Gleason score. The prevalence of aneuploidy in the cancers was similar in both groups.. These findings suggest that androgen deprivation therapy decreases the prevalence and extent of high-grade PIN.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Carcinoma in Situ; Case-Control Studies; Combined Modality Therapy; Diethylstilbestrol; Flutamide; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Neoplasms, Second Primary; Orchiectomy; Prevalence; Prostatectomy; Prostatic Neoplasms

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cohort Studies; Flutamide; Humans; Leuprolide; Male; Neoplasm Invasiveness; Prognosis; Prostatectomy; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Single-Blind Method

This report describes the effects of neoadjuvant hormonal therapy on 16 patients (mean age = 65 y) with clinical stage C adenocarcinoma of the prostate (CaP) who underwent radical prostatectomy from December 1991 to June 1993 at the University of Colorado Health Sciences Center. Staging of CaP was determined by digital rectal exam, transrectal ultrasonography (TRUS), radionuclide bone scanning, abdominal and pelvic computed tomography scanning, transrectal coil magnetic resonance imaging, and serum acid phosphatase. Most patients underwent a laparoscopic lymph node dissection to rule out micrometastasis. Every patient was treated for 4 months with a combination of a gonadotrophin-releasing hormone (GnRH) agonist (Lupron) and an anti-androgen (flutamide, Eulexin). Serial prostate-specific antigen (PSA) levels, post-treatment prostate volume measured by TRUS, and whole-mount sectioning of the surgical specimen were studied. The PSA levels decreased from a mean of 39.1 ng/ml (Hybritech method) to a mean of 0.43 ng/ml; (p < 0.0001). Prostate volumes in all patients demonstrated a mean decrease of 52% (p < 0.0001), and pathological effects of hormonal deprivation were observed in all patients. By whole-mount sectioning of the radical prostatectomy specimens, 3 patients had organ-confined disease (stage B), 6 showed invasion of the capsule with surgical margins free of tumor (stage C1), 3 had extracapsular extension with positive surgical margins (stage C2), and 4 had extracapsular extension with seminal vesicle involvement (stage C3). We conclude that by downsizing and markedly decreasing serum PSA values, neoadjuvant hormonal therapy offers an alternative treatment for stage C carcinoma of the prostate.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Combined Modality Therapy; Flutamide; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Staging; Pilot Projects; Prostate; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

Although the only opportunity to cure prostate cancer is treatment at an early stage, radical prostatectomy has remained relatively unpopular because 40-50% of prostate cancers estimated at diagnosis as confined to the prostate are found to be at a more advanced stage following histopathological analysis of the surgical specimen. This first prospective, randomized trial investigated the potential advantages of 3-month neoadjuvant combination therapy with flutamide and lupron before radical prostatectomy vs. prostatectomy alone in early stage prostate cancer. Cancer-positive margins were reduced from 38.5% (25 of 65) in control patients to only 13.0% (10 of 77) in men who received neoadjuvant combination therapy with the antiandrogen flutamide and the luteinizing hormone-releasing hormone (LHRH) super-agonist Lupron before radical prostatectomy (p = 0.006). Moreover, comparison of the final stage determined by histopathological examination of the surgical specimen with that estimated at diagnosis showed that a more advanced stage (upstaging) was found in 53.8% of controls, but patients who received combination therapy had an opposite effect: a more favorable stage than expected at diagnosis was found in 23.4% of cases (downstaging), a 77.2% advantage of neoadjuvant combination therapy. The concern about radical prostatectomy, underestimation of stage, is thus markedly improved by 3-month neoadjuvant therapy with flutamide and a LHRH superagonist. Cancer-negative margins are expected to be accompanied by a life expectancy not different from that of men of similar age with no prostate cancer; therefore, the present data, combined with efficient detection of early stage prostate cancer, offer the basis for dramatic improvement in the morbidity and mortality of prostate cancer.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Combined Modality Therapy; Flutamide; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Prostatectomy; Prostatic Neoplasms

Two hundred consecutive patients with presumed localized prostate cancer had radical prostatectomy alone (n = 119) or were treated for an average period of 3 months with combination therapy using the antiandrogen flutamide and one luteinizing hormone-releasing hormone (LHRH) agonist (Lupron or Zoladex). The positive margins decreased from 35.3% in the group undergoing prostatectomy alone to 11.5% in the group of men who received combination therapy before radical prostatectomy. In 41 apical tumors, the incidence of positive margins decreased from 50% in the control group to 18.6% in the combination therapy group. In stage C disease, the incidence of positive tumor showed a tendency to decrease with the extended duration of endocrine treatment with a rate of 37.5% after 3 months and 16.7% after 6 months. Whether the decreased incidence of positive surgical margins will all translate into prolonged survival remains to be verified by long-term follow-up of these patients. However, the initial results obtained in the present study are very encouraging.

Topics: Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Combined Modality Therapy; Flutamide; Goserelin; Humans; Leuprolide; Male; Middle Aged; Preoperative Care; Prostatectomy; Prostatic Neoplasms

In a recent intergroup study under the auspices of the National Cancer Institute, 603 eligible patients with newly diagnosed disseminated adenocarcinoma of the prostate were prospectively randomized in a double-blinded clinical trial to receive either a gonadotropin-releasing hormone analogue (leuprolide) and a nonsteroidal antiandrogen (flutamide) or leuprolide and placebo. Of the 603 eligible patients, 300 were in the leuprolide and placebo arm and 303 were in the leuprolide and flutamide arm. At the time of disease progression, the code was broken: Those patients in the placebo arm were given the opportunity to receive flutamide, and the patients in the flutamide arm were treated at their physician's discretion. There was no survival time distribution difference, based on survival measured from the progression data, between the patients who were received flutamide after progression and those who were treated at their physician's discretion after progression. Furthermore, the addition of flutamide to leuprolide at the time of disease progression resulted in a survival-time distribution that is similar to other treatments of hormone-refractory prostate cancer.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Flutamide; Humans; Leuprolide; Male; Neoplasm Metastasis; Prospective Studies; Prostatic Neoplasms; Regression Analysis; Survival Rate

Maximal androgen blockade may improve the effectiveness of treatment of prostate cancer. To test this hypothesis we conducted a randomized, double-blind trial in patients with disseminated and previously untreated prostate cancer (stage D2). All patients (n = 603) received leuprolide, 1 mg/day s.c. in combination with either placebo (n = 300) or flutamide 250 mg p.o. t.i.d. (n = 303). The median progression-free survival times were estimated at 14 months for the leuprolide plus placebo group and 17 months for leuprolide plus flutamide patients: median times for overall survival were 29 vs. 35 months, respectively. Patients with minimal disease and good performance status did particularly well on combination therapy. Median progression-free survival for this subgroup was 19 months for leuprolide plus placebo patients vs. 48 months for patients on combined therapy (p = 0.035) Flutamide appeared to reduce the disease flare associated with leuprolide monotherapy. Combined androgen blockade with leuprolide and flutamide is superior to leuprolide treatment alone in patients with disseminated prostate cancer.

Topics: Adult; Aged; Aged, 80 and over; Double-Blind Method; Drug Therapy, Combination; Flutamide; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Survival Rate

To determine the efficacy of recombinant human leukocyte alpha-interferon (IFL-RA) in advanced hormone-refractory prostate cancer, the authors treated 40 patients with IFL-RA administered intramuscularly at a dose of 10 x 10(6) U/m2 three times weekly. Toxicity was substantial and necessitated at least a 50% dose reduction in all but five patients during the first 1-2 months of therapy. No responses were observed in patients with bone metastases, but complete and partial regression of nodal disease were observed in two patients with extraosseous disease (overall response rate, 5%; 95% confidence interval, 0.64-17.75%). The authors conclude that IFL-RA cannot be recommended at this dose and schedule in patients with advanced prostate cancer, but additional study of its use in patients with nodal disease may be warranted.

Topics: Adenocarcinoma; Aged; Clinical Protocols; Humans; Interferon-alpha; Leuprolide; Lymphatic Metastasis; Male; Middle Aged; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Recombinant Proteins; Remission Induction

When present at diagnosis or when developing in the course of disease, the presence of bone metastases from prostate cancer is generally considered an indication to begin endocrine therapy, as this is clearly the most effective form of treatment for this problem. Endocrine therapy can stop progression of prostate cancer in 80-85% of cases. Endocrine therapy can relieve pain, prevent pathologic fractures, and prevent neurologic complications from bone metastases from prostate cancer. Rarely, bone scans may become normal after the start of endocrine therapy, but partial improvement or stabilization of bone scans are more commonly seen. While endocrine therapy has been the first line of treatment of metastatic prostate cancer for the past 50 years, the recent development of newer forms of endocrine therapy have increased the options in the past few years. In addition to orchiectomy and estrogens, newer alternatives include inhibitors of androgen synthesis, the class of agents termed "antiandrogens", and luteinizing hormone releasing-hormone (LHRH) analogues either alone or in combination. Orchiectomy causes a prompt fall in serum testosterone and is regarded by many as the "standard" form of endocrine therapy, but there is concern about the psychologic impact of surgery. Estrogens are being used less frequently today because of their real or potential side-effects, including cardiovascular and thromboembolic complications. The development of analogues of LHRH has resulted in another major choice for endocrine therapy, and one which is therapeutically equivalent to orchiectomy or estrogens. Since LHRH analogues may cause an early rise or "flare" in serum testosterone before it drops to castrate level, these agents should not be given alone to patients with severe pain or neurologic problems. The newly available antiandrogen flutamide can block the "flare", and may also improve survival when used with LHRH analogues or orchiectomy, especially when disease is less advanced. Not all studies of "combination therapy" support this conclusion. However, the use of flutamide is increasing significantly in the United States. Both the LHRH analogues and flutamide are fairly safe, but they are very expensive. Their use, in combination, is likely to become a progressively more common form of initial endocrine therapy in the future. The growing application of prostate specific antigen (PSA) as a tumor marker for prostate cancer has made the difficulty in interpreting chang

Topics: Actuarial Analysis; Androgen Antagonists; Bone Neoplasms; Combined Modality Therapy; Diethylstilbestrol; Estrogens; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Humans; Ketoconazole; Leuprolide; Male; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Remission Induction; Spironolactone; Survival Rate

Prostate cancer is the most common cancer in American men today. Unfortunately, at the time of diagnosis, most men will have either regional or distant metastatic disease.. Six hundred three patients with advanced prostate cancer who could be examined were randomized in a double-blind, placebo-controlled trial to receive the luteinizing hormone-releasing hormone (LHRH) agonist leuprolide with either flutamide or placebo.. Patients receiving the combined therapy arm of leuprolide and flutamide had an increased progression-free survival time of 16.9 versus 13.8 months and a survival advantage of 35.1 versus 20.3 months. A more striking difference was found in the subset of patients receiving combination therapy who had good performance and minimal disease.. There appears to be a definite advantage of combination therapy over leuprolide alone, especially in patients with minimal disease and good performance. Another larger intergroup study using orchiectomy and flutamide versus orchiectomy and placebo is currently underway.

Topics: Double-Blind Method; Drug Therapy, Combination; Flutamide; Humans; Leuprolide; Male; Neoplasm Metastasis; Prostatic Neoplasms; Survival Rate; United States

Fifteen patients with previously untreated metastatic prostate cancer were treated on a pilot trial with a combination of maximal androgen blockade plus intermittent cytotoxic therapy after androgen priming to stimulate cell division. Androgen blockage was carried out using a gonadotropin-releasing hormone analog (leuprolide) plus a nonsteroidal antiandrogen (flutamide). Carboplatin (CBDCA) (800 mg/m2) was given intravenously every 28 days, preceded for 3 days and followed for 3 days by androgen treatment with fluoxymesterone (5 mg orally twice a day), during which time flutamide was discontinued. Three patients (20%) achieved a complete response (CR), and eight patients (53.3%) achieved a partial response (PR). Four patients (26.7%) had stable disease (SD). The median progression-free survival (PFS) time was 31 months. Nine of 15 patients (60%) remain alive with a median follow-up time of 42+ months (range, 22 to 54 months). Grade 4 thrombocytopenia and Grades 3 or 4 leukopenia were experienced in 87% and 80% of patients, respectively, requiring dose reductions of CBDCA in 85% of the cycles. Six of 15 patients experienced a flare in bone pain with androgen priming. There were no associated spinal cord compressions; however, exclusion of impending spinal cord compression was required before entrance on study.

Topics: Adenocarcinoma; Aged; Androgens; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Drug Evaluation; Fluoxymesterone; Flutamide; Humans; Leuprolide; Male; Middle Aged; Neoplasms, Hormone-Dependent; Pilot Projects; Prostatic Neoplasms; Remission Induction; Survival Analysis

Topics: Aged; Antineoplastic Agents; Delayed-Action Preparations; Drug Administration Schedule; Follow-Up Studies; Humans; Injections, Subcutaneous; Leuprolide; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Survival Rate

A randomized controlled phase III clinical trial comparing TAP-144-SR (TAP) and diethylstilbestrol diphosphate was conducted for patients with prostatic cancer. Patients with Stage B, C, or D disease, who were previously untreated, were enrolled. TAP-144-SR 3.75 mg was administered subcutaneously at 4-week intervals for 12 weeks (a total of 3 injections) in the TAP-144-SR group, while 100 mg of diethylstilbestrol diphosphate was administered orally three times a day (before meals) for 12 weeks in the control group. A total of 141 patients were enrolled using a centralized telephone registration system. Four of these patients were ineligible, and there were 3 drop-outs who never received drugs because they withdrew their consents to participate in the trial. These 7 were excluded from the evaluation, and as a result, 134 patients (66 in the TAP group and 68 in the control group) were evaluable in safety and efficacy. Between the two groups, there were no significant differences in patient characteristics, except the age distribution. Clinical response rates (CR+PR) in evaluable patients according to the criteria of Japanese Prostatic Cancer Study Group were 54.5% in the TAP group and 47.1% in the control group. In addition, the rates according to the criteria for Evaluating the Direct Response to Chemotherapy in Solid Carcinomas and NPCP criteria were 7.6% in the TAP group and 8.8% in the control group and 18.2% in the TAP group and 20.6% in the control group, respectively. Using any of the three criteria, there were no significant differences in response rate between the two groups. The incidence of side effects was 64.1% in the TAP group and 95.4% in the control group; the incidence being significantly higher in the control group (p less than 0.001; chi 2-test). Therefore, the overall safety was significantly greater in the TAP group than in the control group (p less than 0.001; chi 2-test). On the basis of the efficacy and safety the clinical usefulness rate of TAP-144-SR was significantly higher than that of diethylstilbestrol diphosphate (p = 0.038; U-test). In conclusion, TAP-144-SR was confirmed to be more useful than diethylstilbestrol diphosphate as a standard drug for hormonal therapy of prostatic cancer.

Topics: Aged; Aged, 80 and over; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Prostatic Neoplasms

A study carried out in 470 patients with metastasized adenocarcinoma of the prostate confirmed the efficacy of 3.75 mg leuprorelin acetate depot given subcutaneously once monthly. Bone pain was rapidly decreased and the general condition of patients and urinary signs improved. Sexual activity was maintained in 50% of patients. After 3 months' treatment, there was no progression in 95% of patients, complete regression in 39% and partial regression in 49%; 17% of cases were stabilized. Improvement in clinical signs was directly related to a decline in amounts of prostate-specific antigen and was associated with a decline in serum testosterone concentrations within 3-4 weeks of starting treatment. Leuprorelin acetate depot was well tolerated and was easy to store and use.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antigens, Neoplasm; Antineoplastic Agents; Bone Neoplasms; Clinical Trials as Topic; Delayed-Action Preparations; France; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Lymphatic Metastasis; Male; Middle Aged; Multicenter Studies as Topic; Prostate-Specific Antigen; Prostatic Neoplasms; Sexual Behavior

In a phase III, open, multicenter study we evaluated the safety and efficacy of the depot formulation of leuprolide (7.5 mg. injected intramuscularly every 4 weeks) in patients with stage D2 prostate cancer who had not previously received systemic treatment. Serum testosterone, luteinizing hormone and plasma leuprolide levels were monitored during the 24-week study period. Median interval to onset of castrate testosterone levels was 21 days and mean testosterone levels decreased to within the castrate range by week 3 of treatment. After onset of castrate levels there were no escapes (defined as 2 consecutive values of greater than 50 ng./dl.) of testosterone levels during the 24 weeks. Suppression of testosterone did not differ significantly from that observed in patients receiving the daily subcutaneous injection of leuprolide acetate in the first 24 weeks of another study. Objective response (no progression) to treatment occurred in 81% of 53 evaluable patients and adverse (related and unrelated) events were reported in 45 of the 56 patients. The response rate and incidence of adverse events in this study did not differ significantly from those occurring with the daily formulation. We conclude that the depot formulation of leuprolide is safe and effective in the treatment of advanced prostatic cancer, and that the safety and efficacy of this formulation do not differ significantly from those of the daily subcutaneous formulation.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Clinical Trials as Topic; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Humans; Injections, Intramuscular; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Multicenter Studies as Topic; Prospective Studies; Prostatic Neoplasms; Testosterone

In an on-going, non-comparative, open, multicentre phase III study in Germany, 190 patients with advanced prostatic cancer were treated with 3.75 or 7.5 mg leuprorelin acetate depot given subcutaneously or intramuscularly once monthly, with or without concomitant antiandrogen or cytostatic therapy. The two doses and the different routes of administration did not have any significant effects on serum testosterone, dihydrotestosterone, follicle stimulating hormone and luteinizing hormone concentrations, tumour activity or clinical tolerance. Using either dose, the 'no progression' rate (complete remission plus partial remission plus stable disease) was 88.5% overall and was 88.2% in T1-T2 disease and 82.5% in T3-T4 disease after 12 months' treatment. It is concluded that the depot formulation of leuprorelin acetate offers an important alternative in the treatment of advanced prostatic cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Clinical Trials as Topic; Delayed-Action Preparations; Dihydrotestosterone; Dose-Response Relationship, Drug; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Injections, Intramuscular; Injections, Subcutaneous; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Prostatic Neoplasms; Testosterone

The therapeutic efficacy and safety of various doses of leuprorelin acetate depot were determined in an open, multicentre study of patients with locally advanced or metastatic prostatic cancer (stages C, D1 or D2). Patients were randomly assigned to receive 3.75 mg (30 cases), 7.5 mg (eight cases), 15 mg (eight cases) and 30 mg (one patient) leuprorelin acetate depot administered subcutaneously once every 4 weeks. Of the 43 patients evaluable, two (5%) had complete remission, 23 (53%) partial remission and 13 (30%) patients stable disease. No significant differences were observed in response rates in relation to dose, disease stage or previous hormonal therapy. Disappearance or improvement in bone pain and urinary symptoms occurred in 63% and 79% of cases, respectively. Serum androgen concentrations decreased rapidly and persistently to castration levels, without significant differences for different doses. Treatment was well tolerated with a low incidence of mild side-effects - gynaecomastia (16%), nausea/vomiting (13%) and diarrhoea (2%). It is concluded that 3.75 mg leuprorelin acetate depot given subcutaneously once every 4 weeks is able to produce hormonal effects in all patients, an overall objective response comparable to that obtained using higher doses.

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Antineoplastic Agents; Delayed-Action Preparations; Dose-Response Relationship, Drug; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Multicenter Studies as Topic; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Testosterone

In a large multicentre trial, 1 mg/day leuprorelin given subcutaneously was as effective as diethylstilboestrol in the treatment of prostatic cancer but with a lower incidence of side-effects, although leuprorelin could induce tumour flare-up. Total androgen ablation using a combination of leuprorelin and the non-steroidal anti-androgen flutamide in the treatment of prostatic cancer was more effective than either orchidectomy or diethylstilboestrol. The efficacy of 1 mg/day leuprorelin given subcutaneously plus 250 mg flutamide three times a day compared with leuprorelin plus placebo was confirmed in a randomized, double-blind study of 603 patients. Progression-free and overall survival were prolonged, and tumour flare-up and other side-effects were reduced in patients with untreated advanced prostatic cancer and in those with minimal disease.

Topics: Anilides; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Flutamide; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Multicenter Studies as Topic; Prostatic Neoplasms; Randomized Controlled Trials as Topic; United States

A total of 21 patients with advanced prostatic cancer and one patient with benign prostatic hypertrophy received 3.75, 7.5 or 15 mg leuprorelin acetate depot subcutaneously. Serum leuprorelin concentrations increased immediately after injection, reaching a peak concentration (range 13.1-54.5 ng/ml), which was directly proportional to dose, within 3 h. Mean drug levels subsequently declined to a plateau directly proportional to dose at 5 weeks. There was also a significant (P less than 0.01) dose-dependent increase in the area under the concentration-time curve for 0-35 days. Serum concentrations of luteinizing hormone and follicle stimulating hormone rose initially with all doses, followed by a rise in serum testosterone and dihydrotestosterone concentrations, which then fell sharply, within 3 weeks. A reduced level of follicle stimulating hormone subsequently occurred in all 20 evaluable patients and was maintained in 17 patients over 5 weeks. There was also marked initial suppression of luteinizing hormone levels in 15 patients and in 13 this continued. Castration levels of testosterone and dihydrotestosterone were maintained in all patients for up to 5 weeks. In two patients there was a complete response, in 14 a partial response and in three stable disease, with no significant differences in relation to dose. Clinical improvement and serum hormonal changes suggest that leuprorelin acetate depot is effective at a dose as low as 3.75 mg when given once every 4 weeks.

Topics: Aged; Antineoplastic Agents; Delayed-Action Preparations; Dose-Response Relationship, Drug; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Prostatic Neoplasms; Randomized Controlled Trials as Topic

A depot preparation of leuprorelin acetate was assessed in 52 patients with advanced prostatic cancer. Patients received 3.75 mg, or occasionally 7.5 mg, leuprorelin acetate depot subcutaneously every 28 +/- 3 days for up to 2 years. Following treatment, there was one complete remission and 29 partial remissions; in other patients the disease was stable and in five it was progressive, with an estimated median time to progression of 500 days. Significant improvement in performance status, micturition problems and general well-being were reported. Suppression of serum testosterone and luteinizing hormone concentrations was maximal after 28 days and castration levels were maintained for up to 96 weeks. Tumour flare occurred in 15 (29%) patients during the first week of therapy but only one event was serious; sweating and flushing also occurred occasionally during the study. Of all administrations, 97% were free from any adverse local effect, the remaining events being mild in severity. It is concluded that once-monthly administration of leuprorelin acetate depot is effective in the management of advanced prostatic cancer and has an acceptable side-effect profile.

Topics: Acid Phosphatase; Aged; Aged, 80 and over; Alkaline Phosphatase; Antineoplastic Agents; Calcium; Clinical Trials as Topic; Creatinine; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Hemoglobins; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Multicenter Studies as Topic; Prolactin; Prostatic Neoplasms; Testosterone

In a preliminary multicentre clinical trial of 3.75 mg leuprorelin acetate depot 18 previously untreated patients with metastatic prostatic cancer were treated with the depot given subcutaneously once every 4 weeks for 28 weeks. Patients also received 100 mg nilutamide taken orally three times a day for the first 14 days of treatment to prevent flare-up. Leuprorelin acetate suppressed the serum testosterone concentration to castration levels; luteinizing hormone levels were also suppressed. The incidence of progressive disease was low and partial response occurred in five patients after treatment. No side-effects were assigned to the flare-up period. It is concluded that leuprorelin acetate depot is a safe and efficacious treatment for metastatic prostatic cancer.

Topics: Aged; Antineoplastic Agents; Bone Neoplasms; Clinical Trials as Topic; Delayed-Action Preparations; France; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Multicenter Studies as Topic; Prostatic Neoplasms; Testosterone

A total of 40 patients with stages A2 to C prostatic cancer were treated with leuprorelin acetate depot once a month for 2 months before being treated by pelvic irradiation or radical prostatectomy. In the 32 patients who were evaluable, seven (22%) were classified as minor responders after leuprorelin treatment and 23 (72%) as major responders when assessed by rectal examination. Prostate-specific antigens also returned to normal concentrations (5 ng/ml) in 26/31 (84%) patients. Leuprorelin acetate depot suppressed plasma testosterone concentrations to castration values during treatment, but concentrations returned to normal 2 months after completion of treatment. Following radical treatment, there were three deaths--one postoperative and two due to recurrent disease--but there was no isolated local relapse. It is concluded that the protocol was locally well tolerated and was effective in the treatment of stages B2 and C prostatic cancer patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Clinical Trials as Topic; Combined Modality Therapy; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Prostatic Neoplasms

In a randomized, double-blind trial for metastatic prostate cancer (Stage D2), 603 men received leuprolide, a gonadotropin-releasing hormone analog that inhibits the release of gonadotropins, coupled with either placebo or flutamide, a nonsteroidal antiandrogen that inhibits the binding of androgens to the cell nucleus. The 303 men receiving androgen blockade with leuprolide and flutamide demonstrated a longer progression-free survival (16.9 vs. 13.9 months, P = 0.039) and an increased median length of survival (35.0 vs. 27.9 months, P = 0.035). In the subgroup of men with minimal disease and good performance status, the advantages of maximal androgen blockade were more pronounced. It is concluded that combined androgen blockade with leuprolide and flutamide was more effective than leuprolide alone for patients with metastatic cancer of the prostate. The therapeutic benefits, although greatest in patients with minimum disease, need to be evaluated in a prospective, randomized fashion in trials specifically designed for men with minimal disease and good performance status. Exploratory analyses using the black race as an explanatory variable were also performed. Black race is associated with shorter survival times and is also associated with other prognostic factors, including recent weight loss, anemia, elevated phosphatase levels, and pain. These findings suggest the need for future studies of the relationship of black race and response to prostate cancer therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Black People; Double-Blind Method; Flutamide; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Survival Rate

Topics: Aged; Anilides; Antineoplastic Agents; Double-Blind Method; Drug Therapy, Combination; Flutamide; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Survival Rate

In order to test the hypothesis of complete androgen blockade for advanced prostate cancer (D2CaP), an intergroup trial was instituted in 1985 comparing leuprolide (L) alone to the combination of L with flutamide (F). Eligibility requirements included previously untreated histologically confirmed stage D2CaP, measurable bone or soft tissue metastases, performance status (PS) of 3 or better, acceptable renal and hepatic function, no severe cardiac disease, and no prior or concomitant endocrine therapy. Stratification at entry was on the basis of PS and none or minimal disease (MD) versus severe degree (SD) of bone metastases. Six hundred and seventeen patients were entered into this study between March 1985 and April 1986. At the present time, there is a 3-month difference in the median progression-free survival (13.9 vs 16.9 months; P = 0.039) and a 7.1-month difference in survival (27.9 vs 35.01 months; P = 0.035) favoring L + F. In L + F-treated patients with good PS-MD, the median survival recently has been reached and is 51.9 months vs 39.6 months for L + P patients. The 107 black patients in the study had median survival of 26.4 months vs 33.3 months for whites. Discussions of racial differences in survival as well as other prognostic factors will be presented. The combination of L + F is superior to treatment with L alone. The benefits appear greatest in patients with minimal disease.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Drug Evaluation; Flutamide; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Prostatic Neoplasms; Survival Analysis; United States

The effectiveness of leuprolide (an LHRH analog), alone or in combination with flutamide (a non-steroidal antiandrogen) was tested in a double-blind multicenter study involving 603 patients with advanced prostatic cancer. The estimated median survival time was significantly longer in the patients who received combination therapy (35 months vs. 27.9 months), as was the median time to progression (16.9 months vs. 13.9 months). The beneficial effects of combination therapy were most marked in the subgroup of patients with minimal disease and good performance status. Black patients tended to have a shorter survival time than white patients. Both treatments were well tolerated. These results suggest that there are therapeutic advantages in combining medical castration using LHRH analogs with antiandrogens to suppress the actions of adrenal androgens.

Topics: Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Double-Blind Method; Flutamide; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Prostatic Neoplasms; Survival Rate

During a phase III open study of depot leuprolide for stage D2 cancer of the prostate, we studied the effect of depot leuprolide on chronic leuprolide users. To determine whether there was a transient elevation of testosterone or luteinizing hormone (LH) 4-24 h and 3-5 days following the monthly injections, we monitored the changes of testosterone and LH before injection and 24 h post-injection in 10 patients who have been under depot leuprolide Rx for 24-36 weeks, and in 35 patients before injection and 3-5 days post-injection who have received depot leuprolide for 8-24 weeks prior to monitoring. Comparison of the data between pre-injection within 24 h and 3-5 days post-injection showed no significant changes of testosterone and LH values between these levels for either testosterone (P = 0.31) or LH (P = 0.45). We therefore conclude that there was no 'acute on chronic' effect of depot formulation in chronic users of depot leuprolide.

Topics: Clinical Trials as Topic; Delayed-Action Preparations; Drug Administration Schedule; Humans; Leuprolide; Luteinizing Hormone; Male; Neoplasm Staging; Prostatic Neoplasms; Testosterone

Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Flutamide; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Neoplasm Metastasis; Prostatic Neoplasms

To test the hypothesis that maximal androgen blockade improves the effectiveness of the treatment of prostatic cancer, we conducted a randomized, double-blind trial in patients with disseminated, previously untreated prostate cancer (stage D2). All 603 men received leuprolide, an analogue of gonadotropin-releasing hormone that inhibits the release of gonadotropins, in combination with either placebo or flutamide, a nonsteroidal antiandrogen that inhibits the binding of androgens to the cell nucleus. As compared with the 300 patients receiving leuprolide and placebo, the 303 patients randomly assigned to receive leuprolide and flutamide had a longer progression-free survival (16.5 vs. 13.9 months; P = 0.039) and an increase in the median length of survival (35.6 vs. 28.3 months; P = 0.035). The differences between the treatments were particularly evident for men with minimal disease and good performance status; however, further studies should be conducted in this subgroup. Symptomatic improvement was greatest during the first 12 weeks of the combined androgen blockade, when leuprolide alone often produces a painful flare in the disease. We conclude that in patients with advanced prostate cancer, treatment with leuprolide and flutamide is superior to treatment with leuprolide alone.

Topics: Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Flutamide; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Random Allocation

Combined therapy, the treatment of advanced adenocarcinoma of the prostate by total androgen suppression, is still a controversial subject today. Some studies performed during the 1980s support the value of this therapeutic approach, while others have found it to be no more effective than surgical or chemical castration alone. Recently, the results of a randomized, controlled, multicenter intergroup study of combined therapy sponsored by the U.S. National Cancer Institute (NCI) became available. These results suggest that combined therapy offers some advantages over monotherapy in the treatment of advanced prostate cancer. A variety of drugs are available to suppress adrenal androgens. However, the value of these agents in prostate cancer therapy continues to be hotly debated.

Topics: Adenocarcinoma; Androgen Antagonists; Antineoplastic Agents; Combined Modality Therapy; Diethylstilbestrol; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Orchiectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic

The identification of the decapeptide luteinizing hormone-releasing hormone (LHRH) has led to the development of LHRH agonists, which are a new class of drugs for the treatment of advanced prostate cancer. These peptides have a modified amino acid structure that makes them more potent than LHRH. Prolonged administration of LHRH agonists results in down-regulation of the LHRH receptors in the pituitary and decreased secretion of luteinizing hormone. The result is decreased production of testosterone by Leydig cells, which is the basis for the use of LHRH agonists to treat prostate cancer. The effectiveness of LHRH agonists has been demonstrated in the United States in several randomized, controlled clinical trials. Daily administration of leuprolide produced equivalent results compared with diethylstilbestrol (DES). More recently, in two separate, randomized studies, the long-acting LHRH agonist Zoladex (ICI Pharma, Wilmington, Delaware) produced the same objective response rate as DES or bilateral orchiectomy. The equivalent response rates obtained with LHRH agonists indicate that these drugs can now be considered a reasonable treatment option for patients with metastatic prostatic cancer.

Topics: Antineoplastic Agents; Buserelin; Clinical Trials as Topic; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms

Analogs of GnRH constitute a new category of drugs available for the treatment of advanced prostatic cancer. The efficacy and safety of GnRH analogs in the treatment of this disease is now well established. These compounds represent an important alternative therapy for advanced prostatic cancer patients who do not wish to undergo orchiectomy or for whom DES is not tolerable because of the risk of cardiovascular complications. The advent of the monthly depot form of these drugs will make treatment more convenient and less invasive and will enhance patient compliance.

Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Buserelin; Clinical Trials as Topic; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms; Triptorelin Pamoate

Topics: Antineoplastic Agents; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Estramustine; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Neoplasms, Hormone-Dependent; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation

Leuprolide is the first member of the class of gonadotropin-releasing hormone (GnRH) agonist analog to be released in the U.S. The pharmacology of leuprolide is complex and not yet completely defined. This agonist analog is more potent than natural GnRH and appears to be capable of occupying pituitary GnRH receptors. This results in a "down regulation" of the receptors' activity and gonadotropin release, ultimately decreasing serum testosterone levels to those seen following castration. Leuprolide has been found effective in the palliative treatment of advanced cases of prostatic cancer and is not associated with the cardiovascular and thromboembolic toxicity seen with conventional diethylstilbestrol therapy. Leuprolide is administered by daily subcutaneous injections and has been generally well tolerated. The most common adverse effects are hot flashes and a possible flare-up of prostatic carcinoma symptoms on initial dosing. As clinical experience grows in the use of GnRH agonist analog, GnRH will assume a greater role in the treatment of metastatic prostatic cancer.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Diethylstilbestrol; Drug Administration Schedule; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Leuprolide; Male; Palliative Care; Prostatic Neoplasms; Testosterone

The introduction of potent analogues of gonadotropin hormone-releasing hormone (GnRH) into clinical practice and their use in patients with metastatic prostatic carcinoma provides an effective alternative to the exogenous administration of pharmacologic doses of estrogens or surgical castration. Their advantages over estrogens are primarily related to a lower incidence of cardiovascular toxicity and gynecomastia. Their choice over orchiectomy is based on cosmetic and psychologic factors since their endocrine effects and clinical benefits are virtually the same. In this review, we describe the current experience with GnRH analogues in the treatment of prostatic carcinoma and discuss their use in the context of other endocrine manipulations. GnRH analogues act on the pituitary and indirectly affect gonadal function, and represent an opportunity for combination with other compounds capable of suppressing or interfering with the effects of circulating and androgens. The availability of several new compounds affecting different aspects of androgen metabolism provides promise for rational drug selection and testing.

Topics: Buserelin; Clinical Trials as Topic; Diethylstilbestrol; Gonadotropin-Releasing Hormone; Gonadotropins, Pituitary; Goserelin; Humans; Leuprolide; Male; Nafarelin; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Testosterone

Randomized, prospective clinical studies have demonstrated the safety and efficacy of leuprolide, a synthetic LH-RH analog, in patients with metastatic prostatic cancer. Reliable suppression of testosterone to castrate levels is achieved, and response rates are similar to those obtained with conventional endocrine therapy. The lack of side effects associated with this drug makes it an important alternative in selected patients with prostatic cancer, particularly in those who refuse orchiectomy.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Diethylstilbestrol; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Prospective Studies; Prostatic Neoplasms; Random Allocation; Testosterone

In a randomized, prospective trial, 199 previously untreated patients with Stage D2 prostatic cancer were treated with 3 mg/day diethylstilbestrol (DES) or 1 mg/day leuprolide acetate, a luteinizing hormone releasing hormone analog. Both DES and leuprolide suppressed testosterone to the desired castrate levels. Objective measures of disease, such as acid phosphatase levels, and subjective measures, such as bone pain, performance status, and mobility, showed similar decreases in both groups. No progression of disease was seen in 86 per cent of the leuprolide-treated group, compared with 85 per cent of the DES-treated group. The time to disease progression, development of adverse reaction requiring discontinuation of treatment, or death was identical for the two groups. Hot flashes were more common with leuprolide than with DES. Gynecomastia and breast tenderness, nausea and vomiting, and peripheral edema occurred more often in the DES group. Of those taking DES, 13 per cent discontinued treatment because of side effects, compared with 3 per cent of those taking leuprolide.

Topics: Acid Phosphatase; Antineoplastic Agents; Clinical Trials as Topic; Diethylstilbestrol; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Prospective Studies; Prostatic Neoplasms; Random Allocation; Testosterone

In order to achieve a more complete blockade of androgens of both testicular and adrenal origin at the start of treatment, we have administered the pure antiandrogen Flutamide in association with orchiectomy (13 patients) or the LHRH agonist [D-Trp6]LHRH ethylamide (118 patients) to previously untreated patients with clinical stage D2 prostate cancer. The mean duration of treatment was 491 days (102-1208 days). The response was assessed according to the criteria of the U.S. National Prostatic Cancer Project. A complete response has been observed in 30 patients (23%) while partial and stable responses have been achieved in 50 (38%0 and 45 (34%) patients, respectively. A positive objective response has thus been observed in 125 of 131 patients (95%). Serum PAP became normal before 6 months in all except 8 (6.1%) of patients. Quite remarkably, 23 of 48 patients treated for 2 years (47.9%) have achieved a complete response. Of the 20 deaths, 12 (9%) were due to prostate cancer, while 8 (6%) resulted from other causes. The probability of continuing a positive response after 2 years of treatment (according to Kaplan and Meier) is 60% while the probability of survival at the same time interval is 89%. This survival should be compared to values of approx 50% achieved with previous treatments limited to inhibition of testicular androgen secretion or action. The present data demonstrate that the combined blockade of androgens achieved with Flutamide and castration provides an objective response in approx 95% of patients, and markedly prolongs the period of remission while the death rate within the first 2 years is lower than that obtained with previous treatments. The important prolongation of survival is achieved with an excellent quality of life. Two-hundred and three patients have clinical stage D2 prostate cancer previously treated by orchiectomy, estrogens or LHRH agonists alone received, at the time of relapse, the same combination therapy. Patients already castrated received only Flutamide while, for those previously treated with DES, the estrogen was replaced by the LHRH agonist [D-Trp6]LHRH ethylamide in association with Flutamide. Flutamide was given as additional medication to those already receiving an LHRH agonist alone. Complete, partial and stable objective responses assessed according to the criteria of the U.S. National Prostatic Cancer Project were obtained in 11 (5.4%), 17 (8.4%) and 38 (18.7%) patients, respectively, for a total objective respon

Topics: Androgen Antagonists; Antineoplastic Agents; Buserelin; Clinical Trials as Topic; Combined Modality Therapy; Diethylstilbestrol; Flutamide; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Neoplasm Staging; Orchiectomy; Prostatic Neoplasms; Triptorelin Pamoate

Topics: Clinical Trials as Topic; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Neoplasms, Hormone-Dependent; Palliative Care; Prostatic Neoplasms

Leuprolide is a new, potent analogue of gonadotropin-releasing hormone which, after an initial transient stimulation, causes a profound suppression of serum gonadotropins and testosterone. One hundred eighteen patients with advanced carcinoma of the prostate have undergone treatment with leuprolide in a multi-institutional trial. Minimal evidence of objective response was seen in patients who had failed prior endocrine therapy with orchiectomy or estrogens. In patients without previous hormonal treatment, leuprolide induced an objective disease response (72%) comparable to alternative primary endocrine therapy. Considering the lack of significant side effects seen with long-term GnRH agonists, compounds such as leuprolide may prove to be the preferred initial endocrine therapy for selected patients with metastatic carcinoma of the prostate.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Castration; Clinical Trials as Topic; Diethylstilbestrol; Dihydrotestosterone; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Testosterone

Topics: Aged; Antineoplastic Agents; Clinical Trials as Topic; Diethylstilbestrol; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms

In a controlled, prospective, randomized clinical trial, we evaluated the safety and efficacy of leuprolide, a superactive analog of luteinizing hormone releasing hormone, given in a single subcutaneous injection dose of 1 mg per day, versus diethylstilbestrol (DES) 3 mg per day by mouth in patients with previously untreated Stage D2 prostatic adenocarcinoma. Eleven leuprolide patients and 10 DES patients were evaluated for therapeutic response. Eighty per cent of patients in each group experienced subjective improvement in bone pain and urinary obstructive signs and symptoms. Although the pooled percentages of complete, partial, and stable objective responses were greater for the leuprolide group than the DES group, the sums of the percentages of complete and partial objective responses were comparable for both treatment groups during the first forty-eight and sixty weeks of the study, respectively. In addition, patients not responding to leuprolide generally experienced no benefit with crossover to DES, and vice versa. Serious adverse reactions were more common in the DES group and included fatal myocardial infarction, arrhythmia, deep venous thrombosis, and gynecomastia. Vasomotor flushing, disease flare, and injection site irritation occurred most often in leuprolide patients, but did not require modification or discontinuation of treatment.

Topics: Acid Phosphatase; Adenocarcinoma; Antineoplastic Agents; Clinical Trials as Topic; Diethylstilbestrol; Dihydrotestosterone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prostate; Prostatic Neoplasms; Random Allocation; Testosterone; Time Factors

Luteinizing hormone releasing hormone agonists presently are being evaluated in the treatment of patients with metastatic prostatic cancer. To determine the comparative benefits of a specific luteinizing hormone releasing hormone agonist [6-leu (1-9) luteinizing hormone releasing hormone nonapeptide ethylamide] relative to conventional estrogen therapy 23 patients with stage D2 prostatic cancer were randomized to receive either 1 mg. luteinizing hormone releasing hormone agonist daily (12) or 3 mg. diethylstilbestrol per day (11). Both agents were effective in inducing a remission in all patients, although diethylstilbestrol was slightly faster. The early phase of treatment with the luteinizing hormone releasing hormone agonist was dominated by a transient reversible deterioration (the flare) of the patient, which was believed to be related to the agonist-induced increase in serum androgens. At 1 year of followup adverse effects in both groups have been minor but the proportion of patients with progression in the luteinizing hormone releasing hormone agonist group (6 of 12) was significantly higher than that in the diethylstilbestrol group (0 of 11). Further investigation is required to determine the role of luteinizing hormone releasing hormone agonist in the treatment of patients with advanced prostatic cancer.

Topics: Aged; Antineoplastic Agents; Carcinoma; Diethylstilbestrol; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms

Metastatic prostatic cancer can be present in a variety of different ways. The authors describe the differences among stages D-0, D-1, and D-2 disease and present the treatment options for each of the substages. They summarize and integrate the clinical evidence that bears on the potential efficacy of each treatment.

Topics: Acid Phosphatase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Carcinoma; Castration; Clinical Trials as Topic; Combined Modality Therapy; Diethylstilbestrol; Estrogens; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Lymph Node Excision; Lymphatic Metastasis; Male; Neoplasm Staging; Prostatectomy; Prostatic Neoplasms; Radioisotope Teletherapy

We compared the efficacy and safety of the gonadotropin-releasing hormone analogue, leuprolide (1 mg subcutaneously daily), with diethylstilbestrol (DES, 3 mg by mouth daily) in patients with prostate cancer and distant metastases (Stage D2) who had not previously received systemic treatment. Initial therapy (leuprolide or DES) was continued for as long as an objective response was noted; cross-over to the alternative arm occurred at the time of disease progression or intolerable adverse reactions. Ninety-eight patients were randomly assigned to leuprolide, and 101 to DES. Suppression of testosterone and dihydrotestosterone and decreases in acid phosphatase were comparable in the two groups. Patients receiving DES experienced more frequent painful gynecomastia (P less than 0.00001), nausea and vomiting (P = 0.02), edema (P = 0.008), and thromboembolism (P = 0.065) than those receiving leuprolide. The leuprolide group reported more "hot flashes" (P = 0.00001). Overall, 86 per cent of the leuprolide group had an objective response (complete response, 1 per cent; partial response, 37 per cent; stable disease, 48 per cent), as compared with 85 per cent of the DES group (complete, 2 per cent; partial, 44 per cent; stable, 39 per cent). Actual survival rates at one year were 87 per cent for the leuprolide group and 78 per cent for the DES group (P = 0.17). We conclude that leuprolide offers an important alternative treatment that is therapeutically equivalent to and causes fewer side effects than DES for the initial systemic management of metastatic prostate cancer.

Topics: Acid Phosphatase; Adult; Aged; Antineoplastic Agents; Diethylstilbestrol; Drug Evaluation; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Random Allocation

Potent synthetic analogs of gonadotropin-releasing hormone produce parodoxical antireproductive effects when administered chronically. These compounds are minimally toxic and may exhibit no plateau of the dose-response curve even at very high doses. These considerations served as the basis for our systematic evaluation of [D-leucine6-desarginine-glycine-NH2(10)]gonadotropin-releasing hormone (GnRH-A) proethylamide in the very high dose range (i.e., 10-fold larger amounts than previously used). In rats given the analog for 12 wk, prostate, testis, and seminal vesicle weights were suppressed to a greater extent with 200 micrograms q.d. than with 40 micrograms q.d. (P less than 0.01 prostate, less than 0.01 testis, less than 0.01 seminal vesicles), indicating dose-response effects in the very high dose range. 200 micrograms of [D-Leu6-des-Gly-NH2(10]-GnRH-A consistently suppressed leutinizing hormone (LH) values at 6 and 12 wk (basal 71 +/- 9.5; 6 wk 34 +/- 3.8; 12 wk 28 +/- 5 ng/ml) whereas 40 micrograms suppressed LH variably (basal 33 +/- 3.8; 6 wk 17 +/- 3.9; 12 wk 32 +/- 5.2). Testosterone fell to 15 +/- 2.4 and 19 +/- 2.0 ng/100 ml in response to 200 micrograms q.d. and to 27 +/- 6.4 and 22 +/- 7.4 ng/100 ml with the 40-micrograms dose. These findings in the rodent prompted treatment of stage D prostate cancer patients with similarly high doses of [D-Leu6-des-Gly-NH2(10)]-GnRH-A. After treatment for 11 wk with 1,000 or 10,000 micrograms/d of the analog, testosterone and dihydrotestosterone levels transiently rose and then fell into the surgically castrate range (testosterone 19 +/- 4.4 ng/100 ml [D-Leu6-des-Gly-NH2(10)]-GnRH-A vs. surgically castrate 11 +/- 0.9 ng/100 ml, P = NS; dihydrotestosterone 15 +/- 1.7 ng/100 ml GnRH-A vs. surgically castrate 15 +/- 4.1 ng/100 ml. P = NS). However, unlike the chronic stimulatory effect on the pituitary at lower doses, very high dose therapy resulted in profound suppression of plasma and urine LH. Plasma levels fell to the limit of assay detectability, whereas the more sensitive urinary assay detected prepubertal levels of excretion (i.e., 64 +/- 8.4 mlU/h). The highly sensitive rat interstitial cell testosterone bioassay for LH also demonstrated a marked decline in LH to undetectable levels in 17/19 subjects. Clinical results with [D-Leu6-des-Gly-NH2(10)]-GnRH-A simulate those achieved by surgical castration in men with prostatic cancer as suggested by available preliminary data.

Topics: Adenocarcinoma; Adult; Animals; Castration; Clinical Trials as Topic; Dihydrotestosterone; Dose-Response Relationship, Drug; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Hypothalamo-Hypophyseal System; Leuprolide; Luteinizing Hormone; Male; Prostatic Neoplasms; Rats; Testis; Testosterone

GnRH agonists and GnRH antagonists are two of the mainstays of hormonal therapy (HT) for prostate cancer (PCa). These drugs are at increased risk of cardiovascular (CV) adverse events (AEs). Aim of our study was to compare real-life data on AEs associated with GnRH agonists and GnRH antagonists based on Eudra-Vigilance (EV) and Food and Drug Administration (FDA) reported AEs.. EV and FDA databases were queried and the number of CV adverse events (AEs) for degarelix, buserelin, goserelin, leuprorelin, triptorelin until September 2021 were recorded. Specific CV AEs were recorded and data were analyzed per age and severity. pooled relative risk (PRR) was used to compare data between drugs.. CV events were reported in 315/5128 (6%) for Degarelix, in 55/628 for Buserelin (9%), in 843/12,145 (7%) for Goserelin, in 3395/71,160 (5%) for Leuprorelin and in 214/4969 (5%) for Triptorelin. In terms of specific CV disorders, Degarelix presented lower risk of hypertension (PRR 0.60 (95% CI 0.37-0.98), p = 0.04), of myocardial infarction (PRR 0.05 (95% CI 0.01-0.39), p < 0.01) and thrombosis (PRR 0.14 (0.02-1.07), p = 0.06) when compared to GnRH agonists. Overall, younger patients (<65 years) presented a very low risk of CV AEs. Side effects were classified as serious in 90-96% of the cases. Fatal AEs were 5-20% over the CV AEs and 0.2-1% over the total AEs.. Real-life data are consistent with registry studies regarding side effects related to HT. Real-life data suggest GnRH agonists are associated with higher CV AEs when compared to GnRH antagonists. Clinicians should consider these data when prescribing HT especially in patients with CV comorbidities.

Topics: Androgen Antagonists; Buserelin; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms; Triptorelin Pamoate; United States; United States Food and Drug Administration

Androgen-deprivation therapy (ADT) is the primary systemic therapy for treating advanced or metastatic prostate cancer (PCa), which has improved survival outcomes in patients with PCa. However, ADT may develop metabolic and cardiovascular adverse events that impact the quality of life and lifespan in PCa survivors. The present study was designed to establish a murine model of ADT with a gonadotropin-releasing hormone (GnRH) agonist leuprolide and to investigate its effects on metabolism and cardiac function. We also examined the potential cardioprotective role of sildenafil (inhibitor of phosphodiesterase 5) under chronic ADT. Middle-aged male C57BL/6J mice received a 12-wk subcutaneous infusion via osmotic minipumps containing either saline or 18 mg/4 wk leuprolide with or without 1.3 mg/4 wk sildenafil cotreatment. Compared with saline controls, leuprolide treatment significantly reduced prostate weight and serum testosterone levels, confirming chemical castration in these mice. The ADT-induced chemical castration was not affected by sildenafil. Leuprolide significantly increased the weight of abdominal fat after 12-wk treatment without a change in total body weight, and sildenafil did not block the proadipogenic effect of leuprolide. No signs of left ventricular systolic and diastolic dysfunction were observed throughout the leuprolide treatment period. Interestingly, leuprolide treatment significantly elevated serum levels of cardiac troponin I (cTn-I), a biomarker of cardiac injury, and sildenafil did not abolish this effect. We conclude that long-term ADT with leuprolide increases abdominal adiposity and cardiac injury biomarker without cardiac contractile dysfunction. Sildenafil did not prevent ADT-associated adverse changes.

Topics: Adiposity; Androgen Antagonists; Androgens; Animals; Gonadotropin-Releasing Hormone; Heart Diseases; Humans; Leuprolide; Male; Mice; Mice, Inbred C57BL; Prostatic Neoplasms; Quality of Life; Sildenafil Citrate

Leuprolide (LEU), a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH), could exert a direct inhibitory activity on the proliferation of prostate cancer cells. However, the short half-life in blood and the biopharmaceutical problem of LEU limit this anticancer activity.. To improve its druggability for improving anticancer activity, the amine-group targeted LEU was conjugated with different chain lengths of saturated fatty acids (FAs).. LEU-fatty acid conjugates (LFCs) were synthesized by exploiting N-hydroxysuccinimidyl (NHS) conjugation chemistry. The physicochemical properties and the self-assembled behaviors of the conjugates were extensively investigated. The in vitro anticancer activity of three LFCs was extensively studied in both 2D monolayer and 3D spheroid culture models of a prostate cancer cell line, PC3.. Three LFCs could be readily self-assembled into nanoparticles (LFNs) with a small size of around 100 nm, positive charges, and exhibited greater permeability rates compared to the same concentration of LEU, excluding LSN. The chain length of FA in conjugate was positively related to the selectivity index between cancer cells and non-cancerous cell lines. All LFCs showed a superior direct antiproliferative effect on cancer cells in the following order: LSC (98.9%) > LPC (86.7%) > LLC (75.0%) > LEU (8.9%) after repeat daily of the same dose strength of LEU for 4 days. In addition, the 3D spheroid model study indicates that all LFCs with a one-time treatment performed a long-acting inhibitory effect on tumor growth as compared to LEU after 7 days.. The conjugation of LEU with different chain lengths of FAs could provide a novel strategy to improve peptide stability and exert an additional superior direct inhibitory effect for the treatment of several hormone-responsive tumor systems using therapeutic peptides.

Topics: Biological Products; Cell Line, Tumor; Fatty Acids; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms

In this paper we present a new version of a mathematical model of Elishmereni et al. describing androgen deprivation therapy (ADT) for hormone sensitive prostate cancer patients (HSPC). We first focus on the detail description of the model, and then we present mathematical analysis of the proposed model, starting from the simplified model without resistance and ending on the full model with two resistance mechanisms present. We make a step towards personalization proposing an underlying tumor growth law base on a cohort of patients from Mayo hospital. We conclude that the model is able to reflect reality, that is in clinical scenarios the level of testosterone in HSPC patients inevitably rises leading to the failure of ADT.

Topics: Algorithms; Antineoplastic Agents, Hormonal; Cohort Studies; Humans; Leuprolide; Male; Models, Theoretical; Prostatic Neoplasms; Testosterone; Treatment Outcome

Androgen deprivation therapy remains the essential treatment for disseminated prostate cancer. Interstitial pneumonitis following this therapy has been documented for just a few cases. However, reported cases frequently describe the onset of symptoms after recent administration (days or a few weeks) of both GnRH analogues and androgen antagonists, which makes the precise individual impact of each treatment difficult to estimate.. This report presents a case of a 94-year-old patient with interstitial pneumonitis whose onset started three months after the first dose of leuprorelin and bicalutamide for a metastatic prostate cancer.. Once other possible diagnosis were ruled out, empiric corticosteroid treatment was initiated within 48 h of the admission. A spectacular clinical and radiological improvement was observed after 3 doses of steroids, enabling the patient to recover his basal respiratory situation. We considered that the most probable cause was toxic interstitial pneumonitis induced by leuprorelin.. To our knowledge, it describes the longest interval between last administration of antiandrogen therapy and the development of pneumonitis. This fact may support a direct relation with leuprorelin, whose serum levels remain high for months because of its long-acting depot formulation.

Topics: Acetates; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Lung Diseases, Interstitial; Male; Prostatic Neoplasms

Pituitary apoplexy (PA) is a clinical condition characterised by a sudden increase in pituitary gland volume secondary to ischaemia and/or necrosis. Most cases occur in non-functioning pituitary adenoma but can also occur in functioning adenoma. Certain predisposing factors can result in PA and the use of gonadotropin-releasing hormone (GnRH) agonists for prostate cancer (PCa) is one such condition. Once diagnosed, both surgical and conservative management has been used for the treatment of PA. We present a case of a man in his late 50s who developed PA following treatment of PCa with leuprolide. His symptoms developed insidiously and he presented 6 months after symptom onset. Anterior pituitary hormone workup along with pituitary MRI confirmed the diagnosis of PA and patient was subsequently treated with adequate replacement of pituitary hormone with significant improvement in his symptoms. It is very important to keep a high index of suspicion for PA, especially among elderly patients receiving GnRH agonist treatment for PCa.

Topics: Aged; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Pituitary Apoplexy; Pituitary Neoplasms; Prostatic Neoplasms

Topics: Cardiovascular System; Humans; Leuprolide; Male; Oligopeptides; Prostatic Neoplasms

Androgen-deprivation therapy (ADT) is the main therapy for patients with advanced and metastatic prostate cancer (PCa) and, in combination with radiotherapy, for patients with localized high-risk PCa. Due to its favorable tolerability among different treatments available for ADT, leuprorelin acetate is well established as the leading luteinizing hormone-releasing hormone (LHRH) analog. The development of second-generation leuprorelin acetate (LA) depot formulation (Eligard®, Recordati S.p.A) allowed a consistent and controlled release of leuprorelin between injections and a more efficient reduction of testosterone levels with respect to conventional LHRH agonists.. This work provides a summary of the biological and clinical rationale for using LA to manage PCa and presents the current evidence about the therapeutic activity of the LA gel depot formulation, used as an advanced leuprorelin acetate delivery method.. Results of the registration studies and post-marketing clinical trials demonstrate that the LA gel depot provides long-term efficacy in the clinical practice and a good degree of tolerability. Overall, collected data suggest that the LA gel depot can represent the ADT reference therapy in advanced PCa.

Topics: Acetates; Androgen Antagonists; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Prostatic Neoplasms

To explore the cost-effectiveness of degarelix acetate for injection (degarelix) compared to leuprorelin in prostate cancer (Pca) castration treatment from Chinese healthcare system perspective.. A Markov model, adapted from the one established in Finland was conducted for the cost-effectiveness analysis of degarelix and leuprorelin for Pca treatment. The main data were derived from global phase III clinical trials of degarelix (CS21), published study and expert surveys. Outcomes, utility and costs of prostate cancer patients were calculated on a 30-year time horizon. The CS21 study based population of intention-to-treat (ITT) population and three scenarios were modeled. Taking three times of the Gross domestic product (GDP) per capita (242,928 yuan, 2021) as the acceptable threshold for cost-effectiveness. One-way and probabilistic sensitivity analyses were performed on key parameters, including transition probabilities, costs, utility, and discount rate to test the robustness of the model.. Base case analysis for ITT population revealed that total costs of degarelix and leuprorelin were 566,226 yuan and 489,693 yuan, while the total quality-adjusted life years (QALYs) were 5.19 and 4.51 during the 30-year time horizon, resulting an incremental cost effectiveness ratio (ICER) of 112,674 yuan/QALY which was 1.39 times the GDP per capita, lower than willingness-to-pay level of three times the GDP per capita. The results for scenario analyses revealed that compared to leuprorelin, degarelix for Pca treatment in China was cost-effective. One-way sensitivity analysis showed that the model was most sensitive to price of 80 mg degarelix, utility of 1st-line therapy, hazard ratio of PSA recurrence, price of 3.75 mg leuprorelin, response rate of docetaxel per cycle, and discount rate of cost. In probabilistic sensitivity analysis, compared to leuprorelin, the probability of degarelix to be cost-effective was 53 and 81% for willingness-to-pay threshold of one and three times the GDP per capita.. Compared to leuprorelin, degarelix for prostate cancer treatment is cost-effective. Moreover, scenario, one-way, and probabilistic sensitivity analyses revealed that the model was robust.

Topics: China; Clinical Trials, Phase III as Topic; Cost-Benefit Analysis; Humans; Leuprolide; Male; Oligopeptides; Prostatic Neoplasms

Leuprolide is a synthetic nonapeptide drug (pyroGlu-His-Trp-Ser-Tyr-d-Leu-Leu-Arg-Pro-NHEt) that acts as a gonadotropin-releasing hormone agonist. The continuous administration of therapeutic doses of leuprolide inhibits gonadotropin secretion, which is used in androgen-deprivation therapy for the treatment of advanced prostate cancer, central precocious puberty, endometriosis, uterine fibroids, and other sex-hormone-related conditions. To improve the pharmacokinetic properties of peptide drugs, a fatty acid was conjugated with leuprolide for long-term action. In this study, we developed a simple ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of leuprolide and leuprolide-oleic acid conjugate (LOC) levels. The developed method was validated in terms of linearity, precision, accuracy, recovery, matrix effect, and stability according to the US Food and Drug Administration guidelines, and the parameters were within acceptable limits. Subsequently, the pharmacokinetics of leuprolide and LOCs were evaluated. In vivo rat subcutaneous studies revealed that conjugation with fatty acids significantly altered the pharmacokinetics of leuprolide. After the subcutaneous administration of fatty-acid-conjugated leuprolide, the mean absorption time and half-life were prolonged. To the best of our knowledge, this is the first study showing the effects of fatty acid conjugates on the pharmacokinetics of leuprolide using a newly developed UPLC-MS/MS method for the simultaneous quantification of leuprolide and LOCs.

Topics: Androgen Antagonists; Animals; Chromatography, High Pressure Liquid; Chromatography, Liquid; Fatty Acids; Female; Humans; Leuprolide; Male; Prostatic Neoplasms; Rats; Tandem Mass Spectrometry

GnRH analogs are widely used as neoadjuvant agents for radiotherapy in prostate cancer (PCa) patients, with well-documented effects in reducing tumor bulk and increasing progression-free survival. GnRH analogs act locally in the prostate by triggering apoptosis of PCa cells via activation of the GnRH receptor (GnRHR). During PCa progression, the distribution of GnRHR within the cell is altered, with reduced expression in the cell membrane and remaining sequestered in the endoplasmic reticulum. Pharmacoperone IN3 is able to relocalize GnRHR to the cell membrane. The aim of this study was to evaluate the effect of radiation on PCa cells pretreated with leuprolide, alone or in combination with IN3, as radiosensitizers.. PC3 and human PCa primary cell cultures were treated with IN3 for 24 h, followed by different doses of leuprolide for 48 h and, finally, single doses of radiation (3, 6, and 9 Gy). After radiation, cell survival, apoptosis, cell cycle distribution, and colony growth were evaluated.. Radiation reduced cell survival and increased apoptosis in a dose-dependent manner. This effect was also directly related to leuprolide concentration. Pretreatment with IN3 enhanced apoptosis and decreased cell survival, also observing a higher proportion of cells arrested in G2.. Neoadjuvant leuprolide increases radiation-mediated apoptosis of PCa cells. This effect was enhanced by pretreatment with pharmacoperone IN3. Clinical use of IN3 as a radiosensitizer combined with androgen deprivation therapy to improve survival of patients with PCa remains to be evaluated.

Topics: Androgen Antagonists; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostate; Prostatic Neoplasms; Radiation-Sensitizing Agents; Receptors, LHRH

With a growing interest in the use of real-world evidence for regulatory decision-making, it is important to understand whether real-world data can be used to emulate the results of randomized clinical trials.. To use electronic health record and administrative claims data to emulate the ongoing PRONOUNCE trial (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease).. This retrospective, propensity-matched cohort study included adult men with a diagnosis of prostate cancer and cardiovascular disease who initiated either degarelix or leuprolide between December 24, 2008, and June 30, 2019. Participants were commercially insured individuals and Medicare Advantage beneficiaries included in a large US administrative claims database.. Degarelix or leuprolide.. The primary end point was time to first occurrence of a major adverse cardiovascular event (MACE), defined as death due to any cause, myocardial infarction, or stroke, analogous to the PRONOUNCE trial. Secondary end points were time to death due to any cause, myocardial infarction, stroke, and angina. Cox proportional hazards regression was used to evaluate primary and secondary end points.. A total of 32 172 men initiated degarelix or leuprolide for prostate cancer; of them, 9490 (29.5%) had cardiovascular disease, and 7800 (24.2%) met the PRONOUNCE trial eligibility criteria and were included in this study. Overall, 165 participants (2.1%) were Asian, 1390 (17.8%) were Black, 663 (8.5%) were Hispanic, and 5258 (67.4%) were White. The mean (SD) age was 74.4 (7.4) years. Among 2226 propensity score-matched patients, no significant difference was observed in the risk of MACE for patients taking degarelix vs those taking leuprolide (10.18 vs 8.60 events per 100 person-years; hazard ratio [HR], 1.18; 95% CI, 0.86-1.61). Degarelix was associated with a higher risk of death from any cause (HR, 1.48; 95% CI, 1.01-2.18) but not of myocardial infarction (HR, 1.16; 95% CI, 0.60-2.25), stroke (HR, 0.92; 95% CI, 0.45-1.85), or angina (HR, 1.36; 95% CI, 0.43-4.27).. In this emulation of a clinical trial of men with cardiovascular disease undergoing treatment for prostate cancer, degarelix was not associated with a lower risk of cardiovascular events than leuprolide. Comparison of these data with PRONOUNCE trial results, when published, will help enhance our understanding of the appropriate role of using real-world data to emulate clinical trials.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Cohort Studies; Humans; Leuprolide; Male; Oligopeptides; Prostatic Neoplasms; Treatment Outcome; United States

Topics: Humans; Leuprolide; Male; Oligopeptides; Prostatic Neoplasms

Neoadjuvant androgen ablation (neoadjuvant androgen deprivation therapy [NADT]) is used prior to radical prostatectomy, contrary to guidelines, but its long-term effects on quality of life is unknown.. To determine the effect of NADT on patient's long-term recovery following surgery.. From March 2011 to August 2013, 5808 men with newly diagnosed prostate were followed up to 24 mo. A cohort of men who received NADT prior to robotic-assisted laparoscopic prostatectomy (RALP; n=51) was compared 1:3 with a matched group that underwent RALP only (n=153).. Patients were matched on Charlson comorbidities, biopsy Gleason score, and node status on final pathology. The Kruskall-Wallis test was used to compare the groups on their bowel, urinary, sexual, and hormonal domains of the 26-item Expanded Prostate Cancer Index Composite at baseline and at 1, 3, 6, 12, 18, and 24 mo postoperatively.. The urinary irritative, urinary incontinence, and bowel domains were similar in the two groups during the 24 mo (p=0.832, 0.901, and 0.732, respectively). In the hormonal domain, the NADT group did worse (p<0.001). The sexual domain was also worse for the NADT group. However, when accounting for nerve sparing, there was no significant difference in sexual outcomes between the two groups (p=0.069).. Patients who received NADT prior to RALP do not have worse sexual function, but have worse hormonal scores for up to 2yr after surgery.. Neoadjuvant androgen deprivation therapy (NADT) is administered prior to robotic-assisted laparoscopic prostatectomy (RALP), contrary to clinical guidelines. NADT may not have worse sexual function outcomes up to 2yr after RALP.

Topics: Androgen Antagonists; Androgens; Humans; Leuprolide; Male; Neoadjuvant Therapy; Prostate; Prostatectomy; Prostatic Neoplasms; Quality of Life; Urinary Incontinence

Topics: Choroidal Effusions; Humans; Leuprolide; Male; Prostatic Neoplasms

Nonadherence to dosing schedules for androgen deprivation therapy increases the risk of testosterone escape for patients with prostate cancer. Two approved formulations of leuprolide acetate, the most commonly prescribed androgen deprivation therapy in the United States, use different extended release delivery technologies: an in situ gel and microspheres. We evaluated the prevalence and impact of late dosing on testosterone suppression for gel and microsphere formulations of leuprolide acetate.. We retrospectively analyzed records of patients with prostate cancer treated with gel or microsphere delivery of leuprolide acetate. Analyses used 2 definitions of "month," "28-day" (late dosing after day 28, 84, 112 or 168) and "extended" (late dosing after day 32, 97, 128 and 194). Frequencies of late dosing and associated testosterone values were calculated.. A total of 2,038 patients received gel and 8,360 received microsphere formulations of leuprolide acetate. More than 80% and 27% of injections were late for 28-day and extended month, respectively. For 28-day month late injections 10% (gel delivery) and 14% (microsphere delivery) of testosterone values were above 50 ng/dl, and 25% (gel) vs 33% (microsphere) were above 20 ng/dl. For extended month 18% (gel) vs 25% (microsphere) were above 50 ng/dl, and 34% (gel) vs 44% (microsphere) were above 20 ng/dl. Microsphere leuprolide acetate was 1.5 times more likely to have testosterone above 50/20 ng/dl vs gel. Least square mean testosterone was 34 ng/dl (gel) vs 46 ng/dl (microsphere) for 28-day month, and 48 ng/dl (gel) vs 76 ng/dl (microsphere) for extended month.. Leuprolide acetate therapies were frequently administered late. Gel formulation demonstrated higher rates of testosterone 50 ng/dl or less and 20 ng/dl or less than microsphere formulation. Optimal testosterone suppression can impact prostate cancer progression and patient survival, and differences in extended release technology for androgen deprivation therapy appear relevant.

Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Gels; Humans; Leuprolide; Male; Microspheres; Middle Aged; Prostatic Neoplasms; Retrospective Studies; Testosterone; Time Factors; United States; Young Adult

A 55-year old man with a history of meningioma treated with LHRH-agonist plus radiotherapy for prostate cancer (PCa) experienced a meningioma growth during hormone therapy (HT). Meningioma was radically resected revealing an atypical meningioma and HT was continued due to the high risk of PCa relapse until symptomatic meningioma relapse occurred after further 10 months. Gross lesions were radically removed and histology revealed anaplastic meningioma. This is the first case of rapid meningioma evolution to an anaplastic histology during LHRH-agonist.

Topics: Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Neoplasm Recurrence, Local; Prostatic Neoplasms

To perform a propensity-score matched analysis comparing stereotactic body radiation therapy (SBRT) boost and high-dose-rate (HDR) boost for localized prostate cancer.. A single-institution retrospective chart review was conducted of men treated with pelvic external beam radiation therapy (EBRT) and SBRT boost (21 Gy and 19 Gy in 2 fractions) to the prostate for prostate cancer. A cohort treated at the same institution with HDR brachytherapy boost (19 Gy in 2 fractions) was compared. Propensity-score (PS) matching and multivariable Cox regression were used for analysis. Outcomes were biochemical recurrence freedom (BCRF) and metastasis freedom (MF).. One hundred thirty-one men were treated with SBRT boost and 101 with HDR boost with median follow-up of 73.4 and 186.0 months, respectively. In addition, 68.8% of men had high-risk and 26.0% had unfavorable-intermediate disease, and 94.3% received androgen deprivation therapy. Five- and 10-year unadjusted BCRF was 88.8% and 85.3% for SBRT and 91.8% and 74.6% for HDR boost (log-rank P = .3), and 5- and 10-year unadjusted MF was 91.7% and 84.3% for SBRT and 95.8% and 82.0% for HDR (log-rank P = .8). After adjusting for covariates, there was no statistically significant difference in BCRF (hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.37-1.79; P = .6) or MF (HR 1.07; 95% CI, 0.44-2.57; P = .9) between SBRT and HDR boost. Similarly, after PS matching, there was no statistically significant difference between SBRT and HDR (BCRF: HR 0.66, 0.27-1.62, P = .4; MF: HR 0.84, 0.31-2.26, P = .7). Grade 3+ genitourinary and gastrointestinal toxicity in the SBRT cohort were 4.6% and 1.5%, and 3.0% and 0.0% in the HDR cohorts (P = .4, Fisher exact test).. SBRT boost plus pelvic EBRT for prostate cancer resulted in similar BCRF and MF to HDR boost in this single institution, PS matched retrospective analysis. Toxicity was modest. Prospective evaluation of SBRT boost for the treatment of unfavorable-intermediate and high-risk prostate cancer is warranted.

Topics: Aged; Androgen Antagonists; Anilides; Brachytherapy; Cohort Studies; Combined Modality Therapy; Confidence Intervals; Dose Fractionation, Radiation; Humans; Leuprolide; Male; Middle Aged; Nitriles; Propensity Score; Prostate-Specific Antigen; Prostatic Neoplasms; Radiosurgery; Radiotherapy, Intensity-Modulated; Regression Analysis; Retrospective Studies; Tosyl Compounds

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Drug Industry; Female; Humans; Japan; Leuprolide; Male; Prostatic Neoplasms

Long-term androgen deprivation therapy has been associated with decreased bone mineral density in men with prostate cancer. Some evidence suggests that there is no impact on fracture risk despite this bone mineral density loss. Our study aimed to quantify changes in bone mineral density in men with high risk prostate cancer on long-term androgen deprivation therapy and calcium and vitamin D supplementation.. Bone mineral density analysis was conducted for localized high risk prostate cancer patients enrolled in the phase III randomized trial PCS-V (Prostate Cancer Study 5), comparing conventional and hypofractionated radiation therapy. Patients received 28 months of luteinizing hormone-releasing hormone agonist and calcium and vitamin D supplementation (500 mg calcium BID+400 IU vitamin D3 BID). The areal density and T-scores (spine, femoral neck and total femur) at baseline and 30 months of followup were extracted, and the absolute change was calculated. Clinical bone density status (normal, osteopenia, osteoporosis) was monitored.. The lumbar spine, femoral neck and total femoral bone mineral density were measured for 226, 231, and 173 patients, respectively. The mean percent change in bone mineral density was -2.65%, -2.76% and -4.27% for these respective sites (p <0.001 for all). The average decrease in bone mineral density across all sites was -3.2%, with no decline in bone mineral density category in most patients (83%). Eight patients (4%) became osteoporotic.. Despite a mild decline in bone mineral density, the change in clinical bone mineral density category remained low with long-term androgen deprivation therapy. Consequently, calcium and vitamin D supplementation alone may suffice for most localized prostate cancer patients on long-term androgen deprivation therapy.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Bone Density; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Nitriles; Prospective Studies; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Time Factors; Tosyl Compounds

Observational studies generate information on real-world therapy and complement data from prospective randomized trials. LEAN is an open-label, non-interventional, multi-centre, German cohort study on leuprorelin in routine clinical practice.. To extend knowledge on the use, effectiveness, and tolerability of HEXAL/Sandoz leuprorelin (in this article, the term Leuprone® HEXAL® covers Leuprorelin Sandoz® as well) solid implant in patients with prostate cancer (PCa) in a real-world setting.. 959 PCa patients scheduled for androgen deprivation therapy (ADT) received leuprorelin acetate implant. Metabolism, serum prostate-specific antigen (PSA), and testosterone data, if available, were collected at baseline and follow-up visits for ≥12 months.. Of 694 patients in the modified full analysis set, 26.4% received GnRH analogues ≤6 months before enrolment. Fifty-one percent of patients were treated for locally advanced or metastatic PCa. In 19.6% of patients, ADT was used in neoadjuvant or adjuvant settings and in 28.5% with rising PSA after definite therapy. Testosterone levels <0.5 ng/mL were achieved in >90% of patients. Safety profile was in line with the summary of product characteristics. Therapy was well tolerated, with patient-triggered therapy discontinuation in 3.6%.. This interim analysis confirmed previous efficacy findings for leuprorelin implant in a real-world setting. This contemporary cohort showed a shift in the use of ADT to non-metastatic PCa stages.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Cohort Studies; Germany; Humans; Leuprolide; Male; Prostatic Neoplasms; Testosterone; Time Factors; Treatment Outcome

Topics: Aged; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Lutetium; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Radiopharmaceuticals; Treatment Outcome

We aimed to determine whether cardiovascular (CV) risk in patients with prostate cancer (PCa) differs between those who receive gonadotropin-releasing hormone (GnRH) agonist (GnRHa) therapy and those who receive GnRH antagonist therapy.. Using the Taiwan National Health Insurance Research Database, we analyzed data by comparing 666 participants receiving GnRH antagonists and 1332 propensity score-matched participants treated with GnRHa in a 1:2 fashion during the period from May 1, 2015, to September 30, 2018. Cox proportional-hazards models were used to estimate the treatment effect on CV outcomes. Furthermore, we conducted an in vitro study to investigate the effect of a GnRHa (leuprolide) or a GnRH antagonist (degarelix) on matrix metalloproteinase-9 (MMP-9) expression and invasion ability in THP-1 differentiated macrophages.. GnRH antagonist therapy was associated with a lower risk of composite CV events of myocardial infarction, ischemic stroke, or CV death (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.25-0.90) than GnRHa therapy, with a mean follow-up period of 1.21 years. Significantly lower risks of CV death (HR, 0.21; 95% CI, 0.06-0.70) and all-cause mortality (HR, 0.77; 95% CI, 0.61-0.97) were observed in the GnRH antagonist group. In the in vitro study, leuprolide, but not degarelix, significantly increased the expression of MMP-9 activity and the invasive ability of THP-1 differentiated macrophages through gelatin zymography and the matrix invasion assay, respectively.. GnRH antagonists were associated with reduced risk CV events compared with the GnRHa among patients with PCa, which may be through effects on macrophages.

Topics: Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Cohort Studies; Follow-Up Studies; Gonadotropin-Releasing Hormone; Heart Disease Risk Factors; Humans; Leuprolide; Male; Matrix Metalloproteinase 9; Middle Aged; Oligopeptides; Prostatic Neoplasms; Taiwan; THP-1 Cells; Young Adult

Androgen deprivation therapy using gonadotropin-releasing hormone (GnRH) analogues is standard treatment for intermediate and advanced prostate cancer. GnRH agonist therapy results in an initial testosterone flare, and increased metabolic and cardiovascular risks. The GnRH antagonist relugolix is able to reduce serum testosterone levels in men with prostate cancer without inducing testosterone flare. In the HERO Phase III trial, relugolix was superior to leuprolide acetate at rapidly reducing testosterone and continuously suppressing testosterone, with faster post-treatment recovery of testosterone levels. Relugolix was associated with a 54% lower incidence of major adverse cardiovascular events than leuprolide acetate. As the first oral GnRH antagonist approved for the treatment of advanced prostate cancer, relugolix offers a new treatment option.. Lay abstract The male sex hormone testosterone promotes the growth of prostate cancer cells. Some drug treatments for prostate cancer, such as gonadotropin-releasing hormone (GnRH) receptor agonists and antagonists, work to reduce the production of testosterone. However, GnRH receptor agonists like leuprolide acetate can increase testosterone levels at first, before reducing it, and this temporary increase can cause side effects, such as bone pain. Drugs of this type have also been linked to a higher risk of heart attacks, strokes, and death. Relugolix works a different way; it is a GnRH receptor antagonist that reduces testosterone without an initial increase. A clinical study showed that relugolix reduced testosterone levels more quickly than leuprolide acetate, a commonly used injectable drug for the treatment of prostate cancer. After stopping treatment, levels of testosterone in the blood returned to normal faster in men who received relugolix than in men who received leuprolide acetate. Men who received relugolix had a lower incidence of heart attacks, strokes, and death compared with men who received leuprolide acetate. The US FDA approved relugolix as the first oral, once-daily GnRH receptor antagonist for the treatment of advanced prostate cancer, offering men a new treatment option.

Topics: Cardiovascular Diseases; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Gonadotropin-Releasing Hormone; Humans; Incidence; Leuprolide; Male; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Randomized Controlled Trials as Topic; Testosterone; Treatment Outcome

Androgen deprivation therapy (ADT) is a widely used treatment for patients with hormone-sensitive prostate cancer (PCa). However, duration of treatment response varies, and most patients eventually experience disease progression despite treatment. Leuprorelin is a luteinizing hormone-releasing hormone (LHRH) agonist, a commonly used form of ADT. Prostate-specific antigen (PSA) is a biomarker for monitoring disease progression and predicting treatment response and survival in PCa. However, time-dependent profile of tumor regression and growth in patients with hormone-sensitive PCa on ADT has never been fully characterized. In this analysis, nationwide medical claims database provided by Humana from 2007 to 2011 was used to construct a population-based disease progression model for patients with hormone-sensitive PCa on leuprorelin. Data were analyzed by nonlinear mixed effects modeling utilizing Monte Carlo Parametric Expectation Maximization (MCPEM) method in NONMEM. Covariate selection was performed using a modified Wald's approximation method with backward elimination (WAM-BE) proposed by our group. 1113 PSA observations from 264 subjects with malignant PCa were used for model development. PSA kinetics were well described by the final covariate model. Model parameters were well estimated, but large between-patient variability was observed. Hemoglobin significantly affected proportion of drug-resistant cells in the original tumor, while baseline PSA and antiandrogen use significantly affected treatment effect on drug-sensitive PCa cells (Ds). Population estimate of Ds was 3.78 x 10-2 day-1. Population estimates of growth rates for drug-sensitive (Gs) and drug-resistant PCa cells (GR) were 1.96 x 10-3 and 6.54 x 10-4 day-1, corresponding to a PSA doubling time of 354 and 1060 days, respectively. Proportion of the original PCa cells inherently resistant to treatment was estimated to be 1.94%. Application of population-based disease progression model to clinical data allowed characterization of tumor resistant patterns and growth/regression rates that enhances our understanding of how PCa responds to ADT.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Biomarkers; Databases, Factual; Disease Progression; Drug Resistance, Neoplasm; Humans; Leuprolide; Male; Middle Aged; Monte Carlo Method; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate

The aim of this study was to investigate the influence of androgen deprivation therapy (ADT) on the progression of non-alcoholic fatty liver disease (NAFLD) in patients with prostate cancer (PCa) by evaluation of hepatic steatosis on computed tomography (CT).. The study included 77 PCa patients who underwent abdominal CT at baseline and after 6 months of ADT. The degree of hepatic steatosis was evaluated according to the attenuation value for liver parenchyma (CTLP), the attenuation ratio for liver and spleen (LSratio), and the difference in attenuation between LS (LSdif). The associations between these 3 indices and various metabolic syndrome-related factors were analyzed.. The number of NAFLD patients increased from 9 (11.6%) at baseline to 16 (20.7%) after ADT. The CTLP, LSratio, and LSdif values were significantly lower after ADT than before (p < 0.05). There were significant correlations between the percent change in CTLP and the percent change in HbA1c, between the percent change in LSratio and the percent change in abdominal circumference, and between the percent change in LSdif and the percent change in BMI.. Six months of ADT was associated with significant progression of NAFLD in PCa patients. This progression was strongly correlated with changes in HbA1c, abdominal circumference, and BMI.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Disease Progression; Humans; Leuprolide; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Oligopeptides; Prostatic Neoplasms; Retrospective Studies; Tomography, X-Ray Computed

TAK-448 is the investigational metastin/kisspeptin analog, which is known to have an anti-tumor effect through suppression of androgen hormones (luteinizing hormone and testosterone) levels. This study developed pharmacokinetic-pharmacodynamic (PK/PD) models of TAK-448 and leuprorelin acetate (TAP-144) in a rat vertebral-cancer of the prostate (VCaP) androgen-sensitive prostate cancer xenograft model to quantitatively assess and compare the anti-tumor effects of both drugs. A potential contribution of the hormone-independent direct effects of TAK-448 to the tumor growth inhibition was also investigated in the in vivo rat xenograft model, because our in vitro experiments revealed that TAK-448 may also directly suppress VCaP cellular proliferation. The PK/PD model successfully described the time course of tumor growth inhibition after drug treatment as well as the development of resistance to the inhibition of androgen hormones, following drug treatment or castration. The EC

Topics: Animals; Antineoplastic Agents, Hormonal; Cell Line, Tumor; Cell Proliferation; Humans; Kisspeptins; Leuprolide; Male; Models, Biological; Prostatic Neoplasms; Rats; Rats, Nude; Time Factors; Xenograft Model Antitumor Assays

Results from the phase 3 HERO trial(NCT03085095), presented during the 2020 American Society of Clinical Oncology Virtual Scientific Program, indicated that relugolix (Relumina) demonstrated superiority over leuprolide (Lupron) in sustained testosterone suppression through 48 weeks, fast testosterone recovery after discontinuation, and a 50% reduction in major adverse cardiovascular events (MACE) in patients with advanced prostate cancer.

Topics: Antineoplastic Agents, Hormonal; Clinical Trials, Phase III as Topic; Humans; Leuprolide; Male; Multicenter Studies as Topic; Neoplasm Staging; Phenylurea Compounds; Prostatic Neoplasms; Pyrimidinones; Randomized Controlled Trials as Topic; Receptors, LHRH; Testosterone

We report the failure to achieve castrate level of serum testosterone during luteinizing hormone-releasing hormone agonist therapy in a patient with prostate cancer. A 76-year-old man was admitted to our hospital for evaluation of an elevated serum prostate specific antigen (PSA) level (191.10 ng/ml) in August 2011. He was diagnosed with T3aN0M1b prostate adenocarcinoma. A combined androgen blockade using luteinizing hormone-releasing hormone agonist (the 1-month depot of leuprorelin acetate) and antiandrogen was administered. Due to liver dysfunction, antiandrogens, both bicalutamide and flutamide, were stopped. The 1-month depot was switched to the 3-month depot in May 2013, but the patient complained of induration and abscess at the infection site. Leuprorelin acetate was replaced by goserelin acetate. Because no adverse event appeared after injection of the 1-month depot of goserelin acetate, the 3-month depot was administered in October 2013. The PSA level increased gradually, and the testosterone level was greater than 50 ng/dl, that is, above castrate range. The 3-month depot of both leuprorelin acetate and goserelin acetate was not effective for this patient. For this reason, the 1-month depot of leuprorelin acetate was started resulting in a rapid decrease in PSA and testosterone levels. Thereafter, androgen depriving therapy could be continued. Androgen deprivation therapy is the standard treatment for patients with advanced prostate cancer and luteinizing hormone-releasing hormone aims to suppress serum testosterone to castrate range. We recommend assessing the serum testosterone levels during luteinizing hormone-releasing hormone agonist therapy for monitoring treatment efficacy and verifying progression when the PSA level increases.

Topics: Adenocarcinoma; Aged; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Gonadotropin-Releasing Hormone; Goserelin; Humans; Kallikreins; Leuprolide; Male; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Testosterone; Tosyl Compounds

Topics: Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Nitriles; Nocturia; Prostatic Neoplasms; Tosyl Compounds; Urination

Topics: Adenocarcinoma; Aged, 80 and over; Antineoplastic Agents, Hormonal; Arm; Delayed-Action Preparations; Granuloma, Foreign-Body; Humans; Injection Site Reaction; Injections, Subcutaneous; Leuprolide; Male; Microspheres; Neoplasm Grading; Prostatic Neoplasms; Skin

We report a case of drug-induced interstitial lung disease as a result of combined androgen blockade. A 75 year-old male was receiving bicalutamide and reuprorelin acetate treatment for advanced prostate cancer. Two weeks after starting therapy, the patient developed dyspnea due to interstitial lung disease. Based on the clinical diagnosis of drug-induced interstitial lung disease, bicalutamide was withdrawn and steroid therapy was initiated. The patient succumbed 6 days later due to respiratory failure. Drug-induced interstitial lung disease following combined androgen blockade is a rare, but potentially serious adverse effect that requires close attention.

Topics: Aged; Androgen Antagonists; Anilides; Humans; Leuprolide; Lung Diseases, Interstitial; Male; Nitriles; Prostatic Neoplasms; Tosyl Compounds

Androgen-deprivation therapy is one of the options available for treating both advanced and metastatic prostate cancer (PCa). It is used as an adjuvant or neoadjuvant therapy, either alone or in combination with radiotherapy (RT) or surgery. The aim of this study was to appraise adherence to androgen-deprivation therapy (ADT).. A total of 136 PCa patients on ADT (leuprorelin, triptorelin, and degarelix) were monitored between January 2008 and December 2015. Demographic, histopathological, and clinical data were collected.. Mean age was 76 years and PSA was 91.9 ng/mL. Forty-six patients (34%) had a Gleason Score >7. One hundred and eight patients were treated exclusively with ADT (53 [49%] leuprorelin, 45 [42%] triptorelin, and 10 [9%] degarelix). Mean follow-up was 3.5 years, with a mean overall prescription time of 3.4 years. Adherence to ADT was 95%. Sixty-three patients are currently on therapy, while 45 have discontinued treatment. Reasons for discontinuation were death (56%), physician's choice (33%), and patient's preferences (11%).. Adherence to ADT was optimal, probably owing to its balanced side effect and benefit profile. Patient's death was the most frequent reason for discontinuation.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Medication Adherence; Middle Aged; Neoadjuvant Therapy; Neoplasm Grading; Oligopeptides; Prognosis; Prostatic Neoplasms; Retrospective Studies; Triptorelin Pamoate

The complaints of lower urinary tract symptoms (LUTS) in cases with Prostate carcinoma (Pca) depend on coexisting benign prostate hyperplasia (BPH) or aging bladder. We aimed to investigate and compare the effect of goserelin acetate with leuprolide acetate on total prostate volume (TPV), post voiding residue (PVR), International Prostate Symptom Score (IPSS) and maximum flow rate (Qmax) reduction on cases of advanced Pca.. Patients with advanced Pca were treated with goserelin acetate (10.8 mg/3 months) or leuprolide acetate (22.5 mg/3 months) for 6 months. Changes in Prostate specific antigen (PSA), testesterone level, TPV, IPSS, PVR, and Qmax were assessed every 3 months.. Fifty-one patients analyzed in this study. Mean percent decrease in PSA and testesterone from baseline to 6th month was not significantly difference between two groups (respectively; p = 0.9, p = 0.15) but TPV was reduced by -20.2 % ± 4.8 and -15.6 % ± 1.04,  the median total IPSS score was decreased by -34.77 % ± 8.8 and -19.77 % ± 6.1, median Qmax increased by 45.34 % ± 10.16 and 23.21 % ± 6.93, median PVR decreased by -31.54 % ± 8.4 and -19.23 % ± 5.5, respectively for two groups (all parameters (p < 0.05))Conclusion. In this study, we observed that the improvement of voiding parameters goserelin acetate was beter than leuprolide acetate. Especially it was detected the superiority of goserelin acetate group on the reduction of TPV, PVR and IPSS. Oncological outcomes were not different in both groups.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Goserelin; Humans; Leuprolide; Lower Urinary Tract Symptoms; Male; Middle Aged; Prostatic Neoplasms; Retrospective Studies; Tumor Burden; Urination Disorders

This investigation aimed to quantitatively characterize the relationship between the gonadotropin-releasing hormone agonist leuprorelin, testosterone (T) and prostate specific antigen (PSA) concentrations over time, to aid identification of a target T concentration that optimises the balance of the benefits of T suppression whilst reducing the risk of side effects related to futile over-suppression.. Data from a single dose study to investigate the effect of leuprorelin in a 6-month depot formulation on T and PSA in prostate cancer patients were analysed using a population pharmacokinetic-pharmacodynamic modelling approach. The developed model was qualified using external data from 3 studies, in which the effect of different formulations of leuprorelin on T and PSA was evaluated in prostate cancer patients.. The effect of leuprorelin on the relationship between T and PSA was adequately characterized by the Romero model with minor modifications, combined with a turnover model to describe the delay in response between T and PSA. The data were significantly better described when assuming a minimum PSA level that is independent on the treatment-related reduction in T, as compared to a model with a proportional reduction in PSA and T.. The model-based analysis suggests that on a population level, reducing T concentrations below 35 ng/dL does not result in a further decrease in PSA levels (>95% of the minimal PSA level is reached). More data are required to support this relationship in the lower T and PSA range.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Clinical Trials, Phase III as Topic; Drug Monitoring; Humans; Kallikreins; Leuprolide; Male; Middle Aged; Models, Biological; Multicenter Studies as Topic; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Testosterone; Treatment Outcome; Young Adult

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

An 83 year-old male with Gleason score 4+3 prostatic adenocarcinoma status post brachytherapy developed obstructive voiding symptoms 9 years after brachytherapy. Prostate-specific antigen was 0.67. Cystoscopy noted multiple papillary urethral tumors concerning for primary urethral carcinoma. Immunophenotype of biopsies supported diagnosis of Gleason score 4+4 prostatic adenocarcinoma. Androgen deprivation therapy was started. Cystoscopy performed 4 years later, for microhematuria workup, noted complete resolution of the urethral tumors. We present a patient with little serum Prostate-specific antigen change with urethral prostatic adenocarcinoma metastasis that resolved after androgen deprivation therapy.

Topics: Adenocarcinoma; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Nitriles; Prostatic Neoplasms; Remission Induction; Tosyl Compounds; Urethral Neoplasms

Spinal and bulbar muscular atrophy (SBMA) is a progressive hereditary neuromuscular disease caused by the testosterone-dependent accumulation of pathogenic polyglutamine-expanded androgen receptor protein. A 41-year-old man with SBMA received the androgen deprivation agent leuprorelin acetate for 7 years in clinical trials and underwent castration following the trial. Suppression of testosterone levels for 14 years resulted in a slower disease progression, as measured prospectively with quantitative measurements, than the historical control data reported in previous studies. This suggests that long-term androgen deprivation delays disease progression in SBMA.

Topics: Adult; Androgen Antagonists; Animals; Bulbo-Spinal Atrophy, X-Linked; Disease Progression; Follow-Up Studies; Humans; Leuprolide; Male; Orchiectomy; Prostatic Neoplasms

Topics: Androgen Antagonists; Androstenes; Benzamides; Humans; Leuprolide; Male; Nitriles; Phenylthiohydantoin; Prostatectomy; Prostatic Neoplasms

To investigate the changes in testosterone levels and rates of chemical castration following androgen-deprivation therapy (ADT) with goserelin, triptorelin, and leuprolide.. We retrospectively reviewed the medical records of 125 patients with prostate cancer treated with luteinizing hormone-releasing hormone (LHRH) agonists between January 2009 and December 2015. Changes in testosterone concentration during 9 months of ADT with goserelin 11.34 mg, triptorelin 11.25 mg, and leuprolide 11.25 mg were analyzed using a mixed model. The number of patients with serum testosterone below castration levels defined as various values (<50 ng/dL, <20 ng/dL, or <10 ng/dL) at 3, 6, and 9 months were also evaluated.. Of the 125 patients, 59 received goserelin, 44 received triptorelin, and 22 received leuprolide, respectively. The lowest mean testosterone levels during 9 months of treatment were achieved in patients treated with triptorelin, followed by those treated with leuprolide, and then by those treated with goserelin (p=0.001). Significant differences in chemical castration levels were observed only at <10 ng/dL, with 54.2% of goserelin, 93.2% of triptorelin, and 86.4% of leuprolide treated patients (p<0.001).. Three LHRH agonists showed comparable efficacy for achieving castration when the castration threshold was 50 or 20 ng/dL. However, triptorelin was the most potent LHRH agonist, achieving the lowest mean testosterone levels and the highest rate of chemical castration at <10 ng/dL testosterone.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms; Retrospective Studies; Treatment Outcome; Triptorelin Pamoate

Topics: Androgen Antagonists; Androstenes; Benzamides; Humans; Leuprolide; Male; Nitriles; Phenylthiohydantoin; Prostatectomy; Prostatic Neoplasms

We investigated the health-related quality of life (HRQoL) of long-term prostate cancer patients who received leuprorelin acetate in microcapsules (LAM) for androgen-deprivation therapy (ADT).. The observational study was carried out by 30 office-based German urologists in 536 prostate cancer (PCa) patients treated for ≥5 years with LAM and in 116 patients of an age-matched control group (CG). Data on HRQoL and health status was collected prospectively using validated questionnaires QLQ-C30, QLQ-PR25 and Karnofsky Index. Data on effectiveness (clinical response, prostate specific antigen [PSA], testosterone) and safety was collected retrospectively from patients' health records. We used descriptive statistics to analyze the data.. The mean treatment duration was 8.6 years (range 4.5-19.8 years). General health status (QLQ-C30) was comparable for both groups. Differences were observed regarding physical - and role functioning. ADT patients rated single items slightly worse than CG. Karnofsky-Index showed comparable high values (median of 90%). QLQ-PR25 revealed more PCa-related symptoms for ADT patients. Within 6 months, median PSA level declined >90% and median testosterone levels declined below castration level from 4.0 to 0.2 ng/mL. Clinical response (European Organisation for Research and Treatment of Cancer criteria) was observed in at least 90% of ADT patients.. Long-term ADT with LAM is a well-accepted, tolerated, effective, and low-burden treatment option for patients with advanced, hormone-sensitive PCa.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Cancer Survivors; Humans; Leuprolide; Male; Prospective Studies; Prostatic Neoplasms; Quality of Life; Retrospective Studies; Time Factors

We evaluated the efficacy and tolerability of 3- and 6-month leuprorelin acetate (LA) depot formulations (Eligard®, Astellas Pharma GmbH) in patients with advanced prostate cancer treated in routine clinical practice in Germany.. Data was pooled from 2 prospective, open-label, non-interventional studies in which 1,906 patients were treated for 12 months with either the 3-month (n = 633) or 6-month (n = 1,273) LA formulation.. Median prostate-specific antigen levels in the pooled patient population declined from 12.0 ng/mL at baseline to 0.5 ng/mL after 12 months. Prostate-specific antigen reduction was achieved in treatment-naïve and pre-treated patients. Adverse events were documented in 8.8% of patients.. These pooled data from routine clinical practice in Germany indicate that LA 3- and 6-month depot injections can effectively reduce prostate-specific antigen levels in a broad patient population with advanced prostate cancer.

Topics: Aged; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Germany; Humans; Leuprolide; Male; Neoplasm Staging; Prospective Studies; Prostatic Neoplasms; Time Factors; Treatment Outcome

Prostate cancer (PCa) is often associated with psychopathological symptoms such as anxiety. This study evaluated the effects of the luteinizing hormone-releasing hormone agonist therapy leuprorelin acetate (LA) on anxiety and quality of life (QoL) over time in men with PCa.. This observational, non interventional, multicenter study was conducted in France. Patients with PCa eligible for therapy with a 6-month LA depot were enrolled. Patients completed questionnaires assessing anxiety (memorial anxiety scale for prostate cancer [MAX-PC] ; state trait anxiety inventory [STAI]) and QoL (medical outcomes study 12-item short-form health survey [SF-12] physical summary component [PCS] and mental component summary [MSCS] subscales) at baseline and 6 months after 6-month LA depot administration.. Questionnaires were completed by 575 men at baseline and 315 men at 6 months. Mean age was 75.5 years; median time since first diagnosis was 0.4 years. At baseline, the mean (±standard deviation [SD]) MAX-PC score was 17.7±12.0, with anxiety primarily related to the PCa diagnosis. STAI-state and MAX-PC scores were consistent. Following 6 months of LA administration, the mean MAX-PC score decreased (-2.0±10.4 ; P<0.001). The PCa diagnosis negatively affected patients' QoL, as assessed by the SF-12 PCS and MCS subscores. At 6 months, the SF-12 vitality score significantly increased (1.2±9.8; P=0.0142) vs baseline and the SF-12 PCS score decreased by -2.0±8.0 from baseline.. After 6 months of leuprorelin 45mg therapy, prostate cancer patients appeared to be less anxious with a mental health improvement.. 3.

Topics: Aged; Antineoplastic Agents, Hormonal; Anxiety; Humans; Leuprolide; Male; Prostatic Neoplasms; Quality of Life; Time Factors

To identify factors affecting depressive symptoms in patients undergoing androgen-deprivation therapy (ADT) to treat prostate cancer.. The patients with prostate cancer visiting the psychiatry department without referral because of depressive symptoms while undergoing ADT participated. To assess depressive symptoms, the Beck Depression Inventory (BDI) was used. To identify the risk factors affecting depressive symptoms, univariate regression and multiple linear regression analyses were implemented.. The mean (± SD) age, age when initiating ADT, duration of ADT, serum testosterone level and BDI scores of participants (n = 45) were 73.9 ± 7.9 years, 72 ± 8.5 years, 33 ± 31.6 months, 214.9 ± 219.5 ng/dL and 18 ± 13.5 points. The androgen dependent and independent were 26 and 9 patients. Eight of these androgen-independent patients underwent concurrent chemotherapy. Twenty-one patients were treated with bicalutamide and 24 with leuprolide. Of the clinical variables affecting BDI scores, the type of ADT drug (P < 0.001), serum testosterone level (P = 0.003), and age at diagnosis (P < 0.001) were significant.. Efforts to diagnose and treat depression appropriately, especially if depressive symptoms change in patients undergoing ADT to treat prostate cancer who are using an LHRH agonist (leuprolide), have low testosteronelevel, or are older at the age when initiating ADT.

Topics: Age Factors; Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Depression; Humans; Leuprolide; Male; Nitriles; Prostatic Neoplasms; Psychiatric Status Rating Scales; Risk Factors; Testosterone; Tosyl Compounds

Topics: Adenocarcinoma; Administration, Topical; Aged; Antineoplastic Agents, Hormonal; Carcinoma; Collagen Diseases; Glycation End Products, Advanced; Humans; Japan; Leuprolide; Male; Neoplasm Metastasis; Prostatic Neoplasms; Skin Diseases, Genetic; Steroids; Treatment Outcome; Ultraviolet Therapy

Hormotherapy and chemotherapy are still the most important palliative therapeutic approaches for androgen-sensitive prostate cancer (PCa). Recently, the combination of hormotherapy and chemotherapy, namely, chemohormonal therapy has aroused considerable attention. Although synergistic chemohormonal therapy can improve PCa suppression efficacy and prolong the lives of patients, it also leads to severe adverse effects, that is, hormonal tolerance caused by hormotherapy, and leukemia or neutropenia caused by chemotherapy. Therefore, alleviating the adverse effects and improving anti-PCa efficacy are the focuses of the chemohormonal therapy for future researches. In this study, the commercial androgen-deprivation therapy (ADT), polyester microsphere Enantone (ENT), and polypeptide micelles loaded with a clinical antitumor agent mitoxantrone (MTO) are employed for micro/nanocarrier-assisted chemohormonal therapy. Encouragingly, the combined chemohormonal therapy significantly boosts antitumor efficacy and ameliorates side effects in preclinical assessments. With these benefits, the micro/nanocarrier-assisted chemohormonal therapy can be incorporated as an efficient clinical strategy for PCa patients.

Topics: Animals; Antineoplastic Agents; Drug Carriers; Leuprolide; Male; Mice, Inbred C57BL; Micelles; Mitoxantrone; Peptides; Prostate; Prostatic Neoplasms; Rats, Sprague-Dawley

Androgen deprivation therapy (ADT) is a common treatment option for men with biochemical relapse from prostate cancer. ADT is associated with changes in mood, cognition, and quality of life, and most recently with increased risk for Alzheimer's disease (AD). This study examined changes in brain metabolism using positron emission tomography (PET) in men undergoing intermittent ADT.. Nine men with prostate cancer and a rising PSA (biochemical recurrence) without evidence of metastases were treated with intermittent ADT consisting of 9 months of complete androgen blockade achieved with combined leuprolide acetate and flutamide. Patients underwent resting [Fuorine-18] fluorodeoxyglucose PET (. Whole-brain mapping analysis after 9 months of androgen deprivation compared to pretreatment baseline revealed decreased regional cerebral glucose metabolism in the cerebellum, posterior cingulate, and medial thalamus bilaterally. Associations of brain metabolism with measurements of cognition and mood while on androgen deprivation revealed positive correlations between the posterior cingulate, left inferior parietal lobule (BA40), and left mid temporal gyrus (BA39) and spatial reasoning and a negative correlation between left inferior parietal lobule and verbal memory. Several mood indices were negatively correlated with hypothalamus and brainstem.. These findings suggest that complete androgen deprivation may result in changes in regional brain metabolism associated with variation in mood, verbal memory, and spatial performance. Brain regions that were impacted from ADT are similar and overlap with brain regions with metabolic decline found in early AD and diabetes, suggesting possible common mechanisms.

Topics: Affect; Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Brain; Cognition; Flutamide; Humans; Kallikreins; Leuprolide; Male; Middle Aged; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life

Topics: Aged; Androgen Antagonists; Anilides; Hot Flashes; Humans; Leuprolide; Male; Mandelic Acids; Muscarinic Antagonists; Nitriles; Prostatic Neoplasms; Tosyl Compounds

Inducing testosterone deficiency, as the standard treatment of prostate cancer, may cause metabolic disorders including insulin resistance, dyslipidemia, central obesity, cardiovascular diseases, and type 2 diabetes. This study measured responses to testosterone deficiency in high-carbohydrate, high-fat (H) diet-fed rats. We then tested whether eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) ethyl esters (Omacor) reversed these metabolic changes. Male Wistar rats (8⁻9 weeks old) were divided into eight groups with four groups fed corn starch and four groups fed H diet. For each diet, one group received diet only; one group was orchidectomized; one group was given leuprolide (gonadotrophin-releasing hormone agonist, 2 mg/kg every 4th week); and the last group was treated with leuprolide and their diet was supplemented with 3% Omacor for the last eight weeks. The protocol was for 16 weeks. Leuprolide worsened metabolic syndrome symptoms and cardiovascular function, and orchidectomy produced greater responses. In H fed leuprolide-treated rats, Omacor decreased systolic blood pressure and left ventricular diastolic stiffness, reduced infiltration of inflammatory cells and collagen deposition in the heart, and reduced lipid accumulation and inflammatory cell infiltration without improving liver damage. These results suggest that Omacor has potential to attenuate metabolic complications in prostate cancer patients with induced testosterone deprivation.

Topics: Animals; Antineoplastic Agents, Hormonal; Blood Pressure; Diet, Carbohydrate Loading; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Docosahexaenoic Acids; Drug Combinations; Eicosapentaenoic Acid; Humans; Leuprolide; Liver; Male; Metabolic Syndrome; Prostatic Neoplasms; Rats; Rats, Wistar; Testosterone

Gonadotropin-releasing hormone (GnRH) agonists have been used for the treatment of various diseases. Although autoimmune thyroid disease has been reported as a rare complication of these agents, the symptoms are almost always transient and non-life-threatening. We herein report a rare case of an 83-year-old man receiving GnRH agonist treatment for prostate cancer who developed myxedema coma complicated by acute pancreatitis. This is the first report of myxedema coma potentially associated with a GnRH agonist. The follow-up of the thyroid function is necessary for patients undergoing treatment with GnRH agonists, especially those known to have or to be susceptible to autoimmune thyroid disease.

Topics: Acute Disease; Aged, 80 and over; Antineoplastic Agents, Hormonal; Coma; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Myxedema; Pancreatitis; Prostatic Neoplasms

Topics: Aged; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Prostatic Neoplasms; Psychotic Disorders; Schizophrenia; Subcutaneous Absorption

Recent studies suggest that androgen deprivation therapy (ADT) is associated with increased cardiovascular (CV) risk for patients with hormone-sensitive prostate cancer (PCa) and pre-existing CV disease. This risk seems to be different for the gonadotropin-releasing hormone (GnRH) agonists leuprolide and goserelin and GnRH antagonists, whereas the slightly more expensive GnRH antagonist shows a beneficial risk profile. The present study assesses the cost effectiveness of degarelix compared to leuprolide for PCa patients with increased CV risk.. This analysis is based on a pooled analysis of six phase III, randomized, controlled trials comparing the GnRH agonists leuprolide and goserelin with the GnRH antagonist degarelix. For the combined endpoint of CV events or death a superiority of degarelix was determined with a Number-Needed-to-Treat of 12. From the perspective of German statutory health insurance, this evaluation estimates and compares the additional drug costs of degarelix treatment to the cost of one (avoided) CV event. The CV event costs were estimated via emergency treatment and transportation, inpatient treatment, and rehabilitation. The difference of these two cost pools divided by 12 yields the average saving per patient and year.. For every 12 PCa patients with CV history that are treated with GnRH antagonists to prevent one CV event, there will be additional drug costs in comparison with leuprolide treatment of € 3111 per year. Costs of € 8447 per year are prevented. Therefore, each patient with a history of CV who is treated with degarelix instead of a leuprolide generates savings of € 445 per patient and year.. Compared to leuprolide, degarelix is cost effective for patients with increased CV risk.

Topics: Antineoplastic Agents, Hormonal; Cardiovascular Diseases; Cost-Benefit Analysis; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Meta-Analysis as Topic; Oligopeptides; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Risk Factors

Gonadotropin-releasing hormone agonists, used widely in the treatment of metastatic prostate cancer and hormone receptor-positive breast cancer, are associated with a rare but potentially fatal outcome of pituitary apoplexy (PA). An 85-year-old man presented with sudden onset of headache, left eye pain, sensitivity to light, nausea and vomiting. The symptoms started 4 hours after initiation of leuprolide therapy for treatment of recently diagnosed metastatic prostate carcinoma. Radiological imaging of the brain demonstrated a heterogeneously enlarged pituitary gland measuring 19×16×13 mm and T1-hyperintense signal compatible with pituitary haemorrhage. Hormone function tests were indicative of panhypopituitarism, confirming the diagnosis of PA. Due to age, the patient was started on hormonal replacement therapy and eventually symptoms improved.

Topics: Aged, 80 and over; Antineoplastic Agents, Hormonal; Diagnosis, Differential; Headache; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Pituitary Apoplexy; Prostatic Neoplasms

This study aimed to evaluate the economic value for leuprorelin acetate 6-month depot compared with leuprorelin acetate 3-month depot from a societal perspective in Japanese prostate cancer patients.. The cost analysis estimated the reduction in direct and indirect costs as well as intangible costs saved by having one less injection. Claims data were used for the analyses of direct and indirect costs reduction. A discrete choice experiment based on a web-based survey estimated the monetary value of the intangible costs for one injection. Another web-based survey of prostate cancer patients, who had received treatment with leuprorelin acetate injections, was carried out to calibrate the results of the discrete choice experiment.. Reductions in medical costs and loss of productivity for having one less injection in prostate cancer patients receiving leuprorelin acetate were JPY 5,670 and JPY 1,723, respectively. Intangible costs saved by using a 6-month depot formulation instead of a 3-month depot formulation for the injection of leuprorelin acetate were estimated to be JPY 19,872, including the values for a reduction in pain (JPY 3,131), injection site reactions (JPY 11,545), waiting time (JPY 9,479), and subtracting the value of medical consultation (JPY 4,283). The total cost reduction for having one less injection was JPY 27,265.. The respondents from the internet panel provided by a survey company are not necessarily a representative population of Japanese society.. Leuprorelin acetate 6-month depot has an advantage in monetary value in the reduction in medical costs, loss of productivity, and intangible costs for having one less injection in prostate cancer patients compared with leuprorelin acetate 3-month depot. In the costs for treating with leuprorelin acetate, the percentage of intangible costs might not be negligible. The intangible costs will probably be actively evaluated to proceed to patient-centered healthcare in society.

Topics: Age Factors; Aged; Antineoplastic Agents, Hormonal; Cost of Illness; Costs and Cost Analysis; Delayed-Action Preparations; Drug Administration Schedule; Health Expenditures; Humans; Insurance Claim Review; Japan; Leuprolide; Male; Middle Aged; Prostatic Neoplasms

Topics: Aged, 80 and over; Antineoplastic Agents, Hormonal; Granuloma; Humans; Injections, Subcutaneous; Leuprolide; Male; Prostatic Neoplasms; Skin Diseases

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

Data from four open-label, fixed-dose studies were evaluated. Male patients aged 40-86 years with advanced prostatic adenocarcinoma, whom had not undergone prior androgen-deprivation therapy (ADT), were treated with a depot formulation of ADSC-LA: 7.5 mg (1-month, 120 patients), 22.5 mg (3-month, 117 patients), 30 mg (4-month, 90 patients), or 45 mg (6-month, 111 patients). Serum testosterone was sampled at screening, baseline, 2, 4, 8 h after dosing, 1, 2, 3, and 7 days, and every week until the next dose, at which time, the sampling schedule repeated until the end of study (24 weeks for 1- and 3-month formulations, 32 weeks for 4-month, and 48 weeks for the 6-month). The primary analyses were mean serum testosterone concentrations and proportion of patients who achieved concentrations of ≤20 ng/dL.. The mean (SE) serum testosterone concentrations at the end of study were consistently ≤20 ng/dL in each study, at 6.1 (0.4), 10.1 (0.7), 12.4 (0.8), and 12.6 (2.1) ng/dL for the 1-, 3-, 4-, and 6-month formulations, respectively. A high proportion of patients (94%, 90%, 92%, 96% for the 1-, 3-, 4-, and 6-month formulations, respectively) achieved testosterone concentrations of ≤20 ng/dL within 6 weeks, and 90-97% of patients in all studies maintained concentrations of ≤20 ng/dL from weeks 6-24.. Recent studies have shown improved outcomes in patients with prostate cancer who consistently attained a more rigorous level of testosterone suppression (≤20 ng/dL) with ADT than the historical standard (≤50 ng/dL). All doses of ADSC-LA rapidly achieved and maintained mean serum testosterone to the more rigorous target concentration of ≤20 ng/dL. These data suggest that ADSC-LA delivers equivalent testosterone suppression as achieved by surgical castration.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Drug Delivery Systems; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Neoplasm Staging; Polymers; Prospective Studies; Prostatic Neoplasms; Testosterone

Residual cancer morphology in radical prostatectomies (RPs) after neoadjuvant hormone therapy includes inconspicuous cytology, and treated tumour cells can be difficult to identify in lymph nodes. The aim of this study was to evaluate the role of immunohistochemistry (IHC) in identifying occult lymph node metastases following neoadjuvant hormone treatment of prostate cancer.. One hundred and twenty-eight lymph nodes from 24 patients treated with neoadjuvant hormone therapy, including abiraterone acetate alone or combined with leuprolide, were stained with antibodies against keratin AE1/AE3, prostate-specific antigen (PSA), prostate-specific acid phosphatase (PrAP), androgen receptor (AR), and NKX3.1. IHC slides were scored 'blind', and then retrospectively compared with haematoxylin and eosin (H&E)-stained slides and pathology reports. IHC identified carcinoma in six lymph nodes from three patients. All metastases were positive for NKX3.1 and AR, five of six were positive for AE1/AE3, and three of six were positive for PSA; PrAP was negative in all metastatic foci. All six lymph node metastases had been identified by H&E staining at the time of RP.. These findings suggest that routine use of IHC on lymph nodes from neoadjuvant-treated prostate carcinomas is not necessary. Nevertheless, for suspicious small foci of atypical cells in neoadjuvant-treated lymph nodes, NKX3.1 and AR appear to have the greatest sensitivity.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma; Follow-Up Studies; Humans; Immunohistochemistry; Leuprolide; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Pelvis; Prostate; Prostatectomy; Prostatic Neoplasms; Retrospective Studies

Meningiomas are the most common type of benign brain tumor, and the incidence of meningioma in women is more than twofold higher than in men. Several studies have demonstrated that hormones are somehow related to the growth of meningiomas.. A 72-year-old man with benign meningioma underwent tumor resection and had no recurrence for 18 years. He was found to have prostate cancer, and he received hormonal therapy with a luteinizing hormone-releasing hormone (LHRH) agonist. Two years later, he developed severe cognitive dysfunction and gait disturbance. Gadolinium-enhanced brain magnetic resonance imaging revealed a large recurrent mass and obstructive hydrocephalus. Staged resection was performed and stereotactic radiation therapy was administered against the residual tumor. His symptoms improved after endoscopic third ventriculostomy for obstructive hydrocephalus and his residual tumor remains stable.. This is the first report of a case in which an LHRH agonist promoted the growth of a pre-existing meningioma. We suggest that patients with a history of meningioma who are receiving LHRH agonist treatment should be closely monitored.

Topics: Aged; Antineoplastic Agents, Hormonal; Cognition Disorders; Disease Progression; Gadolinium; Gait Disorders, Neurologic; Humans; Ki-67 Antigen; Leuprolide; Magnetic Resonance Imaging; Male; Meningeal Neoplasms; Meningioma; Neoplasm Recurrence, Local; Neoplasm, Residual; Prostatic Neoplasms; Radiosurgery

Androgen deprivation therapy (ADT) is the standard medical approach to the management of prostate cancer. Patients switched from a GnRH antagonist to a GnRH agonist, did not experience a testosterone surge in spite of the occurrence of luteinizing hormone (LH) surge in our protocol of clinical study. To clarify this observation, male mice pre-treated with two different doses of the GnRH antagonist degarelix for 28 days were further administered the GnRH agonist leuprolide or chorionic gonadotropin, and testosterone production of the mice was studied. Serum LH and testosterone levels, the size of Leydig cells, and expression level of steroidogenesis-related genes in the testis were analyzed. Treatment of mice with a high dose of degarelix (0.1 μg/mouse; HDG), but not a low dose (0.05 μg/mouse; LDG), for 28 days reproduced declined steroidogenesis observed in prostate cancer patients during ADT switched from a GnRH antagonist to a GnRH agonist. The size of the Leydig cells in the HDG mice was not significantly different from that in naive mice. Although expression levels of StAR, P450scc, and 17β HSD increased significantly in the LDH testis, those in the HDG testis did not change. Treatment of mice with a high dose of degarelix for 28 days reproduced the decline in steroidogenesis observed in prostate cancer patients during ADT. In this animal model, we demonstrated that initial ADT may inhibit the ability of Leydig cells to produce testosterone by suppressing the expression of genes involved in steroidogenesis, such as StAR, P450scc, and 17βHSD.

Topics: 17-Hydroxysteroid Dehydrogenases; Animals; Antineoplastic Agents, Hormonal; Cell Size; Chorionic Gonadotropin; Disease Models, Animal; Hormone Antagonists; Leuprolide; Leydig Cells; Luteinizing Hormone; Male; Mice; Oligopeptides; Phosphoproteins; Prostatic Neoplasms; Testis; Testosterone

Topics: Androgen Antagonists; Androgens; Anilides; Drug-Related Side Effects and Adverse Reactions; Flutamide; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Libido; Male; Medicare; Neoplasm Metastasis; Nitriles; Penis; Prostatic Neoplasms; Tosyl Compounds; United States

Topics: Alzheimer Disease; Androgen Antagonists; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Prostatic Neoplasms; Risk

Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Humans; Leuprolide; Male; Medication Adherence; Middle Aged; Nitriles; Prostatic Neoplasms; Tosyl Compounds; Tumor Lysis Syndrome

Pituitary apoplexy is a rare complication of the initial administration of leuprolide acetate.. We present the case of a 63-year-old man who experienced headache, blurred vision, and loss of consciousness after initial leuprolide treatment for prostate carcinoma. Neuroimaging showed pituitary hemorrhage.. Clinicians should be aware of this rare but known complication of leuprolide injection so that prompt diagnosis and treatment initiation are performed in patients with leuprolide-associated pituitary apoplexy.

Topics: Antineoplastic Agents, Hormonal; Carcinoma; Cerebral Hemorrhage; Chemotherapy, Adjuvant; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Apoplexy; Prostatectomy; Prostatic Neoplasms

The treatment options for high-risk prostate cancer are either radical prostatectomy or radiotherapy/brachytherapy depending on the patients' prognosis. In older men with multiple comorbidities, radiotherapy with androgen deprivation therapy is an attractive option. Common side effects of androgen deprivation therapy include hot flushes, tiredness, increased risk of fractures, increased risk of metabolic disorders, coronary heart disease, and psychological effects. This case highlights the potential side effect of lipodystrophy secondary to leuprolide acetate injections. To the best of our knowledge, this is the first reported case of such an instance.. In this case report, we describe a 70-year-old white man with prostate-specific antigen of 1.8 ng/mL, clinical stage T2bN0M0, Gleason 4+5=9 prostate cancer who developed an unusual side effect from leuprolide acetate as part of his androgen deprivation therapy. Approximately 2 months after the initial 3-monthly injection of leuprolide acetate (Eligard 22.5 mg) our patient developed abnormal lipid deposition particularly in his deltoid and abdominal region. His upper limb mobility gradually became compromised due to the size of these abnormal fat depositions. He had liposuction to correct this lipodystrophy and had a good functional outcome and cosmesis from the procedure.. To the best of our knowledge, this is the first reported case of lipodystrophy secondary to leuprolide acetate injections. Leuprolide acetate in commonly used as one of the gonadotrophin-releasing hormone agonists and thus we should be mindful of the potential effect of producing lipodystrophy, especially in patients with cirrhosis, and to watch for any signs and symptoms as appropriate. The implication of this potential side effect poses difficult management strategies for such patients, and second-line alternatives such as chemotherapy may need to be considered.

Topics: Aged; Antineoplastic Agents, Hormonal; Drug-Related Side Effects and Adverse Reactions; Humans; Leuprolide; Lipectomy; Lipodystrophy; Male; Prostatic Neoplasms; Shoulder; Treatment Outcome

Prostate cancer patients who receive androgen deprivation therapy (ADT) often experience many physical and psychological side effects. ADT may be associated with increased risk for depression, but the relationship between ADT and depression is not fully understood. This study used a longitudinal design to assess depressive symptomatology in patients receiving ADT compared with two groups of matched controls.. Participants were men initiating ADT treatment (ADT+ group; n = 61) and their matched controls: prostate cancer patients treated with radical prostatectomy (ADT- group; n = 61), and no-cancer controls (CA- group; n = 61). Depressive symptomatology was assessed using the Center for Epidemiological Studies Depression Scale at ADT initiation and again 6 months later. Differences in depressive symptomatology and rates of clinically significant depressive symptomatology were analyzed between groups at each time point and within groups over time.. Between baseline and follow-up, ADT+ participants demonstrated increased depressive symptomatology and increased rates of clinically significant depressive symptomatology (ps < 0.05). ADT+ participants also reported greater depressive symptomatology than both control groups at follow-up (ps < 0.001). Rates of clinically significant depressive symptomatology were higher in the ADT+ group than the ADT- and CA- groups at both time points (baseline: 28%, 5%, 12%; follow-up: 39%, 9%, 11%).. Findings support the hypothesis that ADT administration yields increases in depression and suggest that the mechanism behind ADT's association with depression should be explored and that prostate cancer patients treated with ADT should receive particular focus in depression screening and intervention.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antidepressive Agents; Antineoplastic Agents, Hormonal; Case-Control Studies; Chemotherapy, Adjuvant; Depression; Depressive Disorder; Goserelin; Humans; Leuprolide; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Risk Factors

To determine if androgen-deprivation therapy (ADT) is associated with excess cardiac-specific mortality (CSM) in men with prostate cancer and no cardiovascular comorbidity, coronary artery disease risk factors, or congestive heart failure (CHF) or past myocardial infarction (MI).. In all, 5077 men (median age 69.5 years) with cT1c-T3N0M0 prostate cancer were treated with brachytherapy with or without neoadjuvant ADT (median duration 4 months) between 1997 and 2006. Fine and Gray competing risks analysis evaluated the association of ADT with CSM, adjusting for age, year of brachytherapy, and ADT treatment propensity score among men in groups defined by cardiac comorbidity.. After a median follow-up of 4.8 years, no association was detected between ADT and CSM in men with no cardiac risk factors (1.08% at 5 years for ADT vs 1.27% at 5 years for no ADT, adjusted hazard ratio (AHR) 0.83; 95% confidence interval (CI), 0.39-1.78; P = 0.64; n = 2653) or in men with diabetes mellitus, hypertension, or hypercholesterolaemia (2.09% vs 1.97%, AHR 1.33; 95% CI 0.70-2.53; P = 0.39; n = 2168). However, ADT was associated with significantly increased CSM in men with CHF or MI (AHR 3.28; 95% CI 1.01-10.64; P = 0.048; n = 256). In this subgroup, the 5-year cumulative incidence of CSM was 7.01% (95% CI 2.82-13.82%) for ADT vs 2.01% (95% CI 0.38-6.45%) for no ADT.. ADT was associated with a 5% absolute excess risk of CSM at 5 years in men with CHF or prior MI, suggesting that administering ADT to 20 men in this potentially vulnerable subgroup could result in one cardiac death.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Coronary Disease; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Retrospective Studies; Risk Factors

We used responses to questionnaires included in the CS21 degarelix trial and published mapping algorithms to address the paucity of evidence for health related quality of life in patients with advanced hormone dependent prostate cancer treated with degarelix.. We measured health related quality of life in 610 patients enrolled in the CS21 trial using SF-12® and EORTC QLQ-C30. Based on responses to these questionnaires we estimated patient utility using 4 published mapping algorithms. Utility was tested for relationships with aspects of the symptom and side effect burden that may be affected by degarelix treatment, that is prostate specific antigen progression and adverse events.. Average utility in patients without prostate specific antigen progression or an adverse event was 0.742, similar to previously published utilities for nonprogressed prostate cancer states. Prostate specific antigen progression was associated with a utility decrement of between 0.062 and 0.134 depending on the mapping algorithm used. Of adverse events considered in our analysis musculoskeletal events were associated with the greatest effects on patient utility with a decrement of between 0.029 and 0.086. The 4 mapping algorithms generated similar utility estimates, although values derived from SF-12 were consistently lower than those derived from EORTC QLQ-C30.. Prostate specific antigen progression status and the incidence of treatment and disease related adverse events result in significant decrements to patient health related quality of life. By slowing prostate specific antigen progression degarelix may improve patient utility and the health related quality of life burden.

Topics: Aged; Aged, 80 and over; Algorithms; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Surveys and Questionnaires

Gonadotropin-releasing hormone (GnRH) agonists are widely used in hormone therapy for prostate cancer. We report a patient with pituitary apoplexy following this therapy as a rare complication and review the related literature. A 62-year-old man presented with elevated prostate specific antigen. Transrectal ultrasound guided biopsy of the prostate gland revealed adenocarcinoma. Whole-body (18)F-fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed FDG-uptake in the pituitary region. MRI also demonstrated a pituitary tumor, diagnosed as an incidental non-functioning adenoma. The patient received his first dose of GnRH agonist (leuprolide 11.25mg) against prostate cancer. He complained of a severe headache 10 minutes after leuprolide administration and suffered from right third nerve palsy in the next 48 hours. MRI demonstrated a high intensity area on T1-weighted images, diagnosed as pituitary apoplexy. The patient underwent transsphenoidal surgery. Pathology revealed predominantly necrotic tissue and a gonadotropin secreting pituitary adenoma. Overall, 15 patients, including ours, have been reported with pituitary apoplexy after GnRH agonists with pathologic gonadotropin secreting adenoma. Fourteen of 15 patients were male. Pituitary apoplexy developed within 4 hours after administration of the agents in 8/15 patients. The combined data suggest that GnRH agonists have the potential to precipitate pituitary apoplexy in men with gonadotropin secreting adenoma. Therefore, prior to GnRH agonist therapy for prostate cancer, a known pituitary adenoma should be treated. Otherwise, the patients should be cautiously observed for any symptomatic change following drug administration.

Topics: Adenocarcinoma; Adenoma; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Apoplexy; Pituitary Neoplasms; Prostatic Neoplasms

To compare treatment costs with alternative luteinizing hormone-releasing hormone (LHRH) agonist preparations and determine whether a leuprorelin solid implant is associated with potential cost savings.. A hypothetical population of 1000 prostate cancer patients was apportioned between the three most commonly-prescribed LHRH agonist preparations. Differentiated annual costs for 1- and 3-monthly formulations were calculated for France, Germany, Italy, Spain, the UK (EU5) and Sweden, and compared with the leuprorelin solid implant.. Compared with alternative formulations, leuprorelin solid implants had potential annual cost savings/1000 patients of €353,000 (EU5) and €699,000 (Sweden; 1-month formulations), and €259,000 (EU5) and €300,000 (Sweden; 3-month formulations).. The leuprorelin solid implant was associated with potential cost savings compared with the most commonly used LHRH agonist preparations.

Topics: Antineoplastic Agents, Hormonal; Drug Implants; Humans; Internationality; Leuprolide; Male; Prostatic Neoplasms

The optimal treatment for high-risk prostate cancer (Pca) remains to be established. We previously reported favorable biochemical recurrence-free survival (BRFS) in high-risk Pca patients treated with a neoadjuvant therapy comprising a luteinizing-hormone-releasing hormone (LHRH) agonist plus low dose estramustine phosphate (EMP) (LHRH+EMP) followed by radical prostatectomy (RP). In the present study, we used a retrospective design via propensity score matching to elucidate the clinical benefit of neoadjuvant LHRH+EMP for high-risk Pca.. The Michinoku Urological Cancer Study Group database contained data for 1,268 consecutive Pca patients treated with RP alone at 4 institutions between April 2000 and March 2011 (RP alone group). In the RP alone group, we identified 386 high-risk Pca patients. The neoadjuvant LHRH+EMP group included 274 patients with high-risk Pca treated between September 2005 and November 2013 at Hirosaki University. Neoadjuvant LHRH+EMP therapy included LHRH and EMP administration at a dose of 280 mg/day for 6 months before RP. The outcome measures were overall survival (OS) and BRFS.. The propensity score-matched analysis indicated 210 matched pairs from both groups. The 5-year BRFS rates were 90.4 and 65.8 % for the neoadjuvant LHRH+EMP and RP alone groups, respectively (P < 0.0001). The 5-year OS rates were 100 and 96.1 % for the neoadjuvant LHRH+EMP and RP alone groups, respectively (P = 0.110).. Although the present study was not randomized, neoadjuvant LHRH+EMP therapy followed by RP appeared to reduce the risk of biochemical recurrence. A prospective randomized study is warranted to determine the clinical implications of the neoadjuvant therapy described here.

Topics: Aged; Antineoplastic Agents, Hormonal; Estramustine; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Propensity Score; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Retrospective Studies; Survival Analysis

Topics: Adenocarcinoma; Aged, 80 and over; Antineoplastic Agents, Hormonal; Biopsy; Humans; Leuprolide; Male; Phlebography; Positron-Emission Tomography; Prostatic Neoplasms; Superior Vena Cava Syndrome; Tomography, X-Ray Computed; Treatment Outcome; Vascular Neoplasms

We investigated the incidence of granuloma and its related factors in 180 patients with prostate cancer who showed subcutaneous granuloma formation during androgen deprivation therapy with subcutaneously administered leuprorelin acetate. A granuloma was defined as a persistent induration over 30 mm in diameter in the injected portion. Small indurations which often developed and disappeared after every injection were excluded. The survey was performed using a questionnaire after receiving written informed consent. Among the 180 patients with prostate cancer, 21 (11.7%) developed a granuloma at the injection portion, and subsequently the injection of leuprorelin acetate had to be discontinued. Eighteen of the 21 patients alternatively received goserelin acetate. Three patients had high-grade granulomas with ulcer and abscess formation, and were successfully treated with oral antibiotics. The average duration between the first injection of leuprorelin acetate and granuloma formation was 20.2 months (range : 4 to 62 months). There was no association between granuloma formation and patient backgrounds, such as allergic predisposition and past history. Twenty-one of the 180 prostatic cancer patients developed subcutaneous granuloma induced by the injection of leuprorelin acetate. The investigation showed an unexpectedly high incidence of granuloma formation. We must explain the risk of developing subcutaneous granuloma to the patients before introducing leuprorelin acetate.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Granuloma; Humans; Incidence; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Retrospective Studies; Risk Factors; Surveys and Questionnaires

Androgen deprivation therapy (ADT) is a standard treatment for patients with aggressive prostate cancer. Although ADT improves survival, it increases the risk of diabetes. Emerging evidence suggests that ADT increases adverse cardiovascular events as early as 3 months after initiation in patients with cardiovascular disease, but the mechanism is unknown. We hypothesized that ADT may impair endothelium-dependent vasodilation due to increases in lipids and insulin resistance and may provide a link for heightened cardiovascular risk in this population.. We prospectively evaluated conduit artery endothelium-dependent and -independent vasodilation, lipids, and insulin resistance in 16 consecutively treated men (mean age 66 ± 7 years; 25% with diabetes) with prostate cancer before and after 3 months of ADT. High-resolution B-mode ultrasound was used to assess flow-mediated (endothelium-dependent) and nitroglycerine-mediated (endothelium-independent) brachial artery vasodilation. ADT significantly increased insulin resistance, total cholesterol, HDL, and LDL. Endothelium-dependent vasodilation was greater at 3 months than at baseline (10.8% [interquartile range: 7.7% to 14.6%] versus 8.9% [interquartile range: 4.0% to 12.6%], respectively; P=0.046, allometric P=0.037). Nitroglycerine-mediated vasodilation did not change from baseline (P>0.2). The subset of participants on ADT for 6 months returned for reevaluation at 1 year. In this group, endothelium-dependent vasodilation increased from baseline to 3 months and returned to baseline 6 months after ADT withdrawal (9.4% [interquartile range: 6.9% to 10.9%], 11.6% [interquartile range: 7.9% to 15.2%], and 9.0% [interquartile range: 5.1% to 12.5%], respectively; P=0.05).. In contrast to our expectation, ADT improved endothelium-dependent vasodilation and its cessation returned endothelium-dependent vasodilation to baseline. Determining the mechanism of this change requires further investigation.

Topics: Aged; Androgen Antagonists; Anilides; Brachial Artery; Drug Therapy, Combination; Endothelium, Vascular; Humans; Leuprolide; Male; Nitriles; Prostatic Neoplasms; Tosyl Compounds; Vasodilation

Several abstracts presented at the 2015 European Association of Urology Meeting highlighted new developments in hormone therapy for prostate cancer management. One abstract described how the luteinizing hormone-releasing hormone (LHRH)/gonadotropin-releasing hormone (GnRH) agonist leuprolide, but not the LHRH/GnRH antagonist degarelix, induced plaque instability in a mouse model. A second abstract showed that in patients with a history of severe cardiovascular disease, degarelix was associated with fewer cardiovascular events than treatment with an LHRH agonist. A third abstract showed how primary androgen-deprivation therapy was linked with increased all-cause mortality in a US registry. A fourth abstract showed that in the ANAMEN study, cognitive performance was not significantly affected by 6 months of treatment with GnRH agonists. Last, a fifth abstract showed that low-dose prednisone, with or without abiraterone, was associated with an overall low incidence of corticosteroid-associated adverse events.

Topics: Abiraterone Acetate; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cognition; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Mice; Mortality; Myocardial Infarction; Oligopeptides; Prednisone; Prostatic Neoplasms; Risk Assessment; Stroke

Topics: Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Oligopeptides; Prostatic Neoplasms

Leuprorelin is indicated for the palliative treatment of advanced prostate cancer (APC) and is available as 1, 3, 4 and 6-monthly injections. There are advantages of longer leuprorelin injection intervals in the treatment of APC. Across all injection intervals, efficacy is similar and the majority of patients achieve testosterone suppression and normalisation of prostate-specific antigent. Treatment is well tolerated. Six-monthly leuprorelin injections are less costly to the healthcare system than the shorter interval injections.

Topics: Antineoplastic Agents, Hormonal; Drug Administration Schedule; Humans; Injections; Leuprolide; Male; Palliative Care; Prostatic Neoplasms; Risk Assessment

The authors describe a male patient who developed a large intracranial meningioma during the hormone therapy for pre-existing prostate cancer. A 70-year-old man received a brain check-up, and no intracranial abnormality was detected. Five months later, prostate cancer was diagnosed, and he underwent prostatectomy. Leuprorelin acetate, a luteinizing hormone-releasing hormone (LH-RH) agonist, was subsequently administered to the patient once a month for 3 years. After that he presented with a large parasagittal mass, which was excised. The tumor was histologically diagnosed as meningothelial meningioma, and LH-RH receptors were verified immunohistochemically in the cytoplasm of the tumor cells. Leuprorelin acetate may accelerate the rapid growth of meningioma in this patient.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Gastrectomy; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Meningeal Neoplasms; Meningioma; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Neoplasms, Second Primary; Nitriles; Prostatectomy; Prostatic Neoplasms; Receptors, LH; Stomach Neoplasms; Tosyl Compounds

The aim of the study was to examine the effect of androgen deprivation drugs, i.e. leuprolide and bicalutamide on the immune cross-talk between human peripheral blood mononuclear cells (PBMC) and cells from PC-3 and LNCaP human prostate cancer lines. PBMC, PC-3 and LNCaP were separately incubated without and with two androgen-deprivation drugs, i.e. leuprolide and bicalutamide, and the secretion of IL-1β, IL-6, IL-1ra and IL-10 was examined. In addition, the effect of both drugs on the production of those cytokines was carried out after 24 hours incubation of PBMC with both types of cancer cells. Leuprolide or bicalutamide did not affect the production of the cytokines by PBMC or by the prostate cancer cells from the two lines. Incubation of PBMC with PC-3 or LNCaP cells caused increased production of IL-1β, IL-6 and IL-10 as compared with PBMC incubated without malignant cells. While 10(-7) M and 10(-8) M of leuprolide caused a decreased secretion of IL-1β by PBMC previously incubated with prostate cancer cells without the drug, bicalutamide did not affect this PBMC activity at any drug concentration. This observation suggests the existence of an additional mechanism explaining the effect of androgen deprivation therapy in prostate cancer patients.

Topics: Androgen Antagonists; Anilides; Antineoplastic Agents; Cell Communication; Cell Line, Tumor; Cytokines; Dose-Response Relationship, Drug; Humans; Interleukins; Leukocytes, Mononuclear; Leuprolide; Male; Nitriles; Prostatic Neoplasms; Tosyl Compounds

Topics: Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Nitriles; Prostate; Prostatic Neoplasms; Tosyl Compounds

To clarify clinical predictors for a prostate-specific antigen decrease ≥50% in response to alternative non-steroidal antiandrogen therapy and to develop a nomogram to predict the prostate-specific antigen decrease ≥50% in response to alternative non-steroidal antiandrogen therapy in patients with advanced prostate cancer that relapsed after initial combined androgen blockade. We previously reported that combined androgen blockade with an alternative non-steroidal antiandrogen is effective for advanced prostate cancer that has relapsed after initial combined androgen blockade.. We enrolled 161 patients from 14 medical institutions with histologically confirmed prostate cancer who had been treated with combination therapy and in whom cancer progressed after first-line combined androgen blockade therapy. A nomogram for the prostate-specific antigen decrease ≥50% from baseline prostate-specific antigen in response to alternative non-steroidal antiandrogen therapy was developed based on the final logistic regression model.. Overall prostate-specific antigen decreased ≥50% in 75 of 161 patients (46.6%) in response to alternative non-steroidal antiandrogen therapy. Using five independent risk factors (initial serum level of prostate-specific antigen, hemoglobin, C-reactive protein, prostate-specific antigen nadir to second hormone therapy and Gleason sum), a nomogram was developed for the prediction of prostate-specific antigen decrease ≥50% in response to alternative non-steroidal antiandrogen therapy. The receiver operating characteristic curve showed that the accuracy of the predicted probability was 72.5% for the model.. This predictive nomogram could predict the prostate-specific antigen decrease ≥50% in response to alternative non-steroidal antiandrogen therapy and might be of benefit to determine the sequential treatment strategy in patients with relapse after first combined androgen blockade.

Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; C-Reactive Protein; Cohort Studies; Disease Progression; Drug Administration Schedule; Goserelin; Humans; Kaplan-Meier Estimate; Leuprolide; Male; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Nomograms; Predictive Value of Tests; Prostate-Specific Antigen; Prostatic Neoplasms; Reproducibility of Results; Retrospective Studies; ROC Curve

To observe the clinical effect of tashinone IIA combined with endocrine therapy in treating advanced-stage prostate cancer. 96 cases of advanced-stage prostate cancer were divided into observation group (44 cases received treatment) and control group (46 cases received treatment). Control group was given leuprolide acetate 3.75 mg hypodermic injection per month, combined with bicalutamide 50 mg per os per day for a 6-month treatment course. Observation group was given tashinone IIA injection 60 mg intravenously per day. They were treated for 2 weeks and paused for 2 weeks as one treatment course for six courses in total. After treating for 6 months, the general therapeutic effect, prostate-specific antigen (PSA), free prostate-specific antigen (f-PSA), hemoglobin (Hb), the quality of life questionnaire Core 30 (QLQ-C30), traditional Chinese medicine symptom information score, international prostate symptom score (I-PSS), and adverse effect rate were observed. The effective rate of observation group and control group was 52.3 and 28.3 %, respectively (P < 0.05). PSA, f-PSA, and Hb in two groups had no statistical difference before treatment. PSA and f-PSA in both groups obviously decreased compared to those before treatment, and they were lower in observation group than in control group (P < 0.01). Hb in observation group was higher than before treatment, whereas Hb in control group was lower than before treatment (P < 0.01). Life quality, motive score, the traditional Chinese medicine symptom score, and I-PSS in observation group were significantly better those that in control group after treatment (P < 0.01). Laboratory tests such as hemogram, and liver and kidney function had no obvious change, and adverse effect rate had no statistical difference. Routine endocrine treatment combined with tashinone IIA can enhance the clinical effects on treating advanced-stage prostate cancer and improve the clinical symptom score.

Topics: Aged; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Hemoglobins; Humans; Leuprolide; Male; Neoplasm Staging; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Tosyl Compounds; Treatment Outcome

To determine the cost-effectiveness of the treatment of advanced hormone-dependent prostate cancer with degarelix compared to luteinizing hormone-releasing hormone (LHRH) agonists in the UK using the latest available evidence and the model submitted to AWMSG.. A cost-effectiveness model was developed from the perspective of the UK National Health Service evaluating monthly injection of degarelix against 3-monthly leuprorelin therapy plus anti-androgen flare cover for the first-line treatment of patients with advanced (locally advanced or metastatic) hormone-dependent prostate cancer. A Markov process model was constructed using the patient population characteristics and efficacy information from the CS21 Phase III clinical trial and associated extension study (CS21A). The intention-to-treat (ITT) population and a high-risk sub-group with a PSA level >20 ng/mL were modeled.. In the base-case analysis using the patient access scheme (PAS) price, degarelix was dominant compared to leuprorelin with cost savings of £3633 in the ITT population and £4310 in the PSA > 20 ng/mL sub-group. The chance of being cost-effective was 95% in the ITT population and 96% in the PSA > 20 ng/mL sub-group at a threshold of £20,000 per quality-adjusted life-year (QALY). In addition, degarelix remained dominant when PSA progression was assumed equal and only the benefits of preventing testosterone flare were taken into account. Treatment with degarelix also remained dominant in both populations when the list price was used. The additional investment required to treat patients with degarelix could be offset in 19 months for the ITT population and 13 months for the PSA > 20 ng/mL population. The model was most sensitive to the hazard ratio assumed for PSA progression between degarelix and leuprorelin and the quality-of-life (utility) of patients receiving palliative care.. Degarelix is likely to be cost-effective compared to leuprorelin plus anti-androgen flare cover in the first-line treatment of advanced hormone-dependent prostate cancer.

Topics: Antineoplastic Agents, Hormonal; Clinical Trials, Phase III as Topic; Cost-Benefit Analysis; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Markov Chains; Models, Economic; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Quality-Adjusted Life Years; United Kingdom

The aim of this study was to evaluate bone mass changes after 1 year of four different types of pharmacological intervention. Ninety-seven prostate cancer patients treated with androgen deprivation therapy, and severe osteopenia or osteoporosis were retrospectively studied. Patients were divided in four groups. Group 1: 28 patients treated with denosumab, Group 2: 24 patients treated with alendronate, Group 3: 24 patients with no antiresorptive treatment and Group 4: 21 patients previously treated with alendronate and switched to denosumab. Dual X-ray absorptiometry was performed at baseline and after 1 year. Bone mass changes at the L2-L4 lumbar spine, femoral neck and total hip were evaluated. No differences were found at baseline. After 1 year, men receiving denosumab or alendronate (Group 1 and 2) showed a significant bone mass increase at the lumbar spine (+2.4 and +5.0 %, respectively), while no significant changes were observed in Group 3 and 4. At the femoral neck, Group 1 and 2 patients showed a significant bone mass increase (+3.7 and +3.6 %, respectively), while no significant changes were observed in Group 3 and 4. At the total hip, we observed a significant bone mass increase in Group 1 (+2.9 %) and a significant bone mass loss in Group 3 patients (-1.9 %). No significant changes were observed in Group 2 and 4. Denosumab increased significantly bone mass in all three dual X-ray absorptiometry standard sites, while alendronate did not at total hip. No benefit was observed in men previously treated with alendronate who switched to denosumab treatment.

Topics: Aged; Aged, 80 and over; Alendronate; Androgen Antagonists; Anilides; Antibodies, Monoclonal, Humanized; Bone Density Conservation Agents; Bone Diseases, Metabolic; Denosumab; Femur Neck; Humans; Leuprolide; Lumbar Vertebrae; Male; Nitriles; Osteoporosis; Prostatic Neoplasms; Radiography; Tosyl Compounds

Gonadotropin analogs like leuprolide play an important role in the management of prostate cancer. Pituitary apoplexy has been reported after leuprolide therapy. This report examines whether the presence of a pituitary tumor is a contraindication for leuprolide therapy in patients with prostate cancer.. Two patients with prostate cancer and pituitary tumors were treated with leuprolide and radiation therapy. The first patient with a previously unknown pituitary adenoma had a leuprolide injection for prostate gland downsizing prior to brachytherapy. The second patient with a known pituitary microadenoma had a biochemical recurrence and was treated with leuprolide and radiation therapy.. The first patient developed symptoms of apoplexy a few hours after the leuprolide injection. He underwent a transsphenoidal resection of the sellar mass with complete neurologic recovery. The second patient did not have any adverse events after leuprolide with follow-up MRI scans showing no growth of the microadenomas.. The presence of a pituitary tumor is not a contraindication for leuprolide therapy. While patients with a macroadenoma should have surgery first, those with a microadenoma may be considered for leuprolide therapy after careful evaluation by a multidisciplinary team.

Topics: Aged; Antineoplastic Agents, Hormonal; Contraindications; Humans; Leuprolide; Male; Middle Aged; Neoplasms, Multiple Primary; Pituitary Apoplexy; Pituitary Neoplasms; Prostatic Neoplasms

Kisspeptin/metastin, a hypothalamic peptide, plays a pivotal role in controlling gonadotropin-releasing hormone (GnRH) neurons, and we have shown that continuous subcutaneous administration of kisspeptin analogues suppresses plasma testosterone in male rats. This study examined pharmacologic profiles of investigational kisspeptin analogues, TAK-448 and TAK-683, in male rats. Both analogues showed high receptor-binding affinity and potent and full agonistic activity for rat KISS1R, which were comparable to natural peptide Kp-10. A daily subcutaneous injection of TAK-448 and TAK-683 (0.008-8μmol/kg) for consecutive 7 days initially induced an increase in plasma luteinizing hormone and testosterone levels; however, after day 7, plasma hormone levels and genital organ weights were reduced. Continuous subcutaneous administrations of TAK-448 (≥10pmol/h, ca. 0.7nmol/kg/day) and TAK-683 (≥30pmol/h, ca. 2.1nmol/kg/day) induced a transient increase in plasma testosterone, followed by abrupt reduction of plasma testosterone to castrate levels within 3-7 days. This profound testosterone-lowering effect was sustained throughout 4-week dosing periods. At those dose levels, the weights of the prostate and seminal vesicles were reduced to castrate levels. These suppressive effects of kisspeptin analogues were more rapid and profound than those induced by the GnRH agonist analogue leuprolide treatment. In addition, TAK-683 reduced plasma prostate specific antigen (PSA) in the JDCaP androgen-dependent prostate cancer rat model. Thus, chronic administration of kisspeptin analogues may hold promise as a novel therapeutic approach for suppressing reproductive functions and hormone-related diseases such as prostate cancer. Further studies are warranted to elucidate clinical significance of TAK-448 and TAK-683.

Topics: Animals; Antineoplastic Agents; Calcium; CHO Cells; Cricetulus; Kisspeptins; Leuprolide; Luteinizing Hormone; Male; Organ Size; Prostate; Prostatic Neoplasms; Rats, Inbred F344; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Seminal Vesicles; Testis; Testosterone

Leuprolide acetate, a gonadotropin-releasing hormone agonist, is used in the treatment of prostate cancer. We report a unique case of a disseminated papular rash following leuprolide acetate injections in a 65-year-old man that shares clinical and histopathological features of papuloerythroderma of Ofuji. Leuprolide-induced papuloerythroderma, as well as a limited number of other disseminated cutaneous eruptions caused by this drug, is extremely rare, with only one case previously reported. Our case calls attention to this uncommon side effect in a commonly used hormonal therapy.

Topics: Aged; Antineoplastic Agents, Hormonal; Drug Eruptions; Humans; Leuprolide; Male; Prostatic Neoplasms

Topics: Antineoplastic Agents, Hormonal; Benzamides; Biomarkers, Tumor; Humans; Leuprolide; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Selective Estrogen Receptor Modulators; Testosterone

Therapeutic planning and counseling for advanced prostate cancer patients receiving androgen deprivation therapy (ADT) is complicated because the prognoses are highly variable. The purpose of this study is to identify predictive clinical indicators of biochemical progression (BCP). In this retrospective analysis, data from 107 newly diagnosed patients (from November 1995 to April 2008) with advanced prostate adenocarcinoma receiving Leuprorelin acetate depot were analyzed. Data was collected from the computerized registry of two collaborating medical centers in Taiwan. Cox regression and Kaplan-Meier analyses were used to evaluate the relationship between potential predictive parameters and BCP. Univariate analysis revealed that predictors of BCP included (1) initial serum prostate-specific antigen (PSA) (hazard ratio [HR], 1.00; 95% confidence interval [CI] 1.00-1.00); (2) log of initial PSA (HR, 1.35; 95% CI 1.17-1.56); (3) PSA density at diagnosis (HR, 1.00; 95% CI 1.00-1.01), and (4) pathological bone fracture (HR, 2.22; 95% CI 1.20-4.11). Age (HR, 0.94; 95% CI 0.91-0.98) and hemoglobin levels (HR, 0.86; 95% CI 0.76-0.97) were also associated with greater risk of BCP. After adjusting for age, pathologic fracture, and hemoglobin level, the initial PSA and PSA density were no longer significantly associated with BCP. However, age and hemoglobin levels continued to be associated with greater risk of BCP (P ≤ 0.007). Using Kaplan-Meier analysis, patients with higher initial PSA concentration, pathological bone fracture, and low hemoglobin had a greater probability of BCP. Thus, low hemoglobin and age are predictive indicators of BCP and therefore early indicators of BCP despite ADT therapy.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Delayed-Action Preparations; Humans; Leuprolide; Male; Middle Aged; Prognosis; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms

We experienced a case of granuloma formation by subcutaneous injection of leuprorelin acetate for treatment of prostate cancer. This patient was an 80-year-old man visiting the clinic of gastroenterological surgery as an outpatient after gastric cancer surgery with a one-week's history of rash on the abdomen. Based on the history of gastric cancer and prostate cancer, though ultrasonography and CT were performed, the possibility of metastatic skin tumor could still not be ruled out. Finally, finding of a foreign-body granuloma in the subcutaneous adipose tissue was recognized histological. Then, an interview with the patient revealed that he had received subcutaneous injection of a 3-month depot formulation of leupurorelin acetate at the site of the lesion about two months earlier. Among urologists, as side effects for treatment, foreign body granuloma induced by subcutaneous injection of leuprorelin maybe well known. Therefore, it is tried to analyze as to clinical findings, especially granuloma formation for 335 cases that received leuprorelin acetate treatment at our hospital. In this report, we analyzed reported case and 335 cases that received leuprorelin acetate treatment at our hospital and summarized the cases that developed the granuloma formation by it.

Topics: Aged, 80 and over; Antineoplastic Agents, Hormonal; Granuloma, Foreign-Body; Humans; Injections, Subcutaneous; Leuprolide; Male; Prostatic Neoplasms; Skin; Tomography, X-Ray Computed

Topics: Adenocarcinoma; Anilides; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Bone Neoplasms; Diagnosis, Differential; Fatigue; Glucocorticoids; Humans; Leuprolide; Male; Middle Aged; Nitriles; Plasma Exchange; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Purpura; Purpura, Thrombotic Thrombocytopenic; Thoracic Vertebrae; Tomography, X-Ray Computed; Tosyl Compounds; Treatment Outcome

Topics: Humans; Leuprolide; Male; Oligopeptides; Prostatic Neoplasms

Topics: Humans; Leuprolide; Male; Oligopeptides; Prostatic Neoplasms

Topics: Adenocarcinoma; Androgen Antagonists; Antineoplastic Agents, Hormonal; Bone Density Conservation Agents; Brachytherapy; Diphosphonates; Humans; Imidazoles; Leuprolide; Male; Prostatic Neoplasms; Quality of Life

This study set out to examine the efficacy and tolerability of two innovative implant forms of leuprorelin acetate in men with advanced hormone-dependent prostate cancer in everyday clinical practice.. Data were collected from 818 patients (from 273 centers across Germany) who were pretreated with slow-release luteinizing hormone-releasing hormone (LHRH) agonist formulations and who were about to be switched to the leuprorelin implants. Patients received three injections of 1- or 3-month leuprorelin implant and physicians were asked to complete a case report form specific to each of the three clinic visits. Documented parameters included laboratory measurements, such as testosterone and prostate-specific antigen (PSA) levels, adverse events, and patient- and physician-rated assessments of the therapy.. Compared with baseline, a significant decrease in both testosterone and PSA levels were measured after the first and second injections of leuprorelin implant. These results were confirmed for both the 1-month and 3-month implants in separate analyses. Switching, without treatment interruption, from Trenantone® (Takeda Pharma GmBH, Aachen, Germany) to the leuprorelin implant resulted in a significant decrease in the mean serum testosterone concentrations (P < 0.05) and a nonsignificant increase in the proportion of patients reaching castrate testosterone levels, while the number of patients with PSA values ≤ 4 ng/mL significantly increased (P = 0.045). Similar results were obtained for patients previously treated with goserelin who switched to leuprorelin implant. For 94% of patients, treating physicians rated the efficacy of leuprorelin implant as "very good" or "good." Treatment with leuprorelin implant was well tolerated, with only 61 adverse events reported in 42 (5.1%) patients. Patients and physicians rated the tolerability of leuprorelin implant as "very good" or "good" in 95% and 91% of cases, respectively.. These results confirm the efficacy, tolerability, and ease of use of the leuprorelin implants among a large population of men with advanced, hormone-dependent prostate cancer treated in a clinical practice setting.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Drug Implants; Humans; Kallikreins; Leuprolide; Male; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Outcome

To evaluate the relationship between the body mass index (BMI) and serum testosterone concentrations in men receiving luteinizing hormone-releasing hormone (LHRH) agonist therapy for prostate cancer.. A total of 66 white men were included in the present study. All subjects had received LHRH agonist therapy for ≥ 3 months. The BMI was calculated, and the subjects were classified as normal weight (i.e. BMI <25 kg/m(2)), overweight (BMI 25-30 kg/m(2)), or obese (BMI >30 kg/m(2)). The serum testosterone concentration was determined using the highly sensitive isotope dilution-liquid chromatography-tandem mass spectrometry technique. The sex hormone-binding globulin level was determined using an immunometric assay, and the free serum testosterone concentration was calculated.. The median serum testosterone concentration of the patients with a BMI <25 kg/m(2) was 5.5 ng/dL. The patients with a BMI of 25-30 kg/m(2) had a median serum testosterone concentration of 3.8 ng/dL. Those patients with a BMI >30 kg/m(2) had a median concentration of 5.7 ng/dL. No significant difference in the serum testosterone concentrations among the 3 groups was found. The sex hormone-binding globulin levels declined with an increasing BMI. The concentration of free testosterone was significantly greater in the obese men.. Using an ultrasensitive technique of serum testosterone measurement, the present data have shown that no difference exists in the serum testosterone concentration in the castrate range among normal weight, overweight, and obese patients receiving LHRH agonist therapy for prostate cancer. From our findings and current knowledge, more stringent follow-up or changes in dosage or dosage intervals of LHRH agonist therapy in those with a greater or high BMI is not warranted.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Body Mass Index; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Mass Spectrometry; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Outcome

Topics: Antineoplastic Agents, Hormonal; Combined Modality Therapy; Humans; Leuprolide; Male; Orchiectomy; Prostatic Neoplasms

Androgen deprivation is a cornerstone in prostate cancer management. We present a 69-year-old man, with a poorly differentiated prostate cancer with skeletal and lymph node metastases. After medical and subsequent surgical castration serum testosterone concentrations remained inappropriately high (4.9 and 4.5 nmol/L; castration range < 0.5). For cancer staging a CT was performed which showed bilateral adrenal enlargement. Endocrine workup revealed elevated levels of adrenal androgens and adrenal precursors. Mutation analysis confirmed a non-classical 21-hydroxylase deficiency, that is, a mild form of congenital adrenal hyperplasia (CAH). To suppress adrenocorticotrophic hormone and the excess adrenal androgen secretion, treatment with hydrocortisone and prednisolone was started with success. Inadequate testosterone suppression after castration due to previously undiagnosed CAH has not previously been reported. Considering the estimated prevalence of 1% in selected populations, non-classical CAH should be considered when testosterone is not adequately suppressed after castration in men with prostate cancer.

Topics: Aged; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Nitriles; Orchiectomy; Prostatic Neoplasms; Testosterone; Tosyl Compounds

We present the first Asian case of a 77-year-old man who developed pituitary apoplexy (PA) soon after gonadotropin-releasing hormone agonist (GnRHa) (leuprorelin) injection to treat prostate cancer. Headache, ophthalmoplegia, visual field deficit, nausea, and vomiting are the typical characteristics of pituitary apoplexy. Though the occurrence rate is rare, the consequence of this condition can vary from mild symptoms such as headache to life-threatening scenarios like conscious change. Magnetic resonance imaging is the best imaging modality to detect PA and sublabial trans-sphenoid pituitary tumor removal can resolve most of PA symptoms and is so far the best solution in consensus. We also review 11 previous reported cases receiving GnRHa for androgen deprivation therapy of prostate cancer, and hope to alert clinicians to use GnRHa with caution.

Topics: Aged; Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Pituitary Apoplexy; Pituitary Neoplasms; Prognosis; Prostatic Neoplasms; Tomography, X-Ray Computed

The objective of this study was to assess complex skeletal and metabolic changes in a single cohort of PCa patients taking long-term ADT.. Ninety-five patients with locally advanced PCa (mean age 73.3 ± 6.2 years) were treated with ADT for 24 months. Body mass index (BMI), waist-to-hip ratio (WHR), lipid profile, serum fasting glucose (SFG), and bone mineral density (BMD) of lumbar spine (L1-L4), femoral neck, and total hip BMD were examined at the baseline, and then every 12 months. These measurements were also made to the control group of 88 patients (mean age, 71.9 ± 6.7 years).. After 12 months of ADT, BMI, WHR, low-density lipoprotein, overall cholesterol, and SFG increased significantly; and total hip BMD and BMD L1-L4 decreased significantly in the study group. After 24 months of ADT, BMI, WHR, and SFG increased significantly. BMD was significantly lower in L1-L4, femoral neck, and total hip. Four patients (4.2%) were diagnosed with new onset diabetes. Overall, the incidence of fractures after 24 months of ADT was 7-fold higher in the study group.. ADT leads into unfavorable changes in body composition, unfavorable lipoprotein profile, increase in SFG level and decrease in BMD. The incidence of fractures was 7-fold higher in the study group.

Topics: Aged; Antineoplastic Agents, Hormonal; Blood Glucose; Body Mass Index; Bone Density; Case-Control Studies; Combined Modality Therapy; Femur Neck; Fractures, Bone; Hip; Humans; Leuprolide; Lipid Metabolism; Lipids; Male; Prostatic Neoplasms; Waist-Hip Ratio

To investigate whether prostate cancer patients receiving leuprolide demonstrated objective cognitive decline accompanied by a change in plasma levels of amyloid-β.. Between November 19, 2003, and July 21, 2008, we prospectively enrolled 50 patients with biochemical recurrence of prostate cancer and measured plasma amyloid-β peptide 40 and amyloid-β peptide 42 levels with sandwich enzyme-linked immunosorbent assay at baseline before the first leuprolide injection and at 2, 4, and 12 months. The Mini-Mental State Examination was used to assess 49 patients at baseline and at subsequent visits, and 24 were also assessed by the California Verbal Learning Test-Short Form.. Patients were a median age of 71 years (range, 59-89 years). Compared with baseline levels, plasma amyloid-β peptide 40 levels were increased at 2 months (P=.04) and 4 months (P=.02). Age was correlated with plasma amyloid-β peptide 40 levels (P=.003) and likely accounted for this relationship. Plasma amyloid-β peptide 42 and performance on cognitive tasks did not differ from baseline, but memory measures improved slightly after baseline, most likely due to a practice effect.. Leuprolide therapy was not associated with a decline in cognition or memory function or with elevated plasma amyloid short-term. Larger studies are needed to confirm these findings.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Antineoplastic Agents, Hormonal; Cognition; Humans; Leuprolide; Male; Memory; Mental Status Schedule; Middle Aged; Neoplasm Recurrence, Local; Peptide Fragments; Prostatic Neoplasms

Topics: Amyloid beta-Peptides; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Memory; Neoplasm Recurrence, Local; Peptide Fragments; Prostatic Neoplasms

High cell-surface GnRH receptor (GnRH-R) levels have been shown to have a major influence on the extent of GnRH agonist-mediated tumor growth inhibition. The ability of the GnRH agonist leuprorelin acetate (LA) to induce a post-transcriptional upregulation of GnRH-R at the plasma membrane of androgen-sensitive (LNCaP) and -insensitive (PC-3) prostate cancer (PCa) cells has been previously demonstrated by Western blotting. Here we performed single molecule force spectroscopy by using Atomic Force Microscopy (AFM), which has proven to be a powerful tool allowing for investigation of living cell surface biological features, such as the so far unclear GnRH agonist/receptor interaction. Thus, in the hormone-insensitive PC-3 cells, we characterized the strength of the LA-receptor binding, and the amount and distribution of the functional receptor molecules on the cell surface. The effect of a long and continuous treatment (up to 30 days) with the agonist (10(-11) and 10(-6) M) on the same parameters was also investigated. A GnRH-R increase was observed, reaching the maximum (∼80%) after 30 days of treatment with the highest dose of LA (10(-6) M). The analogue-induced increase in GnRH-R was also demonstrated by Western blotting. In addition, two different receptor bound strengths were detected by AFM, which suggests the existence of two GnRH-R classes. A homogeneous distribution of the unbinding events has been found on untreated and treated PC-3 cell surfaces. The persistence of high receptor levels at the membrane of these living cells may warrant the maintenance of the response to LA also in androgen-unresponsive PCa. Moreover, the determination of ligand/receptor bond strength could shed light on the poorly understood event of LA/GnRH-R interaction and/or address structural/chemical agonist optimizations.

Topics: Antineoplastic Agents, Hormonal; Binding Sites; Binding, Competitive; Blotting, Western; Cell Line, Tumor; Gonadotropin-Releasing Hormone; HEK293 Cells; Humans; Leuprolide; Male; Microscopy, Atomic Force; Prostatic Neoplasms; Receptors, LHRH

Prostate cancer is rarely associated with leptomeningeal metastasis. An 87-year-old man with a history of prostate cancer presented with leptomeningeal metastasis. He received hormonal therapy with leuprolide. Subsequently, he achieved an impressive response, indicated by a constant fall in his PSA levels and by the stabilization of leptomeningeal disease and clinical improvement. Hormonal therapy may be effective in inducing remission in hormone-sensitive prostate cancer with leptomeningeal metastasis.

Topics: Aged, 80 and over; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Meningeal Neoplasms; Neoplasms, Hormone-Dependent; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Remission Induction

Patients receiving androgen deprivation therapy undergo a rapid decline in bone mineral density during the first 6 to 12 months of initiating therapy. The World Health Organization has developed and implemented the Fracture Risk Assessment Tool (FRAX) to predict the ten year risk of a major fracture & hip fracture. Additionally, the National Comprehensive Cancer Network and the National Osteoporosis Foundation have developed osteoporosis guidelines. This study aims to characterize the fracture risk (based on the FRAX tool) and the current management of bone health based on national guidelines compliance.. A retrospective chart review of patients receiving a LHRH agonist at our institution was conducted. Data collection commenced upon Institutional Review Board approval and included demographics, past medical history, medication regimen, history of androgen deprivation therapy, bone health and its management. The ten year fracture risk calculated with the collected information using the FRAX tool.. A total of 174 subjects included with a mean age of 65.5 years, 71.8% had stage II prostate cancer, 97.7% received the LHRH agonist leuprolide for a mean of 13.8 ± 18.1 months. In addition to ADT, 57% of patients had ≥ 2 risk factors for developing osteoporosis. The risk of sustaining a major fracture increased from 4% to 5.6% after the initiation of ADT (P = <0.001). The risk for sustaining a hip fracture rose from 1.3% to 2.2% (P = <0.001). National guideline compliance was found to be 9%, 5% and 3% respectively for obtaining Dual Energy X-ray Absorptiometry (DEXA) scans, calcium supplementation, and vitamin D supplementation.. In addition to predisposing risk factors for osteoporosis, ADT significantly increases the fracture risk in the prostate cancer population. There is room for improvement in the management of bone health as some intervention could have been made in over 90% of patients evaluated.

Topics: Absorptiometry, Photon; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Bone Density; Calcium; Fractures, Bone; Gonadotropin-Releasing Hormone; Guideline Adherence; Humans; Leuprolide; Male; Middle Aged; Osteoporosis; Practice Guidelines as Topic; Prostatic Neoplasms; Retrospective Studies; Risk Factors; Vitamin D

Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Erectile dysfunction is a recognized complication of radical prostatectomy. Androgen deprivation therapy adversely impacts sexual function. Our study shows that the preoperative use of androgen deprivation therapy significantly reduces erectile function recovery after radical prostatectomy. The underneath pathophysiological mechanisms for this to occur are reviewed.. To define the impact of androgen deprivation therapy (ADT), undergone before radical prostatectomy (RP), on erectile function (EF) recovery.. A total of 38 consecutive patients presenting to a sexual medicine clinic after undergoing RP who had received ADT before RP (ADT+ group) were compared with a contemporary, age and comorbidity-matched cohort of 94 patients who did not receive ADT (ADT- group) before undergoing RP. Medical records were reviewed for demographics, comorbidity profiles and duration of ADT exposure. All the patients underwent Doppler penile ultrasonography within 6 months of RP and were administered the International Index of Erectile Function (IIEF) questionnaire. All the patients underwent evaluation of EF recovery. We analysed the incidence of venous leak (VL), mean IIEF EF domain score and proportion of men with EF domain scores ≥ 24 at 18 months after RP.. The mean age, comorbidity profiles, median Gleason score, median pre-treatment PSA level, and mean time to evaluation after RP were similar between the two groups. The median duration of ADT exposure in the ADT+ group was 3 months. The incidence of VL within 6 months of surgery was 60% for the ADT+ and 20% for the ADT- group (P < 0.001). Likewise, the IIEF EF domain scores and proportion of men with EF domain scores ≥ 24 at 18 months were significantly lower in the ADT+ group, even when controlled for nerve-sparing status.. Our data suggest that preoperative use of ADT adversely impacts EF outcomes and should therefore be avoided in the absence of robust data suggesting any oncological benefit.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Erectile Dysfunction; Humans; Leuprolide; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Preoperative Care; Prostatectomy; Prostatic Neoplasms

To assess the outcome of neoadjuvant chemohormonal therapy comprising complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy in Japanese patients with a high risk of localized prostate cancer (PCa).. Complete androgen blockade followed by 6 cycles of docetaxel (30 mg/m2) with estramustine phosphate (560 mg) were given to 18 PCa patients before radical prostatectomy. Subsequently, the clinical and pathological outcomes were analyzed.. No patients had severe adverse events during chemohormonal therapy, and hence they were treated with radical prostatectomy. Two patients (11.1%) achieved pathological complete response. Surgical margins were negative in all patients. At a median follow-up of 18 months, 14 patients (77.8%) were disease-free without PSA recurrence. All 4 patients with PSA recurrence had pathologic T3b or T4 disease and 3 of these 4 patients had pathologic N1 disease.. We found that neoadjuvant chemohormonal therapy with complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy was safe, feasible, and associated with favorable pathological outcomes in patients with a high risk of localized PCa.

Topics: Aged; Androgens; Anilides; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Docetaxel; Estramustine; Female; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Nitriles; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Survival Rate; Taxoids; Tosyl Compounds; Treatment Outcome

Neoadjuvant androgen deprivation in combination with radiotherapy of prostate cancer is used to improve radioresponsiveness and local tumor control. Currently, the underlying mechanism is not well understood. Because hypoxia causes resistance to radiotherapy, we wanted to test whether castration affects the degree of hypoxia in prostate cancer.. In 14 patients with locally advanced prostate cancer, six to 12 prostatic needle core biopsy specimens were taken prior to castration therapy. Bilateral orchidectomy was performed in 7 patients, and 7 were treated with a GnRH-agonist (leuprorelin). After castrationm two to four prostatic core biopsy specimens were taken, and the level of hypoxia-inducible factor-1α (HIF-1α) in cancer was determined by immunofluorescence.. Among biopsy specimens taken before castration, strong HIF-1α expression (mean intensity above 30) was shown in 5 patients, weak expression (mean intensity 10-30) in 3 patients, and background levels of HIF-1α (mean intensity 0-10) in 6 patients. Downregulation of HIF-1α expression after castration was observed in all 5 patients with strong HIF-1α precastration expression. HIF-1α expression was also reduced in 2 of 3 patients with weak HIF-1α precastration expression.. Our data suggest that neoadjuvant castration decreases tumor cell hypoxia in prostate cancer, which may explain increased radiosensitivity after castration.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Biomarkers; Biopsy, Needle; Cell Hypoxia; Down-Regulation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Leuprolide; Male; Middle Aged; Orchiectomy; Prostate; Prostatic Neoplasms; Radiation Tolerance

Topics: Antineoplastic Agents, Hormonal; Drug Administration Schedule; Humans; Injections; Leuprolide; Male; Prostatic Neoplasms

The addition of androgen deprivation therapy (ADT) to definitive external beam radiation therapy (RT) improves outcomes in higher-risk prostate cancer patients. However, the benefit of ADT with salvage RT in post-prostatectomy patients is not clearly established. Our study compares biochemical outcomes in post-prostatectomy patients who received salvage RT with or without concurrent ADT.. Of nearly 2,000 post-prostatectomy patients, we reviewed the medical records of 191 patients who received salvage RT at the University of Pennsylvania between 1987 and 2007. Follow-up data were obtained by chart review and electronic polling of the institutional laboratory database and Social Security Death Index. Biochemical failure after salvage RT was defined as a prostate-specific antigen of 2.0 ng/mL above the post-RT nadir or the initiation of ADT after completion of salvage RT.. One hundred twenty-nine patients received salvage RT alone, and 62 patients received combined ADT and salvage RT. Median follow-up was 5.4 years. Patients who received combined ADT and salvage RT were younger, had higher pathologic Gleason scores, and higher rates of seminal vesicle invasion, lymph node involvement, and pelvic nodal irradiation compared with patients who received salvage RT alone. Patients who received combined therapy had improved biochemical progression-free survival (bPFS) compared with patients who received RT alone (p = 0.048). For patients with pathologic Gleason scores ≤7, combined RT and ADT resulted in significantly improved bPFS compared to RT alone (p = 0.013).. These results suggest that initiating ADT during salvage RT in the post-prostatectomy setting may improve bPFS compared with salvage RT alone. However, prospective randomized data are necessary to definitively determine whether hormonal manipulation should be used with salvage RT. Furthermore, the optimal nature and duration of ADT and the patient subgroups in which ADT could provide the most benefit remain open questions.

Topics: Analysis of Variance; Androgen Antagonists; Anilides; Combined Modality Therapy; Disease-Free Survival; Flutamide; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Nitriles; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Radiotherapy Dosage; Retrospective Studies; Salvage Therapy; Seminal Vesicles; Tosyl Compounds

To evaluate long-term clinical outcomes in cT1c-T3a prostate cancer patients following delayed-combined androgen blockade therapy.. From January 2001 to December 2004, 92 cT1c-T3a prostate cancer cases were enrolled. Medical castration and anti-androgen treatment were used sequentially as delayed-combined androgen blockade therapy. Time to prostate-specific antigen biochemical failure was estimated, and risk factors for prostate-specific antigen biochemical failure were evaluated.. The average patient age was 76.4 years (range, 59-91 years), the median observation period was 52.8 months (range, 26-106.6 months) and the median pre-treatment prostate-specific antigen level was 14 ng/ml (range, 3.68-492 ng/ml). The TNM classification distribution was as follows: T1c, n= 27; T2a, n = 39; T2b, n = 20; and T3a, n = 6. In the multivariate analysis, Gleason's score ≥8 (P < 0.05; hazard ratio, 3.02), prostate-specific antigen nadir >1.4 ng/ml (P = 0.001; hazard ratio, 8.76) and a half-life of the prostate-specific antigen level >1.2 months (P < 0.005; hazard ratio, 6.3) during the initial 6 months of luteinizing hormone-releasing hormone agonist monotherapy were significant independent risk factors for prostate-specific antigen biochemical failure with luteinizing hormone-releasing hormone agonist monotherapy. The high-risk group, which had at least one of these three risk factors, had a shorter time to prostate-specific antigen biochemical failure than the low-risk group, during luteinizing hormone-releasing hormone agonist monotherapy (P < 0.0001). For the total delayed-combined androgen blockade therapy observation period, the free-prostate-specific antigen biochemical failure rate was 88.3% at 5 years. Only a maintenance period following luteinizing hormone-releasing hormone agonist monotherapy (P < 0.005; hazard ratio, 16.8) was revealed to be a significant independent risk factor for prostate-specific antigen biochemical failure with total delayed-combined androgen blockade.. The free-prostate-specific antigen biochemical failure rate of delayed-combined androgen blockade therapy in our study was as valuable as those in other androgen deprivation therapy of previous reports.

Topics: Aged; Aged, 80 and over; Algorithms; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Drug Administration Schedule; Goserelin; Humans; Kaplan-Meier Estimate; Leuprolide; Male; Middle Aged; Multivariate Analysis; Neoplasm Grading; Neoplasm Staging; Nitriles; Odds Ratio; Predictive Value of Tests; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Assessment; Risk Factors; Time Factors; Tosyl Compounds; Treatment Failure; Treatment Outcome

to evaluate the effectiveness of primary hormonal treatment on localized and locally advanced prostate cancer, including the analysis on the survival predictive factors.. patients with localized (T1,T2N0M0) and locally advanced (T3, T4N0M0) prostate cancer who had received primary hormonal treatment between January 1995 and December 2009 were evaluated retrospectively based on their specific medical records at Department of Urology in Cipto Mangunkusumo Hospital (RSCM) and Dharmais Cancer Hospital (RSKD).. about 79 (29.9%) of 264 patients with localized and advanced local prostate cancer received primary hormonal treatment. In the localized prostate cancer group, mean survival was 58.3 months (range: 1.87-170.78) and 5-year survival was 77.3%; while in locally advanced prostate cancer patients, mean survival was 40.87 months (range 7.29-115.29) and 5-year survival was only 22.7%. Hemoglobin level was a significant clinical parameter of survival predictive factors for both localized and locally advanced prostate cancer groups. The lower the hemoglobin level, the survival will be shorter.. there were no significant differences between mean survival and 5-year survival rate, between localized and locally advanced prostate cancer patients who had received primary hormonal treatment. Hemoglobin level is survival predictive factors for localized and locally advanced prostate cancer patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Biomarkers; Combined Modality Therapy; Follow-Up Studies; Goserelin; Hemoglobins; Humans; Leuprolide; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Prostatic Neoplasms; Retrospective Studies; Survival Analysis; Treatment Outcome

Topics: Androgen Antagonists; Flutamide; Humans; Leuprolide; Male; Prostatic Neoplasms; Sexuality; Testosterone

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Flutamide; Humans; Leuprolide; Male; Prostatic Neoplasms; Sexuality; Testosterone

Topics: Adenocarcinoma; Antineoplastic Agents, Hormonal; Flutamide; Humans; Leuprolide; Male; Prostatic Neoplasms

What's known on the subject? and What does the study add? Previous reports, with small numbers of patients, have described the problem of incomplete testosterone suppression (>1.1 or 1.7 nmol/L) with LHRH agonists. Various predisposing factors have been suggested: different drug agents and patient factors such as age, pretreatment testosterone levels and weight. Such incomplete testosterone suppression has been shown in one small report to be associated with increased PSA failure rates and in another report in those with metastases, with worse survival. This study used testosterone assays that are more accurate at low levels than those used in most previous reports in a large dataset of 2196 men, and confirmed incomplete testosterone suppression (breakthrough) rates >1.7 nmol/L of 3.4% and >1.1 nmol/L of 6.6%. We showed that younger age was strongly associated with the risk of breakthrough, with a minor effect of increasing body mass index. Repeated breakthroughs were more common (16%) in those who had already had one breakthrough. Interim measures of cancer control (PSA kinetics during LHRH therapy) were inferior in those with a breakthrough, and those with breakthroughs between 1.1 and 1.7 nmol/L had worse long-term biochemical control rates.. • To describe breakthrough rates above castrate levels of testosterone, in a population-based series of men undergoing adjuvant luteinizing hormone-releasing hormone (LHRH) agonist therapy with curative radiation therapy. • To explore the predisposing factors for such breakthroughs and their impact on subsequent outcomes.. • All men treated for prostate cancer between 1998 and 2007 with curative radiation in the province of British Columbia, Canada were potentially eligible (n= 11752). Of these, 2196 fulfilled the eligibility criteria. • Serial testosterone measurements were obtained during continuous LHRH therapy. • Breakthrough rates >1.1 nmol/L and >1.7 nmol/L were calculated for each LHRH injection and for each patient course. • Predisposing factors were identified, and early surrogates of oncological outcome (neoadjuvant nadir and post-treatment nadir) were determined.. • The risk of a breakthrough >1.1 nmol/L was 6.6%, and >1.7 nmol/L was 3.4% per patient course and 5.4% and 2.2% per LHRH injection (inclusive ranges). • Repeated breakthroughs occurred in 16% of patients. • Younger men were more liable to breakthroughs (P < 0.001). • Early PSA kinetic surrogates of cancer control were inferior in those with breakthroughs. • Neither overall biochemical non-evidence of disease (bNED) nor survival were compromised, although subgroup analysis showed inferior 5-year bNED in those with breakthroughs of 1.1-1.7 nmol/L vs those without (58% vs 73%, respectively; P= 0.048).. • Breakthroughs with LHRH agonists occur occasionally per injection, but occur commonly per patient course of treatment, and adversely affect early surrogate measures of outcome. • The monitoring of testosterone levels during therapy is therefore advised.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Body Mass Index; Buserelin; Drug Therapy, Combination; Follow-Up Studies; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Radioimmunoassay; Retrospective Studies; Testosterone; Treatment Outcome

Androgen deprivation therapy (ADT) for prostate cancer causes an increase in fasting insulin and adverse changes in body composition and serum lipid profile. It is unknown what other metabolic alterations are caused by ADT. To better characterize the metabolic effects of ADT, we measured changes in plasma metabolomic profile at baseline and after the first 3 months of therapy.. Fasting plasma samples were drawn from 36 subjects at baseline and after 3 months of gonadotropin releasing hormone (GnRH) agonist therapy. Extracted samples were split into equal parts for analysis on the gas chromatography-mass spectrometry and liquid chromatography/tandem mass spectrometry platforms.. Of the 292 identified metabolites, 56 changed significantly (P < 0.05) from baseline to 3 months. Notable changes were grouped as follows: (i) Multiple steroids were lower at 3 months, consistent with the effect of therapy on gonadal androgen synthesis. (ii) Most bile acids and their metabolites were higher during treatment. Cholesterol levels changed very little. (iii) Markers of lipid beta-oxidation (acetyl-carnitines and ketone bodies) and omega-oxidation were lower at 3 months. (iv) Two previously identified biomarkers of insulin resistance (2-hydroxybutyrate and branch chain keto-acid dehydrogenase complex products) were stable to lower at 3 months.. Unbiased metabolomic analyses revealed expected, novel, and unexpected results. Steroid levels fell, consistent with the effects of ADT. Most bile acids and their metabolites increased during ADT, a novel finding. Biomarkers of lipid metabolism and insulin resistance fell, unexpected given that ADT has been shown to increase fasting insulin.

Topics: 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); Adenocarcinoma; Antineoplastic Agents, Hormonal; Bile Acids and Salts; Gonadotropin-Releasing Hormone; Humans; Hydroxybutyrates; Insulin Resistance; Leuprolide; Lipid Metabolism; Male; Metabolome; Oxidation-Reduction; Prospective Studies; Prostatic Neoplasms; Steroids

Topics: Aged; Antineoplastic Agents, Hormonal; Endometriosis; Ethinyl Estradiol; Female; Humans; Leuprolide; Male; Prostatic Neoplasms; Urinary Bladder Diseases

Gonadotropin-releasing hormone (GnRH) agonists are widely used for the treatment of advanced prostate cancer (PCa). Agonists activate the GnRH receptor (GnRH-R), triggering apoptosis in PCa cells. In gonadotropes, the amount of GnRH-R in the plasma membrane is regulated by protein folding and endoplasmic reticulum retention, mechanisms that can be overcome by the pharmacoperone IN3. Our aim was to describe the intracellular distribution of GnRH-R in PCa cells and its relation to response to GnRH analog treatments. The expressions of GnRH-R in PCa biopsies were evaluated by immunohistochemistry and the intracellular distribution was determined by immunofluorescence in primary cell cultures from human PCa samples. Cultured cells were pretreated with IN3 and then with leuprolide. Cell survival was evaluated by 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) thiazolyl blue formazan and cell cycle and apoptosis by flow cytometry. We observed that the expression of GnRH-R decreased according to malignant progression. Most GnRH-R are located inside the cell, colocalizing with endoplasmic reticulum markers. The treatment with IN3 decreased cellular GnRH-R retention, increasing plasma membrane expression in approximately 60%. Pretreatment with IN3 decreased PCa cell survival compared with leuprolide-alone treatment, primarily because of an increase in apoptosis. We conclude that the response of PCa cells to leuprolide is related to the amount of GnRH-R in the plasma membrane. Therefore, pretreatment evaluation of the amount of these receptors may be a predictor of the outcome of leuprolide treatment in PCa patients. Assessment of systemic IN3 effect would be necessary to determine its utility as an adjuvant treatment in hormone-resistant tumors.

Topics: Apoptosis; Blotting, Western; Bridged Bicyclo Compounds, Heterocyclic; Cell Culture Techniques; Cell Cycle; Cell Membrane; Cell Survival; Drug Synergism; Endoplasmic Reticulum; Flow Cytometry; Humans; Immunohistochemistry; Indoles; Leuprolide; Male; Prostatic Neoplasms; Protein Folding; Pyridines; Receptors, LHRH; Tumor Cells, Cultured

Topics: Adenocarcinoma; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Bone Neoplasms; Brain Ischemia; Comorbidity; Dabigatran; Hematuria; Humans; Kidney Failure, Chronic; Leuprolide; Male; Prostatic Neoplasms; Pulmonary Disease, Chronic Obstructive; Secondary Prevention; Thrombophilia; Urinary Retention

Topics: Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Oligopeptides; Prostatic Neoplasms; Testosterone

An elderly man had been treated for prostate cancer with radiation and neoadjuvant hormonal therapy. One year after the cessation of radiation therapy, the PSA value was found to be elevated. A non-steroidal antiandrogen bicalutamide was initiated to the patient. Due to poor treatment response the drug was changed for the GnRH agonist leuprorelin acetate, which upon injection caused a sudden deterioration of the patient's general condition. He was delirious and in pain, and was diagnosed with leukocytosis, hypokalemia, hyperglycemia and metabolic alkalosis. The patient was referred to the endocrinological clinic for evaluation of the metabolic-endocrinological problems. He succumbed to disseminated prostate cancer.

Topics: Aged; Alkalosis; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Fatal Outcome; Humans; Hyperglycemia; Hypokalemia; Leukocytosis; Leuprolide; Male; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Tosyl Compounds

Superior vena cava (SVC) syndrome is an uncommon complication of malignant disease caused by the obstruction of venous blood flow in the SVC. When present, a diagnosis of lung cancer or lymphoma will be made in approximately 95% of cases. Although other malignant diseases are occasionally associated with SVC, its occurrence in patients with prostate cancer is rare. We present a case of a patient presenting with SVC obstruction who was subsequently diagnosed with prostate adenocarcinoma. The patient has been successfully treated with GnRH agonist. This case reflects the importance of a full clinical assessment and pathological confirmation of suspected tumour prior to treatment.

Topics: Adenocarcinoma; Antineoplastic Agents; Biopsy; Diagnosis, Differential; Diphosphonates; Drug Therapy, Combination; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Lumbar Vertebrae; Lymph Nodes; Lymphatic Metastasis; Magnetic Resonance Imaging; Male; Mediastinal Neoplasms; Middle Aged; Prostatic Neoplasms; Spinal Neoplasms; Superior Vena Cava Syndrome; Thoracic Vertebrae; Tomography, X-Ray Computed

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Choroid Neoplasms; Humans; Injections, Intramuscular; Leuprolide; Male; Prostatectomy; Prostatic Neoplasms; Ultrasonography; Visual Acuity

E26 transformation-specific-1 (ETS-1), an ETS family transcription factor, has been reported to play an important role in a variety of physiological and pathological processes, but clinical implications of ETS-1 expression in prostate cancer (PCa), particularly high-risk cases, including response to androgen-deprivation therapy (ADT) have yet to be elucidated. We examined the expression of ETS-1 using immunohistochemical staining of paraffin-embedded prostate carcinoma tissue obtained by needle biopsy from 69 mostly advanced PCa patients. ETS-1 expression was compared with the clinicopathological characteristics of the 69 patients, including 25 who underwent ADT as a primary treatment. As a result, PCa patients with higher expression of ETS-1 were significantly more likely to be of high stage and high Gleason score (P<0.05). There was no significant association between ETS-1 expression and the initial prostate-specific antigen (PSA) level. In the 25 patients treated by ADT, the staining score for ETS-1 was significantly associated with rapid development of castration-resistant disease within 24 months (P<0.05), whereas the Gleason score and PSA level were not. In conclusion, increased ETS-1 expression was associated with a higher stage, higher Gleason score and shorter time to castration-resistant progression. These data suggest that immunostaining for ETS-1 could be a molecular marker for predicting a poor clinical outcome for PCa patients, particularly those with high-risk disease.

Topics: Aged; Disease Progression; Goserelin; Humans; Immunohistochemistry; Leuprolide; Male; Neoplasm Grading; Orchiectomy; Prognosis; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Proto-Oncogene Protein c-ets-1

Topics: Adenocarcinoma; Androgen Antagonists; Antineoplastic Agents, Hormonal; Bone Density Conservation Agents; Brachytherapy; Diphosphonates; Humans; Imidazoles; Leuprolide; Male; Prostatic Neoplasms; Quality of Life; Zoledronic Acid

Luteinizing hormone releasing hormone (LHRH) agonist therapy is one of the mainstays of prostate cancer treatment. Three dosing regimens currently exist: calendar-based, intermittent, and a testosterone (T)-based (T-based) regimen. We investigated the differences in development of early castrate resistance rates between these different regimens.. We evaluated 1617 patients with prostate cancer who received LHRH-agonist monotherapy in the Kaiser Permanente Southern California Cancer Registry between January 2003 and December 2006. Patients who had undergone surgery and/or radiation were excluded. Patients were grouped according to their dosing regimen: calendar-based, intermittent dosing, and T-based. Cox proportional hazard-regression analysis was used to estimate the hazards ratio (HR) for treatment failure.. A total of 692 patients who received an LHRH agonist as primary monotherapy for prostate cancer fit our criteria. Calendar-based dosing was used in 325 patients; 252 received T-based dosing and 115 received intermittent dosing. On multivariate analysis controlling for demographic and prostate cancer-related variables, the T-based dosing group showed a significantly lower relative risk of treatment failure (HR = 0.65, P = .02). The intermittent-dosing group trended toward a lower risk treatment failure (HR = 0.80, P = .3). Among the variables analyzed, only a Gleason score >8 (HR = 2.05, P = .01) and a pretreatment prostate-specific antigen >20 (HR = 2.00, P <.01) were associated with a higher risk of treatment failure.. During the time period studied, T-based and intermittent dosing regimen of LHRH agonist had lower rates of early castrate resistance compared with standard calendar dosing, based on measurements for early androgen resistance.

Topics: Aged; Antineoplastic Agents, Hormonal; Drug Resistance, Neoplasm; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms; Retrospective Studies; Time Factors

This work summarizes the highlights of the satellite symposium of the seventh edition of the European Robotic Urology Symposium. Treatment options of T3 prostate cancer were discussed, including the results of the Tap 032 study. In this phase III study, 264 patients with locally advanced prostate cancer were randomized to be treated by leuproreline 11,25 mg for 3 years alone or radiotherapy plus leuproreline 11,25 mg for 3 years. The median of disease free survival (Phoenix definition : PSA nadir + 2 ng/ml) was significantly longer in the group of patients treated with the combined treatment (6,96 years vs 3,46 years, p = 0,0005). No statistical difference was observed in specific survival (93,2% vs 86,1%, p = 0,11). In the second part of the satellite symposium, perioperative, oncological, and functional outcomes of laparoscopic robotic-assisted radical prostatectomy were presented, as well as today and future developments of robotic surgery.

Topics: Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Laparoscopy; Leuprolide; Male; Neoplasm Staging; Prostatectomy; Prostatic Neoplasms; Quality of Life; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Robotics; Treatment Outcome

To identify whether veterans receiving androgen-deprivation therapy (ADT) are screened at any time by bone mass measurement.. Cross-sectional study.. Veterans Administration Tennessee Valley Healthcare System (VA-TVHS).. All male veterans who received at least one dose of goserelin or leuprolide within the fiscal years October 1, 2005, through September 30, 2009.. Data from patients' charts were extracted for demographic information (race, age, and weight prior to the initial injection); date of initiation of therapy; the use of calcium, vitamin D, bisphosphonate, or calcitonin therapy; and documented bone-mineral density testing.. To determine whether veterans receiving ADT with goserelin or leuprolide for prostate cancer were screened at any time for BMD more or less than rates as documented in previous literature.. 22.8% of veterans were screened for BMD, which was statistically significant when compared with results found in previous literature.. Although rates of BMD testing were higher at VA-TVHS compared with previous literature, this rate is still low given the well-known risk of accelerated osteoporosis associated with ADT.

Topics: Aged; Androgen Antagonists; Androgens; Antineoplastic Agents, Hormonal; Bone Density; Cross-Sectional Studies; Goserelin; Humans; Leuprolide; Male; Osteoporosis; Prostatic Neoplasms; Risk Assessment; Veterans

Topics: Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms

Men with castrate resistant prostate cancer have limited treatment options. Although luteinizing hormone-releasing hormone agonists are in the same class, they are slightly different in their pharmacology. We determined whether rechallenging patients with prostate cancer, who were receiving a luteinizing hormone-releasing hormone analogue but had progression, with a different luteinizing hormone-releasing hormone analogue (goserelin or leuprolide acetate) would result in a prostate specific antigen response. Secondary objectives were to calculate the PSA response and determine whether sequence order impacted the response.. We performed a retrospective, ethics approved review of the records of patients with prostate cancer at multiple institutions who received a luteinizing hormone-releasing hormone analogue (goserelin or leuprolide acetate), experienced progression, as measured by 2 consecutive prostate specific antigen increases, and were rechallenged with the other analogue (goserelin or leuprolide acetate). Prostate specific antigen and relevant clinical data were obtained and statistical analysis was done.. Of 39 available men 27 (69%) had decreased prostate specific antigen after 3 months of switching regimens. The median change in prostate specific antigen was -1.5 (IQR -10.0, 0.8), indicating a statistically significant decrease (p=0.01). The median percent prostate specific antigen change for leuprolide acetate to goserelin was -69.3% (IQR -81.5, 26.2) and for goserelin to leuprolide acetate it was -6.4% (IQR -61.7, 21.8, p=0.05). Median time to a subsequent prostate specific antigen increase was 5.2 months (95% CI 3.5-17.4).. Prostate specific antigen decreased after switching luteinizing hormone-releasing hormone therapies. This decrease appeared most significant in the group that switched from leuprolide acetate to goserelin. The duration of response after switching was approximately 5 months. The study is limited by its retrospective nature but should encourage prospective evaluation of this observation.

Topics: Aged; Aged, 80 and over; Disease Progression; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies

Gonadorelin analogues (LHRH) are used for the endocrine treatment of prostatic cancer, central early puberty and various gynaecological conditions. Cutaneous adverse events seldom occur. We report a case of injection-site granulomas induced by leuprorelin acetate (Enantone®).. A 76-year-old man presented with several subcutaneous nodules on his left arm. The nodules were hard but painless. He had received subcutaneous injections of Enantone® for prostatic cancer. Histological examination of a skin biopsy specimen demonstrated granulomatous inflammation with a necrotic centre; screening for an infectious aetiology was negative. Serial sections showed giant cells containing translucent round microspheres in the subcutaneous tissue. Limitation to the leuprorelin acetate injection sites in the arm and detection at histological analysis of microspheres probably bound to an injected product militated in favour of granulomas caused by injections of Enantone®.. Injection-site granulomas caused by Enantone® are rare. Their formation may depend on the mode of administration: the more superficial the injection, the higher the risk of developing granulomas. The formation of these lesions is probably a foreign body reaction to the excipient.

Topics: Aged; Antineoplastic Agents, Hormonal; Granuloma; Humans; Leuprolide; Male; Prostatic Neoplasms

Reduced cell-cell adhesion allows malignant epithelial cells to invade the basal membrane and penetrate the stroma. This implies the potential of the cells to escape from the primary tumor as well as spreading ability. Herein, we investigated the effects of leuprorelin acetate (LA), a GnRH agonistic analogue, alone or in combination with dihydrotestosterone (DHT), on the expression of molecules involved in cell adhesion (E-cadherin, N-cadherin, α-, β- and γ-catenin) or in migration/invasion (c-met, CD44v6 and caveolin-1) in androgen-sensitive (LNCaP) and -insensitive (PC-3) prostate cancer (CaP) cells. We demonstrated by immunoblotting that, in LNCaP cells, molecules present in the adherens junctions (E-cadherin, α-, β- and γ-catenin) were expressed, while α-catenin was absent in PC-3 cells which expressed N-cadherin and c-met. In LNCaP cells, no changes in E-cadherin levels were produced by 10(-9) M DHT while LA (10(-11) or 10(-6) M) up-regulated the protein level (up to 26-30% after 48 h). In the same cells, β- and γ-catenin expression was enhanced either by DHT (24 and 20%, respectively) or LA (up to 18 and 40%, respectively), while α-catenin was not affected. Antagonistic effects were consistently observed between DHT and LA when the two hormones were jointly administered to the cells. Consistent results were obtained by immunocytochemistry. Co-immunoprecipitation analysis, used to verify the integrity of the LNCaP cell adhesion complex, demonstrated the association of E-cadherin with catenins. In PC-3 cells, adhesion molecule expression, analyzed by immunoblotting, was unaffected by LA, while a down-regulation of c-met (up to 28%) was observed after 24 h of treatment but which did not hold up over time (48-144 h). Our findings demonstrate the efficacy of LA in upregulating E-cadherin, β- and γ-catenin in LNCaP cells. This effect, that may be considered as another aspect of the direct antitumor activity of the GnRH analogue in hormone-dependent CaP cells, may contribute to maintenance/restoration of the normal tissue architecture counteracting the tumor cell spreading tendency.

Topics: Antineoplastic Agents, Hormonal; Cell Adhesion Molecules; Cell Line, Tumor; Dihydrotestosterone; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Leuprolide; Male; Prostatic Neoplasms

To report an unusual presentation of metastatic prostate cancer to the orbit in an immunosuppressed patient, who received a novel palliative treatment regimen.. A 56 year old HIV+ man presented with proptosis and unilateral blindness. The diagnosis, work up, and treatment are outlined.. Metastatic prostate cancer to the orbit is diagnosed, and the treatment with IMRT and hormone ablation is explored.. We outline the literature and current thinking surrounding prostate cancer metastases to the orbit. HIV+ patients currently enjoy longer life expectancies, with the caveat that their immunosuppressed status may lead to more unusual metastatic presentations. Treatments and palliation will continue to evolve as these new cases emerge.

Topics: Adenocarcinoma; Anilides; Antineoplastic Agents; Antineoplastic Agents, Hormonal; HIV Seropositivity; Humans; Immunocompromised Host; Leuprolide; Male; Middle Aged; Nitriles; Orbital Neoplasms; Palliative Care; Prostatic Neoplasms; Radiotherapy, Intensity-Modulated; Tosyl Compounds

Primary hormonal therapy has been mostly used for patients with advanced prostate cancer, as international guidelines do not recommend its use for patients at earlier disease stages. However, there seems to be a discrepancy between the guideline recommendations and clinical practice on the use of primary androgen deprivation therapy for localized prostate cancer in Japan. Therefore, we retrospectively analyzed a single-institution experience in primary combined androgen blockade (CAB) for localized prostate cancer.. The study included 187 patients with T1c-T3a prostate cancer unsuitable for local definitive treatment and treated with primary CAB. Clinical outcomes, predictive factors of PSA relapse and adverse events were investigated.. The progression-free, disease-specific, and overall survival rates of all patients at 5 years were 63.0, 99.4 and 95.9%, respectively. Of the several parameters isolated as predictors of prostate-specific antigen (PSA) progression, nadir PSA level and the percentage of positive biopsy cores (%PBC) remained as independent prognostic factors on multivariate analysis. Toxicities were mild to moderate and well tolerated.. Primary CAB treatment brought initial disease control without relapse in the majority of our selected cases. The %PBC may help predict time to relapse in the pretreatment setting. The results implicate that CAB can be an option as a primary treatment for clinically localized prostate cancer unsuitable for local definitive treatment. To confirm the exact efficacy of primary CAB, these findings should be reviewed in a large cohort of patients with long-term follow-up from various viewpoints, including disease control, toxicities, quality-of-life and medical cost.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Androgens; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chlormadinone Acetate; Disease-Free Survival; Flutamide; Follow-Up Studies; Goserelin; Humans; Japan; Kaplan-Meier Estimate; Leuprolide; Male; Middle Aged; Neoplasm Staging; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Tosyl Compounds; Treatment Outcome

Disseminated carcinomatosis of the bone marrow is caused by metastasis to the bone marrow and can cause disseminated intravascular coagulation (DIC), leucoerythroblastosis, and microangiopathic hemolytic anemia (MHA). The prognosis of this syndrome is poor. We report herein two rare cases of disseminated carcinomatosis of the bone marrow in association with prostate cancer. Case 1 involved a 61-year-old man admitted to our department with elevated prostate-specific antigen (PSA) levels. Prostate biopsy revealed prostate cancer, and imaging studies were performed. Under a diagnosis of prostate cancer (T3N1Mx), the patient was treated using hormonotherapy, but died 2 months after admission due to gastrointestinal bleeding of unknown cause, refractory DIC, and cachexia. Bone marrow biopsy after his death revealed metastasis of the prostate cancer to the bone marrow. Case 2 involved a 68-year-old man admitted to our department with gross hematuria. Cystoscopy revealed non-papillary tumor in the prostatic urethra. Transurethral biopsy was performed and histology identified prostate cancer. Treatment was initiated with hormonotherapy and zoledronate. After 8 months, he complained of general fatigue and blood testing identified anemia and thrombocytopenia. Bone marrow biopsy revealed adenocarcinoma in the bone marrow. Alternative androgen therapy and chemotherapy with docetaxel was started, and the patient recovered from pancytopenia and general fatigue.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Anilides; Antineoplastic Agents; Bone Marrow Neoplasms; Carcinoma; Diphosphonates; Disseminated Intravascular Coagulation; Drug Therapy, Combination; Fatal Outcome; Humans; Imidazoles; Leuprolide; Male; Middle Aged; Nitriles; Prostatic Neoplasms; Tosyl Compounds; Treatment Outcome; Zoledronic Acid

Topics: Antineoplastic Agents, Hormonal; Flutamide; Humans; Leuprolide; Male; Multicenter Studies as Topic; Orchiectomy; Prostatic Neoplasms; Radiotherapy Dosage; Randomized Controlled Trials as Topic; Reproducibility of Results

Topics: Adenocarcinoma; Androgen Antagonists; Antineoplastic Agents, Hormonal; Biopsy; Bone Neoplasms; Chemotherapy, Adjuvant; Humans; Leuprolide; Male; Middle Aged; Neoplasm Recurrence, Local; Osteoporosis; Prostate; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

Altered circadian rhythms have been identified in untreated prostate cancer patients. Findings of restored rhythmicity following cancer treatment may have relevance for cancer control and symptom management. This study assessed and compared the cyclic patterns of hot flashes and activity levels in treated prostate cancer patients.. Data were collected during two 24-h periods among 47 prostate patients undergoing androgen deprivation therapy (ADT). Hot flashes were detected objectively through sternal skin conductance and by patients via electronic event marking. Activity levels were recorded on a wrist actigraphy device.. The mean frequency of objectively measured and patient-reported hot flashes was 13.6 (SD = 14.3) and 12.6 (SD = 9.6), respectively. There were significant 24-h circadian rhythms of both hot flashes and activity levels. The peak of the rhythms occurred in early afternoon. There was no significant cross correlation between hot flashes and activity levels.. The acrophases of hot flashes and elevated activity levels in this study may represent a normalisation of circadian rhythms following ADT, pointing to the need for more research, including controlled, prospective chronobiologic studies. Future research may have important implications for the survival of prostate cancer patients and the identification of new and safe hot flash treatments.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Circadian Rhythm; Hot Flashes; Humans; Leuprolide; Male; Middle Aged; Motor Activity; Nitriles; Prostatic Neoplasms; Tosyl Compounds

This study investigated the mechanism of action of a gonadotropin-releasing hormone (GnRH) agonist, leuprolide, on proliferation of the hormone-refractory prostate cancer cell line DU145, transfected with short hairpin RNA (shRNA), to reduce expression of the GNRHR1 gene (which encodes the GnRH type 1 receptor). DU145 cell proliferation in the presence of leuprolide (10(-9) and 10(-7) M) or control medium was measured before and after GnRHR1 knockdown. Reverse transcription-polymerase chain reaction and Western blot analysis were used to measure the degree of GNRHR1 silencing. DU145 cells treated with leuprolide (10(-9) and 10(-7) M) showed significant growth inhibition compared with control-treated DU145 cells. Transfection with GNRHR1 -shRNA significantly decreased GNRHR1 expression at 48 h. DU145 cells transfected with silencing GNRHR1 -shRNA showed normal growth patterns; however, there was no significant inhibition of proliferation of DU145 cells transfected with GNRHR1 -shRNA compared with cells transfected with control-shRNA in response to leuprolide. These data demonstrated that the antiproliferative effect of leuprolide was mediated by the GnRHR1.

Topics: Androgens; Antineoplastic Agents, Hormonal; Base Sequence; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Culture Media; DNA Primers; Gene Silencing; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction

Androgen-deprivation therapy modalities are on continuing evolution. Leuprolide Acetate (LA) Eligard(®)45mg was the first 6-monthly LHRH agonist (agoniste luteinizing hormone-releasing hormone [LHRHa]) treatment available for use in prostate cancer. The objective of this study was to assess the use of the 3-monthly and the 6-monthly LHRHa in patients with prostate cancer.. A two-step survey (registration and follow-up) was held between July 2008 and January 2009. One hundred and sixty doctors included patients treated with LHRHa for prostate cancer. Then, a follow-up registry was implemented for patients who had been prescribed a 3- or 6-monthly LHRHa.. Data analysis showed that the 1853 registered patients had a mean age of 75 years old. Time to diagnosis was 7 months. Among them, 26.4% had an N+ and/or M+ cancer. The most tumor node metastasis (TNM) stage represented was T3N0M0 with Gleason score 7. High prostate specific antigen (PSA) level and metastatic stage were the main motives for LHRHa prescription. Choice criteria for a 3 or a 6-monthly LHRHa were patient autonomy (3.2 vs 18.4%), age (27.2 vs 44%) and anxiety (28 vs 16.8%). Patients for 6-monthly LHRHa were likely to be with low urinary symptoms, older, less autonomous and less anxious. The reported advantage of the 3-monthly LHRHa was the high satisfying quality of medical follow-up. For the 6-monthly form, the advantages were the flexibility and the freedom to stop worrying about their cancer for up to 6 months.. The 6-monthly LHRHa provides more flexibility in the management and follow-up of patients with locally advanced or metastatic prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Biomarkers; Delayed-Action Preparations; Follow-Up Studies; France; Gonadotropin-Releasing Hormone; Health Care Surveys; Humans; Leuprolide; Male; Neoplasm Grading; Neoplasm Staging; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Surveys and Questionnaires; Treatment Outcome

To assess whether short-course total androgen blockade vs. a luteinizing hormone-releasing hormone (LHRH) agonist alone affects the risk of prostate cancer-specific mortality (PCSM) in men with localized but high-risk disease treated with radiotherapy.. The study cohort comprised 628 men with T1-T4, N0, M0 prostate cancer with high-risk disease (prostate-specific antigen level >20 ng/mL, Gleason score >or=8, or clinical category >or=T3) treated with 45 Gy of external beam radiotherapy followed by a brachytherapy boost in addition to receiving a median of 4.3 (interquartile range [IQR], 3.6-6.4) months of hormonal blockade with an LHRH agonist plus an antiandrogen or monotherapy with an LHRH agonist. Fine and Gray's multivariable regression analysis was used to determine whether combination androgen suppression therapy (AST) vs. monotherapy affected the risk of PCSM, adjusting for treatment year, duration of AST, age, and known prognostic factors.. After a median follow-up of 4.9 (IQR, 3.5-6.5) years, men receiving combination AST had a lower risk of PCSM than those treated with monotherapy (adjusted hazard ratio [AHR], 0.18; 95% confidence interval [CI], 0.04-0.90; p = 0.04). An increasing prostate-specific antigen level (AHR, 2.70; 95% CI, 1.64-4.45; p < 0.001) and clinical category T3/4 disease (AHR, 29.6; 95% CI, 2.88-303.5; p = 0.004) were also associated with an increased risk of PCSM.. In men with localized but high-risk prostate cancer treated with external beam radiotherapy and brachytherapy, short-course AST with an LHRH agonist plus an antiandrogen is associated with a decreased risk of PCSM when compared with monotherapy with an LHRH agonist.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Drug Therapy, Combination; Follow-Up Studies; Goserelin; Humans; Leuprolide; Male; Multivariate Analysis; Neoplasm Staging; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy Dosage; Regression Analysis

To value the late genitourinary (GU) morbidity in men treated with a hypofractionated radiotherapy regimen for prostate cancer. Patients with intermediate risk factors according to D'Amico's criteria were selected. The hypofractionated schedule consisted of 15 fractions of 3.63 Gy delivered three times per week for a total dose of 54.3 Gy. Significant changes in storage-symptoms were not found. A significant transient worsening in the score of late effects of normal tissue late effects normal tissue task force (LENT)-subjective, objective, management, analytic (SOMA) urinary-function domain was observed at 12 months with subsequent improvement at 28 months. The assessment of voiding-symptoms and maximum urinary flow rate (Qmax) showed that no significant difference was measurable at 12 and 28 months. For PVR, a transient increase at 12 months with a subsequent decrease at 28 months was measured. No significant increase in alpha-blockers usage and in the percentage of men with pathological nonintubated uroflowmetry (NIF) was observed at 12 and 28 months. Finally, patients did not perceive any clinical worsening in their quality of life (QoL) as attested by the International Prostate Symptom Score (IPSS)-QoL. Our study seems to suggest that our hypofractionated radiotherapy schedule for the treatment of prostate cancer is safe in terms of late urinary morbidity. Further study will be required to confirm our results.

Topics: Aged; Anilides; Combined Modality Therapy; Humans; Leuprolide; Male; Middle Aged; Nitriles; Prostatic Neoplasms; Quality of Life; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Intensity-Modulated; Tosyl Compounds; Treatment Outcome; Urination Disorders; Urogenital System

To determine if the levels of circulating myeloid-derived suppressor cells increase with progression of prostate cancer (PCa); to determine if such cells could contribute to the relative inefficiency of PCa immunotherapy.. We analyzed peripheral blood mononuclear cells isolated from untreated PCa patients (uPCa; N = 18; mean age +/- SD: 72.1 +/- 6.9 years), tPCa (N = 22; 72.8 +/- 9.8 years) and age matched controls (AMC; N = 12; 68.8 +/- 7.5 years). We quantified surface marker phenotype, differentiation potential, effects on T cell proliferation and intracellular cytokines.. We observed an unexpectedly high percentage of a type of myeloid-derived suppressor cells, CD14(+)HLA-DR(low/-) monocytes, in tPCa (30.7 +/- 15.0% of CD14(+) cells) relative to AMC (4.1 +/- 6.5%, P < 0.0001) and uPCa (10.6 +/- 14.3%, P = 0.0001). The levels of CD14(+) HLA-DR(low/-) cells were significantly correlated with circulating PSA levels and treatment with LHRH-agonist leuprolide in combination with either an antiandrogen or dexamethasone. Monocytes from tPCa inhibited autologous T cell proliferation statistically significantly more effectively than AMC monocytes and were defective in their ability to differentiate into phenotypically mature dendritic cells. Isolated CD14(+)HLA-DR(low/-) cells expressed higher levels of intracellular interleukin-10 and suppressed T cell proliferation more effectively than isolated CD14(+)HLA-DR(+) cells.. This is the first report of CD14(+) cells exhibiting reduced expression of HLA-DR molecules in PCa patients. These cells suppress immune cell function in vitro and, plausibly, in vivo, a finding that must be factored into the design of immunotherapy protocols for PCa patients.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Hormonal; Cell Proliferation; Dendritic Cells; Dexamethasone; Disease Progression; Drug Therapy, Combination; HLA-DR Antigens; Humans; Immunosuppression Therapy; Leuprolide; Lipopolysaccharide Receptors; Male; Monocytes; Prostate-Specific Antigen; Prostatic Neoplasms; T-Lymphocytes

In order to assess the efficacy and toxicity of oral estramustine phosphate (EMP) administration, low-dose EMP monotherapy (study 1) and very low-dose EMP therapy with luteinizing hormone-releasing hormone (LH-RH) agonist (study 2) were conducted in previously untreated prostate cancer and long-term outcomes were compared between the 2 study groups.. Studies 1 and 2 were independently performed beginning in June 1999 and November 2001, respectively. Study 1 was composed of 87 patients including 85 assessable patients. All 108 patients recruited for study 2 were assessable. Low-dose EMP monotherapy (2 capsules/day or 280 mg/day) was used in study 1 and very low-dose EMP (1 capsule/day or 140 mg/day) combined with LH-RH agonist was adopted in study 2.. Overall prostate specific antigen (PSA) -response rates in studies 1 and 2 were 92.3% and 94.2%, respectively, and overall toxicity rates were 54.1% and 38.9%, respectively. EMP discontinuation due to side effects was encountered more often in study 1 (45.9%) than in study 2 (27.8%). Among the adverse side effects gastrointestinal toxicity was most prevalent in both studies. One patient died of acute pulmonary embolism in study 1, but no one died in study 2. There were 6 cancer deaths in the gastrointestinal tract in study 1 but only 2 cancer deaths in study 2.. Our data indicate that the overall PSA response rate was comparable between both studies. However, rates in overall toxicity and drug discontinuation were higher in study 1 than in study 2. We consider that study 2 is more promising for the treatment of previously untreated advanced prostate cancer, although the rate of adverse side effects is still high as compared with other hormonal therapies. In order to overcome the high toxicity rate, especially the gastrointestinal toxicity, we recently elaborated a method employing tailor-made medicine using SNPs of 1A1 gene in cytochrome P-450 for decreasing the rate of gastrointestinal toxicity. Using this method of patient selection, study 3 has been successfully launched on September 2005 with high drug compliance. Better clinical results are being accumulated.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Biomarkers, Tumor; Cause of Death; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Estramustine; Follow-Up Studies; Gonadotropin-Releasing Hormone; Goserelin; Humans; Injections, Intravenous; Kaplan-Meier Estimate; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prostate-Specific Antigen; Prostatic Neoplasms

Prostate adenocarcinoma can manifest as a fairly indolent tumor or as a very aggressive cancer with significant invasive and metastatic potential. Common metastatic sites include bone, liver, lymph nodes, and adrenal glands. Dermatologic manifestations are rare. We present a case of a man who presented with breast skin changes that mimicked inflammatory breast carcinoma with specialized testing ultimately giving a diagnosis of metastatic prostatic adenocarcinoma. A 78-year-old man presented with left breast redness and swelling. Examination revealed an erythematous rash with subcutaneous edema over the left hemithoracic area. A breast ultrasound showed no focal mass, and a breast core biopsy had no evidence of tumor. A skin biopsy showed metastatic carcinoma in dermal lymphatics, and the tumor was found to have no estrogen or progesterone receptors or HER2 expression. Computed tomography scans, positron emission tomography, and a nuclear bone scan revealed widespread skeletal metastases. The patient received a 3-month course of capecitabine and cyclophosphamide with no improvement in his skin lesions. Subsequent immunohistochemical staining on the tumor specimen was positive for prostate-specific antigen (PSA) and alpha-methyl-CoA-racemase, confirming a diagnosis of metastatic prostatic adenocarcinoma. He received leuprolide and bicalutamide and demonstrated significant improvement with near-complete resolution of his skin lesions and a decrease in his PSA level. Prostatic adenocarcinoma presenting initially as a breast malignancy is a rarely recognizable clinical event. Undoubtedly, increased awareness and recognition of the rare entity described herein will allow for the prompt initiation of specific therapies, which might be of benefit to many patients.

Topics: Adenocarcinoma; Aged; Anilides; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms, Male; Capecitabine; Carotid Stenosis; Coronary Artery Disease; Cyclophosphamide; Deoxycytidine; Diabetes Mellitus; Fluorouracil; Humans; Immunohistochemistry; Leuprolide; Male; Nitriles; Osteoarthritis; Positron-Emission Tomography; Prostate-Specific Antigen; Prostatic Neoplasms; Pulmonary Disease, Chronic Obstructive; Tomography, X-Ray Computed; Tosyl Compounds

Leuprolide (Lupron) is a synthetic analog of naturally occurring gonadotropin-releasing hormone (GnRH). Leuprolide is used as a hormonal antagonist in the treatment of advanced prostatic cancer, and as hormonal therapy in the treatment of endometriosis. Off-label, it is also used in premenopausal or perimenopausal women with hormone-responsive breast cancer for the purpose of ovarian ablation. Ever since its FDA approval in 1985, many adverse reactions have been reported in association with leuprolide ranging from local skin irritation to severe anaphylactoid reactions. In this case report, we present a case of hypersensitivity vasculitis (serum sickness) in a patient who received leuprolide for his prostate cancer. Serum sickness has never been reported as a side-effect of leuprolide. Our case is the first case of serum sickness associated with leuprolide. We emphasize that physicians using leuprolide should be wary of signs and symptoms of hypersensitivity vasculitis or serum sickness.

Topics: Aged; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Prostatic Neoplasms; Vasculitis, Leukocytoclastic, Cutaneous

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Drug Prescriptions; Gonadotropin-Releasing Hormone; Goserelin; Health Resources; Humans; Leuprolide; Male; Medicare; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; SEER Program; United States

Side effects of cancer treatment have been found to have a significant impact on patients' psychological well-being. Each of the primary treatment options for prostate cancer is associated with significant side effects that can have a dramatic impact on quality of life. Hot flashes are a notable side effect of androgen deprivation therapy (ADT) and a potential source of distress due to their episodic nature and low frequency in a normal aging male population. The current study sought to examine the relationship between hot flashes and cancer-related distress during the first three months of ADT.. Participants were 68 men with various stages of prostate cancer scheduled to begin ADT for the first time. Study measures were completed at the beginning of treatment and 3 months later.. Repeated measures ANOVA indicated that men who did not experience hot flashes had a significant decrease in total cancer-related distress and avoidance over the 3-month period, while men with hot flashes exhibited no change in distress. Among men with hot flashes, results of hierarchical regression analyses indicated that a worse experience with hot flashes was a significant predictor of greater increases in intrusion and total cancer-related distress over the 3-month period.. These results suggest that hot flashes serve to maintain levels of distress during the treatment period. Further research should extend these findings by lengthening the follow-up period and using ecological momentary assessment to refine measurement of these constructs and provide evidence for the direction of causality between hot flashes and distress.

Topics: Adaptation, Psychological; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Combined Modality Therapy; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Goserelin; Hot Flashes; Humans; Injections, Intramuscular; Leuprolide; Male; Middle Aged; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Sick Role; Surveys and Questionnaires

Platelet derived growth factor receptor inhibitor therapy improves the efficacy of taxane chemotherapy in preclinical models of prostate cancer. Men with high risk localized prostate cancer were treated with platelet derived growth factor receptor inhibitor therapy, docetaxel and hormone ablation in the preoperative setting, and clinicopathological outcomes were evaluated.. A total of 36 men with cT2 or greater disease, Gleason grade 8-10, serum prostate specific antigen more than 20 ng/ml or cT2b and prostate specific antigen more than 10 ng/ml and Gleason 7 disease, without radiological evidence of metastases, were scheduled to receive intramuscular leuprolide, 600 mg daily oral imatinib and 30 mg/m(2) weekly docetaxel x 4 every 42 days for 3 cycles before radical prostatectomy (beta [0.02, 1.98] prior on the possibility of pathological complete remission). Unresectable disease, postoperative prostate specific antigen 0.2 ng/ml or greater, or administration of postoperative radiation or hormones were defined as treatment failure.. A total of 39 men were registered over 15 months. Median patient age was 57 years (range 44 to 71). Risk factors included T3 disease (22 of 39), Gleason 8-10 disease (31 of 39) and prostate specific antigen more than 20 ng/ml (12 of 39). Three men were ineligible or declined therapy, 29 of 36 (81%) received 3 cycles of therapy and 7 of 36 (19%) discontinued therapy related to toxicity. Grades 3-4 toxicity included rash (4), diarrhea (4), fatigue (6) and neutropenia (1). The surgical approach was feasible, without excessive or unusual complications such as wound dehiscence. No pathological complete remissions were defined. At a median followup of 39 months 53% were free from progression.. Evidence for a favorable impact of platelet derived growth factor receptor inhibitor therapy on the efficacy of neoadjuvant docetaxel and hormonal ablation in high risk localized prostate cancer was not obtained.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Benzamides; Disease-Free Survival; Docetaxel; Drug Therapy, Combination; Gonadotropin-Releasing Hormone; Humans; Imatinib Mesylate; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Piperazines; Prostatic Neoplasms; Pyrimidines; Receptors, Platelet-Derived Growth Factor; Risk Factors; Survival Rate; Taxoids

Castration-resistant prostate cancer (CRPC) is an incurable disease with limited treatment options. Herbal supplements are unconventional treatments for a variety of diseases. Active hemicellulose compound (AHCC) is a Japanese supplement discovered by hybridizing several mushrooms used in traditional healing for the purpose of maintaining 'super immunity'. We report on a 66-year-old gentleman with CRPC with an excellent serologic response to AHCC. This case hypothesizes that AHCC may have potential activity against CRPC.

Topics: Adenocarcinoma; Anilides; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Basidiomycota; Combined Modality Therapy; Drug Resistance, Neoplasm; Humans; Leuprolide; Lumbar Vertebrae; Male; Nitriles; Phytotherapy; Plant Extracts; Polysaccharides; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes; Remission Induction; Samarium; Self Medication; Spinal Neoplasms; Tosyl Compounds

To examine the duration of serum testosterone and prostate-specific antigen suppression after each dose of a 4-month depot leuprolide acetate for 18 months and to assess the potential for using serum testosterone as a guide for redosing the luteinizing hormone-releasing hormone analogs instead of using fixed dosing intervals. Luteinizing hormone-releasing hormone analogs are well established for the treatment of prostate cancer (PCa). However, many open questions remain regarding the optimal dosing.. Thirteen patients with PCa were enrolled in a longitudinal study. Serum testosterone levels were obtained at baseline and then monthly beginning 4 months after the first injection and every 2 months after the subsequent injections, for a total of 18 months. The median number of days from injection to the first serum testosterone level > or = 50 ng/dL was estimated using the Kaplan-Meier product-limit method.. The median duration of effect was 159, 189, and 163 days for the first, second, and third treatment cycle, respectively. The prostate-specific antigen values from entry to completion decreased in all subjects. The total number of injections was reduced in all but one subject who completed the 18-month trial. One patient developed hormone-refractory PCa.. Serum testosterone measurement might be a useful method for redosing luteinizing hormone-releasing hormone analogs. Using testosterone levels to determine the time of reinjection has a significant economic impact. Monitoring serum testosterone not only helps to identify patients who fail to achieve testosterone suppression but also provides close monitoring for the potential development of hormone-refractory PCa.

Topics: Aged; Antineoplastic Agents, Hormonal; Drug Monitoring; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prospective Studies; Prostatic Neoplasms; Testosterone; Time Factors

Topics: Antineoplastic Agents, Hormonal; Clinical Trials, Phase III as Topic; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Oligopeptides; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic

To evaluate the influence of patient- and treatment-related factors on freedom from biochemical failure (FFbF) in patients with intermediate-risk prostate cancer.. From a prospectively collected database of 2250 men treated at Mount Sinai Hospital from 1990 to 2004 with low-dose-rate brachytherapy for prostate cancer, 558 men with either one or more intermediate-risk features (prostate-specific antigen [PSA] level 10-20 ng/mL, Gleason score 7, or Stage T2b) were identified who had a minimum follow-up of 24 months and postimplant CT-based dosimetric analysis. Biologically effective dose (BED) values were calculated to compare doses from different isotopes and treatment regimens. Patients were treated with brachytherapy with or without hormone therapy and/or external-beam radiotherapy. Patient- and treatment-related factors were analyzed with respect to FFbF. The median follow-up was 60 months (range, 24-167 months). Biochemical failure was defined according to the Phoenix definition. Univariate analyses were used to determine whether any variable was predictive of FFbF. A two-sided p value of <0.05 was considered significant.. Overall, the actuarial FFbF at 10 years was 86%. Dose (BED <150 Gy(2) vs. >or=150 Gy(2)) was the only significant predictor of FFbF (p < 0.001). None of the other variables (PSA, external-beam radiotherapy, Gleason score, treatment type, hormones, stage, and number of risk factors) was found to be a statistically significant predictor of 10-year FFbF.. Radiation dose is an important predictor of FFbF in intermediate-risk prostate cancer. Treatment should continue to be individualized according to presenting disease characteristics until results from Radiation Therapy Oncology Group trial 0232 become available.

Topics: Analysis of Variance; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Biopsy; Brachytherapy; Flutamide; Follow-Up Studies; Goserelin; Humans; Iodine Radioisotopes; Leuprolide; Male; Nitriles; Palladium; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes; Radiotherapy Dosage; Relative Biological Effectiveness; Tosyl Compounds; Treatment Failure

GnRH receptors (GnRH-R) have been found in various malignancies, including prostate cancer (PCa). They mediate the direct antitumor effects of GnRH analogs. Nevertheless, few reports concern drug-induced modulation of GnRH-R levels. In this study, we investigated GnRH-R expression in androgen-sensitive (LNCaP) and -insensitive (PC-3) PCa cells treated for 4 and 6 days with a GnRH agonist (Leuprorelin acetate, LA, 10(-11) or 10(-6) M), Dihydrotestosterone (DHT, 10(-9) M), Cyproterone acetate (CA, 10(-7) M), and Epidermal growth factor (EGF, 10 ng/ml), either alone or combined. The RT-PCR analysis showed no variation in GnRH-R mRNA levels of both treated LNCaP and PC-3 cells. On the contrary, immunoblotting indicated that in LNCaP and PC-3 cells, LA upregulated membrane GnRH-R expression (up to 92%). In androgen-sensitive cells, DHT induced a GnRH-R increase (up to 119%) always comparable to that occurring in the presence of CA. GnRH-R upregulation by LA/DHT or CA/DHT association was similar to that promoted by the single agents. In PC-3 cells, EGF upregulated GnRH-R (up to 110%). A prolonged treatment (for 12 days) determined a greater EGF-induced increase in GnRH-R levels (142%). Lower (or no) receptor enhancement occurred when LA and EGF were associated. Our findings indicate that LA post-transcriptionally upregulates its own membrane receptor in androgen-sensitive and -insensitive PCa cells, counteracting the receptor enhancement produced by DHT and EGF. The effects, obtained with a relatively long and continuous treatment, may have implications in the choice of therapy modality with GnRH analogs and may render the receptor a novel therapeutic target, particularly in hormone-refractory PCa.

Topics: Androgen Antagonists; Androgens; Antineoplastic Agents, Hormonal; Blotting, Western; Cell Line, Tumor; Cyproterone Acetate; Dihydrotestosterone; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Leuprolide; Male; Prostatic Neoplasms; Receptors, LHRH; RNA, Messenger; Up-Regulation

Ghrelin is a natural growth hormone segretagogue (GHS), involved in the biology of a number of diseases such as lung cancer and prostate cancer. The aim of this study is to assess the relationship existing between ghrelin and testosterone, insulin, and PSA in prostate adenocarcinoma.. A patient population and a control population were studied. The former consisted of 18 individuals, age range 50-75 years, with a primary histological diagnosis of prostate adenocarcinoma that were divided into two equal groups of 9 patients each. The control population consisted of 40 normogonadic healthy males aged between 23 and 77 years (average age 43). The first group was treated with oral bicalutamide with a daily dose of 150 mg, while the second group was treated with an intramuscular injection of 11.25 mg of leuprorelin every three months. Total ghrelin was measured with a radio immunological direct method using Phoenix's ghrelin human RIA kit. Intra-assay variance was 8.2% and inter-assay variance was 11.4% . Acylated-ghrelin was measured by applying an extraction method using C18 columns followed by radio immunological dosage with antibody and peninsula tracer. Intra-assay variance was 6.1% and inter-assay variance was 8.7% . All other blood parameters were analysed at the central laboratory of the S. Orsola-Malpighi Polyclinic in Bologna. PSA and testosterone were used to assess response to treatment. The PSA monitoring was achieved with a chemio-luminescence assay method (Roche Modular analytics E 170). Free T was also measured using a direct RIA kit (Diagnostic Systems Laboratories, Inc.).. In the four months during which patients underwent pharmacological treatment, testosterone values varied significantly (p<0.05) in both groups. No variations (p>0.05) were found for ghrelin, acylated-ghrelin and insulin.. It is concluded that in patients with prostate neoplasms there is no correlation between the variations of circulating levels of ghrelin and those of testosterone.

Topics: Acylation; Adenocarcinoma; Adult; Aged; Ghrelin; Humans; Insulin; Leuprolide; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

Leuprorelin acetate-induced granulomas in subcutaneous injection sites have been occasionally reported, but there have been no detailed morphological examinations. Histopathology of leuprorelin acetate-induced granulomas in six patients was studied, and one of them was evaluated by electron microscopy. Study using haematoxylin and eosin staining revealed that there were many intracytoplasmic vacuoles in the granulomas and degeneration of fat tissue. Ultrastructurally, electron-lucent spherical bodies (microcapsules of leuprorelin acetate products) were observed in the granuloma cells. Needle-shaped crystalloid structures in lipid droplets (degenerated lipid droplets) were observed in the granuloma cells and fat tissue. Degeneration of fat tissues caused by leuprorelin acetate is one of main factors responsible for granuloma formation.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Granuloma; Humans; Injections, Subcutaneous; Leuprolide; Male; Microscopy, Electron; Prostatic Neoplasms

Our goal was to study the hormonal regulation of immune cell infiltration in prostate cancer patients treated by androgen deprivation therapy (ADT) using an optimized computer-assistance quantification approach.. The relative density of immune cell subtypes (CD3(+), CD8(+), CD20(+), CD56(+), CD68(+) and Foxp3(+)) was analyzed by immunohistochemistry in archived prostate specimens from control patients (radical prostatectomy only, n=40) and ADT-treated patients (ADT prior to radical prostatectomy, n=35) using an image analysis software and a whole-slide scanner.. ADT-treated patients had significantly increased relative density of CD3(+) (p<0.001) and CD8(+) T lymphocytes (p<0.001) as well as CD68(+) macrophages (p<0.001). Elevated abundance of CD56(+) Natural Killer (NK) cells was associated with a lower risk of prostate cancer progression (p=0.044), while a high density of CD68(+) macrophages was related to an increased risk of biochemical recurrence (p=0.011).. Our results demonstrate that the infiltration of specific immune cell subtypes is modulated by ADT. Furthermore our data confirm that NK cells have a protective role against tumor progression while macrophages seem to favor the development of advanced prostate cancer.

Topics: Androgen Antagonists; Androgens; Antineoplastic Agents, Hormonal; Cyproterone; Flutamide; Humans; Killer Cells, Natural; Leuprolide; Lymphocytes, Tumor-Infiltrating; Macrophages; Male; Neoplasm Recurrence, Local; Prostatic Neoplasms; T-Lymphocytes

The incidence of, and mortality from, prostate cancer (PCa) has increased in Asian countries over the past decades, partly due to a change in dietary habits. Recent reports have revealed differences in the molecular basis of PCa among people of differing racial or ethnic backgrounds. PCa xenograft models established from Asian patients would be useful for understanding the basis of PCa in Asian populations; we therefore established and characterized a novel PCa xenograft model, JDCaP, from a metastatic skin lesion of a Japanese hormone-refractory prostate cancer (HRPC) patient.. Skin metastatic tissue derived from poorly differentiated prostatic adenocarcinoma in a 61-year-old Japanese male was transplanted to nude mice and JDCaP was established by serial passage. Expression of androgen receptor (AR) and prostate-specific antigen (PSA) was evaluated by immunohistochemistry and the AR sequence was analyzed. Hormone sensitivity of JDCaP was investigated in vivo by orchiectomy followed by administration of steroid hormones, including testosterone, estradiol, progesterone, and hydrocortisone. Therapeutic effects of leuprorelin acetate, bicalutamide, flutamide, diethylstilbestrol (DES), and estradiol were investigated.. JDCaP expressed wild-type AR and PSA and showed androgen dependence. Only testosterone administration maintained tumor proliferation after orchiectomy. Administration of leuprorelin acetate, bicalutamide, and flutamide inhibited tumor growth. DES and estradiol also demonstrated significant antitumor effects.. JDCaP expresses wild-type ARs and exhibits androgen dependence despite its origin from a HRPC patient. The model may be useful to elucidate the molecular basis of PCa in Asian populations and to develop prevention and therapeutic strategies.

Topics: Adenocarcinoma; Animals; Antigens, Neoplasm; Antineoplastic Agents, Hormonal; Asian People; Diethylstilbestrol; Humans; Leuprolide; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Receptors, Androgen; Skin Neoplasms; Specific Pathogen-Free Organisms; Transplantation, Heterologous

Topics: Adult; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Bone Density; Female; Flutamide; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Neoplasms; Osteoporosis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prostatic Neoplasms; Survivors

Gonadotrophin-releasing hormone (GnRH) receptor blockers (antagonists) are the latest addition to the hormonal therapy armamentarium for patients with prostate cancer. In contrast to the GnRH agonists, GnRH blockers have an immediate onset of action and do not cause an initial surge in testosterone levels that can lead to clinical flare in patients with advanced disease. Degarelix (Firmagon is a new GnRH blocker that has recently been approved by the EMEA and US FDA for the treatment of men with hormone-sensitive advanced prostate cancer. In this article, we briefly review the Phase III trial data for degarelix 240/80 mg (licensed dose) versus leuprolide 7.5 mg that led to these recent approvals.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Clinical Trials, Phase III as Topic; Drug Approval; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Oligopeptides; Prostatic Neoplasms

Topics: Adenocarcinoma; Aged, 80 and over; Antineoplastic Agents, Hormonal; Biopsy; Drug Eruptions; Humans; Injections; Leuprolide; Male; Patch Tests; Prostatic Neoplasms

Topics: Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms; Rats; Taxoids; Testosterone

To explore whether the presence of occult disseminated tumor cells (DTCs) in the bone marrow before neoadjuvant hormone therapy influences the prognosis of patients with organ confined prostate cancer treated by radical prostatectomy.. Pretreatment bone marrow aspirates from 193 cT (1-4) pN0M0 prostate cancer patients submitted to neoadjuvant hormone therapy (mean, 8 months) followed by radical prostatectomy were immunohistochemically evaluated by anticytokeratin antibody A45-B/B3 previously validated for the detection of DTCs. Bone marrow status was compared with established clinical and histopathologic risk parameters. Patients' outcome was evaluated using prostate-specific antigen (PSA) blood serum measurements as surrogate marker for recurrence over a median follow-up of 44 months.. DTCs were detected in 44.6% of patients. Bone marrow status neither correlated with tumor grade and stage, nor with the pretreatment PSA risk category (all P values > .05). In the univariate Kaplan-Meier analysis, the presence of DTCs was a significant prognostic factor with respect to poor PSA progression-free survival (log-rank test P = .0035). Using a multivariable piecewise Cox regression model, the presence of DTCs was an independent predictor of PSA relapse (relative risk 1.82; P = .014).. The presence of DTCs in the bone marrow of patients with prostate cancer before neoadjuvant hormone therapy and subsequent surgery represents an independent prognostic parameter, suggesting that DTCs may contribute to the failure of current neoadjuvant hormone therapy regimens.

Topics: Aged; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Bone Marrow Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Flutamide; Follow-Up Studies; Goserelin; Humans; Leuprolide; Male; Multivariate Analysis; Neoadjuvant Therapy; Neoplastic Cells, Circulating; Nitriles; Prognosis; Prostatectomy; Prostatic Neoplasms; Tosyl Compounds

Haemoglobin levels often decline into the anaemic range with androgen deprivation therapy (ADT). We conducted a chart review of patients receiving ADT for metastatic prostate cancer to assess anaemia-related symptoms.. 135 stage IV prostate cancer cases were reviewed for treatment type; haemoglobin values before and after treatment; and symptoms of anaemia. Mean haemoglobin levels before and after for all treatment forms, for leuprolide alone, and for combination leuprolide/bicalutamide were calculated and evaluated for significant differences. The numbers of patients developing symptoms were recorded and the effects of specific therapies evaluated.. For all ADT treated patients, mean haemoglobin declined by -1.11 g/dL (p<.0001). Leuprolide-alone treated patients had a mean decline of -1.66 g/dL (p<0.0001). Leuprolide and bicalutamide combination treatment caused a mean decline of -0.78 g/dL (p=0.0426). 16 of 43 patients had anemia symptoms. Contingency analysis with Fisher's exact test shows patients receiving leuprolide therapy alone versus other forms of ADT were significantly less likely to have symptoms (chi(2)=0.0190).. The present study confirms that ADT results in a significant drop in haemoglobin levels into the anaemic range. A number of patients become symptomatic from this change. Practitioners should monitor haemoglobin levels, and treat symptomatic patients.

Topics: Aged; Androgen Antagonists; Anemia; Anilides; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Goserelin; Hemoglobins; Humans; Leuprolide; Linear Models; Male; Neoplasm Metastasis; Nitriles; Prostatic Neoplasms; Retrospective Studies; Tosyl Compounds

Topics: Aged; Androgen Antagonists; Animals; Antineoplastic Agents, Hormonal; Buserelin; Drug Prescriptions; Flutamide; Humans; Imidazolidines; Leuprolide; Male; Patient Education as Topic; Patient Satisfaction; Prostatic Neoplasms; Retrospective Studies; Risk Assessment; Risk Factors; Survival Analysis

A 74-yr-old man with prostatic adenocarcinoma underwent magnetic resonance 1H-spectroscopic imaging (1H-MRSI) of the prostate. Based on the results, he was treated with combination therapy using complete androgen blockade (leuprorelin acetate 3.75 mg every 4 wk plus bicalutamide 50 mg daily) and a somatostatin analogue (lanreotide acetate 60 mg every 4 wk). Serum prostate-specific antigen and chromogranin A levels steadily decreased over a 12-mo follow-up period, at which time the patient is alive without disease progression and with a complete objective and symptomatic response.

Topics: Acromegaly; Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Agents; Diagnosis, Differential; Drug Therapy, Combination; Follow-Up Studies; Humans; Leuprolide; Magnetic Resonance Spectroscopy; Male; Peptides, Cyclic; Prostatic Neoplasms; Severity of Illness Index; Somatostatin; Time Factors

Leuprorelin acetate is an agonist of gonadotropin-releasing hormone, used as a first choice treatment in patients with prostate carcinoma. The impact of leuprorelin therapy in liver function and metabolism is largely unknown. We report about a patient who had been treated for 32 months with leuprorelin acetate, who developed a nonalcoholic fatty liver disease (NAFLD), associated with a focal lesion at the IV hepatic segment where histologic features appeared to be more severe. The patient, in addition to NAFLD, presented a marked iatrogenic hypotestosteronemia and full-criteria meeting the diagnosis of metabolic syndrome, including insulin resistance. The radiologic and clinical findings, the histopathologic features, and the absence of any hepatic abnormalities before treatment, support a causal role of leuprorelin in inducing metabolic derangement that, most likely secondary to androgen-deprivation, were, in turn, responsible for the development of NAFLD. In conclusion, this is the first case report of NAFLD with focal fatty liver associated with leuprorelin therapy. Patients in leuprorelin should be carefully monitored for the development of liver disease.

Topics: Aged; Antineoplastic Agents, Hormonal; Carcinoma; Fatty Liver; Humans; Hypogonadism; Insulin Resistance; Leuprolide; Liver; Male; Prostatic Neoplasms; Testosterone

To compare the effects of leuprolide acetate and goserelin acetate for suppressing serum testosterone levels in Japanese patients with prostate cancer, as several recent studies suggested that serum testosterone is not always suppressed below the upper limit of the castration range in patients using luteinizing hormone-releasing hormone (LH-RH) agonists, especially leuprolide acetate.. In all, 232 patients with prostate cancer, whose serum testosterone levels were measured before and during treatment using a 1- or 3-monthly formulation of leuprolide or goserelin, were enrolled in a retrospective study. The mean age of the patients was 69.8 years and the mean testosterone level before the LHRH treatment was 4.54 ng/mL. The patients had their testosterone levels assessed a mean (range) of 5.4 (1-35) times during the LHRH treatment. A castrate serum testosterone level was defined as

Topics: Aged; Aged, 80 and over; Analysis of Variance; Androgen Antagonists; Antineoplastic Agents, Hormonal; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Testosterone; Treatment Outcome

Gonadotropin-releasing hormone agonists increase fat mass, decrease insulin sensitivity, and increase serum triglycerides. To better characterize the metabolic effects of gonadotropin-releasing hormone agonist treatment, we prospectively evaluated the changes in body composition, insulin sensitivity, and levels of adiponectin, resistin, C-reactive protein (CRP), and plasminogen activator inhibitor type 1 (PAI-1). We also assessed the relationships among changes in adipocytokines, body composition, and insulin sensitivity.. In this prospective, 12-week study, 25 nondiabetic men with locally advanced or recurrent prostate cancer and no radiographic evidence of metastases were treated with leuprolide depot and bicalutamide. The outcomes studied included changes from baseline to week 12 in body composition, insulin sensitivity, and levels of adiponectin, resistin, CRP, and PAI-1.. The mean +/- standard error percentage of fat body mass increased by 4.3% +/- 1.3% from baseline to week 12 (P = 0.002). The insulin sensitivity index decreased by 12.9% +/- 7.6% (P = 0.02). The serum adiponectin levels increased by 37.4% +/- 7.2% from baseline to week 12 (P <0.001). In contrast, the resistin, CRP, and PAI-1 levels did not change significantly. Changes in body composition tended to be associated with changes in adiponectin, but not insulin sensitivity.. Combined androgen blockade with leuprolide and bicalutamide significantly increased fat mass and adiponectin levels and decreased insulin sensitivity but did not alter the resistin, CRP, or PAI-1 levels. This pattern of metabolic changes appears distinct from the classic metabolic syndrome.

Topics: Adipokines; Aged; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Body Composition; Drug Therapy, Combination; Humans; Insulin Resistance; Leuprolide; Male; Nitriles; Obesity; Prospective Studies; Prostatic Neoplasms; Tosyl Compounds

In men with prostate cancer, gonadotropin-releasing hormone (GnRH) agonists increase fat mass, decrease insulin sensitivity, and increase triglycerides, features that are shared with metabolic syndrome. To the authors' knowledge, however, less is known regarding the effects of GnRH agonists on other attributes of the metabolic syndrome.. In an open-label prospective study, 26 men with recurrent or locally advanced prostate cancer were treated with leuprolide for 12 months. Outcomes included changes in blood pressure, body composition, lipids, adipocytokines, and C-reactive protein.. The mean weight, body mass index, and waist circumference increased significantly from baseline to Month 12 (P < .001 for each comparison). Fat mass increased by 11.2% +/- 1.5% (P < .001) and the percentage lean body mass decreased by 3.6% +/- 0.5% (P < .001). The total abdominal fat area increased by 16.5% +/- 2.6% (P < .001), with the accumulation of subcutaneous fat accounting for 94% of the observed increase. The waist-to-hip ratio and blood pressure did not change significantly. Serum high-density lipoprotein (HDL) cholesterol concentrations increased significantly (P = .002). Serum adiponectin levels increased by 36.4 +/- 5.9% from baseline to Month 3 and remained significantly elevated through Month 12 (P < .001). Resistin and C-reactive protein levels did not change significantly.. The term metabolic syndrome does not appear to adequately describe the effects of GnRH agonists in men with prostate cancer. In contrast to the metabolic syndrome, GnRH agonists increase subcutaneous fat mass, HDL cholesterol, and adiponectin, and do not alter the waist-to-hip ratio, blood pressure, or C-reactive protein level.

Topics: Adiponectin; Aged; Antineoplastic Agents, Hormonal; Blood Pressure; Body Composition; Body Mass Index; C-Reactive Protein; Gonadotropin-Releasing Hormone; Humans; Insulin Resistance; Leuprolide; Lipids; Male; Metabolic Syndrome; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Syndrome

Topics: Adiponectin; Adipose Tissue; Antineoplastic Agents, Hormonal; Body Mass Index; Body Weight; Cholesterol, HDL; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Metabolic Syndrome; Prostatic Neoplasms

Topics: Administration, Topical; Aged; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Lupus Erythematosus, Cutaneous; Male; Prostatic Neoplasms; Sunlight; Treatment Outcome

Topics: Antineoplastic Agents, Hormonal; Diethylstilbestrol; Disease Progression; Humans; Leuprolide; Male; Orchiectomy; Prostatic Neoplasms; Treatment Failure

Androgen-independent prostate carcinoma is characterized by a high proliferation rate and by a strong metastatic behavior. We have previously shown that GnRH agonists exert a direct and specific inhibitory action on the proliferation of androgen-independent prostate cancer cells (DU 145). These compounds mainly act by interfering with the mitogenic activity of growth factors, such as the insulin-like growth factor-I (IGF-I). The present experiments were performed to clarify whether GnRH agonists might also affect the migratory and the invasive behavior of androgen-independent prostate cancer cells and to define their mechanism of action. First we showed that the GnRH agonist Leuprolide reduces the migration of DU 145 cells towards a chemoattractant and their ability to invade a reconstituted basement membrane. Experiments were then performed to clarify whether the GnRH agonist might act by interfering with the pro-metastatic activity of IGF-I. We found that, in androgen-independent prostate cancer cells, Leuprolide: a) interferes with the IGF-I system (receptor protein expression and tyrosine-phosphorylation); b) abrogates the IGF-I-induced phosphorylation of Akt (a kinase previously shown by us to mediate the pro-metastatic activity of IGF-I in prostate cancer cells); c) counteracts the migration and the invasive activity of the cells stimulated by IGF-I; d) abolishes the effects of IGF-I on cell morphology, on actin cytoskeleton organization and on alphavbeta3 integrin expression/cellular localization. These data indicate that GnRH agonists, in addition to their well known antiproliferative effect, can also exert a significant inhibitory activity on the migratory and invasive behavior of androgen-independent prostate cancer cells, expressing the GnRH receptor. GnRH agonists act by interfering with the pro-metastatic activity of the growth factor IGF-I.

Topics: Androgens; Antineoplastic Agents, Hormonal; Cell Line, Tumor; Cell Movement; Gonadotropin-Releasing Hormone; Humans; Insulin-Like Growth Factor I; Leuprolide; Male; Microscopy, Electron, Scanning; Neoplasm Invasiveness; Prostatic Neoplasms

Topics: Antineoplastic Agents, Hormonal; Disease Progression; Humans; Leuprolide; Male; Prostatic Neoplasms; Testosterone; Treatment Failure

We determined penile length alterations in men treated with androgen suppression plus radiation therapy for local or locally advanced prostate cancer.. From November 2000 to November 2005, 47 patients were enrolled in this prospective study. After clinical staging all patients received hormonal therapy (luteinizing hormone releasing agonist, leuprolide acetate or goserelin every 3 months for a total of 3 injections) and at month 7 of hormonal therapy radiation therapy was begun (total 70 Gy) for 7 weeks. Stretched penile length measurements were performed before starting androgen suppression therapy and every 3 months thereafter with a paper ruler.. With the initiation of therapy a gradual decrease in stretched penile length was observed. Penile shortening was statistically significant at a mean followup of 18 months (mean 14.2 to 8.6 cm, p <0.001).. Our findings support observations of decreased penile length after neoadjuvant hormonal therapy plus external beam radiation therapy for local or locally advanced prostate cancer. Patients should be counseled before therapy that penile shortening may occur.

Topics: Aged; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Disease Progression; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Penis; Prospective Studies; Prostatic Neoplasms

Degarelix (FE 200486) is a member of a new class of water-soluble (>50 mg/ml) gonadotropin-releasing hormone (GnRH) antagonists in clinical development for prostate cancer. Upon subcutaneous administration, degarelix forms a gel that results in a sustained release of the compound into the circulation, immediately blocking GnRH receptors in the pituitary and inducing a fast and sustained suppression of gonadotrophin secretion in rats and primates. One of the few animal models of prostate adenocarcinoma is the Dunning R-3327H rat carcinoma transplanted into Copenhagen rats. The growth of the Dunning tumor can be inhibited by various treatments reported to be effective in the clinic, such as GnRH superagonists, antiandrogens, 5-alphareductase inhibitors, tyrosine kinase inhibitors, and surgical castration. We report in this study that degarelix produces a fast and sustained suppression of the pituitary gonadal axis in rats and a similar inhibition of tumor growth compared with surgical castration in the Dunning R-3327H rat carcinoma model. First, degarelix as been compared with d-Trp(6)-luteinizing hormone-releasing hormone and surgical castration on a short-term study (2 months); and second, degarelix has been compared with leuprolide and surgical castration on a long-term study (12 months). In both studies, degarelix demonstrated a sustained inhibition of tumor growth at least comparable with surgical castration. These data provide a convincing profile of degarelix as a potential candidate for the clinical management of sex steroid-dependent pathologies, such as prostate cancer, where long-term reversible chemical castration is required.

Topics: Animals; Antineoplastic Agents; Castration; Gonadotropin-Releasing Hormone; Leuprolide; Male; Neoplasm Transplantation; Oligopeptides; Organ Size; Prostatic Neoplasms; Rats; Rats, Inbred Strains; Testis; Testosterone

Controversy and a notable paucity of published clinical data best characterize the current knowledge of testosterone-replacement therapy (TRT) for hypogonadism after treatment for early, localized prostate cancer. The objective of this study was to assess the risk of biochemical failure with TRT after treatment of early prostate cancer with permanent transperineal brachytherapy with or without external beam therapy in patients with low serum levels of testosterone and clinical symptoms of hypogonadism.. Patients who underwent prostate brachytherapy from 1996 to 2004 and received subsequent TRT for symptomatic hypogonadism were reviewed to detail cancer characteristics and treatment as well as pre- and post-TRT serum testosterone and prostate-specific antigen (PSA) values.. Thirty-one men received TRT after prostate brachytherapy for 0.5 to 8.5 years (median, 4.5 years), with a follow-up that ranged from 1.5 years to 9.0 years (median, 5.0 years) postbrachytherapy. TRT was started from 0.5 years to 4.5 years (median, 2.0 years) after brachytherapy. Serum total testosterone levels ranged from 30 ng/dL to 255 ng/dL (median, 188 ng/dL) before TRT and rose to 365 ng/dL to 1373 ng/dL (median, 498 ng/dL) on TRT. Transient rises in PSA were observed in 1 patient. The most recent PSA level was <0.1 ng/mL in 23 patients (74.2%), <0.5 ng/mL in 30 patients (96.7%), and <1 ng/mL in 31 patients (100%). No patients stopped TRT because of cancer recurrence or documented cancer progression.. For patients with low serum testosterone levels and symptoms of hypogonadism, TRT may be used with caution and close follow-up after prostate brachytherapy.

Topics: Aged; Antineoplastic Agents, Hormonal; Brachytherapy; Disease-Free Survival; Goserelin; Hormone Replacement Therapy; Humans; Hypogonadism; Leuprolide; Male; Middle Aged; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Outcome

To evaluate effects of obesity on sex steroid levels during treatment with a gonadotropin-releasing hormone agonist in men with prostate cancer.. Forty-nine hormone-naïve men with recurrent or locally advanced prostate cancer were included in the analyses. All subjects were treated with leuprolide 3-month depot for 48 weeks. Serum levels of estradiol, sex hormone-binding globulin, total testosterone, and free testosterone were assessed at baseline, 24 weeks, and 48 weeks. Subjects were categorized by body mass index (BMI) and percent body fat.. Pretreatment serum sex hormone-binding globulin and total testosterone levels were significantly lower in overweight and obese men than in men with normal BMI. In the overall study population, mean serum testosterone concentrations decreased from 372 +/- 18 ng/dL at baseline to 13 +/- 1 ng/dL at week 48 (P < 0.001). Free testosterone decreased from 6.75 +/- 0.33 ng/dL at baseline to 0.21 +/- 0.02 ng/dL at week 48 (P < 0.001). During treatment with leuprolide, obese men had significantly higher total and free testosterone levels than men with normal BMI. Compared with normal men, total and free testosterone levels during treatment were 1.8-fold and 2.3-fold higher in obese men. Similar results were observed when subjects were categorized by body fat.. Despite lower pretreatment serum testosterone levels, obese men have higher total and free testosterone levels during leuprolide treatment than men with normal BMI. These differences may contribute to the association between obesity and increased prostate cancer mortality.

Topics: Aged; Body Mass Index; Estradiol; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Obesity; Prospective Studies; Prostatic Neoplasms; Sex Hormone-Binding Globulin; Steroids; Testosterone; Time Factors; Treatment Outcome

We analyzed clinical effects of flutamide as a second-line agent for maximum androgen blockade (MAB) in patients with relapsing prostate cancer who received bicalutamide as the first-line MAB agent. This study included 13 patients with progressive prostate cancer who had relapsed after first-line MAB, with bicalutamide at 80 mg/day. After checking for antiandrogen withdrawal syndrome, they were given flutamide at 375 mg/day as second-line MAB. The effectiveness of that therapy was evaluated by changes in prostatic specific antigen (PSA) levels, with response defined as a decrease of greater than 50% from the start of therapy. We also compared several factors between responders and non-responders. Nine (69.2%) of the 13 patients showed a decrease in PSA levels, of whom five (38.5%) had a greater than 50% decrease and were defined as responders. The median duration of PSA response was 11.0 months (range 5-20 months). Patients who had a longer duration of response to first-line MAB had a significantly greater response to second-line MAB. For advanced prostate cancer patients who progressed on first-line MAB with bicalutamide, flutamide administration as a second-line antiandrogen was found to be relatively effective, especially for those who showed a longer duration of response to the first-line MAB. Our results confirm previous findings that MAB using flutamide is an effective second-line hormonal therapy.

Topics: Aged; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Biopsy, Needle; Drug Resistance, Neoplasm; Drug Therapy, Combination; Endosonography; Flutamide; Follow-Up Studies; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Neoplasm Staging; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Tomography, X-Ray Computed; Tosyl Compounds; Treatment Outcome

We present our experience with 7 patients who developed injection site granuloma with leuprorelin acetate injection. Although isolated case reports exist, this is the largest collection of cases from a single center. The exact mechanism of the granuloma formation is not well understood, although theories are associated with the vehicle used for injection. Our discussion focuses on the nature of the granuloma formation and its etiology. The reaction appears to be more common with leuprorelin acetate than with other forms of luteinizing hormone-releasing hormone analogues.

Topics: Antineoplastic Agents, Hormonal; Granuloma; Humans; Injections; Leuprolide; Male; Prostatic Neoplasms; Skin Diseases

We report a patient with adenocarcinoma of the prostate, who eventually developed Cushing syndrome due to ectopic adrenocorticotropic hormone (ACTH) secretion from the tumor. At first, maximal androgen blockade (MAB) therapy was effective for the prostate carcinoma, which was positive for prostate-specific antigen (PSA) and negative for ACTH on the biopsy specimen. However, 3 years later, the patient complained of bilateral leg edema. A chest computed tomographic (CT) scan showed bilateral pleural effusion and inflammatory changes, focused on the right upper-lobe. While his PSA was not elevated, and there were no obvious tumor metastases, his serum cortisol and ACTH levels were elevated, without any evidence of lesions that could release ectopic ACTH. Two weeks later, the patient complained of dyspnea and bilateral pleural effusion, and inflammatory changes were worse. Although the patient was administered inhibitors of adrenocorticoid synthesis-metyrapone, they did not have enough clinical efficiency. Steroid pulse therapy was also administered but the patient's severe pneumonia and pleural effusion did not improve and he finally died of respiratory failure. In contrast to the initial biopsy specimen findings, on autopsy, the tumor was negative for PSA but positive for ACTH. Thus, it would appear that the tumor began to produce and release ectopic ACTH after therapy, which resulted in the development of Cushing syndrome in this patient with prostate carcinoma.

Topics: Adrenocorticotropic Hormone; Aged; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Cushing Syndrome; Humans; Leuprolide; Male; Nitriles; Prostatic Neoplasms; Tosyl Compounds

A 66-year-old man with clinically localized prostate cancer had elected brachytherapy as the primary management of his disease. During induction of neoadjuvant androgen deprivation for purposes of cytoreduction, the patient experienced anaphylaxis immediately after his first injection of a leuprolide acetate depot. He required emergent intubation and extended hospitalization. Anaphylactic reactions to leuprolide acetate depots have been described as exceedingly rare. To our knowledge, we report the first case of an anaphylactic reaction to a leuprolide acetate depot injection in an American man undergoing treatment for prostate cancer.

Topics: Aged; Anaphylaxis; Antineoplastic Agents, Hormonal; Brachytherapy; Humans; Injections; Leuprolide; Male; Prostatic Neoplasms

Granulomas resulting from the administration of luteinizing hormone-releasing hormone analogues (LH-RH analogues) are thought to be very rare. We report on our clinical experience with injection-site granulomas that result from the administration of LH-RH analogues, and we evaluate the incidence rate of these granulomas.. We used the clinical records of 118 patients who were administered LH-RH analogues in 2005. We describe the clinical data of patients who experienced injection-site granulomas and evaluated the incidence rate.. Five patients demonstrated injection-site granulomas due to LH-RH analogue administration. The incidence rate was 4.2% (5 of 118 patients). Most of the granulomas occurred after the first or second administration of 11.25mg of leuprorelin acetate.. The occurrence of granulomas resulting from the administration of LH-RH analogues was thought to be very rare. Our study, however, revealed a higher incidence rate than expected, especially for leuprorelin acetate.

Topics: Aged; Aged, 80 and over; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antineoplastic Agents, Hormonal; CD3 Complex; Gonadotropin-Releasing Hormone; Goserelin; Granuloma; Humans; Injections, Subcutaneous; Leuprolide; Male; Prostatic Neoplasms

Topics: Body Mass Index; Body Weight; Drug Administration Schedule; Humans; Leuprolide; Male; Obesity; Peptides; Prostatic Neoplasms; Time Factors; Treatment Outcome

Fibroepithelial lesions are uncommon in the male breast. Most published reports describe phyllodes tumors. Fibroadenomas are very common in female breasts, but are exceedingly rare in the male breast. Gynecomastia and/or lobular differentiation have been known to coexist in both types of fibroepithelial lesions in men. We report an exceptional case of recurrent, bilateral fibroadenomas in a man under treatment for prostatic carcinoma. Intracytoplasmic inclusion bodies in stromal cells identical to those seen in infantile digital fibromatosis were identified in one fibroadenoma. To the best of our knowledge, this is the first reported case of bilaterally occurring fibroadenomas in the male breast, one of which also contained digital fibroma-like inclusions, a second unreported phenomenon.

Topics: Aged; Breast Neoplasms, Male; Fibroadenoma; Fibroma; Humans; Inclusion Bodies; Leuprolide; Male; Prostatic Neoplasms

Topics: Adenocarcinoma; Aged, 80 and over; Breast Neoplasms, Male; Fertility Agents, Female; Genes, BRCA2; Humans; Leuprolide; Male; Mutation; Prostatic Neoplasms

We investigated the change in dihydrotestosterone in the prostate during androgen deprivation therapy in connection with prostate cancer aggressiveness using the Gleason score.. A total of 28 patients with clinically localized prostate cancer who were treated with androgen deprivation therapy for 6 months were enrolled in this study. Dihydrotestosterone in the prostate and serum were analyzed using liquid chromatography/electrospray ionization-mass spectrometry after polar derivatization before and after androgen deprivation therapy.. The change in dihydrotestosterone during androgen deprivation therapy in the prostate with Gleason score 7 to 10 prostate cancer was significantly smaller than that in the prostate with Gleason score 6 or less (p = 0.016). There were no significant differences between patients with Gleason score 7 to 10 prostate cancer and patients with Gleason score 6 or less in dihydrotestosterone in the prostate, in serum androgens and in serum androgen ratios before and after androgen deprivation therapy.. Low dihydrotestosterone in the prostate is probably sufficient to propagate the growth of aggressive prostate cancer. Furthermore, the prostate with aggressive prostate cancer can produce androgens from adrenal precursors more autonomously than the prostate with nonaggressive prostate cancer under a low testosterone environment with testicular suppression.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Biomarkers, Tumor; Dihydrotestosterone; Disease Progression; Flutamide; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Orchiectomy; Prognosis; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

Luteinizing hormone-releasing hormone (LH-RH) analogues have become the main focus of androgen deprivation therapy for prostatic cancer. The occurrence of injection-site granulomas due to the administration of LH-RH analogues has been thought to be a rare reaction. We herein report a rare case presenting injection-site granuloma due to the administration of leuprorelin acetate, mimicking metastatic nodule. A 90-year-old man presented with subcutaneous nodules at the injection-site of leuprorelin acetate 11.25 mg (for 3-month use). Ultrasound examination and computed tomography (CT) revealed two nodules in the bilateral abdominal walls mimicking metastatic nodule. Although he was surgically treated because of the possibility of malignancy, in the end, no evidence of malignancy was found. We should keep in mind that LH-RH analogues may cause injection-site granulomas mimicking metastatic nodule, and therefore we must inform patients undergoing the administration of leuprorelin acetate that it may cause injection-site granuloma and thus when a patient demonstrates a subcutaneous nodule it is essential to confirm whether or not he has received an injection of the LH-RH analogue at the site of nodule.

Topics: Abdominal Wall; Aged, 80 and over; Antineoplastic Agents, Hormonal; Diagnosis, Differential; Granuloma; Humans; Injections; Leuprolide; Male; Prostatic Neoplasms

The authors evaluated whether the duration of androgen suppression (AS) after the completion of hormone therapy (HT) was associated with the risk of prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM).. The study cohort was comprised of 220 men who received radiation therapy (RT) and 6 months of HT for prostate cancer between 1996 and 2005. The duration of AS was defined as the time to return to the baseline testosterone level after the completion of HT. Grays and Cox regression analyses were used to evaluate whether the duration of AS after the completion of HT was associated with the time to PCSM and ACM, respectively, after adjusting for known prognostic factors.. An increasing duration of AS was associated with a decreased risk of PCSM (adjusted hazards ratio [HR], 0.89; P = .003) and ACM (HR, 0.94; P = .007). Men who had prostate cancer with Gleason scores from 8 to 10 had significantly lower cumulative incidence estimates of PCSM (P = .04) if the duration of AS plus the length of HT administration was >/=2 years compared with <2 years. After a median follow-up of 6.1 years, the respective 5-year estimates were 0% and 38%.. The duration of AS after 6 months of HT was associated with the risk of PCSM and ACM. This duration could be used to identify men who have prostate cancer with Gleason scores from 8 to 10 in whom 6 months of HT produces long-term testosterone suppression, which may provide the cancer-specific survival benefit observed with long-term HT.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Cohort Studies; Combined Modality Therapy; Follow-Up Studies; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy, Intensity-Modulated; Survival Rate; Time Factors; Treatment Outcome

Although injection-site granulomas caused by leuprorelin acetate have been reported, there have been no reports of granulomas caused by both leuprorelin acetate and goserelin acetate. An 81-year-old man presented with subcutaneous nodules of the abdominal wall and upper arm, where 11.25 mg of leuprorelin acetate had been injected for the treatment of prostate cancer. Because of these nodules, treatment was changed to goserelin acetate. Nevertheless, he presented with another subcutaneous nodule at the injection site. Histological examination showed that these nodules consisted of numerous giant cells that were CD3-positive T lymphocytes and CD68-positive histiocytes associated with granulomatous changes. The granulomas had likely been caused by delayed-type hypersensitivity to leuprorelin acetate injection. The granuloma that formed after goserelin acetate injection might thus have developed owing to the immunogenicity of the previous leuprorelin acetate injections. The patient underwent surgical castration. The present case suggests that both leuprorelin acetate and goserelin acetate can cause injection-site disorders.

Topics: Aged, 80 and over; Goserelin; Granuloma; Humans; Injections; Leuprolide; Male; Prostatic Neoplasms

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma; Fatal Outcome; Flutamide; Humans; Leuprolide; Liver Neoplasms; Male; Prostatic Neoplasms; Tumor Lysis Syndrome

A 63-year-old man with a T1c adenocarcinoma of the prostate, Gleason score of 7 (4+3), and a pretreatment prostate-specific antigen (PSA) level of 9.5 ng/mL was treated with external-beam radiation therapy (45 Gy) and 2 magnetic resonance imaging-guided high-dose rate brachytherapy boosts (10 Gy each.) The patient also received neoadjuvant, concurrent, and adjuvant hormonal treatment with leuprolide for 7 months total. Without any further intervention the patient had 2 separate and prolonged PSA increases and decreases 12-35 months after therapy. His PSA nadir was <0.2 ng/mL and rose slowly over several months to 4.2 ng/mL, resolved, and then rose 2.3 ng/mL before again slowly resolving. After prostate irradiation, many patients experience a transient rise in serum PSA levels and a subsequent decline without any treatment. This is known as a PSA "bounce" or "bump." Some patients experience a second transient rise in PSA levels after irradiation. To our knowledge, this case report is the first documentation of a second PSA bump in a patient treated with external-beam radiation therapy and high-dose rate boost therapy and provides context to address concerns and therapeutic decisions confronting physicians and patients.

Topics: Adenocarcinoma; Antineoplastic Agents, Hormonal; Brachytherapy; Follow-Up Studies; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy Dosage; Radiotherapy, Conformal; Treatment Outcome

Androgen deprivation therapy (ADT) is a commonly used treatment for metastatic prostate cancer. A 78-year-old patient with metastatic prostate cancer had transfusion-dependent anemia develop while on ADT. The patient also had hereditary hemorrhagic telangiectasia (HHT), with chronic gastrointestinal blood loss. Blood transfusions were required every 3 weeks for 4 months to keep hemoglobin levels above 8 g/dL, despite discontinuation of ADT. The anemia, which had been well managed with iron therapy before ADT, was worsened by the loss of bone marrow-stimulating testosterone effects. The case highlights testosterone's important role in erythrocyte production. Practitioners should monitor hemoglobin levels in patients undergoing ADT.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Anemia; Antineoplastic Agents, Hormonal; Blood Transfusion; Gastrointestinal Hemorrhage; Hemoglobins; Humans; Leuprolide; Male; Prostatic Neoplasms; Telangiectasia, Hereditary Hemorrhagic

Luteinizing hormone-releasing hormone agonist (LH-RH analogue) therapy, is one of the most widely used hormonal therapies. Recently, subcutaneous injection of a new long acting 3-month LHRH analogue depot has been developed. We investigated the adverse events induced by injection of an LH-RH analogue in 82 patients (median age was 75 year old, 59-87) using our questionnaire. Forty-eight and 34 cases had been administered leuprorelin acetate (LSR) and goserelin acetate (ZLA). The presentation rate of skin reaction was 8.8% (3/34) in the ZLA group and 14.6% (7/48) in the LSR group. There was no significant difference in rate of skin reaction between the LSR and ZLA group (p = 0.5113). Eight patients had induration (6 in LSR 2 in ZLA). We also present a case of subcutaneous granuloma formation at the injection site after using the three-month type preparation of leuprorelin acetate. We should be aware of the risk of skin reactions at the injection site and monitor carefully when using an LH-RH analogue.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Goserelin; Granuloma; Humans; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Skin

Unlike goserelin, leuprorelin and triptorelin have not been assessed for their impact on survival in patients with locally advanced prostate cancer. The main adverse effects of these two drugs are similar, but convenience of use differs.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Castration; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms; Treatment Outcome; Triptorelin Pamoate

In a cross-sectional, retrospective, non-randomised study to investigate the possibility that some patients treated with luteinizing hormone releasing hormone analogues (LHRH analogues) fail to reach castration levels of serum testosterone.. 40 patients treated with a 3-monthly formulation of leuprolide acetate and continuous use of an oral antiandrogen ("Leu group") and 25 patients treated with a 3-monthly formulation of goserelin acetate and an oral antiandrogen for one month ("Gos group") were identified from our hospital's registry. Serum testosterone was measured during treatment with the respective LHRH-analogue and compared between the two groups. In the Leu group, serum testosterone was measured during week 11 or 12 of treatment. In the Gos group, serum testosterone was assessed during week 23 or 24.. Four patients (10%) treated with leuprolide acetate failed to reach the castration level of serum testosterone after treatment with one injection of a three-monthly formulation of leuprolide acetate. All patients treated with goserelin acetate achieved the castration level.. Although the overwhelming majority of prostate cancer patients during treatment of LHRH analogue achieve serum testosterone values within the castration range, individual patients may fail to reach this therapeutic goal, probably more often during treatment with leuprolide acetate than with goserelin acetate.

Topics: Aged; Antineoplastic Agents, Hormonal; Cross-Sectional Studies; Disease Progression; Humans; Leuprolide; Male; Prostatic Neoplasms; Retrospective Studies; Testosterone; Treatment Failure

Prostate cancer (PCa) growth initially depends on circulating androgens. Gonadotropin-releasing hormone (GnRH) agonists are currently used for the treatment of PCa. However, after an initial responsiveness to hormonal deprivation, PCa progresses and metastasizes. Recently, also GnRH antagonists have been used for clinical trials in patients with PCa and the results seem promising. The components of the plasminogen activator (PA) system (urokinase-type PA, uPA; PA inhibitors, PAI-1/2; uPA receptor, uPAR) have been implicated in the local degradation of the extracellular matrix (ECM) and PCa progression. The aim of this study was to test the possible effects of the treatment with an agonist (Leuprolide, GnRH-A) and an antagonist (Cetrorelix, GnRH-ANT) of GnRH on the expression and activity of uPA and PAI-1 in the conditioned media of DU145 and PC3, two PCa androgen-independent cell lines. The involvement of the PA system in the control of cellular migration was also investigated. The results obtained in DU145 and PC3 cells show that both GnRH-A and GnRH-ANT: i) inhibit cell proliferation; ii) significantly decrease the enzymatic activity and the secretion of uPA; iii) significantly increase the protein levels of PAI-1; iv) induce a significant decrease of the migratory and invasion PCa capabilities. This study suggests that GnRH analogues exhibit not only an antiproliferative effect, but also an anti-metastatic action exerted through the inhibition of the activity of PA system and might provide a rational basis for the development of clinical strategies for those tumours that progress towards an androgen-independent condition characterized by a higher metastatic potential.

Topics: Antineoplastic Agents, Hormonal; Blotting, Western; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leuprolide; Male; Neoplasm Invasiveness; Plasminogen Activators; Prostatic Neoplasms

We assessed the relationship between GnRH agonists and the risk of clinical fractures in men with prostate cancer.. Using a database of medical claims from 16 large American companies we identified a study group of 3,779 men with prostate cancer who received treatment with a GnRH agonist and a control group of 8,341 with prostate cancer who were not treated with a GnRH agonist. Men with 1 or more medical claims for bone metastases were excluded. The rates of any clinical fracture, hip fracture and vertebral fracture were compared between the groups.. The rate of any fracture was 7.91/100 vs 6.55/100 person-years at risk in men who received vs did not receive a GnRH agonist (relative risk 1.21, 95% CI 1.09 to 1.34). The rates of hip fracture (relative risk 1.76, 95% CI 1.33 to 2.33) and vertebral fracture (relative risk 1.18, 95% CI 0.94 to 1.48) were also higher in men who received a GnRH agonist. GnRH agonist treatment was independently associated with fracture risk on multivariate analyses.. GnRH agonists increase the risk of clinical fracture in men with prostate cancer.

Topics: Aged; Aged, 80 and over; Fractures, Spontaneous; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Risk Factors; Triptorelin Pamoate

Topics: Aged; Antineoplastic Agents, Hormonal; Dermatitis Herpetiformis; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms

We report the case of a T3 prostate cancer in a 70-year-old white man. Hormone therapy represents a prominent branch in the treatment of locally advanced and metastatic prostate cancer. Gonadotropin-releasing hormone agonists have been proven to have a double effect on androgen metabolism: an initially stimulating, followed by an inhibitory, effect on the pituitary gland. This phenomenon may be noxious in the case of gonadotroph adenoma, with subsequent symptoms of intracranial hypertension. Gonadotropin-releasing hormone antagonists (abarelix), by avoiding the flare-up reaction, might be used in such instances.

Topics: Adenocarcinoma; Adenoma; Aged; Antineoplastic Agents, Hormonal; Biopsy; Diagnosis, Differential; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Pituitary Neoplasms; Prostatic Neoplasms; Tomography, X-Ray Computed

To prospectively evaluate the time-course of recovery of serum testosterone levels after a short course of luteinizing hormone-releasing hormone analogue (LHRHa) and radical radiotherapy to the prostate.. Testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were sequentially measured prospectively in 59 men who received short-course LHRHa treatment and radiotherapy for localized prostate cancer. Measurements were made before treatment (baseline), during LHRHa treatment, and at 6, 12, 18, 24 and >40 weeks after the last LHRHa injection.. The median (range) time from the first to last LHRHa injection was 116 (54-194) days. The mean (95% confidence interval) testosterone levels (in nmol/L) at baseline, during treatment and at 6, 12, 18, 24 and >40 weeks afterward were 12.0 (10.8-13.1), 0.6 (0.5-0.7), 1.4 (0.6-2.2), 11.4 (9.7-13), 12.2 (10.5-14), 10.4 (8.9-12) and 11.7 (10.5-13). Four men had low baseline testosterone levels (<6.1 nmol/L). At 6 weeks after the last LHRHa injection, no men had testosterone levels in the 'normal' range; 35% were in the normal range at 12 weeks, 85% at 18 weeks, 89% at 24 weeks, and 96% at 1 year.. After LHRHa treatment and radiotherapy, the testosterone levels of most men had recovered to normal by 18-24 weeks after the last LHRHa injection.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Follicle Stimulating Hormone; Goserelin; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Multivariate Analysis; Neoadjuvant Therapy; Prospective Studies; Prostatic Neoplasms; Testosterone; Treatment Outcome

Leuprorelin acetate, a chemotherapeutic agent used to treat prostate cancer, is a synthetic luteinizing hormone-releasing hormone (LHRH) agonist. We report a 75-year-old man who presented with several large subcutaneous nodules at the site of leuprorelin acetate injections for his prostatic cancer. A biopsy of the nodules disclosed epithelioid granulomatous inflammation and resulted in a diagnosis of drug-induced granulomatous reaction to leuprorelin acetate.

Topics: Abdomen; Aged; Antineoplastic Agents, Hormonal; Diagnosis, Differential; Gonadotropin-Releasing Hormone; Granuloma; Humans; Injections, Subcutaneous; Leuprolide; Male; Prostatic Neoplasms; Skin Neoplasms

We report a case in a 70-year-old patient indicated to have a metastatic lesion from a chest X-ray taken during a medical examination. His blood prostatic specific antigen level was very high at 100 ng/ml (normal, less than 4.0 ng/ml). Palpation of the prostate disclosed enlargement to hen's egg size with an irregular surface and indurations bilaterally. Transrectal sextant needle biopsy of the prostate was performed, revealing moderately differentiated adenocarcinoma. Computed tomography (CT) scan and bone scintigraphy showed intrapelvic lymphnode adenopathy and metastasis to the right pubic bone. Under a diagnosis of stage D2 prostate cancer, we initiated endocrine therapy (luteinizing hormone-releasing hormone analogue depot every 4 weeks and bicalutamide). Androgen blockage was very effective and after 6 months, the PSA level had decreased markedly to below 0.2 ng/ml. Sixteen months later, pulmonary metastasis completely disappeared. He is currently free from recurrence and progressing well.

Topics: Adenocarcinoma; Aged; Anilides; Antineoplastic Agents, Hormonal; Drug Administration Schedule; Humans; Leuprolide; Lung Neoplasms; Male; Neoplasm Staging; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Tomography, X-Ray Computed; Tosyl Compounds

Health-related quality of life (HQOL) research is a means of broadening the assessment of treatment effects. This longitudinal study investigated the dynamic change to quality of life (QOL) and testosterone dependant physiology in men commencing an intermittent maximal androgen blockade program (IMAB). Two hundred and fifty men were accrued to the multi-centre study of IMAB (Flutamide 250 mg TDS, Leuprolide 22.5 mg depot) ceasing treatment after 9 months if PSA <4 ng/ml, and restarting when PSA >20 ng/ml. QOL was assessed every 3 months for 30 months using the EORTC QLQ-C30 and EORTC QLQ-PR25 module. Data completion for the whole study was 90%. At baseline, our cohort was less symptomatic and had better function than the EORTC reference cohort, which may be related to a shift in clinical practice with time. Testosterone suppression (AS) lead to a significant reduction in global HQOL and deterioration in most function and symptom scales. During the off period, there was a trend of progressive improvement in HQOL that paralleled testosterone recovery but was slower than the rate of deterioration during the treatment phase. Maximum recovery of HQOL occurred most frequently by months 9-12. Testosterone recovery was slower and less complete in older men, and lead to concomitant poorer HOQL recovery. Whilst the magnitude of mean change to scale scores was small, there was a consistent and simultaneous deterioration during maximal androgen blockade (MAB) and improvement during androgen recovery. Older men are more likely to show an impaired testosterone recovery, and this was paralleled by a slower HQOL recovery. Newer methods of analysis to describe results in a way that has meaning to the individual patient are warranted.

Topics: Aged; Androgen Antagonists; Flutamide; Humans; Leuprolide; Longitudinal Studies; Male; Middle Aged; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Surveys and Questionnaires; Testosterone

Gonadotropin-releasing hormone (GnRH) agonists have become the treatment of choice for locally advanced and metastatic prostate cancer. We report a case of prostate cancer in which this treatment led to severe symptoms of intracranial hypertension due to the concomitant presence of an asymptomatic functional pituitary adenoma. A 70-year-old white man was initially evaluated for a multifocal adenocarcinoma, Gleason score 6 (3+3) with perineural invasion suggesting an extracapsular extension. A conformational external beam radiation (74 Gy) with a concomitant GnRH agonist (leuprolide) was initiated. Almost 10 days after the administration of leuprolide the patient complained of visual disturbance, diplopia and other symptoms of intracranial hypertension. Magnetic resonance imaging (MRI) of the brain demonstrated a large sella mass lesion. To relieve the patient's symptoms, a transsphenoidal subtotal tumorectomy was necessary. The histopathological examination revealed an invasive gonadotroph pituitary adenoma. Two years later, there is no sign of progression either on his prostatic disease (prostate-specific antigen of 0.21 ng/mL) or on his pituitary disease (FSH, 4.7 UI/L, LH, 3.1 UI/L and total testosterone, 627 ng/dL) with values of the hypothalamic-pituitary axis in the normal range. We advocate that a high index of suspicion of pituitary tumor must be considered in any case of intracranial hypertension following the administration of GnRH agonist. Abarelix could have a place in such cases.

Topics: Adenocarcinoma; Adenoma; Aged; Antineoplastic Agents, Hormonal; Diagnosis, Differential; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Neoplasms, Multiple Primary; Pituitary Neoplasms; Prostatic Neoplasms; Tomography, X-Ray Computed

We describe a patient with advanced prostate cancer who failed to achieve testosterone suppression with depot leuprolide after developing sterile abscesses at the injection sites. When the patient was switched to depot goserelin, he did not have any evidence of inflammation at the injection sites, but testosterone suppression again failed. This case suggests variable mechanisms for failure of gonadotropin-releasing hormone agonist therapy and highlights the necessity of prospective testosterone monitoring in patients who have developed sterile abscesses, even if switched to another gonadotropin-releasing hormone agonist.

Topics: Abscess; Adenocarcinoma; Aged; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Bone Neoplasms; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Nitriles; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Tosyl Compounds; Treatment Failure

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.

Topics: Adenocarcinoma; Androgen-Binding Protein; Animals; Animals, Genetically Modified; Antigens, Polyomavirus Transforming; Antineoplastic Agents, Hormonal; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Immunohistochemistry; Leuprolide; Luteinizing Hormone; Male; Oligonucleotide Array Sequence Analysis; Prostate; Prostatic Neoplasms; Rats; Receptors, Androgen; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Seminal Vesicles; Testosterone

Topics: Antineoplastic Agents, Hormonal; Carcinoma; Drug Resistance, Neoplasm; Humans; Leuprolide; Male; Neoplasm Staging; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Failure

The mechanisms by which a GnRH analogue, leuprorelin acetate (LA), antagonizes the mitogenic effect of dihydrotestosterone (DHT) or epidermal growth factor (EGF) in prostate cancer cells is poorly understood. The mitogen-activated protein kinase system has a central role in growth regulation and, for this reason, we investigated the involvement of the extracellular signal-regulated kinase (ERK1/2) pathway in the response of both androgen-sensitive (LNCaP) and -insensitive (PC-3) prostate cancer cells to LA alone or combined with EGF or DHT. The evaluation of ERK activation was performed by using Western blot analysis and immunocytochemistry. EGF specifically induced ERK1/2 activity in both models and this effect was counteracted by an inhibitor of EGF-receptor phosphorylation. The addition of LA produced an appreciable reduction of ERK phosphorylation promoted by EGF in LNCaP cells, while it generally determined an increase in ERK activity in androgen-unresponsive PC-3 cells. The slight ERK activation induced by DHT in LNCaP cells was counteracted by LA and this effect was evident only by immunocytochemistry. Our findings suggest that the antiproliferative effect of LA in prostate cancer cells stimulated by hormones and growth factors may be, at least in part, mediated by the reduction of ERK1/2 activation in LNCaP cells and linked to the unexpected increase of this activity produced by the analogue in PC-3 cells.

Topics: Antineoplastic Agents, Hormonal; Cell Line, Tumor; Cell Proliferation; Dihydrotestosterone; Dose-Response Relationship, Drug; Epidermal Growth Factor; ErbB Receptors; Humans; Leuprolide; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasms, Hormone-Dependent; Phosphorylation; Prostatic Neoplasms; Protein Kinase Inhibitors; Quinazolines; Time Factors; Tyrphostins

Although prostate cancer specific mortality is decreasing, there is little effect on overall mortality in this population, suggesting the possibility of an increased risk of death from nonprostate cancer related causes. Androgen deprivation therapy could adversely affect cardiovascular health. We investigated changes in lipid and glucose during androgen deprivation therapy.. We performed an exploratory analysis of pooled data from 3 prospective clinical trials aimed at achieving medical castration by comparing the gonadotropin releasing hormone antagonist abarelix, the gonadotropin releasing hormone agonist leuprolide acetate and leuprolide acetate plus the antiandrogen bicalutamide. Most patients were treated in the neoadjuvant setting or because of biochemical recurrence. Fasting serum lipid, glucose and hemoglobin A1C were determined in 1,102 men at baseline, and on treatment days 85 and 169. In the current study men were categorized into 3 treatment groups according to the type of androgen deprivation therapy, that is leuprolide acetate, leuprolide acetate plus bicalutamide or abarelix, and statin therapy.. Significant increases in total cholesterol, triglyceride and high density lipoprotein-cholesterol were observed in patients on leuprolide acetate or abarelix but not in patients on leuprolide acetate plus bicalutamide. Consistent changes in low density lipoprotein-cholesterol were not detected. Increased total cholesterol was usually due to an increase in high density lipoprotein-cholesterol. Hemoglobin A1C increased from baseline to day 85 only and there were no significant changes in fasting glucose measurements. The type of androgen deprivation therapy did not affect these parameters.. Short-term androgen deprivation therapy affects serum lipid and hemoglobin A1C independent of statin therapy.

Topics: Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Blood Glucose; Cholesterol; Fasting; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Nitriles; Oligopeptides; Prostatic Neoplasms; Tosyl Compounds

Clinically unsuspected pituitary adenomas are common among adults on autopsy and MRI survey. Acute pituitary hemorrhage is far more rare. We report a case of a 61-year-old male patient with locally advanced prostate cancer who presented with an acute picture of pituitary apoplexy after his first dose of leuprolide. He developed headache and neck pain within a few hours of treatment followed by nausea, vomiting, ptosis and diplopia. Pituitary apoplexy is a potentially life threatening medical emergency. Although the pathophysiology is poorly defined, various conditions and treatments have been reported to trigger apoplexy. Apoplexy has been reported in response to pituitary stimulation by GnRH or GnRH-agonists. Initial stimulatory effects of gonadotropin releasing hormone (GnRH) analogue may induce apoplexy in patients with asymptomatic gonadotroph adenomas.

Topics: Adenoma; Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Humans; Hypophysectomy; Leuprolide; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Apoplexy; Pituitary Neoplasms; Prostatic Neoplasms; Risk Factors; Treatment Outcome

The objective of this study was to evaluate the therapeutic significance of a longer duration of neoadjuvant hormonal therapy (NHT) followed by radical prostatectomy (RP) in Japanese men with high-risk prostate cancer.. This study included a total of 42 patients with high-risk prostate cancer who were treated with NHT for >or=8 months prior to RP. In this series high-risk prostate cancer was defined as clinical stage T2c or T3, pretreatment serum prostate-specific antigen (PSA) >20 ng/ml and/or a biopsy Gleason score of 8-10. Biochemical recurrence was defined as a serum PSA level of >or=0.2 ng/ml. The data of these patients were retrospectively reviewed to clarify the relationships between treatment outcomes and various clinicopathological parameters.. The clinical stage was T2c in 13 patients and T3 in 29, the median value of pretreatment serum PSA was 43.3 ng/ml (range 9.7-322.2), and the biopsy Gleason score was 6 in 3 patients, 7 in 16 and >or=8 in 23. Following NHT (median 12 months, range 8-27), the median value of serum PSA decreased to 0.05 ng/ml (<0.01-18.3 ng/ml), and 15 patients (35.7%) were pathologically downstaged. During the median follow-up of 38 months (range 8-58), 11 patients (26.2%) developed biochemical recurrence, and the multivariate analysis identified pretreatment serum PSA, biopsy Gleason score and percentage of positive biopsy core as independent predictors of biochemical recurrence. The 3-year biochemical recurrence-free survival rate of the 42 patients was 68.3%, which was not significantly different from that of 34 patients who underwent RP for high-risk prostate cancer without NHT during the same period.. A longer duration of NHT followed by RP for patients with high-risk prostate cancer resulted in a comparatively favorable outcome. However, despite the nonrandomized retrospective analysis, the present findings suggest no significant impact of long-term NHT on biochemical recurrence. Longer follow-up is needed to determine whether this therapeutic strategy is beneficial for high-risk prostate cancer patients.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Humans; Japan; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Nitriles; Preoperative Care; Prostatectomy; Prostatic Neoplasms; Retrospective Studies; Risk Factors; Time Factors; Tosyl Compounds

Topics: Aged; Delayed-Action Preparations; Granuloma; Humans; Injections, Subcutaneous; Lactic Acid; Leuprolide; Male; Polyesters; Polymers; Prostatic Neoplasms; Suppuration

We describe the treatment outcome in 17 patients who received combined salvage brachytherapy and short-term androgen deprivation therapy for local prostate cancer relapse after prior external beam irradiation.. Median patient age was 68 years. Local relapse after external beam irradiation was confirmed by biopsy. Median prostate specific antigen at local relapse was 4.7 ng/ml. Five of the 17 patients were enrolled in a protocol combining androgen deprivation therapy with brachytherapy and the remaining men were treated off protocol. All patients received neoadjuvant androgen deprivation therapy for a median of 3 months, followed by ultrasound guided brachytherapy using 125I in 9 and 103Pd seeds in 8. Five patients also received adjuvant leuprolide for a median of 6 months. Biochemical failure was defined using the American Society for Therapeutic Radiology and Oncology definition. Toxicity was graded with a modified Radiation Therapy Oncology Group scale.. Median followup was 44 months. The actuarial 4-year biochemical control rate was 75%. Three patients died of intercurrent diseases. No prostate cancer mortality or local failure had occurred at last followup. One patient had bone metastasis. No clinical or treatment factor was associated with biochemical control. Grade 3 and 4 genitourinary toxicity developed in 7 (41%) and 1 patients (6%), respectively. Grade 2 and 3 gastrointestinal toxicity occurred in 5 (29%) and 1 patients (6%), respectively.. Our series suggests that salvage brachytherapy and short-term androgen deprivation therapy can achieve biochemical control in select patients with local relapse after prior external beam irradiation. The major side effects are urinary complications, including grade 3 and 4 complications in 41% and 6% of cases, respectively.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Brachytherapy; Combined Modality Therapy; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Neoplasm Recurrence, Local; Prostatic Neoplasms; Salvage Therapy; Time Factors

Topics: Antineoplastic Agents, Hormonal; Drug Implants; Humans; Leuprolide; Male; Prostatic Neoplasms

The histological diagnosis of prostate cancer treated with hormonal agents is often difficult because of various morphological changes induced by androgen ablation. Immunostaining of cytokeratins may be useful to prevent the underdetection of cancer cells. We examined prostatic specimens with histological diagnosis of 11 pTO patients who had undergone neoadjuvant endocrine therapy followed by radical prostatectomy. Anti-cytokeratin antibody, AE1/AE3 was used to detect the prostatic epithelial cells. Anti-cytokeratin antibody, 34/3 E12 was used to detect the prostatic basal cells. The loss of basal cells indicates the acini to be cancer. The immunostaining with these antibodies revealed that 2 out of 11 cases had residual cancer and were not pTO. The immunostaining of cytokeratins was useful to detect the residual prostatic cancer after endocrine therapy.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Flutamide; Humans; Keratins; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prostate; Prostatic Neoplasms

The changes in serum prostate specific antigen (PSA) concentrations can be used as a prognostic factor in patients undergoing maximum androgen blockade for metastatic prostate cancer.. A total of 149 patients followed up in our department were classified into 4 groups on the basis of PSA changes: group 1; those with normalisation of PSA levels within the first 3 months, group 2; those with normalisation PSA between months 3 and 6, group 3; those with a decrease in PSA but not reaching normal range, group 4; those with no decrease. The gleason scores and the number of bone metastases were also compared between the groups.. The time to progression was significantly delayed in group 1 (mean: 23.3 months) compared to those with group 2 (mean: 16.9 months) (P<0.02). The time to progression in group 3 (mean: 8.45 months) was significantly shorter compared to the first two groups (P<0.001). Also, in patients with gleason scores 5-7 (grades 2) and gleason scores over 7 (grade 3) and group 1, the time to progression (mean: 21.2 months) was significantly delayed compared to those with the same gleason scores but with group 2 (mean: 13.4 months) (P<0.001).. The decrease in PSA level is more important than gleason scores in determining the time to progression. Early normalisation of PSA delays the time to progression, and when combined with gleason scores, PSA is an important prognostic factor in predicting the success of the therapy.

Topics: Aged; Antineoplastic Agents, Hormonal; Goserelin; Humans; Leuprolide; Male; Middle Aged; Monitoring, Physiologic; Neoplasm Metastasis; Orchiectomy; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies

Androgen ablation is often used in addition to low-dose-rate brachytherapy in the treatment of prostate cancer, particularly for disease with adverse features. We report a single-institution experience and analysis of the role of androgen ablation with brachytherapy in patients with prostate cancer.. A cohort of 189 consecutive patients receiving low-dose-rate brachytherapy for prostate cancer at our institution who had demographic, disease and treatment information and a minimum of 2 years of follow-up available, constituted the analysis study group. This cohort was divided into two major categories based on the use of androgen ablation. Using two successive prostate- specific antigen (PSA) rises above 1 ng/mL as the definition of failure, biochemical failure-free survival (BFFS) curves were constructed for the androgen ablation and no-androgen ablation groups and compared using the log rank test; additionally, a multivariate analysis of all major disease and treatment factors was performed using the Cox proportional hazards model. These analyses were conducted for the whole cohort as well as for subgroups defined by the use of external beam radiotherapy (EBRT).. The 4-year BFFS in the androgen ablation versus no-androgen ablation groups was 76% versus 70% (p = 0.230) for the whole cohort, 75% versus 62% (p = 0.182) for EBRT patients, and 75% versus 82% (p = 0.764) for no-EBRT patients. For the whole cohort, the use of EBRT was the only factor reaching significance on multivariate analysis (p = 0.040). When analysing the EBRT and no-EBRT subgroups separately, no factor, including androgen ablation, reached significance on multivariate analysis.. In our study, addition of androgen ablation conferred no biochemical control advantage when added to low-dose-rate brachytherapy for the treatment of patients with prostate cancer.

Topics: Aged; Antineoplastic Agents, Hormonal; Brachytherapy; Humans; Leuprolide; Male; Prostatic Neoplasms

Here we demonstrate 2 patients who showed marked hyperglycemia after androgen-deprivation therapy for prostate cancer and the efficacy of the thiazolidinedione pioglitazone on their glycemic control. Case 1 was a 61-year-old man diagnosed with prostate cancer who had type 2 diabetes mellitus for 7 years. His glycemic control had been good for the previous 5 years because of diet therapy and acarbose administration. He was given the gonadotropin-releasing hormone agonist leuprolide acetate and the androgen receptor antagonist flutamide for the treatment of prostate cancer. After the second injection of leuprolide acetate, fasting glucose and hemoglobin A1c (HbA1c) levels were found to be markedly elevated (22.8 mmol/L and 10.5%, respectively). Case 2 was an 81-year-old man whose fasting glucose and HbA1c had been normal 10 months ago. He was injected with leuprolide acetate for the treatment of prostate cancer. Six months after starting the leuprolide treatment, the patient complained of thirst and weight loss and was diagnosed with diabetes mellitus with a fasting glucose of 19.4 mmol/L and HbA1c of 9.9%. The correct homeostasis model assessment evaluation indexes for pancreatic beta-cell function (HOMA-%beta )A and for insulin sensitivity (HOMA-%S) were reduced in these 2 patients compared with control men. Their serum testosterone and 17beta -estradiol concentrations were depressed. After improvement of hyperglycemia by insulin treatment, their glycemic control remained good after treatment with pioglitazone without use of insulin. The values of HOMA-%beta and HOMA-%S increased to control ranges. Insulin resistance after the androgen-deprivation therapy might lead to marked hyperglycemia in these patients.

Topics: Aged; Aged, 80 and over; Androgen Receptor Antagonists; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Islets of Langerhans; Leuprolide; Male; Middle Aged; Pioglitazone; Prostatic Neoplasms; Thiazolidinediones

Dermatitis herpetiformis (DH) is a chronic, pruritic, papulovesicular dermatosis on extensor surfaces that is characterized by a neutrophilic infiltrate and granular immunoglobulin A deposition at the dermal papillae. Although the presence of immunoglobulin A in the skin and the severity of DH are known to be associated with gluten intake, few drugs have been implicated in the induction of DH. We report a case of DH triggered by intramuscular injections of leuprolide acetate, a gonadotropin-releasing hormone analog, in a patient with a history of prostate cancer.

Topics: Aged; Antineoplastic Agents, Hormonal; Dermatitis Herpetiformis; Humans; Leuprolide; Male; Prostatic Neoplasms

The concept of a prostate-specific antigen (PSA) "nadir" has been used as a predictive marker for treatment success in patients treated with radiotherapy for localized prostate carcinoma. However, this approach is not applicable in patients who are concomitantly treated with short-term hormonal therapies. To address this, the authors sought to develop a new predictive marker in such patients after prostate brachytherapy (BT).. Between March 1997 and November 2002, 194 men with clinical Stage T1A-T3N0M0 prostate carcinoma (according to the 1992 International Union Against Cancer/American Joint Committee on Cancer TNM classification system) were treated with interstitial palladium (103Pd3) BT and androgen ablation therapy with or without external beam radiotherapy (EBRT). Based on tumor characteristics, 127 patients received an antiandrogen, finasteride, and BT whereas 67 received an antiandrogen, leuprolide, and EBRT followed by a BT boost. Hormonal therapy was initiated 2-3 months before any radiotherapy for a total duration of 8-9 months. Follow-up included physical examination and determining the PSA level at 3-month intervals. Postoperative serum testosterone was evaluated in preoperatively potent patients with erectile dysfunction > 6 months after therapy. A PSA level < or = 0.06 ng/mL or < or = 0.20 ng/mL detected during a 6-12-month window after the implant were evaluated as predictors of biochemically disease-free survival (DFS), defined as the time to a PSA level > or = 1.0 ng/mL.. Of the 194 patients, 163 were available for analysis. The median length of follow-up was 48 months. In those patients with a PSA level < or = 0.20 ng/mL at 6-12 months, the DFS at 48 months after the implant was 96% (95% confidence interval [95% CI], 91-99%) compared with the remainder of the patients, whose DFS decreased to 80% (95% CI, 65-89%) (P < 0.001). When a PSA level < or = 0.06 ng/mL was used as an indicator, the 48-month DFS was 99% (95% CI, 91-100%) compared with that for patients with a PSA level > 0.06 ng/mL, in whom the DFS was 85% (95% CI, 74-92%) (P = 0.004). Furthermore, because testosterone levels may occasionally remain low after the cessation of luteinizing hormone-releasing hormone agonist therapy and result in erectile dysfunction and an artificially low PSA level, the authors reviewed the serum testosterone levels in 23 patients who were so treated and were experiencing erectile dysfunction. None had PSA values below the lower limit of normal.. A PSA level < or = 0.20 ng/mL or < or = 0.06 ng/mL measured at 6-12 months after BT appears to be a useful predictive marker for detecting early success in patients with prostate carcinoma who are treated with neoadjuvant androgen ablation and BT. These markers may be used to identify those patients who are at an increased risk of biochemical failure and may be useful in stratifying patients for closer follow-up, long-term adjuvant therapies, or clinical trials. A longer follow-up period will be needed to verify whether these are predictive of long-term cancer control.

Topics: Adenocarcinoma; Androgen Antagonists; Antineoplastic Agents, Hormonal; Brachytherapy; Combined Modality Therapy; Enzyme Inhibitors; Finasteride; Humans; Leuprolide; Male; Neoadjuvant Therapy; Neoplasm Staging; Palladium; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes; Risk Factors; Survival Rate; Testosterone; Treatment Outcome; Ultrasonography, Interventional

We report a case of interstitial pneumonitis induced by bicalutamide and/or leuprorelin acetate given as therapy for prostate cancer, in which the pneumonitis was successfully managed by steroid treatment. Steroids were given promptly on the day following onset of pneumonitis, and the patient (72 years old) recovered almost completely within one and a half months. Interstitial pneumonitis, induced by hormone treatment given for prostate cancer, is a reversible condition and a quick diagnosis followed by prompt, proper treatment is important to ensure a successful recovery. The patient had been free of interstitial pneumonitis for 14 months, but died of pneumothorax.

Topics: Adenocarcinoma; Aged; Anilides; Anti-Inflammatory Agents; Antineoplastic Agents, Hormonal; Bone Neoplasms; Humans; Leuprolide; Lung Diseases, Interstitial; Male; Methylprednisolone Hemisuccinate; Nitriles; Prostatic Neoplasms; Tosyl Compounds

To evaluate the prognostic significance of magnetic resonance imaging (MRI) tumour stage in clinically localised prostate cancer.. Between 1988 and 1999, 199 men with clinically localised prostate cancer (T -T4, N0/Nx, M0) were treated with neo-adjuvant androgen deprivation and radical radiotherapy, and were staged using MRI. Concordance between clinical tumour (cT) stage, as determined by digital rectal examination, and MRI tumour (mT) stage was assessed. Univariate and multivariate analyses using the Cox proportional hazards model were used to study the prognostic role of cT stage and mT stage in addition to established prognostic factors.. Of these 199 patients, 103 (52%) were upstaged on MRI, seven (3%) were downstaged, and in 89 (45%) cT and mT stages were concordant. With median follow-up of 3.8 years, 5-year freedom from prostate-specific antigen (PSA) failure was 48% (95% confidence interval (CI) 39-56%). On univariate analysis, freedom from PSA failure was associated with mT stage (P = 0.009) as well as Gleason score (P < 0.001) and initial PSA (P < 0.001), but not cT stage (P = 0.449). On multivariate analysis, Gleason score (P = 0.001), initial PSA (P < 0.001), but not mT stage (P = 0.112) remained independent determinants of freedom from PSA failure. For the subgroup of 149 patients with cT1-2 disease, mT stage was a significant predictor of increased risk of PSA failure on univariate analysis (P = 0.005), but not multivariate analysis (P = 0.19).. Freedom from PSA failure was more closely associated with mT stage than cT stage. Future studies are warranted to determine whether mT stage is an independent determinant of treatment outcome.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Prostatic Neoplasms; Radiotherapy; Treatment Outcome

To evaluate, in a pilot study, the tumor control outcomes of our approach and define the pretreatment characteristics that predict a response to therapy. Patients with advanced clinically localized prostate cancer have a high likelihood of prostate-specific antigen (PSA) failure 3 to 5 years after initial treatment. We adopted trimodality therapy (neoadjuvant and adjuvant androgen ablation, external beam radiotherapy [RT], and a brachytherapy boost) to augment biochemical disease-free survival in this patient population.. From 1997 to 2000, 93 patients with clinical Stage T2b or greater, or PSA level greater than 10 ng/mL, or Gleason score 7 or greater were treated with external beam RT followed by palladium-103 brachytherapy. Two to three months before external beam RT, an 8 to 9-month regimen of leuprolide and an oral antiandrogen was initiated. Patients were followed up at 3 to 4-month intervals with PSA determination and digital rectal examination. Perineural invasion, the percentage of cancer in biopsy cores, pretreatment PSA level, clinical T stage, and Gleason score were analyzed as prognostic factors for biochemical failure defined by both the American Society for Therapeutic Radiology and Oncology (ASTRO) criteria and PSA level greater than 0.2 ng/mL.. The median length of follow-up was 45 months. The overall probability of biochemical failure using a PSA level greater than 0.2 ng/mL at 4 years was 79% (95% confidence interval 69% to 89%). With the ASTRO criteria, the overall failure rate at the same point was 77% (95% confidence interval 68% to 87%). Gleason score (P = 0.07) showed a trend toward predicting biochemical failure using the PSA level greater than 0.2 ng/mL criterion.. Trimodality RT offers excellent tumor control in patients with poor prognosis who often relapse early. Longer follow-up will be important to determine whether these results are durable over time.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Brachytherapy; Chemotherapy, Adjuvant; Combined Modality Therapy; Disease-Free Survival; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Palladium; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes

GnRH analogs have antiproliferative and/or apoptotic effects on prostate cancer cells. Also, neurotrophin receptors TrkA and p75 have been reported in normal prostate suggesting a role in the gland growth control. In prostate cancer, TrkA receptors seem to be overexpressed and p75 receptors show a decreased expression. These changes in neurotrophin receptors may be related with unbalanced growth in malignant cells. In the present study we investigate the effects of GnRH analogs (leuprolide and cetrorelix) on the expression of TrkA and p75 neurotrophin receptors in primary cultures of human prostate cancer cells.. Tissue was obtained from radical prostatectomies due to prostate adenocarcinoma. Cells were isolated after sequential enzyme digestion and cultured in defined media. Nerve growth factor (NGF) receptors in untreated cultures were estimated by immunofluorescence. Cultures were treated with leuprolide (agonist) or cetrorelix (antagonist) and expression of TrkA and p75 receptors were evaluated by semi quantitative RT-PCR (polymerase chain reaction) and western blot. Cell proliferation was estimated by MTT method and apoptosis through COMET assay.. Both leuprolide and cetrorelix induced a significant increase in p75 receptor gene and protein expression at a concentration that induce apoptosis and decrease proliferation. TrkA receptors showed no changes in presence of GnRH analogs.. GnRH analogs, leuprolide, and cetrorelix, change the ratio between neurotrophin receptors TrkA and p75 by increasing gene and protein expression of p75 receptor. Considering that TrkA receptor is related with proliferation and p75 with apoptosis, we suggest that our findings may explain, in part, the effect of GnRH analogs on prostate cancer growth.

Topics: Adenocarcinoma; Antineoplastic Agents, Hormonal; Apoptosis; Blotting, Western; Cell Proliferation; Comet Assay; Epithelial Cells; Formazans; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms; Receptor, Nerve Growth Factor; Receptor, trkA; Receptors, Nerve Growth Factor; Reverse Transcriptase Polymerase Chain Reaction; Tetrazolium Salts

To analyze the impact of neoadjuvant hormone therapy (HT) on acute gastrointestinal (GI) and genitourinary (GU) toxicity from radiotherapy (RT).. The toxicity rates of 480 consecutive prostate cancer patients were reviewed and compared using the chi2 test. Ordered logit regression analyses were performed including the major demographic, disease, and treatment factors. Although no reduction in acute GI toxicity from HT use was observed (P=0.067), a lower rate of acute GU toxicity was observed (P=0.002). No factor reached statistical significance on regression analysis.. Observed toxicity rates were similar or lower in patients receiving HT. Thus, increased RT toxicity should not be a concern when deciding to add neoadjuvant HT to RT for prostate cancer.

Topics: Aged; Anilides; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Brachytherapy; Cohort Studies; Flutamide; Gastrointestinal Tract; Goserelin; Hormones; Humans; Leuprolide; Male; Middle Aged; Nitriles; Prognosis; Prostatic Neoplasms; Radiation Injuries; Radiotherapy; Radiotherapy Dosage; Regression Analysis; Testosterone; Time Factors; Tosyl Compounds; Treatment Outcome; Urogenital System

Cancer of the prostate can be associated with coagulopathy characterized as primary fibrinolysis or diffuse intravascular coagulopathy (DIC) with secondary fibrinolysis. These complications are usually associated with surgical manipulation of the prostate or with advanced metastatic disease. This report describes a patient with DIC and fibrinolysis following medical management of advanced prostate cancer with gonadotropin-releasing hormone leuprolide, while receiving the androgen receptor blocking agent flutamide. This report suggests that release of procoagulant material from prostatic carcinoma may be so rapid following hormonal management that consumptive coagulopathy with fibrinolysis can follow. Shortened Abstract: Medical management with gonadotropin releasing hormone allowed the expression of consumptive coagulopathy in patients with metastatic prostate cancer.

Topics: Aged; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Drug Therapy, Combination; Fibrinolysis; Flutamide; Humans; Leuprolide; Male; Prostatic Neoplasms

A case of granuloma which developed following a subcutaneous injection of leuprorelin acetate is presented. A prominent induration developed at the site of injection with a three-month type preparation, and radical retropubic prostatectomy and simultaneous excision of the granulomas were requested by the patient since they were large, infectious and painful. Our experience may indicate the necessity of conversion from leuprorelin acetate to other drugs (e.g., goserelin acetate, castration) if a local induration, caused by a subcutaneous injection of leuprorelin acetate, has developed to a large granuloma.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Granuloma; Humans; Inflammation; Injections, Subcutaneous; Leuprolide; Male; Prostatic Neoplasms

To analyze the impact of hormonal therapy (HT) on late gastrointestinal (GI) and genitourinary (GU) toxicity from external beam radiotherapy (RT).. The records of 445 consecutive patients with prostate cancer undergoing RT with or without HT were reviewed. Late toxicity rates, using established toxicity scoring guidelines, were tabulated in the two groups and compared using the chi-square test. Ordered logit regression analyses were performed that included the major demographic, disease, and treatment factors.. The chi-square analyses demonstrated lower rates of GI toxicity (P = 0.013) and GU toxicity (P = 0.041) in the cohort receiving HT; this reduction in toxicity appeared to be consistent across different toxicity grades. However, on regression analysis, the only factor reaching statistical significance in predicting late GI and late GU toxicity was the radiation dose (P = 0.004 and P = 0.047, respectively). In particular, on regression analysis, HT did not reach statistical significance in predicting late GI toxicity (P = 0.229) or late GU toxicity (P = 0.910).. Observed late RT toxicity rates were generally similar in patients who did and did not receive HT. Thus, increased late RT toxicity should not be a major concern when deciding to add HT to RT for treatment of localized prostate cancer.

Topics: Aged; Anilides; Antineoplastic Agents, Hormonal; Flutamide; Gastrointestinal Diseases; Goserelin; Humans; Leuprolide; Male; Male Urogenital Diseases; Nitriles; Prostatic Neoplasms; Radiation Injuries; Time Factors; Tosyl Compounds

To compare several characteristics of alternative definitions of biochemical failure (BF) in men with extended follow-up after radiotherapy (RT) with or with androgen deprivation therapy (ADT) for prostate cancer.. From December 1, 1991, to April 30, 1998, 688 men with Stage T1c-T3NX-N0M0 prostate cancer received RT alone (n = 586) or RT plus ADT (n = 102) with a minimal follow-up of 4 years and five or more "ADT-free" posttreatment prostate-specific antigen levels. BF was defined by three methods: (1) the ASTRO definition (three consecutive rises in prostate-specific antigen level); (2) a modified American Society for Therapeutic Radiology Oncology (ASTRO) definition requiring two additional consecutive rises when a decline immediately subsequent to three consecutive rises occurred; and (3) the "Houston" or nadir plus 2-ng/mL definition (a rise of at least 2 ng/mL greater than the nadir). The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were determined for each using clinical progression as the endpoint. Furthermore, the misclassification rates for a steadily rising prostate-specific antigen level, ability to satisfy the proportional hazards (RT with or without ADT), effects of short follow-up, and intervals to the diagnosis of BF were compared.. The misclassification rate for BF using the nadir plus 2-ng/mL definition was 2% for RT alone and 0% for RT plus ADT compared with 0% and 0% for the modified ASTRO definition, and 5% and 23% for the ASTRO definition, respectively. The hazard rates for RT alone and RT plus ADT were proportional only for the nadir plus 2 ng/mL definition and seemingly unaffected by the length of follow-up. For RT with or without ADT, the nadir plus 2 ng/mL definition was the most specific (RT, 80% vs. RT plus ADT, 75%) with the greatest positive predictive value (RT, 36% vs. RT plus ADT, 25%) and overall accuracy (RT, 81% vs. RT plus ADT, 77%). A greater proportion of BF was diagnosed in the first 2 years of follow-up with the nadir plus 2 ng/mL definition compared with the ASTRO definition (13% vs. 5%, p = 0.0138, chi-square test).. The nadir plus 2 ng/mL definition was the best predictor of sustained, true, biochemical, and clinical failure, and was not affected by the use of ADT or follow-up length.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Combined Modality Therapy; Follow-Up Studies; Goserelin; Humans; Leuprolide; Male; Middle Aged; Predictive Value of Tests; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy, Conformal; Sensitivity and Specificity; Treatment Failure

Gonadotropin analogues are used in patients with prostate cancer for Leydig cell suppression with serum testosterone levels within the range after castration. Insufficient effect may have adverse consequences on the clinical course.. At the Norwegian Radium Hospital, serum testosterone is routinely analysed in patients who use gonadotropin analogues and are referred to the hospital for treatment of hormone-resistant prostate cancer.. Analyses of serum testosterone in two patients with advanced prostate cancer revealed insufficient androgen suppression in spite of continuous treatment with leuprorelin 11.25 mg. After substitution of leuprorelin by goserelin, serum testosterone decreased to levels compatible with those after surgical castration. In patients with advanced prostate cancer who use leuprorelin, monitoring of serum testosterone is necessary, with onset no later than 12 weeks after start of treatment. The diagnosis of "hormone resistant prostate cancer" requires that the patient's serum testosterone is measured within the range corresponding to surgical castration.

Topics: Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

This exploratory study was intended to investigate men's ways of integrating and understanding experiences with Androgen Deprivation Therapy (ADT), including how hormone treatment affected their sense of identity.. Twelve men, averaging 61 years of age and treated with ADT, participated in a single interview about their experiences with prostate cancer and hormone treatment. In keeping with a qualitative approach, questions were initially open-ended, with patients encouraged to describe experiences in their own words.. Seven prominent themes appeared in the interviews: 1) starting on hormones, 2) matching expectations with reality, 3) tracking changes, 4) dealing with changes in sexuality, 5) navigating relationships, 6) putting things in context, and 7) interpreting gender-relevant changes.. The effects of ADT on men with prostate cancer were varied and often substantial in their impact. Additionally, men often receive insufficient information to prepare them to deal with side effects. While the physiological situation of the men in our study could be described as "liminal" (i.e., straddled between two categories of gender), interview data showed that they refuse their liminality, claiming to be neither less masculine nor more feminine because of treatment. While men are grateful to receive potentially life-extending treatment, the challenge for the health care system is to provide them with the information and clinical support that will make their remaining years the best that they can be.

Topics: Aged; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Buserelin; Drug Therapy; Humans; Interview, Psychological; Leuprolide; Male; Middle Aged; Nitriles; Prostatic Neoplasms; Quality of Life; Sexuality; Social Identification; Tosyl Compounds

Topics: Androgens; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Clinical Trials, Phase III as Topic; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Testosterone

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Anilides; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Humans; Insulin Resistance; Leuprolide; Male; Nitriles; Prostatic Neoplasms; Tosyl Compounds

Pure red cell aplasia (PRCA) is characterized by anemia with reticulocytopenia but with normal leukocyte and platelet counts, and a bone marrow with a selective absence of erythroid precursor cells. Drug-induced PRCA is a rare secondary form of PRCA, and is usually acute and fully reversible by the withdrawal of the causative drugs. We report a rare case of PRCA in a prostate cancer patient treated with combined androgen blockade (CAB) consisted of leuprolide acetate as a luteinizing hormone-releasing hormone agonist and chlormadinone acetate as an antiandrogen. This case demonstrated that these drugs could be a cause of PRCA, and suggests that regular close monitoring for anemia is needed in prostate cancer patients treated with these drugs.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Chlormadinone Acetate; Drug Therapy, Combination; Erythrocyte Transfusion; Humans; Leuprolide; Male; Prostatic Neoplasms; Radiotherapy, Adjuvant; Red-Cell Aplasia, Pure

Stage pT0 following prolonged neoadjuvant endocrine therapy (PPNET) of prostate cancer is of great clinical interest, because this finding suggests maximum tumor damage. Therefore pT0 patients are expected to have an extremely favorable PSA progression rate. The purpose of this study was to assess whether the PSA progression rate of pT0 patients after PPNET is lower than that of non-pT0 patients after PPNET.. 174 patients with previously untreated, clinical stage cT1-3 carcinomas were submitted to PSA monitored complete androgen deprivation therapy followed by radical prostatectomy (RP). In 138 patients the RP specimens showed residual cancer, in 36 patients no residual cancer was found. Biochemical progression was defined as PSA >/=0.2ng/ml. To control for confounding prognostic factors (Gleason score, cT-stage) between both groups a matched-pair analysis for the cumulative risk of biochemical failure was performed, resulting in 30 matched pairs.. With a median follow-up of 37.9 and 46.0 months in the matched non-pT0 and pT0 cohort respectively, matched-pair analysis failed to demonstrate significant differences in crude PSA relapse-free survival between both groups (p=0.7758).. The results suggest that patients converted into pT0 after PPNET do not represent a subgroup with an extremely favorable prognosis. However our results have to be confirmed by the assessment of larger cohorts of pT0 patients with a longer follow-up. The presented data do not allow drawing any conclusions on the prognostic impact of PPNET in general.

Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Flutamide; Follow-Up Studies; Goserelin; Humans; Leuprolide; Male; Matched-Pair Analysis; Neoplasm Staging; Nitriles; Prognosis; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Time Factors; Tosyl Compounds

Anti-androgen (AA) therapy will cause hormone-sensitive prostate cancer cells to undergo apoptosis and/or enter the resting phase of the cell cycle. Although the decrease of tumor burden would be an advantage for tumor control when irradiation is subsequently added, the cells in resting phase would seemingly be less vulnerable to the usual type of radiation-induced cell killing via DNA strand breakage. In this study of patients with prostate cancer, we examined the proliferative index via Ki-67 staining of biopsy material before, during, and after withdrawal of leuprolide. We studied 15 previously untreated patients with locally advanced prostate cancer. Prostate biopsies were taken at three times: 1) initial diagnosis; 2) after 3 consecutive months of intramuscular 7.5 mg depot; and c) 6 weeks after the last dose. External beam radiation (EBRT) then delivered 66 Gy in 33 sessions to local fields. We used the ASTRO definition of prostate-specific antigen (PSA) failure. We measured serum luteinizing hormone and total testosterone coinciding with each biopsy date. Immunohistochemical staining was performed using Ki-67 antibody clone MIB-1. The follow-up ranged from 36 to 73 months (median 52 months). We discerned two perturbation patterns of Ki-67 with hormonal manipulation. Pattern 1 demonstrated a drop of Ki-67 labeling after leuprolide was in effect and then after leuprolide withdrawal, the Ki-67 rebounded to less than 120% of baseline. Pattern 2 also showed an initial drop with leuprolide but rebounded to more than 120%. Among eight patients demonstrating pattern 1, only one patient had a PSA failure. In contrast among patients with pattern 2, six of seven failed biochemically (Fisher's exact, p = 0.018). All patients had a LH less than 1.0 during leuprolide effect that rose with its withdrawal. There was no correlation of PSA failure with whether total testosterone did or did not rise to more than 100 ng/dl by the time of the withdrawal phase biopsy. Neither the percent of PSA decline during leuprolide nor the minor PSA rebound 6 to 8 weeks after leuprolide withdrawal correlated with the Ki-67 pattern. The pattern of perturbation of immunohistochemical staining for Ki-67 predicts biochemical failure after moderate-dose EBRT in patients with prostate cancer. Several recent analyses of combined EBRT and AA suggest that some patients may benefit from more prolonged use of AA. Because AA can have substantial side effects and is expensive, a method to selec

Topics: Aged; Antineoplastic Agents, Hormonal; Apoptosis; Biopsy; Cell Cycle; Humans; Ki-67 Antigen; Leuprolide; Male; Middle Aged; Neoplasms, Hormone-Dependent; Pilot Projects; Prostatic Neoplasms; Radiotherapy Dosage

Once metastatic, prostate cancer was regarded as a systemic disease that is not amenable to surgical therapy. We present a case of a solitary pulmonary recurrence of prostate cancer after radical prostatectomy that was resected, resulting in 12 years of biochemical remission without additional therapy.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Combined Modality Therapy; Cough; Disease-Free Survival; Dyspnea; Flutamide; Follow-Up Studies; Humans; Leuprolide; Lung Neoplasms; Male; Neoplasm Proteins; Pneumonectomy; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Remission Induction

To better understand bone metabolism and predict bone loss in treatment using gonadotropin-releasing hormone agonist for patients with prostate cancer.. The changes in bone mineral density and blood levels of bone metabolism markers and the level of pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen, a specific marker of bone resorption, and carboxy-terminal pro-peptide of human type I procollagen, a specific marker of bone formation, were examined in 27 consecutive patients with prostate cancer without bone metastasis.. After 2 years of gonadotropin-releasing hormone treatment, the bone mineral density was significantly lower (median 0.937 g/cm2) than before treatment. Pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen began to increase significantly 6 months after the start of treatment (3.0 to 8.3 ng/mL, median 4.6, at baseline versus 3.4 to 8.2 ng/mL, median 5.2, after 6 months). Carboxy-terminal pro-peptide of human type I procollagen began to show a significant rise 1 year after the start of treatment (from 72.8 to 221.5 ng/mL, median 102.0, at baseline to 82.7 to 293.4 ng/mL, median 132.0, at 1 year).. Functional coupling between bone resorption and formation was noted, and a decrease in bone mass, even in men, owing to androgen deficiency, was biochemically demonstrated. Fluctuations in these two bone metabolism markers preceded the decrease of bone mineral density. Therefore, these markers might be a predictor of bone loss.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Biomarkers; Bone and Bones; Bone Density; Bone Remodeling; Bone Resorption; Collagen Type I; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Osteoporosis; Peptide Fragments; Peptides; Procollagen; Prostatic Neoplasms; Testosterone

Topics: Adenocarcinoma; Antineoplastic Agents, Hormonal; Biopsy; Combined Modality Therapy; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Leuprolide; Male; Middle Aged; Prostate; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Radionuclide Imaging; Radiotherapy, Conformal; Spinal Neoplasms; Tomography, X-Ray Computed

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Cognition; Drug Therapy, Combination; Flutamide; Humans; Leuprolide; Male; Neuropsychological Tests; Nitriles; Prostatic Neoplasms; Tosyl Compounds

Topics: Aged; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Muscular Disorders, Atrophic; Prostatic Neoplasms; Treatment Outcome

We describe a prostate cancer patient whose initial symptom was intermittent double vision. Intracranial magnetic resonance imaging demonstrated a pituitary mass extending to the cavernous sinus, which caused the double vision. After hormonal therapy for prostate cancer, the pituitary mass disappeared, and double vision was completely resolved without local therapy for the brain. In the 19 months of follow-up after hormone treatment, the prostate cancer remained stable, and the patient remained neurologically intact.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Chlormadinone Acetate; Diplopia; Humans; Leuprolide; Magnetic Resonance Angiography; Male; Pituitary Neoplasms; Prostatic Neoplasms; Remission Induction

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Electromyography; Humans; Leuprolide; Male; Muscular Diseases; Prostatic Neoplasms; Time Factors

To evaluate prospectively the effects of intermittent androgen suppression (AS) on bone mineral density (BMD) in patients with prostate cancer without bone metastases.. A total of 19 hormone-naive patients with Stage D0 disease were treated with a luteinizing hormone-releasing hormone analog and an antiandrogen for 9 months, after which AS was discontinued. When the prostate-specific antigen level reached a predetermined threshold, AS was restarted. BMD was measured at baseline, after 9 months of AS, and at the end of the first off-treatment period or at 1 year, whichever occurred first.. Of the 19 patients, 17 had normal BMD at baseline; 2 patients with osteopenia at baseline were excluded from the analysis. All but 1 of the 17 patients with normal baseline BMD experienced a decline in BMD in the lumbar spine or hip, or both, during AS. After 9 months, the mean BMD in these patients had decreased by 4.5% at the lumbar spine (P = 0.0007) and by 2.5% at the hip (P = 0.00013). After a median off-treatment period of 7.9 months, the mean change in BMD of the lumbar spine and hip relative to the post-AS values was 1.5% (P = 0.06) and -0.01% (P = 0.09), respectively.. The observed loss of BMD during 9 months of AS is significantly greater than the expected 0.5% to 1% annual loss. Interruption of AS attenuated the rate of bone loss, although full recovery to the baseline BMD was not achieved in all patients. These data suggest that men treated with AS should undergo baseline and periodic follow-up BMD assessments, because significant bone loss can occur during the first 9 months of AS.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Bone Density; Flutamide; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Testosterone

In an effort to determine the safety and efficacy of laparoscopic radical prostatectomy (LRP) in patients who have received neoadjuvant hormonal therapy (NHT), our initial series of 65 patients undergoing successful LRP was analyzed, specifically comparing 5 patients who received neoadjuvant hormonal therapy to 60 who did not.. From March 2000 to March 2002, 68 patients were scheduled for LRP. Three cases, none post-NHT, were converted to open radical retropubic prostatectomy (RRP). Clinical and pathologic data were recorded on the remaining 65 patients, 5 of who had received NHT. Forty-two bilateral and 16 unilateral nerve sparing LRP were performed in the non-NHT cohort, and 3 bilateral and 1 unilateral nerve sparing LRP in the NHT cohort.. The mean patient age, preoperative prostate specific antigen (PSA), clinical stage, and biopsy grade were similar for the NHT and the non-NHT LRP cohorts. The mean estimated blood loss (EBL) and serum hemoglobin decrease (preoperative to postoperative day 1) were lower in the NHT cohort than the non-NHT cohort: 160 mL and 2.4 g/dL vs. 317 mL and 3.1 g/dL, respectively. The mean operative time and hospital stay were similar: 5.7 hours and 2.4 days for the NHT cohort and 5.8 hours and 2.8 days for the non-NHT cohorts. As expected, the mean prostate weight was lower for the NHT cohort: 36.8 g vs. 46.5 g. All NHT cohort tumors were pathologic stage pT2, with negative margins. Eleven (18%) of the non-NHT cohort had pathologic T3 (10 patients) or T4 (1 patient) tumors and 10 (17%) specimens had a positive surgical margin. Four of 5 (80%) NHT cohort and 21 of 25 (84%) non-NHT cohort patients are continent (no pad use) 3 to 6 months postsurgery. One NHT cohort patient (20%) and 20 (33%) non-NHT cohort patients had an elevated drain fluid creatinine 24 hours postoperatively. There were no other complications in the NHT cohort. All 5 NHT cohort patients have no evidence of recurrent disease, whereas 2 non-NHT cohort patients (3.3%) have developed PSA recurrence. No NHT patient and only 1 non-NHT patient received a blood transfusion postoperatively.. LRP appears to be a safe and efficacious procedure in patients who have received NHT. Perioperative morbidity of NHT patients undergoing LRP appears equivalent to non-NHT patients, with slightly lower EBL, hemoglobin decrease, urinary extravasation, positive margin, and complication rates.

Topics: Antineoplastic Agents, Hormonal; Biopsy; Blood Loss, Surgical; Blood Transfusion; Hemoglobins; Humans; Laparoscopy; Length of Stay; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

Giant multilocular cystadenoma of the prostate is a rare, benign, but locally recurrent, tumor that is usually treated by surgery. We report a case initially treated by surgical resection and followed by evaluation of serum prostate-specific antigen values. After evidence of biochemical failure, pathologic recurrence was confirmed and treated by the gonadotropin-releasing hormone antagonist Lupron, with excellent results. The patient was stable without biochemical or radiologic evidence of progression during the last 2.5 years. This result offers a new treatment option for patients with this rare tumor.

Topics: Aged; Antineoplastic Agents, Hormonal; Cystadenoma; Humans; Leuprolide; Male; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

To analyse tumour volume (TV) in clinically localised prostate cancer patients treated with neo-adjuvant combined androgen blockade (CAB) therapy prior to radical prostatectomy.. Two hundred consecutive patients treated between 1996 and 2000 were retrospectively analysed. Fifty patients underwent radical prostatectomy alone and 45 were treated with CAB for 1-3 months, 83 for 4-6 months and 22 for more than 6 months before surgery. Logistic regression analysis was performed to identify the strongest independent prognosticator of organ-confined disease.. No evidence of residual cancer was found in 11 specimens (5.6%). Regarding TV, 20 specimens showed less than 0.1cc, 33 between 0.1 and 0.49cc and 86 more than 0.5cc. Smaller TV was found in CAB-treated patients. Significant correlation was observed between treatment duration and TV. In logistic regression analysis, only CAB duration and TV were significantly correlated with organ-confined disease.. Prominent regressive features and lower TV were found after neo-adjuvant CAB. It seems that more prolonged treatment may lead to greater tumoural regression. Only tumour burden and length of CAB therapy were independent variables significantly correlated with pathologically localised prostate cancer.

Topics: Androgen Antagonists; Anilides; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Chi-Square Distribution; Humans; Leuprolide; Logistic Models; Male; Nitriles; Prostatectomy; Prostatic Neoplasms; Retrospective Studies; Statistics, Nonparametric; Time Factors; Tosyl Compounds; Treatment Outcome

The use of complementary/alternative medicine (CAM) has recently received considerable attention throughout the world. We evaluated the prevalence and predictors of CAM use among Japanese patients with localized prostate cancer.. A total of 177 patients with localized prostate carcinoma underwent radical retropubic prostatecotomy or external beam radiation therapy between January 1994 and January 2001. Of them, 138 (78%) answered a self-administered questionnaire on CAM use and were eligible for this study. The overall prevalence, types of CAM used, and costs of CAM were assessed. The effects of age, prostate-specific antigen (PSA) level, clinical stage, pretreatment Gleason score, patients' income, patients' final educational status, and general health-related quality of life at baseline and 1 year after treatment, as estimated using the European Organization for Research and Treatment of Cancer Prostate Cancer Quality of Life Questionnaire on the prevalence of CAM use, were evaluated.. Twenty-seven patients (20%) had once used or had been using some types of CAM. Herbal medicine and vitamins were the most common types of CAM used. Preoperative Gleason score was significantly associated with CAM use, as determined by the chi(2) test ( P = 0.0198), and PSA level and posttreatment physical function domain were marginally associated with CAM use, as determined by the Mann-Whitney U-test ( P = 0.0734 and P = 0.0597, respectively). Patient age, income, and final educational status had no impact on CAM use.. A relatively small proportion of Japanese patients with localized prostate cancer have tried CAM compared with the proportions of patients described in previous reports from Western countries.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Carcinoma; Complementary Therapies; Cross-Sectional Studies; Follow-Up Studies; Hormone Replacement Therapy; Humans; Japan; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Predictive Value of Tests; Prevalence; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Radiotherapy, Computer-Assisted; Surveys and Questionnaires; Treatment Outcome

The shrinking effect of 3-month neoadjuvant androgen deprivation (NAD) on preradiotherapy prostate gland volume is well documented. However, recently, it has been shown that the cancerous prostate gland keeps shrinking up to 12 months after NAD start. Thus, if such a reduction is not taken into account, a larger than planned portion of the surrounding normal tissues might shift in the high-dose region during conformal radiotherapy (3DCRT) course. The present study was undertaken to quantify this issue.. Prostate gland volume reduction between planning CT (plCT) and the last week of 3DCRT (tmtCT) was prospectively assessed in 33 consecutive patients with localized prostate carcinoma. The median time interval between plCT and tmtCT was 2.5 months (2.1-2.7 months). A single observer was asked to draw on each slice prostate gland volume as appropriate. The observer was 'blind' to the timing of CT (plCT vs. tmtCT). In order to estimate intra-observer variability, prostate gland delineation was repeated twice for each data set. Mean prostate gland change, plCT and tmtCT cumulative dose volume histogram (DVH) calculations for the rectum were analyzed for each patient. Results were correlated to AD status and its duration before plCT. Means were compared by non-parametric rank tests.. Based on an internal protocol, 14 patients (42%) did not receive AD, while 19 patients (58%) had undergone neoadjuvant and concomitant AD. The median duration of AD before plCT ranged from 0.2 to 6 months (median: 2.9 months). Although individual data were highly variable, compared to plCT volume, mean prostate gland volume change at the end of 3DCRT was similar for patients receiving (-7.3%) or not (-7%) androgen deprivation (P=0.77). However, within the group of patients treated with hormones, patients starting AD within 3 months from plCT had a significantly larger reduction in prostate volume (-14.2%) than patients with longer NAD duration (-1.1%, P=0.03). At tmtCT, on average, patients undergoing 3DCRT within 3 months from AD start showed an increase of the amount of rectum receiving 40-75 Gy compared to plCT values. At 40 Gy (V40) the mean difference between tmtCT and plCT was +7.5%. In the other two groups, average variations of V40-70 were within +/-2% of plCT values. However, these differences are not significant.. For patients who undergo plCT and 3DCRT shortly after AD start, prostate gland shrinkage may be substantial. In some of these patients, this might lead to an unexpected increase of the percentage of rectal wall exposed to intermediate doses.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Dose-Response Relationship, Radiation; Flutamide; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Observer Variation; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy, Conformal; Rectum; Treatment Outcome

Androgen deprivation as a treatment for prostate cancer has evolved since the pioneering studies of Huggins and Hodges 60 years ago using surgical castration or estrogen treatments. The most common hormonal treatments today use injections of luteinizing hormone-releasing hormone (LHRH) agonists. The US Food and Drug Administration (FDA) has approved 5 LHRH agonist formulations for treatment of prostate cancer in the United States. Of these approved products, 3 involve different delivery systems for the LHRH superagonist leuprolide acetate. Sustained-release formulations of 2 distinct LHRH agonists, goserelin acetate and triptorelin pamoate, are also commercially available. This review focuses on new data on a novel formulation of leuprolide acetate (Eligard; Atrix Laboratories Inc., Fort Collins, CO) that incorporates a unique mixture of selected polymers and solvents to achieve sustained drug delivery after subcutaneous injection. The FDA has approved 1-month and 3-month formulations of Eligard, and 4-month and 6-month products are in development. In clinical trials, Eligard achieves reliable and sustained suppression of serum testosterone to castration levels (< or =50 ng/dL). Of the patients treated with the 1-month and 3-month formulations, 98% (115 of 117) and 94% (104 of 111), respectively, reached testosterone levels of < or =20 ng/dL. Breakthroughs, defined as testosterone levels >50 ng/dL after achievement of castration levels, occurred rarely at 0% (0 of 117) for the 1-month and at 0.9% (1 of 111) for the 3-month formulations in patients receiving Eligard. The degree of disease control and the adverse-events profile are commensurate with the effectiveness of the testosterone suppression; the incidence of severe hot flashes is actually lower than anticipated. Additional studies with these novel formulations are warranted.

Topics: Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Drug Approval; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms; Triptorelin Pamoate; United States; United States Food and Drug Administration

Patients with large prostate volumes undergoing interstitial brachytherapy (BT) are currently believed to have worse urinary symptoms and quality of life (QOL) following the implant. We sought to determine if data from patients treated with neoadjuvant androgen ablation followed by BT at our institution supported this notion using a cross-sectional study design.. From 14 March 1997 to 25 August 2000, 248 patients underwent neoadjuvant androgen ablation followed by BT monotherapy (BTM) or BT combined with external beam (BTC) for treatment of localized prostate cancer. FACT-G and AUASS questionnaires were mailed to all patients on 1 September 2001. Overall FACT-G scores along with the irritative (IAUA) and obstructive (OAUA) subscales of the AUASS were calculated for each patient. Prostate volume (one to two weeks prior to BT), number of seeds, and implant method (ultrasound or CT guided) were compared with the outcomes on the two validated instruments. All analyses were adjusted for time since procedure and patient age.. 169 of 248 (68%) patients returned questionnaires. The median prostate volume was 37cc and number of seeds implanted was 95. Our data shows little correlation between total FACT-G or AUASS scores and volume of the prostate. Likewise, neither FACT-G nor IAUA scores appeared related to the number of seeds implanted. A correlation was seen when comparing number of seeds with OAUA scores, but this result appeared to be driven by the BTC group. Number of needles implanted did not appear to be related to total FACT-G scores. The number of needles inserted was related to both IAUA and OAUA scores in the BTC group, but not in BTM group.. Quality of life and urinary function scores do not appear to be strongly related to pre-implant prostate volume or method of implantation and thus patients should not be dissuaded from considering neoadjuvant androgen ablation followed by BT solely due to prostate size.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Brachytherapy; Cross-Sectional Studies; Finasteride; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Prostate; Prostatic Neoplasms; Quality of Life; Surveys and Questionnaires; Urination Disorders

Topics: Adenocarcinoma; Graft Rejection; Heart Transplantation; Hormone Replacement Therapy; Humans; Leuprolide; Male; Prostatic Neoplasms; Risk Factors; Stroke Volume; Testosterone; Ventricular Function, Left

Primary signet-ring cell carcinoma (SRCC) of the prostate is very rare and has a poor prognosis, even when treated with aggressive therapy. We report herein a case of a 72-year-old man with prostatic SRCC. The patient had a tumor that extended directly to the rectum. Maximal androgen blockade was started and 20 months later, the patient was alive without evidence of recurrence. The present case of prostatic SRCC responded well to medical therapy, however, tumors can recur after a long period of time. Therefore, adjuvant therapy is recommended.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Carcinoma, Signet Ring Cell; Humans; Leuprolide; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

We report here two cases of pituitary apoplexy or pseudoapoplexy revealing a gonadotroph adenoma. A 69-year-old man, who had just started antiandrogen treatment (Gn-RH agonist) for prostatic cancer, was admitted to neurosurgery emergency because of increasing headache and visual impairment. The CT-scan disclosed the presence of a large pituitary mass with lateral invasion of the left cavernous sinus. Hormonel testing showed panhypopituitarism. A few days later, diabetes insipidus appeared. The patient first received corticosteroid therapy and underwent surgical adenomectomy. Immunostaining of the tumor tissue was positive for FSHbeta, confirming the diagnosis of gonadotroph adenoma. Three months after surgery, the endocrine evaluation showed pituitary insufficiency. An 81-year-old man complained of mnemonic disorders. The CT-scan revealed a pituitary mass without extension. The Ophthalmological examination showed left temporal upper quadranopsia. Endocrinological tests with administration of GN-HR triggered headache and vomiting. A second CT-scan was unchanged. Hormone testing revealed increased serum levels of FSH and decreased serum levels of LH. Surgical management of the primary tumor was undertaken due to the visual field alteration. Immunohistochemical studies confirmed the diagnosis of gonadotroph FSHbeta adenoma.

Topics: Adenoma; Aged; Aged, 80 and over; Follicle Stimulating Hormone; Follicle Stimulating Hormone, beta Subunit; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Pituitary Apoplexy; Pituitary Neoplasms; Prostatic Neoplasms; Tomography, X-Ray Computed

Prostate carcinoma presenting initially as multiple pulmonary nodules in an asymptomatic patient without previous prostate carcinoma is unusual. Whether the incidence of prostate carcinoma is significantly increased in patients treated previously for germ cell tumors is unclear. We report such a patient, who responded to combination androgen blockade therapy.

Topics: Adenocarcinoma; Adult; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Combined Modality Therapy; Etoposide; Flutamide; Humans; Leuprolide; Lung Neoplasms; Male; Neoplasms, Germ Cell and Embryonal; Neoplasms, Multiple Primary; Neoplasms, Second Primary; Orchiectomy; Postoperative Complications; Prostatic Neoplasms; Radiography; Testicular Neoplasms

Macro CK (creatine kinase) as a reason for high CK values has been known since 1979. Even in the era of troponin determination for the diagnosis of myocardial infarction, an elevated CK value can still cause confusion, especially as CK-MB rises earlier than troponin. The case report should remind us of this often forgotten differential diagnosis of elevated CK.. A 73-year-old patient was treated with leuprorelin hormone therapy for prostate cancer (stage pT1c G2). In addition, he received percutaneous radiation therapy of the prostate and high-dose-rate brachytherapy twice with 10 Gy each. Close to 1 year later, he complained for the first time of dyspnea on exertion and thoracic tightness. Serum CK was 232 U/l, and CK-MB 62 U/l, which was confirmed by several controls. Troponin T test was negative, and GOT, GPT, LDH, and PSA were all within the normal range. Acute myocardial infarction was ruled out on clinical grounds and by six sequential ECGs. Subsequently, the patient remained without further cardiac complaints and in good condition. Isoenzyme electrophoresis finally solved the problem and revealed CK-BB-IgG complex type 1 (macro CK-1).. High CK-MB values in cardially healthy patients should remind us of the possibility of macro CK which is seen in approximately 0.5% of cases and should be included in the differential diagnosis.

Topics: Adenocarcinoma; Aged; Antigen-Antibody Complex; Antineoplastic Agents, Hormonal; Brachytherapy; Chest Pain; Combined Modality Therapy; Creatine Kinase; Creatine Kinase, MB Form; Diagnosis, Differential; Electrocardiography; Humans; Immunoglobulin G; Isoenzymes; Leuprolide; Macromolecular Substances; Male; Myocardial Infarction; Neoplasm Staging; Prostatic Neoplasms; Radiotherapy, Adjuvant

Maximal androgen blockade therapy is the standard endocrine treatment for advanced prostate cancer. We report here an unusual case of interstitial pneumonitis induced by bicalutamide and/or leuprorelin acetate treatment for metastatic prostate cancer.

Topics: Aged; Anilides; Antineoplastic Combined Chemotherapy Protocols; Follow-Up Studies; Glucocorticoids; Humans; Leuprolide; Lung Diseases, Interstitial; Male; Methylprednisolone Hemisuccinate; Nitriles; Prostatic Neoplasms; Tosyl Compounds; Treatment Outcome

The role of hormone therapy in the current era of widespread testing for prostate-specific antigen (PSA) continues to evolve. Although still used in patients with metastatic disease, the most common uses of luteinizing hormone-releasing hormone (LHRH) agonist therapy are in the adjuvant and neoadjuvant settings with radiotherapy and sometimes with radical prostatectomy, as well as in the treatment of PSA-only recurrence. Immediate (adjuvant) hormone therapy after prostatectomy may provide a survival advantage relative to deferred treatment in high-risk patients, whereas the survival benefit of adjuvant therapy with radiation is clearer. Combined androgen blockade with an LHRH agonist and a nonsteroidal antiandrogen provides a very modest but statistically significant survival benefit relative to LHRH agonist monotherapy in patients with metastatic disease, but it has not been proved in those with less advanced disease. Intermittent hormone therapy appears to be effective in maintaining disease control for several years, but randomized studies are needed to determine if survival is at least equivalent to continuous therapy. Finally, LHRH agonist therapy is commonly used in the setting of biochemical or PSA-only recurrence. However, there are no randomized controlled trials to prove a survival benefit over observation. In summary, hormone therapy now plays a more important role at earlier stages of disease, consistent with the changing epidemiology of prostate cancer. Additional studies are needed, however, to define how to optimally use hormone therapy across various patient types.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Orchiectomy; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic

Malignancies may cause cholestatic jaundice through well-recognized mechanisms (e.g., bile duct obstruction or widespread hepatic infiltration). Paraneoplastic syndromes associated with malignancy, particularly with renal cell carcinoma (Stauffer's syndrome) and malignant lymphoproliferative diseases, can induce a reversible form of cholestasis through an unclear pathogenetic mechanism. Prostate cancer presenting initially with cholestatic jaundice without any obvious cause (i.e., obstruction or infiltration) has been reported in 2 cases in the medical literature. We report a patient who presented with pruritus and cholestatic jaundice. During the diagnostic work-up, prostate cancer was diagnosed. Conjugated bilirubin and alkaline phosphatase levels were increased markedly with modest increases of gamma-glutamyltranspeptidase and transaminase levels. The results of appropriate investigations performed during the patient's hospitalizations indicated no evidence of hepatic metastases or extrahepatic biliary obstruction. After treatment with flutamide and leuprolide, the patient's symptoms and the laboratory abnormalities reversed rapidly. We regard the cholestatic jaundice of this patient as part of a paraneoplastic syndrome; the cause of cholestasis remains an enigma. Patients with unexplained cholestasis should be investigated for malignancies, including prostate cancer.

Topics: Adenocarcinoma; Aged; Alkaline Phosphatase; Antineoplastic Agents, Hormonal; Bilirubin; Biomarkers, Tumor; Cholangiopancreatography, Endoscopic Retrograde; Diagnosis, Differential; Flutamide; gamma-Glutamyltransferase; Humans; Jaundice, Obstructive; Leuprolide; Male; Paraneoplastic Syndromes; Prostatic Neoplasms; Pruritus; Tomography, X-Ray Computed; Transaminases

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Diagnosis, Differential; Granuloma; Humans; Injections; Leuprolide; Male; Neoplasm Recurrence, Local; Prostatic Neoplasms; Skin Diseases; Skin Neoplasms

Disseminated intravascular coagulation (DIC) revealing a prostatic adenocarcinoma is rare. Most of the case are limited to biological abnormalities. We report a case of a 73 year old man with metastatic prostatic carcinoma and CIVD. The patient consulted for epistaxis and ecchymosis with thrombocytopenia and low coagulate factors. The prostatic specific antigen was 2200 ng/ml and fine needle aspiration of bone marrow biopsy detected metastatic cells. The patients received hormonotherapy, heparine and antithrombine III with a good follow up. About this case, we discuss the management of the patient with metastatic prostatic cancer and CIVD.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Anticoagulants; Antithrombin III; Bone Neoplasms; Disseminated Intravascular Coagulation; Fibrinolysis; Follow-Up Studies; Heparin; Humans; Injections, Subcutaneous; Leuprolide; Male; Prostatic Neoplasms; Sternum; Time Factors

Topics: Aged; Angiogenesis Inhibitors; Anilides; Antineoplastic Agents, Hormonal; Capillaries; Chemotherapy, Adjuvant; Drug Therapy, Combination; Finasteride; Humans; Leuprolide; Male; Neoplasm Recurrence, Local; Nitriles; Prostatic Neoplasms; Skin; Telangiectasis; Tosyl Compounds; Treatment Outcome

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Luteinizing Hormone; Male; Prostatic Neoplasms; Radiotherapy, Conformal; Reference Values; Testosterone

The effect of neoadjuvant hormonal therapy (NHT) prior to radical prostatectomy (RP) on pathological downstaging of prostate cancer and biochemical relapse of serum prostate specific antigen (PSA) level was evaluated.. Twenty selected patients with prostate cancer, who were treated with hormonal therapy and demonstrated biochemical downstaging by reduction of PSA prior to RP and bilateral pelvic node dissection at the Tohsei National Hospital between January 1997 and August 2001, are reported on. The complete RP specimens of these 20 men were used for accurate evaluation of the pathological stage. All 20 patients received NHT; ten patients were treated with leuprolide plus flutamide and 10 received leuprolide plus chlormadinone acetate (CMA).. Decreases in serum PSA values were demonstrated from a pre-hormonal average of 49.7 ng/ml to an average of 0.52 ng/ml after NHT. Of the three clinical stages, A2-C, for cancer patients, two of the 20 patients had stage A2, two had stage B1, nine had stage B2, and seven had stage C. Of the 20 patients with biochemical downstaging, two had pathological stage B1, seven had pathological stage B2, eight had pathological stage C, and three had positive pelvic lymph nodes. Ten (50%) of the 20 patients were reported to have positive surgical margins. Seminal vesical extension was observed in two cases, and penetration was not observed. Positive nodes were identified in three (15%) patients. Among the seven clinical stage C patients, one had pathological stage B1 disease and two had pathological stage B2. Four of nine patients with clinical stage B2 prostatic cancer had pathological stage C disease. The actuarial incidence of a rising PSA at 3 years for the leuprolide plus CMA group was 28.9% compared with 37.5%for the group receiving leuprolide plus flutamide. The cases of biochemical relapse did not necessarily indicate a high stage and had no tendency to be high for baseline PSA level, positive margin rates or Gleason scores.. A significant decrease in the rate of penetration could be observed after NHT, though it was not so effective for pathological downstaging, and changes in the preoperative PSA level did not predict those patients who might have a favorable result.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Chlormadinone Acetate; Flutamide; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

Topics: Aged; Antineoplastic Agents, Hormonal; Cerebral Hemorrhage; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Pituitary Diseases; Prostatic Neoplasms

In patients presenting with clinically localized prostate cancer, the risk of biochemical failure increases significantly with higher Gleason scores, prostate specific antigen (PSA) levels, and clinical stages. Current surgical and radiotherapeutic approaches appear to offer limited success in patients with highly adverse prognostic factors. In an attempt to improve on these outcomes, we have combined external beam radiotherapy (EBRT) with a brachytherapy (BT) boost and neo adjuvant and adjuvant androgen ablation in a population at significant risk of biochemical failure. Here we present early biochemical progression data for this approach. From October 1997 to July 1999, 72 men with a serum PSA >or=10 ng/ml or Gleason score >or=7 or clinical stage >or=T2c (AJC/UICC 1992) underwent EBRT followed by palladium-103 BT. All patients underwent 8 months of combined androgen ablation with leuprolide and an oral antiandrogen beginning 3 months prior to initiation of EBRT. Patients were followed by PSA and digital rectal examination (DRE) at 3-month intervals and a chart review on all patients was carried out during July 2001. To allow comparisons to contemporary literature, Kaplan-Meier survival curves were generated utilizing three alternate definitions of biochemical recurrence: PSA >0.2 ng/ml, PSA >1.0 ng/ml, and the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus definition of three consecutive rising PSAs. Our results indicate that when PSA >0.2 ng/ml was used to define biochemical progression, 88% (95% CI 80-97) of patients remained free of disease at 24 months. When PSA >1.0 ng/ml was used, 97% (CI 92-100) of patients remained disease free at 24 months. ASTRO criteria yielded 90% (CI 82-98) recurrence-free survival at 24 months. In conclusion, this very early report indicates that in patients who are at increased risk of biochemical failure, EBRT with a BT boost in conjunction with short-term androgen ablation offers potentially superior biochemical disease-free survival to contemporary alternative approaches in the literature. Clearly, longer follow-up is required to confirm the durability of this approach.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Brachytherapy; Combined Modality Therapy; Humans; Leuprolide; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Risk

The objective of this work was to determine the effect of androgen deprivation therapy (ADT) on rates of bone mineral density (BMD) loss in men with prostate cancer. It was a prospective study comparing men receiving ADT to age matched controls for 2 y. Subjects received a history, physical exam, bone mineral density measurement, and laboratory evaluation every 6 months. Thirty-nine subjects receiving continuous ADT for prostate cancer (subjects) were compared to 39 age-matched controls not receiving ADT (controls). Twenty-three subjects and 30 controls completed the study through 24 months. Men in the ADT group demonstrated greater rates of bone mineral density loss than men in the control group at every site except the lumbar spine. Twenty-four month per cent of bone mineral density loss is presented as mean+/-standard error (s.e.). At the distal forearm, the ADT group value was -9.4%+/-1.0% and -4.4%+/-0.3% for controls (P<0.0005). The ADT group femoral neck values were -1.9%+/-0.7% and 0.6%+/-0.5% in the control group (P=0.0016). The ADT group total hip value was -1.5%+/-1.0% and 0.8%+/-0.5% in the control group (P=0.0018). The ADT group trochanter value was -2.0%+/-1.3% and -0.1%+/-0.5% in the control group (P=0.0019). The ADT group lumbar spine value was -0.2%+/-0.8 % and 1.1%+/-0.6% in the control group (P=0.079). Our data demonstrate greater rates of bone mineral density loss in men receiving androgen deprivation therapy for prostate cancer.

Topics: Absorptiometry, Photon; Adenocarcinoma; Aged; Amino Acids; Androgen Antagonists; Androgens; Anilides; Antineoplastic Agents, Hormonal; Biomarkers; Bone Density; Bone Remodeling; Calcium; Drug Therapy, Combination; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Neoplasms, Hormone-Dependent; Nitriles; Orchiectomy; Osteoporosis; Prospective Studies; Prostatic Neoplasms; Testosterone; Tosyl Compounds

To determine the expected time to serum testosterone normalization after short-course neoadjuvant androgen deprivation therapy (NAAD) and three-dimensional conformal radiotherapy for patients with localized prostate cancer and to identify pretreatment predictors that correlated with the time to testosterone normalization.. Between 1993 and 1999, 88 patients with localized prostate cancer, treated with NAAD and external beam radiotherapy, were prospectively monitored after treatment with sequential testosterone levels. NAAD was administered before and during the entire course of radiotherapy and discontinued at the end of treatment. The median duration of NAAD was 6 months. The actuarial rate of serum testosterone normalization from the end of treatment was evaluated, and the presence or absence of androgen deprivation-related symptoms was correlated with serum testosterone levels. Symptoms assessed included weight gain, loss of libido, breast tenderness, breast enlargement, hot flashes, and fatigue.. Serum testosterone levels returned to the normal range in 57 (65%) of the 88 patients and failed to normalize in 31 patients (35%). The median time to normalization was 18.3 months. The actuarial rate of normalization at 3, 6, 12, and 24 months was 10%, 26%, 38%, and 59%, respectively. In a multivariate analysis, a pretreatment testosterone level in the lower range of normal was the only variable that predicted for delayed testosterone normalization after NAAD (p = 0.00047). Among 45 patients with information concerning androgen deprivation-related symptoms recorded 1 year after cessation of NAAD, 24 (53%) had normalized testosterone levels, but in 21 patients (47%), the levels had not yet returned to normal. At 1 year, only 1 (4%) of 24 patients whose testosterone level had returned to normal experienced NAAD-related symptoms compared with 14 (67%) of 21 patients who did not have normal testosterone levels (p <0.001).. Testosterone levels often remain depressed for extended periods after cessation of short-course NAAD. Lower baseline testosterone levels predict for a delay in testosterone normalization, and the persistence of symptoms related to androgen deprivation correlates with low testosterone levels.

Topics: Androgen Antagonists; Anilides; Antineoplastic Combined Chemotherapy Protocols; Humans; Leuprolide; Male; Multivariate Analysis; Neoadjuvant Therapy; Nitriles; Prospective Studies; Prostatic Neoplasms; Radiotherapy, Conformal; Reference Values; Regression Analysis; Testosterone; Time Factors; Tosyl Compounds

To study the impact of hormonal therapy (HTx) on intermediate- to high-risk prostate cancer treated with permanent radioactive seed implantation.. Patients with Stage T1b-T3bN0 prostate cancer, and Gleason score > or = 7 or prostate-specific antigen (PSA) level >10 ng/mL were treated with seed implantation with or without HTx. Their disease was defined as intermediate risk (PSA 10-20, Gleason score 7, or Stage T2b) or high risk (two or more intermediate criteria, or PSA >20 ng/mL, Gleason score 8-10, or Stage T2c-T3). The median follow-up for 201 eligible patients was 42 months (range 18-110). Biochemical failure was defined as a rising PSA >1.0 ng/mL. Pretreatment disease characteristics, implant dose, and HTx were evaluated using univariate and multivariate analyses.. HTx significantly improved 5-year actuarial freedom from biochemical failure rate, 79% vs. 54% without HTx. In addition, high-dose, PSA < or = 15 ng/mL, intermediate risk, and Stage T2a or lower significantly improved outcome in the univariate analyses. HTx was the most significant predictor of 5-year actuarial freedom from biochemical failure (p <0.0001) in a multivariate analysis. The best outcome was in the intermediate-risk patients treated with a high implant dose and HTx, resulting in a 4-year actuarial freedom from biochemical failure rate of 94%.. In this retrospective review, HTx improved outcome in intermediate- to high-risk prostate cancer patients treated with brachytherapy. HTx was the most important prognostic factor in the univariate and multivariate analyses.

Topics: Adult; Aged; Analysis of Variance; Androgen Antagonists; Brachytherapy; Combined Modality Therapy; Follow-Up Studies; Goserelin; Humans; Iodine Radioisotopes; Leuprolide; Male; Middle Aged; Neoplasm Staging; Palladium; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes; Radiopharmaceuticals; Retrospective Studies; Risk; Treatment Failure

Hormone therapy with leuprolide acetate (Lupron) is frequently used to treat prostate cancer, a common malignancy expected to be diagnosed in >180,000 men in the United States this year. In addition, testosterone supplementation is frequently recommended for adult men with reduced libido or impotence and decreased serum levels of testosterone. Although these hormone therapies are generally considered benign, we describe 3 cases of acute cardiac rejection temporally associated with the use of these drugs in men who have undergone cardiac transplantation. To our knowledge, this is the first such description of this phenomenon in the literature.

Topics: Acute Disease; Adenocarcinoma; Aged; Graft Rejection; Heart Transplantation; Hormone Replacement Therapy; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Risk Factors; Stroke Volume; Testosterone; United States; Ventricular Function, Left

We characterize the consequences of androgen deprivation therapy on body composition in elderly men.. Using a dual energy x-ray absorptiometry instrument, we determined the changes in bone mineral density, bone mineral content, fat body mass and lean body mass in 35 patients with prostate cancer without bone metastases who received luteinizing hormone releasing hormone analogue for 12 months.. At baseline conditions 46% of cases were classified as osteopenic and 14% as osteoporotic at the lumbar spine and 40% were osteopenic and 4% osteoporotic at the hip. Androgen deprivation significantly decreased bone mineral density either at the lumbar spine (mean gm./cm.2 [SD] 1.00 [0.194], 0.986 [0.172] and 0.977 [0.182] at baseline, and 6 and 12 months, respectively, p <0.002) or the hip (0.929 [0.136], 0.926 [0.144] and 0.923 [0.138], p <0.03). A more than 2% decrease in bone mineral density was found at the lumbar spine in 19 men (54.3%) and at the hip in 15 (42.9%). Bone mineral content paralleled the bone mineral density pattern. Lean body mass decreased (mean gm. [SD] 50,287 [6,656], 49,296 [6,554] and 49,327 [6,345], p <0.003), whereas fat body mass consistently increased (18,115 [6,209], 20,724 [6,029] and 21,604 [5,923] p <0.001).. Serial bone densitometry evaluation during androgen deprivation therapy may allow the detection of patients with prostate cancer at risk for osteoporotic fractures, that is those with osteopenia or osteoporosis at baseline and fast bone loss. The change in body composition may predispose patients to accidental falls, thus increasing the risk of bone fracture.

Topics: Absorptiometry, Photon; Adipose Tissue; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Body Composition; Body Mass Index; Bone Density; Bone Diseases, Metabolic; Flutamide; Hip Joint; Humans; Leuprolide; Lumbar Vertebrae; Male; Middle Aged; Osteoporosis; Prostatic Neoplasms; Thinness

We assessed the degree of prostate downsizing using androgen deprivation, and determined its relation to clinical and pathological variables.. From June 1994 to January 2000, 107 patients with prostate cancer received androgen deprivation before interstitial brachytherapy at our hospital. All charts were reviewed for clinical, pathological and treatment related variables. Prostate volume was measured using transrectal ultrasound. All variables were analyzed with regard to the degree of prostate downsizing.. Mean percent volume reduction of the prostate was 33% after a 3.7-month average duration of androgen deprivation. Larger prostate volume before androgen deprivation and longer deprivation duration statistically correlated with mean percent volume reduction. Simple linear and multiple regression analyses revealed that these 2 variables remained significant predictors of percent volume reduction. Subgroup analysis indicated that a significant difference was seen in patients who received androgen deprivation with luteinizing hormone releasing hormone agonists alone versus those who received treatment with total androgen blockade (luteinizing hormone releasing hormone agonists plus antiandrogens 30% versus 35%, p = 0.04), and when prostate volume before androgen deprivation was less than 50 cc versus larger volumes (30% versus 35%, p = 0.01). Of patients with an initial prostate volume of greater than 50 cc 82% achieved a volume of less than 50 cc after androgen deprivation therapy.. Androgen deprivation therapy before brachytherapy is a method of downsizing the prostate to overcome anatomical limitations, including larger gland volume and pubic arch interference.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Brachytherapy; Combined Modality Therapy; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prostate; Prostatic Neoplasms; Regression Analysis; Ultrasonography

Estimating prognosis with patients with metastatic disease is important for patient counseling, guiding treatment selection, and assessing treatment outcomes. For patients with noncastrate metastatic disease, androgen ablation is considered first-line therapy, with upward of 80% of patients showing clinical benefit. For these patients, information about duration of response to hormones and overall survival is important. Most patients eventually relapse, at which point the mortality from cancer greatly exceeds that from other causes. This article focuses on prognostic models for patients with progressive noncastrate and castrate metastatic prostate cancer.

Topics: Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Orchiectomy; Outcome and Process Assessment, Health Care; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate

Topics: Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Prostatic Neoplasms

Topics: Adenocarcinoma; Antineoplastic Agents, Hormonal; Disease Progression; Drug Resistance, Neoplasm; Follow-Up Studies; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms

We provide a relative cost comparison of medical versus surgical androgen suppressive therapy for prostate cancer.. Comparison is based on a cohort of 96 patients who began androgen suppressive therapy for prostate cancer between 1988 and 1990. Patients were followed until death or the end point of study in June 2000 at which time 15% were alive. Current Medicare orchiectomy reimbursements were compared to 1999 wholesale drug costs.. For an individual patient the cost of luteinizing hormone releasing hormone (LH-RH) agonist treatment surpassed the cost of surgery at less than 4.2 to 5.3 months, and for combined androgen blockade (LH-RH agonists and nonsteroidal antiandrogens) at less than 2.7 to 3.4 months. For 5 (5.2%) patients on combined androgen blockade and 6 (6.3%) on LH-RH agonists alone, medical therapy would have had a cost advantage over bilateral orchiectomy. For the androgen suppression cohort the cost of LH-RH agonist treatment was 10.7 to 13.5 times and combined androgen blockade was 17.3 to 20.9 times the cost of bilateral orchiectomy. Urology resource use comparisons are provided. These findings significantly underestimate the cost advantage of surgery. A seventh of the patients were alive at study end point, and prostate specific antigen induced stage shifting and changes in practice patterns resulted in earlier and more frequent androgen suppressive treatment.. Except for patients with short anticipated survivals current medical androgen suppressive treatment options are more costly than bilateral orchiectomy. There is a need for a cost comparable medical option to orchiectomy.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Cohort Studies; Costs and Cost Analysis; Diethylstilbestrol; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Longitudinal Studies; Male; Medicare; Orchiectomy; Prostatic Neoplasms; Time Factors; United States

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Androgen Antagonists; Antineoplastic Agents, Hormonal; Estradiol; Flutamide; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Testosterone

After the initiation of androgen suppression in men with prostate cancer, the serum prostate-specific antigen (PSA) level generally declines. A subsequent PSA rise during that suppression usually reflects the presence of a significant component of hormonally refractory prostate cancer. We report a patient with a rising PSA level and elevated testosterone level after depot leuprolide in whom the PSA level subsequently declined with administration of bicalutamide.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Anilides; Antineoplastic Agents; Delayed-Action Preparations; Humans; Injections, Intramuscular; Leuprolide; Male; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Tosyl Compounds; Treatment Outcome

Erythropoiesis is stimulated by androgens either through a direct action on bone marrow cells or through increased erythropoietin production. Androgen deprivation is a known cause for anaemia. The aim of this study was to evaluate the effect of neoadjuvant hormone therapy prior to radical surgery on haemoglobin (Hb) and haematocrit (Ht) levels in localised prostate cancer.. 47 patients with clinical localised prostate cancer were given LH-RH analogs plus flutamide for complete androgenic blockade (CAB) for at least 3 months prior to radical prostatectomy. A blood profile was obtained prior to start CAB and 3 months after therapy, and peri-operative transfusional requirements were evaluated. To assess any significant changes. Student's t test was used in the statistical analysis of paired data.. In our study all patients (100%) showed decreased Hb and Ht levels after 3 months on CAB. Mean decline for Hb was 1.9 g/dL (range 1.6-2.2) p:0.0001, and for Ht 5.8% (range 4.8-6.8) p:0.0001. Hb was lower than 12 g/dL in 10.6% patients after hormone therapy and anaemia results were normocytic-normochromic. 60% patients needed peri-operative blood transfusion, 2 units of packed cells on average.. Neoadjuvant CAB prior to radical prostatectomy results in a significant decline of Hb and Ht levels after 3 months treatment. Such decline may contribute to increase peri-operative transfusional requirements in a group of patients undergoing aggressive surgery which in itself involves a significant blood loss.

Topics: Androgen Antagonists; Anemia; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Flutamide; Hematocrit; Hemoglobins; Humans; Leuprolide; Male; Prostatic Neoplasms; Triptorelin Pamoate

Various reports suggest a role for endothelin-1 in prostatic carcinoma. The objective of the current study was to evaluate the changes of the immunodetectable endothelin-1 in prostatic carcinomas characterized by different grades of regression due to total androgen withdrawal.. An immunohistochemical study was made on eleven prostatic carcinomas treated with neoadjuvant hormonal therapy for 3 months, followed by radical prostatectomy. Another ten specimens of untreated carcinomas were studied for comparison. An appraisal of androgen receptors was associated. A highly specific polyclonal antibody against endothelin-1 and a commercial monoclonal mouse antibody for androgenic receptors were used.. In all cases, a prevalent quantity of androgenic receptor-positive tumor cells were present. Neoplastic cells of untreated carcinomas showed a strong and heterogeneous staining for endothelin -1. In unregressed areas of treated cases, the features of endothelin-1 and androgen-receptor staining were the same as those of untreated cases. In areas characterized by moderate histologic regression, the endothelin-1 staining became more heterogeneous. In areas of strong histologic regression, a diffuse membrane staining was often noted. Only in completely regressed cancer cells was a definite loss of immunodetectable endothelin-1 and androgenic receptors observed.. Endothelin-1 is one of the proteins intrinsic to prostatic epithelial cells, both benign and malignant. In cases treated with androgen withdrawal, histologic regression is not uniform. In unmodified areas, immunodetectable endothelin-1 and androgenic receptors also are unmodified, thus suggesting some mechanism that substitutes for the action of androgen. Only neoplastic cells with complete histologic regression also lose androgenic receptors and endothelin-1, whereas the preserved immunostaining in deeply modified prostatic neoplastic cells seems to indicate that these cells still are potentially active.

Topics: Aged; Antineoplastic Agents, Hormonal; Cyproterone Acetate; Endothelin-1; Goserelin; Humans; Immunoenzyme Techniques; Leuprolide; Male; Middle Aged; Prostatectomy; Prostatic Neoplasms; Receptors, Androgen; Treatment Outcome

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

Topics: Adenocarcinoma; Adult; Antineoplastic Agents, Hormonal; Follow-Up Studies; Humans; Leuprolide; Male; Neoplasm Staging; Prostatectomy; Prostatic Neoplasms; Treatment Failure; Treatment Outcome

An osmotically driven implantable system was designed and characterized for the delivery of leuprolide over a year-long duration. Leuprolide has been used in the treatment of prostate cancer since the 1980s. The DUROS implant consists of a titanium alloy cylinder, measures 4 mm in diameter by 45 mm in length and holds approximately 150 microl of formulation. Stability studies indicated that leuprolide was stable, as a solution formulation in DMSO, for several years at 37 degrees C. In vitro release rate testing, at weekly intervals, showed zero-order delivery for 1 year. DUROS implants demonstrated release rates that were reproducible and similar to one another after storage at 25 degrees C for 18 months prior to testing. In vivo studies, with implants placed subcutaneously, revealed delivery rates comparable to those observed under in vitro conditions. Leuprolide stability was also comparable between in vivo and in vitro conditions. Steady leuprolide serum levels produced by the implant resulted in the desired pharmacodynamic efficacy endpoint of testosterone suppression, both in canines and in humans. The good agreement between in vivo/in vitro delivery rates was as expected for a delivery system based on the principles of osmosis.

Topics: Alloys; Animals; Antineoplastic Agents, Hormonal; Chromatography, High Pressure Liquid; Diffusion; Drug Implants; Drug Stability; In Vitro Techniques; Leuprolide; Male; Osmosis; Prostatic Neoplasms; Radioimmunoassay; Rats; Rats, Inbred F344; Spectrophotometry, Ultraviolet; Testosterone; Titanium

Topics: Adenocarcinoma; Anticarcinogenic Agents; Carotenoids; Drug Resistance, Neoplasm; Humans; Leuprolide; Lycopene; Male; Middle Aged; Prostatic Neoplasms

To update the cycling characteristics and patterns of treatment in patients receiving intermittent androgen deprivation (IAD) for clinically localized and recurrent prostate cancer.. We report our experience with 61 patients treated with IAD. Thirty-four patients had received no prior treatment, and 27 had developed recurrent disease after previous local therapy. No patient had clinically apparent metastatic disease before the initiation of therapy. The mean and median serum prostate-specific antigen (PSA) level before treatment was 25.3 ng/mL and 16.0 ng/mL, respectively (range 0.5 to 190 ng/mL). For each cycle, androgen deprivation was continued until PSA became undetectable or a nadir level was reached. Patients were then observed without treatment, and therapy was reinstituted after the serum PSA value reached a predetermined level. Patients were no longer eligible to cycle off treatment when their serum PSA increased despite ongoing androgen deprivation or if any objective evidence of disease progression was present on imaging studies.. Follow-up ranged from 7 to 60 months (mean 30) from the start of treatment. Patients received from one to five treatment cycles (median two), with a median cycle length of 14 months. The median nadir serum PSA level during androgen deprivation was 0.01 ng/mL and was reached within an average of 6 months (range 4 to 9) after beginning treatment. Patients spent an average of 45% of the time not receiving therapy, but the time off therapy decreased as the number of treatment cycles increased. Five patients (8.1%) demonstrated progressive disease, with a median time to progression of 48 months. When examining the cycling characteristics of these patients, no consistent pattern of failure emerged.. IAD appears to be a viable treatment option in select patients with localized prostate cancer. With each consecutive cycle, the amount of time the patient was not receiving therapy decreased, despite achieving a low nadir PSA. Longer follow-up with more patients failing IAD will be required before clear patterns of failure emerge in these patients.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Castration; Disease Progression; Drug Administration Schedule; Follow-Up Studies; Humans; Injections, Intramuscular; Leuprolide; Male; Middle Aged; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms; Testis; Treatment Outcome

Luteinizing hormone-releasing hormone (LHRH) antagonists work by directly inhibiting LHRH without any initial stimulation of the LHRH receptor. The physiologic response is a direct and rapid decrease in luteinizing hormone, follicle-stimulating hormone, and testosterone without any flare. Although there has been extensive basic-science work on these medications, practical shortcomings have limited clinical studies in prostate cancer. Many of these compounds induce significant histamine-mediated side effects, and until recently, no depot form existed. In 2 recent phase-3 studies comparing abarelix depot with leuprolide and with leuprolide plus bicalutamide, abarelix lowered serum testosterone more quickly. None of the 89 patients on leuprolide alone were castrate on day 8 as opposed to 72% of the 180 patients randomized to abarelix (P <0.001). Similarly, none of the combination group were castrate by day 8, whereas 68% of the abarelix patients were castrate (P <0.001). In addition, 82% of the patients treated with leuprolide and 86% of those given leuprolide/bicalutamide had testosterone surge, whereas none of the abarelix patients did (P <0.001 for both studies). Both phase 2 and phase 3 data show abarelix to be well tolerated. In conclusion, LHRH antagonists offer the physiologic response of orchiectomy without surgery. These medications are well tolerated and a depot form now exists. The expansion of indications for androgen deprivation, such as downsizing or intermittent therapy, could provide many opportunities for their use. Despite these encouraging advances, however, their routine use for advanced prostate cancer may depend on demonstration of a survival advantage in avoiding flare.

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Disease-Free Survival; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leuprolide; Male; Oligopeptides; Orchiectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Testosterone; Therapeutics; Treatment Outcome

To compare health-related quality-of-life outcomes after primary androgen deprivation (AD) therapy with orchiectomy versus luteinizing hormone-releasing hormone (LHRH) agonists for patients with prostate cancer.. Men (n = 431) newly diagnosed with all stages of prostate cancer from six geographic regions who participated in the Prostate Cancer Outcomes Study and who received primary AD therapy but no other treatments within 12 months of initial diagnosis were included in a study of health outcomes. Comparisons were statistically adjusted for patient sociodemographic and clinical characteristics, timing of therapy, and use of combined androgen blockade.. More than half of the patients receiving primary AD therapy had been initially diagnosed with clinically localized prostate cancer. Among these patients, almost two thirds were at high risk of progression on the basis of prognostic factors. Sexual function outcomes were similar by treatment group both before and after implementation of AD therapy. LHRH patients reported more breast swelling than did orchiectomy patients (24.9% v 9.7%, P <.01). LHRH patients reported more physical discomfort and worry because of cancer or its treatment than did orchiectomy patients. LHRH patients assessed their overall health as fair or poor more frequently than did orchiectomy patients (35.4% v 28.1%, P =.01) and also were less likely to consider themselves free of prostate cancer after treatment.. Most endocrine-related health outcomes are similar after surgical versus medical primary hormonal therapy. Stage at diagnosis had little effect on outcomes. These results provide representative information comparing surgical and medical AD therapy that may be used by physicians and patients to inform treatment decisions.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Cross-Sectional Studies; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Orchiectomy; Patient Satisfaction; Prostatic Neoplasms; Quality of Life; Regression Analysis; Sexuality

This study was carried out to evaluate the possible long-term endocrine effect of short-term neoadjuvant leuteinizing hormone-releasing hormone analogue (LHRHa) administration in localized prostate cancer. A total of 419 men were treated for 3-6 months at The Royal Marsden NHS Trust by neoadjuvant androgen suppression using monthly depot injections of LHRHa before radical radiotherapy. Serum testosterone (852 measurements), leuteinizing hormone (LH) (799 measurements), and follicle-stimulating hormone (FSH) levels (801 measurements) were grouped according to their timing in relation to hormonal treatment and then analysed. Suppression of pituitary gonadotrophins and testosterone after the administration of LHRHa and their recovery after cessation of the drug was clearly observed. Median serum testosterone levels decreased from 16 nmol/l to 14 nmol/l when comparing prehormonal and follow-up phases. The same comparison showed an increase in median serum LH and FSH levels, with the median LH rising from 5 u/l to 8 u/l and the median serum FSH rising from 6 u/l to 20 u/l. On long-term follow-up, three of 256 men have remained with testosterone levels in the castrate range. Similar highly significant results were seen in subgroup of 103 men who had both pre-LHRHa and follow-up hormone levels analysed (P=0.012, P<0.001, P<0.001 for testosterone, LH and FSH respectively). Our data suggest the possibility of residual gonadal dysfunction after short-term LHRHa administration and radical radiotherapy in localized prostate cancer. Serum testosterone levels are restored to normal levels in the majority of patients, with a compensatory increase in serum levels of LH.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Follicle Stimulating Hormone; Goserelin; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Neoadjuvant Therapy; Prostatic Neoplasms; Testosterone

Topics: Administration, Inhalation; Antineoplastic Agents, Hormonal; Bone Density; Bone Resorption; Diphosphonates; Female; Glucocorticoids; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Osteoporosis; Pamidronate; Prostatic Neoplasms; Triamcinolone Acetonide

We report a pilot study on a novel protocol of intermittent androgen deprivation (IAD) treatment of prostate cancer (PC), in which androgen deprivation is restarted when serum prostatic specific antigen (PSA) level reached more than 2 ng/ml and is stopped when PSA level decreased below 0.3 ng/ml. Thirty-two patients (aged 60 to 86 years, median 74 years) with prostate cancer (Stage A in 4 patients, B in 20, C in 1, D in 5, and relapse after radical prostatectomy in 2) were treated with IAD. Median serum PSA prior to the start of endocrine therapy was 15.65 (range 2.67 to 306.3) ng/ml. Eleven patients were treated with lutenizing-hormone-releasing hormone (LHRH) agonist alone and 21 were treated with LHRH agonist plus an antiandrogen. Median duration of first endocrine therapy was 572 (range 100 to 1,543) days. Median serum PSA at the start of first off-phase was 0.038 (range 0.003 to 0.489) ng/ml. After a median of 207 days (range 140 to 843) of follow-up, 19 patients were in the first cycle, 9 in the second cycle, 3 in the third cycle, 1 in the fourth cycle. Two patients developed androgen-independent PC. The median duration of first off-phase of IAD was 287 days. There was a significant inverse relation between the duration of the first on-phase and testosterone level measured 4 months after the cessation of first on-phase therapy (R = -0.518). These results suggest that our protocol provides a reasonable length of off-phase duration and that the long term-androgen deprivation phase might delay the recovery of the testicular endocrine function which should be maintained during the off-phase of IAD.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Drug Administration Schedule; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Nitriles; Pilot Projects; Prostatic Neoplasms; Tosyl Compounds

Topics: Antineoplastic Agents, Hormonal; Drug Industry; Fraud; Humans; Illinois; Leuprolide; Liability, Legal; Male; Medicaid; Medicare; Prostatic Neoplasms

To determine the accuracy of combined magnetic resonance (MR) imaging and three-dimensional (3D) proton MR spectroscopic imaging in localizing prostate cancer to a sextant of the gland in patients receiving hormone deprivation therapy.. Combined MR imaging/3D MR spectroscopic imaging examinations were performed in 16 hormone-treated patients and 48 nontreated matched control patients before radical prostatectomy and step-section histopathologic analysis. At MR imaging, cancer presence within the peripheral zone was assessed on a per sextant basis by two readers. At 3D MR spectroscopic imaging, cancer was identified by using (choline plus creatine)-to-citrate ratios at cutoff values of 2 and 3 SDs above mean normal peripheral zone values. Data were compared by using receiver operating characteristic analysis.. There was no significant difference in the ability of combined MR imaging/3D MR spectroscopic imaging to localize prostate cancer in treated versus control patients. For MR imaging alone, the sensitivity and specificity were 91% and 48% (reader 1) and 75% and 60% (reader 2) in treated patients versus 79% and 60% (reader 1) and 84% and 43% (reader 2) in control patients. For 3D MR spectroscopic imaging alone (>3 SDs cutoff), higher specificity (treated, 80%; controls, 73%) but lower sensitivity (treated, 56%; controls, 53%) was attained. In treated patients, high sensitivity or specificity (up to 92%) was achieved when either or both modalities indicated cancer.. When performed within 4 months after initiating hormone deprivation therapy, combined MR imaging/3D MR spectroscopic imaging had the same accuracy in localizing prostate cancer as in nontreated patients.

Topics: Antineoplastic Agents, Hormonal; Case-Control Studies; Deuterium; Goserelin; Humans; Leuprolide; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Observer Variation; Prostatic Neoplasms; Reproducibility of Results

A 78-year-old man admitted with clinical jaundice and pelvic pain had a total bilirubin level of 6.56 mg/dL, an alkaline phosphatase level of 855 U/L, and a prostate specific antigen (PSA) level of 9996 ng/mL. A computed tomogram demonstrated marked retroperitoneal, peripancreatic, periceliac, and periaortic lymphadenopathy. A bone scan revealed increased radiolabeled technetium uptake in the pelvis, vertebral column, parietooccipital region, ribs, and appendiceal skeleton. A biopsy of one pelvic lesion revealed metastatic prostate cancer. This man's obstructive jaundice and bone pain had a dramatic response to treatment with a gonadotropin-releasing hormone analog (leupro lide) and antiandrogen (bicalutamide). All bone pair and clinical signs of jaundice disappeared in 1 week His total bilirubin decreased to 0.84 mg/dL by 2 weeks His PSA values reflected this clinical response, decreasing to 4022 ng/mL in 1 week, 2680 ng/dL after 2 weeks and 1028 ng/mL after 1 month of the above therapy.

Topics: Aged; Alkaline Phosphatase; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bilirubin; Bone Neoplasms; Cholestasis; Humans; Leuprolide; Lymphatic Metastasis; Male; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Tosyl Compounds; Treatment Outcome

To investigate any differences in changes in serum prostate specific antigen (PSA) levels in patients with benign and malignant prostatic disease in response to the testosterone surge after administering a luteinizing hormone-releasing hormone (LHRH) analogue.. The study included 54 patients referred to the urology clinic with intermediate PSA levels (4-10 ng/mL) or an abnormal digital rectal examination. Forty-five patients received a single injection of LHRH analogue depot each at one week before prostate biopsy and nine served as a control group. Changes in PSA levels in response to the testosterone surge from the LHRH analogue were recorded after 5 and 7 days, and were correlated with the biopsy results. The PSA changes were compared with basal PSA levels and the free/total PSA ratio(f/tPSA).. Of the 45 patients who underwent prostate biopsy, histopathology showed prostate cancer in 11, benign prostatic hyperplasia in 33 and prostatic intraepithelial neoplasia in one. Patients with cancer had a significantly greater increase in serum PSA levels during the first week after LHRH injection than those in the benign and control groups. Receiver operating characteristic curves showed that the percentage change in PSA level on day 5 was more diagnostic than total PSA and f/tPSA.. There was a marked difference in the PSA response of patients with benign or malignant disease to the testosterone surge produced by the LHRH analogue. Although a larger study would be needed before LHRH-induced provocation could be proposed as a clinical test, in this small series the response was better than that for total PSA or f/tPSA in differentiating benign and malignant disease.

Topics: Aged; Aged, 80 and over; Case-Control Studies; Humans; Leuprolide; Male; Middle Aged; Predictive Value of Tests; Prostate; Prostate-Specific Antigen; Prostatic Hyperplasia; Prostatic Neoplasms; ROC Curve; Testosterone

Permanent androgen ablation has been the mainstay of treatment for advanced prostate cancer. However, the favorable outcome seen in recent pilot studies of intermittent androgen ablation raises the possibility of overtreatment.. This study included 35 Japanese men with advanced prostate cancer. Initial androgen ablation continued for 2 months after PSA levels decreased to <4.0 ng/ml, then was withdrawn. Androgen ablation was reinstituted 2 months after PSA reached levels >10 ng/ml, when indicated clinically or on patient request. Cycling continued until androgen independence was reached.. Mean follow-up was 21.0 months, representing an average of 2.5 cycles. Nine patients developed androgen independence at an average of 16.0 months following androgen ablation; three of these have died. Six of the nine patients with early biochemical progression had elevated alkaline phosphatase levels at entry; five of these exhibited a flare in alkaline phosphatase activity after initiation of androgen ablation. Mean bone mineral density (BMD) in the lumbar spines of 17 patients was 81.5 mg/cm3 at 23 months following therapy. The BMD of 10 of these patients was normal for their age. Four patients suffered bone fractures, none pathological.. Intermittent androgen ablation may be an option for patients with advanced prostate cancer and may be especially beneficial for those with initially low BMD levels. Patients with elevated alkaline phosphatase levels at entry or a flare in its activity may not be ideal candidates. Whether prolonging time to androgen independence will provide benefit remains to be investigated in a randomized, prospective study.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Alkaline Phosphatase; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Density; Disease Progression; Drug Administration Schedule; Flutamide; Follow-Up Studies; Fractures, Bone; Goserelin; Humans; Leuprolide; Lumbar Vertebrae; Male; Middle Aged; Pilot Projects; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Remission Induction; Survival Rate; Testosterone; Treatment Outcome

We evaluate the quality of life of asymptomatic men with nonmetastatic prostate cancer who receive androgen deprivation therapy.. Quality of life was longitudinally evaluated in a cohort of 144 men with locally advanced prostate cancer or prostate specific antigen relapse after local therapy who chose to receive (79 patients) or not to receive (65 patients) androgen deprivation therapy. Androgen deprivation therapy consisted of orchiectomy, leuprolide alone or leuprolide plus flutamide. Multivariate analysis of variance was used to test the effect of different treatment regimens on patient quality of life.. Men who received androgen suppression had more fatigue, loss of energy, emotional distress and a lower overall quality of life than men who deferred hormone therapy. Combined androgen blockade had a greater adverse effect on quality of life than monotherapy.. Androgen deprivation therapy may significantly impair the physical and emotional health of asymptomatic patients with nonmetastatic prostate cancer.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Drug Therapy, Combination; Flutamide; Health Status Indicators; Humans; Leuprolide; Male; Middle Aged; Orchiectomy; Prostatic Neoplasms; Quality of Life; Stress, Psychological

Patients scheduled for prostatectomy often receive androgen deprivation therapy to make malignant tumors more amenable to resection and improve the postoperative course. These hormonal therapies may significantly alter the histomorphology of carcinoma of the prostate detected on subsequent needle biopsies.. Needle specimens were obtained from resected prostates harboring biopsy-proven carcinoma previously treated with leuprolide. The tissue was examined by light microscopy to note architectural and cytologic characteristics.. A high proportion of treated carcinomas had an atrophic, infiltrative appearance. Nuclear and nucleolar enlargement were consistently observed. Macronucleoli, blue-tinged mucin, and intraluminal pink amorphous material was frequently identified.. The markedly atrophic nature of the cells and glands may result in either overgrading of prostate carcinoma or failure to recognize the more subtle patterns of this malignant neoplasm. It is imperative that clinicians convey a history of hormone treatment to pathologists when core biopsies of the prostate are submitted for histologic evaluation.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Biopsy, Needle; Communication; Humans; Interprofessional Relations; Leuprolide; Male; Middle Aged; Military Medicine; Military Personnel; Pathology, Clinical; Physician's Role; Prostatectomy; Prostatic Neoplasms

Topics: Antineoplastic Agents, Hormonal; Drug Approval; Drug Implants; Humans; Leuprolide; Male; Palliative Care; Prostatic Neoplasms; United States; United States Food and Drug Administration

The incidence of flutamide-induced liver toxicity was studied in 30 consecutive patients with prostate cancer who were treated with total androgen blockage (TAB) therapy (luteinizing hormone releasing hormone [LHRH] analogue and flutamide) in our hospital during the last 3 years and in 20 consecutive patients with prostate cancer who were treated by partial androgen blockage (PAB) therapy (LHRH analogue alone).. Liver function test, including measurement of serum levels of aspartate aminotransferase (AST) alanine aminotransferase (ALT), total cholesterol, total bilirubin, gamma-glutamyl transpeptidase (gamma-GTP), and cholinesterase were performed at regular interval.. The incidence of liver toxicity in patients receiving TAB (10 cases of 25 patients) was significantly higher than in patients receiving PAB (2 of 18 patients). Two patients in whom severe liver toxicity developed after receiving TAB were hospitalized. However, after flutamide was discontinued all patients with liver damage recovered with normalization of AST and ALT levels. Levels of total cholesterol and gamma-GTP did not differ significantly in either patient group. In two patients receiving TAB total bilirubin levels showed slight, transient elevations after maximum elevations of AST and ALT. In 80% of patients receiving TAB serum levels of cholinesterase were significantly higher than those in patients receiving PAB.. These data suggest that the risk of flutamide-induced liver toxicity is significant in patients receiving TAB. However, this damage can be normalized after flutamide has been discontinued. Serum levels of cholinesterase also increase significantly in patients receiving TAB. This previously unreported phenomenon suggests an unknown effect of flutamide on liver function in patients with prostate cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Chemical and Drug Induced Liver Injury; Cholinesterases; Drug Therapy, Combination; Flutamide; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Liver Diseases; Liver Function Tests; Male; Middle Aged; Prostatic Neoplasms

Luteinizing hormone-releasing hormone (LHRH) agonists are popularly used drugs in the treatment of prostatic cancer. However, it has been reported that continuation of a low testosterone level following a longterm administration of these drugs reduces the bone mineral density and makes for osteoporosis, which is accountable for fracture, we measured the bone mineral density and bone metabolic markers in the cases who suffered fracture receiving LHRH agonists for prostatic cancer.. Between 1994 and 1998, 196 patients (mean age 78.1 years) were treated with LHRH agonists for prostatic cancer. Of these patients, 13(7%) who had bone fracture during treated with LHRH agonists were divided into fracture group, and 70 patients who had not bone fracture divided into non-fracture group. Fracture by traffic accident was excluded. The bone density in the third lumbar vertebra was measured using quantitative computed tomography (QCT). Osteocalcin, 1, 25- (OH)2 vitamin D, urinary type 1 collagen cross-linked N-telopeptides (NTx), parathyroid hormone (PTH) and calcitonin were measured as bone metabolic markers.. The mean age of fractured cases was 78 years. The period from the start of treatment to fracture was 11 to 45 months (mean 27 months). No case of fracture at the site of metastasis of prostatic cancer was found. The bone density was significantly low in the fracture group compared with that of non-fracture group. Of the bone metabolic markers, NTx showed high values in the fracture group.. There is a need to measure bone mineral density and bone metabolic markers periodically and to evaluate secondary osteoporosis in the patients receiving LHRH agonists for prostatic cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Bone Density; Fractures, Bone; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Osteoporosis; Prostatic Neoplasms; Spine

To assess the effectiveness of palladium-103 brachytherapy in stage T1 and T2 adenocarcinoma of the prostate.. The charts of 1048 patients treated between 1991 and 1999 with transperineal realtime ultrasound-guided (103)Pd (Theraseed) implants were reviewed to assess the effects on serum prostate specific antigen (PSA) values and tissue (biopsy). Of the 1048 patients, 780 had sufficient data for this report. Preoperative total androgen blockade (leuprolide and flutamide) was used selectively in patients whose prostate size was >50 cc and those whose tumors had a Gleason score of >7.. At 1 year, 86% of the evaluable 766 patients had stable PSA concentration <1.5 ng/mL; at 5 years, 86% of the 166 patients with data available had stable PSA values <1.5 ng/mL. Biopsies were negative in 92% of the patients studied at 2 years. Patients with pretreatment PSA values <10 ng/mL had the best outcomes, and those treated with (103)Pd plus hormone ablation achieved PSA reduction more rapidly than those treated with radioisotope monotherapy. There was one disease-related death; the principal morbidity was short-term bladder and bowel irritation without permanent sequelae. Impotence occurred in approximately 15% of patients, and incontinence occurred in 5% of those who had undergone prior transurethral resection of the prostate.. The technique used in this study proved effective in reducing PSA concentrations to <1.5 ng/mL and in producing negative biopsies 1 and 2 years postoperatively. These results are comparable to those of external-beam radiation therapy and radical prostatectomy while demonstrating a significant reduction in morbidity.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Biopsy; Brachytherapy; Combined Modality Therapy; Flutamide; Humans; Leuprolide; Male; Middle Aged; Palladium; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Radioisotopes; Ultrasonography

To assess the effects of 8 months of neoadjuvant therapy on pathologic stage and biochemical recurrence rates.. One hundred fifty-six men with clinically localized prostate cancer were treated with neoadjuvant combined androgen withdrawal therapy for 8 months prior to radical prostatectomy. Preoperative clinical stage, Gleason score, and serum prostate-specific antigen (PSA) levels were compared with treatment outcome (pathologic stage and PSA recurrence).. PSA at diagnosis was 10 microg/L or higher in 36% with a mean of 11.5 microg/L. Clinical stage was T1c in 18%, T2 in 74%, and T3a in 8%. Gleason score was 6 or lower in 76% and 7 or higher in 24%. Pathologic stage was T0 in 13%, T2 in 66%, T3 (specimen confined) in 13%, T3 (margin positive) in 6%, and TxN+ in 2%. Incidence of positive margins increased with clinical stage T3a versus organ-confined disease (25% versus 4%, P <0.05), pretreatment Gleason scores 7 or higher versus Gleason scores 6 or lower (11% versus 4%, P = NS), and pretreatment PSA levels higher than 10 microg/L compared with PSA levels lower than 10 microg/L (15% versus 0%, P <0.01). Overall PSA recurrence rate was 12.2% after a mean postoperative follow-up of 54 months. Risk of PSA recurrence increased with clinical stage (25% T3 versus 11% organ confined, P <0.01), pretreatment PSA (7% if PSA lower than 10 microg/L versus 21% if 10 microg/L or higher, P <0.02), Gleason score (9% if 6 or lower versus 22% if 7 or higher, P <0.02), and pathologic stage (6% of pT2, 24% of pT3M-, and 56% of pT3M+, P <0.01). PSA recurrences occurred in 6% of patients with no adverse preoperative risk factors, 12% with any one of the high-risk factors, and 29% with any two of the high-risk factors.. Risk of PSA recurrence after 8 months of neoadjuvant therapy is low after 5 years of follow-up and remains proportional to the presence of adverse preoperative risk factors. Prospective randomized studies are required to determine whether longer duration of neoadjuvant therapy reduces the risk of biochemical recurrence after radical prostatectomy.

Topics: Adult; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Cyproterone Acetate; Diethylstilbestrol; Drug Therapy, Combination; Flutamide; Follow-Up Studies; Humans; Leuprolide; Lymph Node Excision; Male; Middle Aged; Neoadjuvant Therapy; Postoperative Complications; Prostatectomy; Prostatic Neoplasms; Recurrence; Treatment Outcome

Fine-needle aspiration of prostatic carcinoma usually yields an acinar carcinoma that is immunoreactive for prostatic-specific antigen (PSA) and prostatic acid phosphatase (PAP). We report on two FNAs of metastatic sarcomatoid prostatic carcinoma that were PSA- and PAP-negative. Our methods included a review of the medical records and pathology results. Both cases presented with elevated serum PSA levels and prostate needle biopsies with Gleason score 8 and 9 tumors, respectively. Both cases developed retroperitoneal/pelvic lymphadenopathy, and fine-needle aspirations were performed. These showed high-grade, sarcomatoid tumors with marked anisonucleosis. Immunocytochemical staining for PSA and PAP was negative in both cases. Clinical and radiologic evaluation failed to reveal any other potential primary sites. Metastatic, sarcomatoid, PSA- and PAP-negative prostatic carcinoma is a rare diagnosis of exclusion that should be considered in the characteristic clinical setting.

Topics: Acid Phosphatase; Adenocarcinoma; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Carcinoembryonic Antigen; Flutamide; Humans; Immunohistochemistry; Keratins; Leuprolide; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Sarcoma

We report the failure to achieve a castrate level of testosterone associated with 3-month depot luteinizing hormone releasing hormone (LH-RH) agonist therapy, which to our knowledge is a previously unrecognized outcome.. We prospectively enrolled in our study 38 men with prostate cancer on 3-month depot LH-RH agonist therapy. We monitored total serum testosterone and prostate specific antigen every 28 days beginning 90 days after the last depot LH-RH agonist injection. Data were analyzed with castrate testosterone defined as less than 50 and 20 ng./dl. or less.. Using the 50 and 20 ng./dl. definitions of castrate testosterone 2 (5%) and 5 (13%) of the 38 men, respectively, failed to achieve castrate testosterone. A patient with a nadir testosterone of 70 ng./dl. subsequently underwent orchiectomy and testosterone decreased to 10 ng./dl. thereafter.. A small but potentially important subgroup of men on depot LH-RH agonist therapy fail to achieve a castrate level of testosterone. Our findings support monitoring testicular response when LH-RH agonist therapy is initiated.

Topics: Aged; Aged, 80 and over; Algorithms; Antineoplastic Agents, Hormonal; Body Mass Index; Decision Making; Delayed-Action Preparations; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Logistic Models; Luminescent Measurements; Male; Middle Aged; Orchiectomy; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testis; Testosterone; Treatment Failure

The cost of luteinizing hormone releasing hormone analogue and antiandrogen for prostate cancer is being scrutinized by the Health Care Finance Administration and other insurers. We compared the discounted present value cost of medical hormonal therapy to that of orchiectomy as well as the value created by these treatments from the insurer and patient perspectives.. We performed a telephone survey of 42 patients receiving hormonal therapy to estimate the value created by medical versus surgical castration from the patient perspective. The cost of medical hormonal therapy was discounted back to the present value and compared with the cost of bilateral orchiectomy.. The total cost of bilateral orchiectomy was $2,022, while the discounted present value cost using the average wholesale price for 30 months of medical hormonal therapy was $13,620. Therefore, medical hormonal therapy costs $11,598 more than orchiectomy ($13,620 - $2,022). A discounted payment of $386 per month for 30 months is necessary to recoup the $11,598 difference. All surveyed patients on medical hormonal therapy stated that avoiding orchiectomy was worth $386 per month and it was an appropriate insurer expense. If patients paid $386 per month out-of-pocket, 22 of the 42 (52%) would pay the additional monthly expense, while 20 (48%) indicated that they could not afford the additional expense.. These results indicate that medical hormonal therapy costs significantly more than bilateral orchiectomy but creates positive value for men with prostate cancer by enabling them to avoid orchiectomy.

Topics: Algorithms; Androgen Antagonists; Antineoplastic Agents, Hormonal; Attitude to Health; Centers for Medicare and Medicaid Services, U.S.; Cost of Illness; Financing, Personal; Gonadotropin-Releasing Hormone; Health Care Costs; Hospital Charges; Humans; Insurance Carriers; Leuprolide; Male; Maryland; Neoplasm Metastasis; Orchiectomy; Patient Satisfaction; Prostatic Neoplasms; Relative Value Scales; United States

To investigate the incidence of bone fractures in patients receiving luteinizing hormone-releasing hormone agonists (LHRH-a) for prostate cancer (in whom a continued low testosterone level after the long-term administration of these drugs reduces bone mineral density), and thus determine the risk of secondary osteoporosis.. Between 1994 and 1999, 218 patients (mean age 77.3 years) were treated for >/= 6 months with LHRH-a for prostate cancer; of these, 14 (6%) had a bone fracture during their treatment. Patients with fracture associated with motor vehicle accidents were excluded. The bone density in the third lumbar vertebra was meas-ured using quantitative computed tomography. Osteocalcin, 1,25-(OH)2 vitamin D, urinary type 1 collagen cross-linked N-telopeptides (NTx), parathyroid hormone and calcitonin were measured as metabolic markers.. The mean age of the patients with fracture was 78 years; the mean (range) interval from the start of treatment to fracture was 28 (11-46) months. There was no case of a bone fracture at the site of a metastasis from prostate cancer. The bone density was significantly lower in the patients with a fracture than in those without. Of the bone metabolic markers, NTx was higher in those with a fracture.. There is a need to measure bone mineral density and bone metabolic markers periodically, and to evaluate secondary osteoporosis in patients receiving long-term LHRH-a for prostate cancer.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Antineoplastic Agents, Hormonal; Bone Density; Fractures, Spontaneous; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Lumbar Vertebrae; Male; Middle Aged; Prostatic Neoplasms; Risk Factors

Topics: Antineoplastic Agents, Hormonal; Drug Delivery Systems; Humans; Leuprolide; Male; Prostatic Neoplasms

Patients with prostate cancer are treated with neoadjuvant, adjuvant and intermittent androgen deprivation therapy. Prostate specific antigen (PSA) is altered during androgen deprivation therapy, and as a result the prognostic significance and accuracy of PSA values measured before serum testosterone has normalized are questionable because the patient is still effectively on androgen deprivation therapy. We determine the time it takes for serum testosterone to return to normal after withdrawal of androgen deprivation therapy.. Serial serum testosterone was prospectively measured at 3-month intervals in 68 men after withdrawal of androgen deprivation therapy. The number of months to return to normal serum testosterone 270 ng./dl. or greater, was calculated for each patient. Patients were stratified according to duration of androgen deprivation, age and type of luteinizing hormone releasing hormone agonist used.. Median patient age was 71 years (range 46 to 88). Median time to normalization of testosterone was 7 months (range 1 to 58). At 3, 6 and 12 months 28%, 48% and 74% of men had normal serum testosterone, respectively. Serum testosterone took significantly longer to return to normal in patients on androgen deprivation therapy for 24 months or greater compared to those on therapy for less than 24 months (log-rank p = 0.0034). There was no statistical significance based on age or type of luteinizing hormone releasing hormone agonist used.. Androgen deprivation has an effect on serum testosterone that extends beyond the cessation of treatment. Serum testosterone should be measured in all men until normalization. These results should be applied to the interpretation of PSA levels after withdrawal of androgen deprivation therapy. In addition, these data have implications regarding dose scheduling and definition of biochemical (PSA) failure after primary therapy.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Testosterone; Time Factors

Androgen ablation may improve the efficacy of radiation therapy.. A total of 296 patients who had either (125)I (206; 70%) or (103)Pd (90; 30%) transperineal prostate brachytherapy (no external-beam radiation) had routine transrectal ultrasound-guided needle biopsy (minimum six cores) 2 years after treatment without regard to disease status. Neoadjuvant hormonal therapy (NHT: leuprolide acetate and flutamide) was used in 115 patients (39%) for 3 months prior to and 3 months after the implant.. Of the 296 patients, 30 (10%) had positive prostate biopsies. Biopsies were positive in 4 of 115 (3.5%) v 26 of 181 (14%) of those who received or had not received NHT, respectively (P = 0.002). When patients were separated into low risk (PSA < or = 10 ng/mL, stage < or = T(2a), and Gleason score < or = 6) and high risk (all others), it was seen that low-risk patients did not benefit from NHT (3.8 v 7.7% positive biopsy rate; P = 0.5) whereas high-risk patients did (3.4% v 21.1%; P = 0.003).. Prostate brachytherapy yields high negative biopsy rates (90%) 2 years after treatment. Neoadjuvant hormonal therapy can improve the local control rates (as determined by biopsy) in patients undergoing (125)I or (103)Pd seed implantation. These results are most significant for patients who present with PSA >10 ng/mL, stage > or = T(2b) diseases, or Gleason score > or = 7 (high-risk status).

Topics: Androgen Antagonists; Androgens; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Brachytherapy; Flutamide; Humans; Leuprolide; Male; Neoadjuvant Therapy; Prostate; Prostatic Neoplasms; Treatment Outcome; Ultrasonography

The discovery of a novel estrogen receptor (ER), ER-beta, has given rise to new possibilities regarding estrogen's roles in the prostate. Although ER-beta is reported to be expressed preferentially in the rat prostate, its expression in the human prostate and relationship to cancer development has not been investigated. Thus the purpose of the study was to examine mRNA levels of ER-alpha and ER-beta in benign prostatic hyperplasia and prostate carcinoma.. Samples of 15 prostate cancers obtained at radical prostatectomy were examined. All the patients had been maintained on androgen withdrawal therapy for at least 3 months. ER-alpha and ER-beta mRNAs were measured with a competitive PCR technique.. Both ER-alpha and ER-beta mRNAs were detected in all of the prostate cancer tissues examined, as well as in PC3 and LNCap cells, although the levels varied among specimens. Interestingly, both types were significantly decreased in cases with lymph node metastasis. However, there was no correlation between ER mRNA levels and any other clinicopathological parameters.. (1) Both ER-alpha and ER-beta mRNAs are expressed in prostate cancer and (2) expression of ER mRNA may not be related to cancer progression but may be negatively correlated with metastasis.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Estrogen Receptor alpha; Estrogen Receptor beta; Gene Expression Regulation, Neoplastic; Humans; Leuprolide; Male; Middle Aged; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Estrogen; RNA, Messenger

135 patients with stage T1-3N0M0 prostatic carcinoma were submitted to prolonged PSA-monitored neoadjuvant endocrine treatment (PPNET). The rate of pT0 reports was three times higher (15%) than after the standard 3-month therapy (5%). The present work was done to elucidate the initial characteristics of these tumors, to see if additional workup of these prostatectomy specimens is able to detect tumor vestiges and, if so, to describe their morphology.. The original clinical and histopathological data of 20 pT0 cases were reviewed and an additional histopathological workup of the prostatectomy specimens was done.. The majority of patients had initially small (9 patients cT1, 8 patients cT2, 3 patients cT3) and well-differentiated tumors (18 patients Gleason score <7). Microscopic assessment of 4,503 slides revealed very small tumor remnants (mean volume 0.2 ml) in 13 of the 20 prostatectomy specimens. Severe tumor regression was seen in 3 cases, slight to moderate regression in 10 cases.. A pT0 report following detailed routine histopathological workup has to be regarded as a maximal therapeutic effect, but not as tumor elimination. PPNET clearly increases the rate of pT0 reports, implicating that the conventional 3 months of pretreatment does not exploit the possibilities of neoadjuvant therapy.

Topics: Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Flutamide; Humans; Leuprolide; Male; Neoplasm, Residual; Nitriles; Prostate; Prostatectomy; Prostatic Neoplasms; Time Factors; Tosyl Compounds

Suramin has been shown to have an effect on bone resorption in in vitro models. It is not clear if a similar effect is seen in patients treated with suramin. The clinical effect of suramin treatment on total serum calcium was examined in two groups of patients with hormone-refractory prostate cancer. In all, 28 patients in group 1 were examined within 2 weeks before and 2 weeks after suramin treatment and 72 patients in group 2 were examined within 2 weeks before, during, and after treatment with suramin. In addition, calcium controls spiked with suramin were run in three different commercially available assays for evaluation of the effect of suramin dose on calcium determination. Group 1 patients showed a decrease in serum calcium after treatment with suramin. The mean uncorrected serum calcium level was 2.29 +/- 0.025 mmol/l before treatment and 2.09 +/- 0.025 mmol/l after treatment (P < 0.0001, paired Wilcoxon test). The mean serum calcium value corrected for albumin was 2.33 +/- 0.02 mmol/l before treatment and 2.24 +/- 0.02 mmol/l after treatment (P = 0.0022, paired Wilcoxon test). Group 2 patients also displayed a decrease in serum calcium after treatment with suramin. The mean baseline value was 2.23 mmol/l (median 2.26 mmol/l, range 1.20-2.54 mmol/l). The mean level of serum calcium corrected for albumin as determined at the end of treatment was 2.14 mmol/l (median 2.16 mmol/l, range 0.98 2.46 mmol/l). In all, 48 patients for whom pre- and post-treatment values were available for analysis displayed a median calcium decrease of 0.09 mmol/l (P = 0.0005, Wilcoxon signed-rank test for the null hypothesis of no change). For 68 patients in group 2, data on serial serum calcium measurements during treatment were available for analysis. A projected median decrease in serum calcium of 0.06 mmol/l (range 0.43 to 0.72 mmol/l) over an 8-week interval of suramin therapy was found. Overall, 47 of the 68 slopes were negative (P = 0.0022, Wilcoxon signed-rank test). Nine patients were treated with suramin for less than 6 weeks. These patients' calcium levels were significantly higher than those of 50 patients treated for longer periods (median value 2.24 versus 2.16 mmol/l, P = 0.035, Wilcoxon rank-sum test). No correlation was found between suramin dose and calcium level using the Kodak Ektachem, Hitachi 914, or Synchron Clinical System CX3 method. In conclusion, suramin treatment was consistently associated with decreases in serum calcium in two groups of patie

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Calcium; Drug Administration Schedule; Drug Resistance; Hormones; Humans; Hydrocortisone; Leuprolide; Male; Pilot Projects; Prostatic Neoplasms; Retreatment; Retrospective Studies; Suramin

Topics: Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Humans; Leuprolide; Male; Preoperative Care; Prostatectomy; Prostatic Neoplasms; Survival Rate

Topics: Aged; Antineoplastic Agents, Hormonal; Flutamide; Humans; Leuprolide; Lung Diseases, Interstitial; Male; Prostatic Neoplasms

We investigated modulation of cell growth and prostate-specific antigen (PSA) gene expression in prostatic cancer cells by the luteinizing hormone-releasing hormone analog (LH-RHa), leuprorelin acetate, alone or combined with other agents.. The effect of the analog on proliferation of both androgen-sensitive and -insensitive prostate cancer cells, maintained in different culture conditions, was evaluated by cell counts at various intervals of time. Basal expression of PSA gene and its variations were determined by a reverse transcriptase-polymerase chain reaction assay.. LH-RHa is ineffective in regulating cell growth, when used alone in both hormone-sensitive and -insensitive cell lines. Nevertheless, it counteracts the stimulatory action of androgens on proliferation of LNCaP cells, which respond to low concentrations of dihydrotestosterone. Moreover, LH-RHa has an inhibitory effect on the mitogenic action of epidermal growth factor (EGF) in androgen-unresponsive PC-3 cells. The analog reduces PSA gene expression in both hormone-sensitive and -insensitive cells. Interestingly, it counteracts the gene expression induced by androgens in LNCaP cells and by EGF in PC-3 cells.. These data show that LH-RHa may behave like a negative growth factor, which directly regulates cell growth and PSA gene expression. Moreover, our findings support the idea that growth factors may interfere with the androgen signalling pathway.

Topics: Antineoplastic Agents, Hormonal; Cell Division; Culture Media; Dihydrotestosterone; Epidermal Growth Factor; Gene Expression Regulation; Humans; Leuprolide; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured

To determine the efficacy, safety and feasibility of intermittent androgen deprivation (IAD) in patients with prostate-specific antigen (PSA) relapse after radical prostatectomy or with an incidental prostate cancer (pT1B) after transurethral resection of the prostate (TURP).. Open, nonrandomized, prospective pilot study using the luteinizing hormone-releasing hormone analogue (LH-RHa), leuprorelin acetate (1-month depot) and cyproterone acetate.. Forty-four patients have been enrolled. After a 30-64 months' follow-up no progression to androgen-independent status has been observed. Of the entire observation period, 26.6 months (44-58%) remained treatment-free. During the treatment-free periods, normal testosterone levels were obtained, resulting in a cessation of the symptoms of androgen suppression and an improvement in quality of life.. These results indicate that IAD is an effective and feasible therapy in patients with early stages of prostate cancer. Larger trials are necessary to confirm these encouraging results. Therefore, a European prospective, randomized, multicenter study (RELAPSE study) has been started to compare IAD with continuous androgen blockade in terms of time to tumor progression, safety and quality of life in patients with PSA relapse after radical prostatectomy.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Cyproterone; Drug Administration Schedule; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Pilot Projects; Prospective Studies; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Testosterone

Luteinizing hormone-releasing hormone (LHRH) agonists have been widely used as effective agents in endocrine therapy for prostate cancer. Continuous administration of the drug results in profound suppression of testicular androgen production. However, the side effects on erectile function have not been fully investigated.. We studied the influences of testosterone suppression on male sexual function and nocturnal penile tumescence in nine sexually active patients with prostate cancer who were treated with an LHRH agonist.. Following reduction of serum testosterone concentrations to a castration level by the administration of the LHRH agonist, sexual desire, sexual interest and sexual intercourse were totally annulled, with significant changes in frequency, magnitude, duration and rigidity of nocturnal erections observed in all patients.. These results demonstrate that the LHRH agonist strongly suppresses erectile function and sexual activity. Taking into account the quality of sexual function for relatively young and sexually active patients and their partners, it is necessary to establish effective modalities that minimize the adverse effects on sexual function for the treatment of patients with prostate cancer.

Topics: Aged; Antineoplastic Agents, Hormonal; Circadian Rhythm; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Penile Erection; Prolactin; Prostatic Neoplasms; Radioimmunoassay; Retrospective Studies; Sexual Dysfunction, Physiological; Sexuality; Testosterone; Treatment Outcome

The indolocarbazole analogue CEP-751 is a potent and selective tyrosine kinase inhibitor of the neurotrophin-specific trk receptors that has demonstrated antitumor activity in nine different models of prostate cancer growth in vivo. In the slow-growing, androgen-sensitive Dunning H prostate cancers, which express trk receptors, CEP-751 induced transient regressions independent of effects on cell cycle. Because androgen ablation is the most commonly used treatment for prostate cancer, we examined whether the combination treatment of CEP-751 with castration would lead to better antitumor efficacy than either treatment alone. For a 60-day period, H tumor-bearing rats received treatment with either castration, CEP-751 (10 mg/kg once a day s.c. for 5 days every 2 weeks), a combination of both, or vehicle. Castration caused tumor regression, followed by tumor regrowth in 4-6 weeks, whereas intermittent CEP-751 treatments resulted in tumor regressions during each treatment, which were followed by a period of regrowth between intermittent drug treatment cycles. Overall, both monotherapies significantly inhibited tumor growth compared with the vehicle-treated control group. However, the combination of castration and concomitant CEP-751 produced the most dramatic results: sigificantly greater tumor regression than either therapy alone, with no signs of regrowth. A related experiment using an orally administered CEP-751 analogue (CEP-701), as the trk inhibitor, and a gonadotrophin-releasing hormone agonist, Leuprolide, to induce androgen ablation demonstrated similar results, indicating that these effects could be generalized to other forms of androgen ablation and other trk inhibitors within this class. In addition, when CEP-701 was given sequentially to rats bearing H tumors, which were progressing in the presence of continuous androgen ablation induced by Leuprolide, regression of the androgen-independent tumors occurred. In summary, these data demonstrate that CEP-751 or CEP-701, when combined with surgically or chemically induced androgen ablation, offer better antitumor efficacy than either monotherapy and suggest that each therapy produces prostate cancer cell death through complementary mechanisms.

Topics: Adenocarcinoma; Administration, Oral; Androgens; Animals; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Carbazoles; Combined Modality Therapy; Drug Screening Assays, Antitumor; Drug Synergism; Furans; Indoles; Injections, Subcutaneous; Leuprolide; Male; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Proto-Oncogene Proteins; Rats; Receptor Protein-Tyrosine Kinases; Receptor, trkA; Receptors, Nerve Growth Factor

Topics: Antineoplastic Agents, Hormonal; Drug Administration Schedule; Goserelin; Humans; Leuprolide; Male; Neoadjuvant Therapy; Prostatic Neoplasms; Testosterone; Time Factors

Topics: Antineoplastic Agents, Hormonal; Drug Administration Schedule; Goserelin; Humans; Leuprolide; Male; Neoadjuvant Therapy; Prostatic Neoplasms; Testosterone; Time Factors

To determine the change in volume of the prostate as a result of neoadjuvant androgen deprivation prior to prostate implant and in the early postimplant period following transperineal ultrasound guided palladium-103 brachytherapy for early-stage prostate cancer.. Sixty-nine men received 3 to 6 months of androgen deprivation therapy followed by treatment planning ultrasound followed 4 to 8 weeks later by palladium-103 implant of the prostate. All patients had clinical and radiographic stage T1c-T2b adenocarcinoma of the prostate. A second ultrasound study was carried out 11 to 13 days following the implant to determine the change in volume of the prostate as a result of the implant. The prehormonal and preimplant volumes were compared to the postimplant volume to determine the effect of hormones and brachytherapy on prostate volume.. The median decrease in prostate volume as a result of androgen deprivation was 33% among the 54 patients with prostate volume determinations prior to hormonal therapy. The reduction in volume was greatest in the quartile of men with the largest initial gland volume (59%) and least in the quartile of men with smallest glands (10%). The median reduction in prostate volume between the treatment planning ultrasound and the follow-up study after implant was 3%, but 23 (33%) patients had an increase in prostate volume, including 16 (23%) who had an increase in volume >20%; 11 of these patients (16%) had an increase in volume >30%. The time course of development and resolution of this edema is not known. The severity of the edema was not related to initial or preimplant prostate volume or duration of hormonal therapy.. Prostate edema may significantly affect the dose delivered to the prostate following transperineal ultrasound guided brachytherapy. The effect on the actual delivered dose will be greater when shorter lived isotopes are used. It remains to be observed whether this edema will affect outcome.

Topics: Adenocarcinoma; Antineoplastic Agents, Hormonal; Brachytherapy; Combined Modality Therapy; Dose-Response Relationship, Radiation; Goserelin; Humans; Iodine Radioisotopes; Leuprolide; Male; Palladium; Prostatic Neoplasms; Radiopharmaceuticals; Ultrasonography, Interventional

We reviewed our institution's experience treating patients with prostate cancer with 3-dimensional conformal radiation therapy (3DCRT) and short-term adjuvant hormonal therapy to determine biochemical no evidence of disease (bNED) and clinical outcome compared with patients treated with 3DCRT alone. Between 4/1/89 and 11/30/94, 558 patients with clinically localized prostate cancer received treatment at Fox Chase Cancer Center (Philadelphia, Pa.); 484 patients were treated with 3DCRT alone (Group I); 74 patients were treated with 3DCRT and hormones (Group II). Five-year actuarial rates of bNED control, distant metastasis-free survival (DMFS), cause-specific survival (CSS), and overall survival (OS) were calculated for pretreatment PSA, Gleason score, T stage, use of hormones, treatment field size, age, and dose. A matched case/control analysis was performed to further evaluate the effect of hormones on treatment with 3DCRT. Median follow-up was 47 months (range: 2-97 months). The 5-year actuarial rates of bNED control, DMFS, CSS, and OS were 66%, 93%, 98%, and 86%, respectively, for Group I patients and 68%, 93%, 98%, and 89%, respectively, for Group II patients. Multivariate analysis demonstrated that hormone use was an independent predictor of bNED control only. A significant difference in bNED control was observed between Group I and II (43% vs. 71%) using the matched case/control analysis (P = 0.02). A trend towards significance was observed for different rates of DMFS between Group I and II (79% vs. 94%, P = 0.09). Patients with clinically localized prostate cancer with poor prognostic features (pretreatment PSA > or = 10 ng/ml, Gleason score > or = 7, and/or T2c or greater palpation stage) show improved rates of bNED control and a trend towards improved DMFS when treated with 3DCRT and short-term adjuvant hormones compared with 3DCRT alone. Long-term observation will be necessary to see if improvements in bNED control will translate into improvements in overall survival.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Disease-Free Survival; Follow-Up Studies; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Radiotherapy, Conformal; Retrospective Studies; Survival Rate; Treatment Outcome

Elevated serum chromogranin A (CgA) levels have been detected in patients with prostate cancer who have developed resistance to hormonal therapy. We would like to reexamine these cases by using serial specimens to determine whether such elevated levels are also detectable in prostate cancer patients not undergoing hormonal therapy. Serum CgA was measured in both random and serial specimens from prostate cancer patients with and without undergoing hormonal therapy. We found that serum CgA levels became elevated much earlier than did the levels of serum PSA in approximately one-third of prostate cancer patients developing resistance to hormonal therapy. On the other hand, serum CgA levels became elevated at later, more advanced stages of the disease in patients not undergoing hormonal therapy. Elevated serum CgA levels were usually detected in specimens containing highly elevated PSA. The early rise of serum CgA levels provides an early signal allowing a change of therapy to be made before the disease progresses to a fatal stage. Drugs targeting neuroendocrine cells should be considered for prostate cancer patients with elevated serum CgA levels.

Topics: Antineoplastic Agents, Hormonal; Chromogranin A; Chromogranins; Flutamide; Humans; Immunoenzyme Techniques; Leuprolide; Male; Prostate-Specific Antigen; Prostatic Neoplasms

The objective of this study was to elucidate the mechanism underlying the further suppression of serum testosterone (T) by diethylstilbestrol diphosphate (DES-DP) in patients with prostate cancer refractory to hormonal treatment. These patients received an LHRH agonist with or without a non-steroidal androgen-receptor blocker or a gestagen before DES-DP. We measured serum levels of total and free T, dihydrotestosterone (DHT), estradiol (E2), dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione, cortisol, aldosterone before and during intravenous administration of high doses of DES-DP (500 or 1000 mg/day). DES-DP administration suppressed the serum levels of FSH (p=0.04) and total T (p=0.02), and eliminated free T (p=0.04) and E2 (p=0.04) from serum, while reducing serum DHEA-S to approximately two-thirds of the pretreatment level (p=0.03). In contrast, serum levels of SHBG (p=0.02) and cortisol (p=0.02) were markedly increased after DES-DP administration. The latter had no significant effect on serum levels of LH, DHT, ACTH, 17alpha-hydroxypregnenolone, 17alpha-hydroxyprogesterone, DHEA, androstenedione, or aldosterone. The results suggest that the potent suppression of circulating total T by DES-DP is caused, in part, by the inhibitory effect of DES-DP on serum DHEA-S level. In most patients, high-dose DES-DP treatment completely suppressed the serum level of free T, while possibly elevating serum SHBG and decreasing serum total T. The mechanisms that maintain the serum level of serum DHT during DES-DP treatment require further elucidation.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents; Chlormadinone Acetate; Dehydroepiandrosterone Sulfate; Diethylstilbestrol; Drug Resistance, Neoplasm; Estradiol; Follicle Stimulating Hormone; Goserelin; Hormones; Humans; Hydrocortisone; Leuprolide; Male; Middle Aged; Progesterone Congeners; Prostatic Neoplasms; Sex Hormone-Binding Globulin; Testosterone

Topics: Clinical Trials as Topic; Drug Implants; Endometriosis; Female; Humans; Leuprolide; Male; Prostatic Neoplasms

To study the pathological changes of the effect of combined endocrine therapy on normal prostate, benign prostatic hyperplasia, prostatic adenocarcinoma and testis.. 11 radical prostatectomy specimens, 3 core-needle biopsies of prostate and 3 testes obtained after at least 3 months of enatone-flutamide inhibition therapy were studied. Step-section was performed on radical specimens and average 16 sections per case were reviewed. PSA, PSAP and AE1/AE3 were immunostained on 14 cases of prostate cancer and a comparative study pre- and post-treatment was made.. No residual tumor was recognized in 2 cases. Such characteristic changes were found in 9 cases as prominent acinar atrophy, decreased ratio of acini to stroma, stromal fibrosis, squamous metaplasia of carcinoma, cytoplasmic vaculation, nuclear shrinkage, and nucleolar shrinkage. No apparent change was discovered in 3 cases. Secretory epithelial atrophy and basal cell hyperplasia were the popular change in BPH and normal prostate. The expressions of both PSA and PSAP were markedly reduced in prostate carcinoma and nonneoplastic glands. Pathological downstaging of the tumor was not found statistically. Epithelial atrophy also existed in seminal vesicles and Leydig cells of the testes after hormone therapy.. Combined endocrine therapy results in histologically distinctive changes that can be found in both nonneoplastic and neoplastic prostate tissue. However, the drugs can not eradicate prostate cancer completely. Testis atrophy is the direct action of the therapy.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Atrophy; Drug Therapy, Combination; Flutamide; Humans; Leuprolide; Male; Middle Aged; Prostate; Prostatic Neoplasms; Testis

To assess the feasibility of intermittent hormone therapy for metastatic prostate cancer.. Sixteen patients with metastatic carcinoma of the prostate were treated using a protocol of intermittent hormone therapy with the luteinizing hormone-releasing hormone (LHRH) analogue leuprorelin at a dose of 3.75 mg every 4 weeks. The protocol required that hormone therapy be stopped when the response was stable, and was designed to assess the duration of the unmaintained response and the probability of a second response to re-initiation of leuprorelin.. Eleven of the 16 patients had a stable hormone response and stopped therapy 3-9 months (mean 5.5) from the start of treatment. The mean (range) duration of the unmaintained response, as judged by monitoring symptoms and serum prostate specific antigen (PSA) levels every month was 4 (2-8) months in the seven patients who had bone metastases and was 3, 3 and 6 months in the three with only loco-regional disease (one patient temporarily discontinued follow-up). As the immediate re-induction of hormone therapy was not mandatory in asymptomatic patients at the time of progression, the mean (range) period off hormone therapy was 8 (3-13) months in those eight patients with bone metastases and was 3, 36 and 42 + months in the three presenting with loco-regional disease. All 10 patients who re-initiated hormone therapy had a second hormone response, in six of which led to a decline in PSA level to < 2 ng/mL. During the period off hormone therapy no patient developed irreversible symptoms.. The temporary cessation of hormone therapy early during the response in patients with metastatic carcinoma of prostate is associated with biochemical evidence of relatively early progression in most cases, but can be associated with significant periods off therapy and with a high chance of a second hormone response. The value of this approach to the quality and duration of patients' lives requires a prospective comparative evaluation.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cyproterone Acetate; Feasibility Studies; Follow-Up Studies; Humans; Leuprolide; Male; Pilot Projects; Prostate-Specific Antigen; Prostatic Neoplasms

The objective of this study is to determine whether in a dialysis patient with prostate cancer leuprorelin acetate blood levels were abnormally high or low due to kidney failure or because of dialysis.. Sustained-release leuprorelin acetate 3.75 mg was given every 4 weeks for prostate cancer in a 79-year-old dialysis patient. Changes in serum level of leuprorelin acetate in this patient were measured before and after dialysis.. Leuprorelin acetate appeared to have a dialysance close to that of vitamin B12, which has a similar molecular weight. The amount dialyzed did not exceed 8.3% of the amount released per day. Mean blood levels of leuprorelin acetate, as measured in this patient, were higher (0.64 to 1.31 ng/ml) than those in prostate cancer patients with normal kidney function (mean +/- SD, 0.24 +/- 0.12 to 0.50 +/- 0.32 ng/ml).. Sustained-release leuprorelin acetate can be used safely in dialysis patients with prostate cancer.

Topics: Aged; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Prostatic Neoplasms; Renal Dialysis; Renal Insufficiency

Neoadjuvant combination endocrine therapy that uses leuprolide and flutamide may result in various histologic changes in nontumoral and cancerous prostatic tissues. Posttreatment pseudomyxoma ovariilike change in prostatic adenocarcinoma is a distinctive alteration that may be the only evidence of regressed tumor and can be potentially confused with mucinous carcinoma. We studied 53 clinically localized prostatic adenocarcinomas after 3 to 5 months of treatment with leuprolide and flutamide. Alterations in prostatic adenocarcinoma in posttreatment radical prostatectomy specimens were assessed and compared with pretreatment needle biopsies. All radical prostatectomy specimens exhibited previously well-characterized therapy-associated changes in benign and malignant elements. Thirteen (20%) cases exhibited a distinctive alteration not seen in pretreatment needle biopsies that consisted of minute to large pools of extravasated secretions that resembled pseudomyxoma ovarii and that dissected through prostatic stroma with an infiltrative appearance when viewed at low power. Associated recognizable tumor was present in 10 of 13 (77%) of these cases. Secretions were basophilic in routine sections and contained occasional degenerated cells. Rare pancytokeratin positive cells were seen at the secretion/stroma interface with uniformly negative staining for the high molecular weight keratin 34 beta E-12. The secretions were periodic acid-Schiff positive after diastase digestion and were mucicarminophilic and reactive with Alcian blue at a pH of 2.5. These foci comprised < 5% of the tumor in 5 cases and 5-40% in 5 cases. In 3 cases, 1-2 foci < 1.0 mm exhibited the pseudomyxoma ovariilike changes and were the only evidence of treated tumor. There was no correlation between the presence of pseudomyxomalike change and dose/duration of neoadjuvant therapy, postprostatectomy clinical follow-up, original or final Gleason pattern/score, or pathologic stage. Pseudomyxoma ovariilike change consists of extravasated acid mucin, lacks prostatic basal cells, often occurs in intimate association with residual prostatic adenocarcinoma in posttreatment radical prostatectomy specimens, and probably represents tumor regression as a result of tumor cell attrition secondary to androgen ablation.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Female; Flutamide; Humans; Leuprolide; Male; Middle Aged; Myxoma; Ovary; Prostate; Prostatic Neoplasms

Combined androgen blockade using a pure antiandrogen in association with a LHRH agonist or surgical castration is the most logical approach. This paper demonstrated that flutamide combined with leuprorelin acetate produced a significant reduction in the growth rate of Dunning R3327-H prostatic adenocarcinoma. Dunning R3327-H prostatic adenocarcinoma, provided by Dr. Norman H. Altmann (University of Miami, USA) was subcutaneously inoculated into the lateral region of male Copenhagen x Fischer F1 hybrid rat abdomen. The efficacy of the tumor growth rate was evaluated by measuring tumor size at 10 weeks after the inoculation. Flutamide was orally administered for 10 weeks and leuprorelin acetate was subcutaneously administered every 4 weeks. The effective dose of flutamide and leuprorelin acetate was determined in preliminary studies, and the following doses were used in the study; 15 mg/kg for flutamide, 0.1 mg/kg or 0.4 mg/kg for leuprorelin acetate. In combination of flutamide with leuprorelin acetate at 0.1 mg/kg and 0.4 mg/kg, the tumor inhibition was 94% and 97%, respectively. In addition, the weight of accessory sex organs coincided with the antitumor effect. Taking the above results into consideration, combined androgen blockade using flutamide and leuprorelin acetate may have some beneficial effect on prostatic cancer.

Topics: Adenocarcinoma; Androgen Antagonists; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Drug Administration Schedule; Flutamide; Leuprolide; Male; Organ Size; Prostatic Neoplasms; Rats

Radical prostatovesiculectomy, radiation therapy, and complete androgen deprivation are acknowledged therapeutic concepts in the treatment of organ-confined prostate cancer. With cryoablation of the prostate, minimal invasive therapy has become available since 1991. Improvements in cryotechnique and progress in transrectal high-resolution ultrasound permit thermo-induced damage to the whole gland to be curative. Downstaging of prostate cancer by hormone ablative therapy remains a controversial issue at this time, but the use of androgen ablation decreases the size of the prostate gland which facilitates cryosurgery and improves the results. The freezing equipment has a limited capacity, and in certain instances large gland volumes prevent adequate freezing of the prostate. Since percutaneous prostate cryosurgery leaves dead tissue in situ to be resorbed over time, downsizing reduces the amount of necrotic tissue to be resorbed, reducing the potential for complications, particularly abscesses. The use of androgen ablation also increases the deposition of fat in the area of the Denonvillier's fascia, making freezing of the rectum less likely during the procedure. In our study androgen ablative therapy was completed before performing cryosurgery in 26 of 43 patients (58%). The 17 patients not given androgen ablation therapy had gland volumes < 40 ml, tumor volumes < 3 ml, and no evidence of extracapsular tumor. The neoadjuvant therapy consisted of a 3- to 10-month course of leuprolide acetate combined with an antiandrogen.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Cryosurgery; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Humans; Imidazoles; Imidazolidines; Leuprolide; Lung Diseases, Interstitial; Male; Prostatic Neoplasms

To assess the effectiveness of palladium 103 (Pd-103) brachytherapy in Stage T1 and T2 adenocarcinoma of the prostate.. Charts of 474 patients treated between 1991 and 1996 with transperineal real-time ultrasound-guided Pd-103 implants were reviewed to assess post-treatment prostate-specific antigen (PSA) levels and follow-up biopsy results. Of 474 patients, 434 had sufficient data for this report. The implant technique used allows precise placement of seeds and accurate dose delivery of the entire prostate. Preoperative neoadjuvant leuprolide (Lupron) and flutamide (Eulexin) were given selectively to reduce prostate size greater than 50 cc and for Gleason grade lesions greater than 7.. Of 434 patients, successful cancer control was demonstrated in 81% of patients by a decrease in PSA levels to less than 1.5 ng/mL at 1 year. Biopsies were negative in 88% of patients 1 year after the procedure and in 89% at 2 years. Analysis of the data suggests that patients with pretreatment PSA levels less than 10 ng/mL had the best outcomes. There were no disease-related deaths; the predominant morbidity was short-term bladder and bowel irritation without permanent sequelae. Incontinence occurred in less than 5% of patients who had undergone prior transurethral resection of the prostate. Impotence occurred in less than 15% of patients.. The technique used in this study proved effective in reducing PSA levels to less than 1.5 ng/mL and in producing negative biopsies 1 and 2 years postoperatively. Results are comparable to external-beam radiation therapy, demonstrating a significant reduction in morbidity.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Ambulatory Care; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Brachytherapy; Chemotherapy, Adjuvant; Flutamide; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Palladium; Prostate-Specific Antigen; Prostatic Neoplasms; Radiation Injuries; Radioisotopes; Radiopharmaceuticals; Radiotherapy Dosage; Retrospective Studies; Treatment Outcome; Ultrasonography, Interventional

The application of modern technology in basic research often requires fresh tissue from human organs. The acquisition of this tissue challenges the anatomic pathologist to balance the needs of the basic scientist with the requirements of quality patient care. Our experience indicates that fresh tissue adequate for research can be obtained from neoplastic prostate glands without compromising patient care. The process requires dedicated, knowledgeable individuals and extensive documentation. Potential problems include low yield for research studies, loss of all residual carcinoma, compromise of the specimen margin, and unforeseen costs. Best collaborations occur in situations in which basic scientists and anatomic pathologists establish a working relationship and develop a mutually supportive means of funding.

Topics: Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Patient Care; Prostatectomy; Prostatic Neoplasms; Research Design; RNA, Neoplasm; Specimen Handling

Topics: Adenocarcinoma; Adenoma; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Humans; Hypophysectomy; Leuprolide; Luteinizing Hormone; Male; Neoplasms, Multiple Primary; Pituitary Neoplasms; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Treatment Failure

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Glucocorticoids; Hemoglobins; Humans; Leuprolide; Male; Orchiectomy; Prednisone; Prostatic Neoplasms; Red-Cell Aplasia, Pure; Reticulocyte Count

We sought to determine the prevalence of hot flushes after neoadjuvant hormonal therapy.. Forty-three patients who received neoadjuvant hormonal therapy before radical prostatectomy were asked to complete a questionnaire regarding hot flushes.. Complete information was available for 35 of the 43 patients. No hot flushes were noted in 20%; in 69%, hot flushes were noted during treatment but resolved after termination of treatment; and in 11%, hot flushes continued for at least 3 months after cessation of hormonal therapy. Analyzing the data with respect to duration of hormonal therapy showed that patients receiving neoadjuvant hormonal therapy for more than 4 months had the highest incidence of persistent hot flushes.. Hot flushes will be noted in 80% of patients who receive neoadjuvant hormonal therapy. In approximately 10%, hot flushes will continue for a significant period after hormonal therapy is terminated. Patients should be apprised of this potential side effect.

Topics: Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Flutamide; Hot Flashes; Humans; Leuprolide; Male; Prostatectomy; Prostatic Neoplasms; Surveys and Questionnaires

To identify prognostic variables that predict for improved biochemical and local control outcome in patients with localized prostatic cancer treated with neoadjuvant androgen deprivation (NAAD) and three-dimensional conformal radiotherapy (3D-CRT).. Between 1989 and 1995, 213 patients with localized prostate cancer were treated with a 3-month course of NAAD that consisted of leuprolide acetate and flutamide before 3D-CRT. The purpose of NAAD in these patients was to reduce the preradiotherapy target volume so as to decrease the dose delivered to adjacent normal tissues and thereby minimize the risk of morbidity from high-dose radiotherapy. The median pretreatment prostate-specific antigen (PSA) level was 15.3 ng/mL (range, 1 to 560 ng/mL). The median 3D-CRT dose was 75.6 Gy (range, 64.8 to 81 Gy), and the median follow-up time was 3 years (range, 1 to 7 years).. The significant predictors for improved outcome as identified in a multivariate analysis included pretreatment PSA level < or = 10.0 ng/mL(P < .00), NAAD-induced preradiotherapy PSA nadir < or = 0.5 ng/mL (P < .001), and clinical stage < or = T2c (P < .04). The 5-year PSA relapse-free survival rates were 93%, 60%, and 40% for patients with pretreatment PSA levels < or = 10 ng/mL, 10 to 20 ng/mL, and greater than 20 ng/mL, respectively (P < .001). Patients with preradiotherapy nadir levels < or = 0.5 ng/mL after 3 months of NAAD experienced a 5-year PSA relapse-free survival rate of 74%, as compared with 40% for patients with higher nadir levels (P < .001). The incidence of a positive biopsy among 34 patients pretreated with androgen ablation was 12%, as compared with 39% for 117 patients treated with 3D-CRT alone who underwent a biopsy (P < .001).. For patients treated with NAAD and high-dose 3D-CRT, pretreatment PSA, preradiotherapy PSA nadir response, and clinical stage are important predictors of biochemical outcome. Patients with NAAD-induced PSA nadir levels greater than 0.5 ng/mL before radiotherapy are more likely to develop biochemical failure and may benefit from more aggressive therapies.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Flutamide; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy, Computer-Assisted; Retrospective Studies; Treatment Outcome

We objectively compare the costs associated with the medical and surgical treatment of metastatic prostate cancer.. We analyzed and compared itemized billing statements for 28 men with metastatic adenocarcinoma of the prostate. Half of the men were treated medically with the luteinizing hormone-releasing hormone analogue leuprolide, while the other half underwent bilateral therapeutic orchiectomy. In addition, differences in hospital cost to treat these men were calculated.. During a mean followup of 24 months leuprolide treated patients were charged $500.00 per month of treatment compared to average monthly expenditure of $226.00 for orchiectomy patients during a 23-month interval. By 9 months charges incurred by both groups were equal and by 20 months medically treated patients accumulated urological charges twice that of the surgically treated patients. The true hospital cost to treat these patients followed the same trend, that is the medically treated group cost twice as much to treat by 15 months. For the average stage D2 case leuprolide therapy charges were $9,420, or 63%, more than orchiectomy. Similarly, leuprolide cost the hospital $8,924 more than surgery.. Medical management of metastatic prostate cancer is expensive. With broadening applications and androgen deprivation being initiated earlier in the course of disease, the amount spent on medical therapy will continue to escalate. For patients with a life expectancy of more than 9 months orchiectomy is the most cost-effective treatment option.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Costs and Cost Analysis; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Orchiectomy; Prostatic Neoplasms

It is well known that androgens play an important role in bone metabolism and male hypogonadism induce osteoporosis. Luteinizing hormone-releasing hormone analogue (LHRH-a) which is essential for conservative therapy of prostatic carcinoma (CaP) ultimately reduces circulating testosterone to castration levels. The purpose of this study was to determine the risk of decrease of bone mineral density in men receiving LHRH-a for CaP.. Fifty-three man with CaP aged 63 to 95 years (mean 75.5 years) were included in this study. Seven patients received LHRH-a with estrogen drug, forty-six patients received LHRH-a with or without anti androgen drug. To estimate patient's bone density we use the second metacarpal bone density using a microdensitometry method.. Blood level of sex hormone of the forty-six patients who were received LHRH-a without estrogen, was the same as that of castration. Patients who were treated more than twelve months had less bone density than patients who were treated less than eleven months. As the duration of medical castration period was prolonged, patients bone density were reduced. Whereas seven patients who received estrogen drug did not find a decrease of bone density regardless of duration of treatment period.. Hypogonadism induced LHRH-a also reduce bone density, so there is a risk of iatrogenic osteoporosis caused by therapy for CaP with LHRH-a. Patients with osteoporosis easily suffer from a much complicated and pernicious bone fracture, so we should measure bone density of male patients same as female treated with LHRH-a for a long-term.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Bone Density; Estrogens; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Osteoporosis; Prostatic Neoplasms; Risk

Serum concentrations of luteinizing hormone (LH), testosterone, prostatic acid phosphatase (PAP) and prostatic specific antigen (PSA) were measured in 16 patients with advanced prostatic cancer before and after treatment with luteinizing hormone-releasing hormone (LHRH) analogue. An initial rise of serum LH and testosterone levels was observed on day 2 of the treatment. Subsequently, serum concentrations of PAP and PSA showed a transient increase on day 5 of the treatment. This indicates that LHRH analogues had better be given in combination with antiandrogens in patients with metastatic carcinoma of the prostate.

Topics: Acid Phosphatase; Aged; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Bone Neoplasms; Carcinoma; Follow-Up Studies; Humans; Immunoenzyme Techniques; Injections, Subcutaneous; Leuprolide; Luteinizing Hormone; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Radioimmunoassay; Testosterone; Treatment Outcome

Topics: Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Marriage; Patient Education as Topic; Prostatic Neoplasms; Sexual Behavior

There has been a resurgence of interest in cryosurgical ablation of the prostate for the treatment of carcinoma. This is due to recent advances in cryosurgical technology, which have resulted in relatively lower morbidity. The objective of this study was to evaluate the effectiveness of ultrasound-guided cryosurgical ablation of prostate carcinoma.. Eighty-three patients who had biopsy-proven prostate carcinoma underwent cryosurgical ablation of their entire prostate gland. The initial group of 12 patients had their procedures performed under ultrasound guidance only. The other 71 patients had cryosurgery performed with temperature monitoring in combination with ultrasound guidance. Twelve patients who had positive biopsies underwent a second cryosurgical procedure. All patients had prostate specific antigen (PSA) levels measured at 3, 6, 12, 18, 24, and 30 months after cryosurgery. Ultrasound-guided sextant biopsies were performed at 3-6, 12-18, and 24 months.. The median PSA dropped by 95%, from a preoperative value of 4.3 ng/mL to 0.2 ng/mL 30 months after cryosurgery. The authors experienced a high failure rate (positive biopsies) of 83% for the initial group of 12 patients who did not have temperature monitoring during the cryosurgical procedure. This was in contrast to a success rate of 90% (negative biopsies) for the next 71 patients, who did have temperature monitoring (P < 0.05, chi-square test). Twelve patients underwent a second cryosurgery, and the success rate for this group was 91% (11 of 12 patients). The combined success rate for both the first cryosurgery and the second was 94% (62 of 77 patients). Complications included urethral sloughing, urinary incontinence, impotence, bladder neck contracture, and bladder contracture. The majority of patients recovered rapidly from their cryosurgical procedures and were able to resume normal activities 3-4 weeks afterward.. These preliminary results demonstrate that cryosurgical ablation of the prostate is a viable treatment option for prostate carcinoma. In the authors' experience, ultrasound alone may not be adequate for monitoring the entire cryosurgical procedure. The authors found that temperature monitoring shortened their learning curve, enabled them to freeze prostate tissue more aggressively, and may have contributed to their overall success.

Topics: Aged; Carcinoma; Cryosurgery; Erectile Dysfunction; Humans; Leuprolide; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Thermometers; Urethral Diseases; Urinary Bladder Diseases; Urinary Incontinence

Turosteride (FCE 26073) is a new, potent, and selective 5 alpha-reductase inhibitor. We have investigated its effect on tumor growth, organ weight, and serum hormone levels in rats bearing the androgen sensitive Dunning R3327 prostatic carcinoma.. Animals with tumor diameters of 0.5-1.5 cm were treated for 9 weeks with turosteride (50 and 200 mg/kg/day, 6 days a week, orally), flutamide (25 mg/kg/day, 6 days a week, orally), and leuprolide (300 micrograms/rat, every 3 weeks, subcutaneously) or they were castrated.. Turosteride was ineffective at the dose of 50 mg/kg/day, whereas at 200 mg/kg/ day it significantly decreased tumor growth by 45%. Flutamide and leuprolide were highly effective in reducing tumor growth (70 and 77%), although their effect was slightly lower than that of castration (85%). A significant reduction of ventral prostate weight occurred in rats treated with turosteride at 50 and 200 mg/kg/day (53% and 60%). In contrast to leuprolide and castration, the inhibitory effect of turosteride on tumor growth and prostate weight was not associated to any decrease in serum testosterone.. Turosteride has antitumor activity on Dunning prostatic tumor growth and its role in prostatic cancer treatment is worthy of further investigation.

Topics: 5-alpha Reductase Inhibitors; Adenocarcinoma; Androstenedione; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Dihydrotestosterone; Enzyme Inhibitors; Finasteride; Flutamide; Leuprolide; Luteinizing Hormone; Male; Organ Size; Pituitary Gland, Anterior; Prostate; Prostatic Neoplasms; Random Allocation; Rats; Seminal Vesicles; Testis; Testosterone

To assess the factors that predict late GI and GU morbidity in radiation treatment of the prostate.. Seven hundred twelve consecutive prostate cancer patients treated at this institution between 1986 and 1994 (inclusive) with conformal or conventional techniques were included in the analysis. Patients had at least 3 months follow-up and received at least 65 Gy. Late GI Grade 3 morbidity was rectal bleeding (requiring three or more procedures) or proctitis. Late Grade 3 GU morbidity was cystitis or stricture. Multivariate analysis (MVA) was used to assess factors related to the complication-free survival. The factors assessed were age, occurrence of side effects > or = Grade 2 during treatment, irradiated volume parameters (use of pelvic fields, treatment of seminal vesicles to full dose or 57 Gy, and use of additional rectal shielding), dose, comorbidities, and other treatments (hormonal manipulation, TURP).. Acute GI and GU side effects (Grade 2 or higher) were noted in 246 and 201 patients, respectively; 67 of these patients exhibited both. GI side effects were not correlated with GU side effects acutely. Late and acute morbidities were correlated (both GI and GU). Fifteen of the 712 patients expressed Grade 3 or 4 GI injuries 3 to 32 months after the end of treatment, with a mean of 14.3 months. One hundred fifteen patients expressed Grade 2 or higher GI morbidity (mean: 13.7 months). The 43 Grade 2 or higher GU morbidities occurred significantly later (mean: 22.7 months). Central axis dose was the only independent variable significantly related to the incidence of late GI morbidity on MVA. No treatment volume parameters were significant for Grade 3. The following parameters were significantly related (by MVA) to Grade 2 GI morbidity: central axis dose, use of the increased rectal shielding, androgen deprivation therapy starting before RT. Acute and late GI morbidities were highly correlated. History of diabetes, treatment of pelvic nodes, and age less than 60 years were significantly related to acute GI side effects. The parameters significantly related to late Grade 2 or higher GU morbidity were central axis dose, androgen deprivation therapy (Zoladex or Lupron) prior to radiation therapy (RT), history of obstructive symptoms, and acute GU side effects. There were too few late Grade 3 GU morbidities to perform multivariate analysis. Acute GU side effects were highly correlated with late GU injury. The following were correlated with acute GU side effects: history of diabetes (+), treatment with conformal fields (-), TURP before RT (-), presentation with urinary obstructive symptoms.. Both late GI and GU morbidity demonstrate a dose dependence, but only the volume dependence observed is a reduction in late Grade 2-4 GI morbidity by increasing the rectal shielding in the lateral fields for the final 10 Gy. Moreover, both late GI and GU morbidity was increased in patients treated with hormone manipulation prior to RT. GI and GU injuries were correlated with their corresponding acute side effects. GI and GU complications must not be combined for analysis to determine the factors related to their occurrence.

Topics: Antineoplastic Agents, Hormonal; Digestive System; Dose-Response Relationship, Radiation; Goserelin; Humans; Leuprolide; Male; Middle Aged; Morbidity; Multivariate Analysis; Prostatic Neoplasms; Radiation Injuries; Risk Factors; Time Factors; Urogenital System

Androgen deprivation therapy with analogues of luteinizing hormone-releasing hormone produces distinctive histological changes in neoplastic and nonneoplastic prostate tissue. Others have described these features in cases in which treatment status was known. To our knowledge the specificity and sensitivity of luteinizing hormone-releasing hormone effects based only on histology and possible reasons for interobserver variation have not been addressed previously.. Slides from 97 prostatectomies performed in a 3-year period were reviewed by 2 observers blinded to knowledge of previous hormonal treatment. The observers evaluated each case, recording the presence or absence of 14 features associated with androgen deprivation therapy, and then made an overall assessment regarding treatment status.. Of the 97 patients 31 had received androgen deprivation therapy with the luteinizing hormone-releasing hormone agonist leuprolide. A luteinizing hormone-releasing hormone effect was identified by the 2 observers in 26 and 28, respectively, of the 31 cases (83.9 versus 90.3% sensitivity and 92.4 versus 80.3% specificity). Including focal changes as consistent with androgen deprivation therapy increased sensitivity but decreased specificity. Of the 14 features 12 had a significant association for predicting treatment status.. Interobserver variations in interpretation occurred although both examiners were experienced in the evaluation of luteinizing hormone-releasing hormone effects and they used exactly the same criteria. These variations were apparently due to differences in the value (mental weight) given by each observer to the features assessed in each case. Predicting treatment status was optimized by noting a luteinizing hormone-releasing hormone effect only when changes were diffuse, improving specificity significantly with only a modest decrease in sensitivity.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Middle Aged; Observer Variation; Predictive Value of Tests; Prostatic Neoplasms; Sensitivity and Specificity

Combined androgen blockade (CAB) (medical or surgical castration plus antiandrogen therapy) is considered by many to be the optimal endocrine maneuver for patients with metastatic prostate carcinoma. When progression occurs after CAB, the discontinuation of the antiandrogen is recommended. The authors present a patient that had a clinical complete response to flutamide withdrawal plus hydrocortisone that, at last follow-up, had been maintained for more than 46 months.. A 71-year-old man with a positive family history of prostate carcinoma presented in 1989 with urinary frequency and a suspicious digital rectal examination. He was found to have a poorly differentiated adenocarcinoma (Gleason 4+4). He was started on CAB and his prostate specific antigen (PSA) concentration declined from 96 ng/mL to the normal range and was maintained for the next 24 months. In 1991 his PSA began to rise, and reached 64 ng/mL by 1993. The patient was enrolled on a clinical trial that discontinued the flutamide administration and hydrocortisone was initiated.. Physical examination at the time of enrollment was unremarkable. His PSA declined to below the limits of detection after this maneuver and at last follow-up had been maintained there for more than 46 months. In 1995, the patient underwent a repeat biopsy of the prostate and all six tissue cores were negative for carcinoma. At last follow-up in December 1996, the patient had no evidence of disease and was being followed routinely; however, the authors were continuing treatment with testicular suppression (leuprolide) plus hydrocortisone.. The authors believe the residual androgens and steroids produced by the adrenal cortex play a meaningful role in prostate carcinoma cell proliferation. Based on this case and data from trials supporting the activity of flutamide withdrawal plus adrenal suppression, it appears reasonable to evaluate prospectively the discontinuation of antiandrogen versus antiandrogen withdrawal plus adrenal suppression in individuals failing CAB.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Anti-Inflammatory Agents; Antineoplastic Agents, Hormonal; Biopsy; Disease Progression; Disease-Free Survival; Flutamide; Follow-Up Studies; Humans; Hydrocortisone; Leuprolide; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Remission Induction

Topics: Antineoplastic Agents, Hormonal; Humans; Leuprolide; Male; Pituitary Apoplexy; Prostatic Neoplasms

Occult dissemination of tumor cells mainly determines the prognosis of patients with primary prostate cancer. The effect of androgen deprivation on micrometastatic tumor cells in these patients is currently unknown. We therefore used an immunocytochemical assay with monoclonal antibodies (MAbs) directed against epithelial cytoskeleton proteins (i.e., cytokeratins) to monitor the concentration of isolated tumor cells in the bone marrow of 36 prostate cancer patients (stage C), who underwent hormonal androgen deprivation with Flutamide and Leuprorelin acetate. Tumor cells in cytologic bone marrow preparations were detected using an assay that employed the MAb CK2 directed against cytokeratin (CK) 18 and the alkaline anti-alkaline phosphatase staining method. Prior to therapy, we detected between 1 and 38 CK-positive cells per sample of 2 x 10(6) nucleated cells in 21 patients, while the remaining 15 patients displayed tumor-free marrow samples. There was no significant correlation between the concentration of CK-positive cells and the volume of hypo-echogenic lesions as an indicator of the primary tumor volume or the serum level of prostate-specific antigen (PSA). After androgen deprivation, 20 of the 21 initially positive patients either became negative (n = 16) or showed at least a reduction in the concentration of CK-positive cells (n = 4). Moreover, only 2 of the 15 patients with negative pre-treatment findings became positive. All of the 7 patients with remaining tumor cells in the bone marrow after therapy showed no detectable amounts of PSA in their serum. Our findings suggest that serum PSA concentration is no indicator of micrometastatic disease in bone marrow. Neoadjuvant androgen deprivation appears to eliminate disseminated CK-positive tumor cells present in bone marrow, a preferred site of overt metastasis in prostate cancer patients.

Topics: Adenocarcinoma; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Neoplasms; Chemotherapy, Adjuvant; Combined Modality Therapy; Disease-Free Survival; Flutamide; Follow-Up Studies; Humans; Keratins; Leuprolide; Male; Neoplasm Proteins; Prognosis; Prostatectomy; Prostatic Neoplasms; Treatment Outcome; Ultrasonography

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Flutamide; Hemoglobins; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Renal Dialysis

Apoptosis in prostate cancer was evaluated after three months of combined endocrine therapy to investigate the association with tumour grade, tumour stage, and the immunohistochemical detection of p53 and bcl-2 in tumour cells before and after therapy.. Twenty six formalin fixed, paraffin wax embedded core biopsies and corresponding prostatectomy specimens, excised after three months of combined endocrine therapy, were analysed for the presence of apoptotic cells by the terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labelling (TUNEL) method, and for p53 and bcl-2 overexpression by immunohistochemistry.. All 26 adenocarcinomas were clinically localised at diagnosis. In biopsies performed before combined endocrine therapy, the apoptotic indices varied between 0.09% and 1.73%, while the tumour grade fell between Gleason score 1 and 8. The mean (SD) apoptotic count pretherapy was 0.71% (0.50). There was a significant association between elevated apoptotic counts and higher Gleason scores in the biopsies (p = 0.005). After three months of therapy, the percentage of apoptotic tumour cells increased independently of tumour stage, while a significant association with Gleason grade was found (p = 0.0018) and all the tumours had Gleason scores of < 7. In eight cases the apoptotic index was more than twice its pretherapy value. The remaining tumours showed less of an increase in the apoptotic index (five cases) or a reduction in the percentage of apoptotic cells. The overall moderate increase in apoptotic index after combined endocrine therapy was not statistically significant (p = 0.8). Immunoreactivity to p53 was absent in all cases, before and after therapy, while a slight increase in the number of cells overexpressing bcl-2 was observed in five of the 13 tumours (38.1%) with reduced apoptotic indices after therapy.. After three months of combined endocrine treatment a minority of clinically localised prostate neoplasms showed regressive epithelial alterations, associated with an increase in apoptotic tumour cells; an increase in cells overexpressing bcl-2 was observed in five of the 13 tumours with reduced apoptotic indices.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Flutamide; Humans; Immunoenzyme Techniques; In Situ Hybridization; Leuprolide; Male; Middle Aged; Neoplasm Proteins; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2

An 81-year-old man on chronic hemodialysis was referred to our hospital with urinary difficulty. Transperineal needle biopsy of a hard nodule in the prostate revealed moderately differentiated adenocarcinoma. He was diagnosed to have stage C prostate cancer. A standard dose of luteinizing hormone-releasing hormone (LH-RH) analogue, leuprorelin acetate (3.75 mg), was administered every 4 weeks for 15 months. No adverse effects were observed throughout the period. The clinical response to LH-RH analogue was excellent, with normalization of serum prostate-specific antigen level and relief of dysuria. Thus the standard dosage of LH-RH analogue is considered to be adequate for hemodialysis patients.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Diabetic Nephropathies; Humans; Leuprolide; Luteinizing Hormone; Male; Prostatic Neoplasms; Renal Dialysis; Testosterone

Suramin has demonstrated modest activity against prostate cancer and is being investigated in clinical trials. We describe a patient with metastatic prostate cancer who developed nonoliguric renal failure during treatment with suramin. Other potential causes of renal failure were not present in our patient and his renal function gradually recovered with the cessation of suramin treatment. Acute renal failure should be recognized as a potential complication of suramin treatment.

Topics: Acute Kidney Injury; Adenocarcinoma; Androgen Antagonists; Anti-Inflammatory Agents; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Flutamide; Humans; Hydrocortisone; Leuprolide; Lumbar Vertebrae; Male; Middle Aged; Prostatic Neoplasms; Sacrum; Spinal Neoplasms; Suramin; Thoracic Vertebrae

Metastatic involvement of the pituitary gland is a very unusual presentation of prostatic cancer. We report a favorable response to medical treatment in such a patient.. A 77-year-old man presented with blindness, ophthalmoplegia in his left eye, and mild impairment of memory and mental status. Neuroradiological studies showed a huge intra- and suprasellar lesion that destroyed the sellar floor and extended into the sphenoid sinus. Transsphenoidal biopsy of the lesion demonstrated a prostatic adenocarcinoma. Postoperative studies revealed an enlarged prostate gland and multiple lytic bone lesions. The patient was treated with a combination of leuprolide acetate plus flutamide. Four months later, the patient exhibited a marked improvement in his neurologic status and regained vision in the right eye (visual acuity 6/20). Repeat magnetic resonance imaging of the sellar region confirmed a striking shrinkage of the prostatic metastasis. The clinical status remained stable for 22 months, after which time the disease progressed and the patient died 25 months after beginning treatment.. A favorable response to combined androgen blockade suggests that medical therapy should be considered the therapy of first choice when surgical removal of the metastatic lesion in the pituitary is impossible or too risky.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Bone Neoplasms; Diagnosis, Differential; Flutamide; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Neoplasm Metastasis; Pituitary Neoplasms; Prostatic Neoplasms; Time Factors

Cooperative groups have investigated the outcome of androgen deprivation therapy combined with radiation therapy in prostate cancer patients with variable pretreatment prognostic indicators. This report describes an objective means of selecting patients for adjuvant hormonal therapy by a retrospective matched case/control comparison of outcome between patients with specific pretreatment characteristics who receive adjuvant hormones (RT+H) vs. patients with identical pretreatment characteristics treated with radiation therapy alone (RT). In addition, this report shows the 5-year bNED control for patients selected by this method for RT+H vs. RT alone.. From 10/88 to 12/93, 517 T1-T3 NXM0 patients with known pretreatment PSA level were treated at Fox Chase Cancer Center. Four hundred fifty-nine of those patients were treated with RT alone while 58 were treated with RT+H. The patients were categorized according to putative prognostic factors indicative of bNED control, which include the palpation stage, Gleason score, and pretreatment PSA. We compared actuarial bNED control rates according to treatment group within each of the prognostic groups. In addition, we devised a retrospective matched case/control selection of RT patients for comparison with the RT+H group. Five-year bNED control was compared for the two treatment groups, excluding the best prognosis group, using 56 RT+H patients and 56 matched (by stage, grade, and pretreatment PSA level) controls randomly selected from the RT alone group. bNED control for the entire group of 517 patients was then analyzed multivariately using step-wise Cox regression to determine independent predictors of outcome. Covariates considered for entry into the model included stage (T1/T2AB vs. T2C/T3), grade (2-6 vs. 7-10), pretreatment PSA (0-15 vs. > 15), treatment (RT vs. RT+H), and center of prostate dose. bNED failure is defined as PSA > or = 1.5 ngm/ml and rising on two consecutive determinations. The median follow-up for the 112 matched case/control patients was 41 months. The median follow-up was 46 months for the RT (range 11-102 months) and 37 months for the RT+H group (range 6-82 months).. Univariate analysis according to treatment for the prognostic factors of palpation stage, Gleason score, and pretreatment PSA demonstrates a significant improvement in 3-year bNED control with the addition of hormones for patients with T2C/T3, Gleason score 7-10, or pretreatment PSA > 15 ngm/ml. A comparison of bNED control according to treatment demonstrates improvement in 5-year bNED control of 55% for patients treated with RT+H vs. 31% for those patients treated with RT alone (p = 0.0088), although there is not a survival advantage. Multivariate analysis demonstrates that hormonal treatment is a highly significant independent predictor of bNED control (p = 0.0006) along with pretreatment PSA (p = 0.0001), palpation stage (p = 0.0001), grade (p = 0.0030), and dose (p = 0.0001).. (1) Patients with specific adverse pretreatment prognostic factors (i.e., T2C/T3, Gleason score 7-10, pretreatment PSA > 15) benefit from adjuvant hormonal therapy. (2) Upon multivariate analysis, hormonal therapy is determined to be a highly significant predictor of bNED control, after adjusting for all other covariates. (3) The 5-year bNED control rates of 55% for RT+H vs. 31% for RT alone represents the magnitude of benefit from adjuvant hormone therapy. (4) The bNED control curves are separated by about 20 months, representing a delay in disease progression with adjuvant hormonal therapy, as there is no overall survival difference.

Topics: Analysis of Variance; Androgen Antagonists; Antineoplastic Agents, Hormonal; Case-Control Studies; Combined Modality Therapy; Flutamide; Goserelin; Humans; Leuprolide; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies

Treatment of prostatic cancer with GnRH agonist is a medical alternative to surgical castration, although hyperstimulation of the tumor can occur. We describe an unusual unwanted effect of such a treatment which unmasked a clinically silent gonadotroph adenoma. A 62-year-old man developed after the first injection of leuprorelin-depot a sudden intracranial hypertension, which was related to apoplexy of an unknown pituitary adenoma. Its gonadotroph origin was recognized after surgery by immunocytochemistry. Retrospectively, the tumor was shown to secrete in vivo both FSH and LH when on therapy with the agonist, demonstrating the lack of desensitization. Testosterone levels were also markedly and sustainly high when on therapy, a particularly unwanted effect in prostatic cancer. As gonadotroph adenomas occur in men in the same age group as prostatic cancer, the question is raised whether hormonal testing and pituitary imaging should be performed before starting a therapy with GnRH agonist in men.

Topics: Adenoma; Delayed-Action Preparations; Follicle Stimulating Hormone; Humans; Leuprolide; Luteinizing Hormone; Magnetic Resonance Imaging; Male; Middle Aged; Orchiectomy; Pituitary Apoplexy; Pituitary Neoplasms; Prostatic Neoplasms; Testosterone

Localized seminal vesicle amyloidosis is an unusual finding in surgical pathology material. Previous studies have demonstrated that the amyloid is directly produced by the seminal vesicle epithelial cells. We investigated the possible association of seminal vesicle amyloid in patients hormonally treated for prostate carcinoma.. Cases were collected from over 200 prostate needle biopsies, seminal vesicle biopsies, and prostatectomy specimens from the surgical pathology files at The Mount Sinai Hospital, New York, NY. None of the patients with seminal vesicle amyloidosis had a chronic inflammatory disorder, serum or urine protein abnormalities, or other identifiable masses.. Six cases of localized seminal vesicle amyloidosis were found in the surgical pathology material examined. Five of the six cases had prostatic carcinoma, and one case was seen in a biopsy for benign prostatic hyperplasia. Four of the five carcinoma cases had prior hormonal treatment (luteinizing hormone-releasing hormone agonist with an antiandrogen agent, and one patient, in addition, had received radiotherapy). The amyloid deposits were limited to the seminal vesicle lamina propria without involvement of vascular walls. The amyloid reacted with Congo red staining that was sensitive to potassium permanganate. Immunohistochemically, all cases were negative for AA amyloid, beta 2-microglobulin, and kappa and lambda light chains.. We raise the possibility that in some instances, prior hormonal therapy may act as a seminal vesicle epithelial stimulant for the elaboration of this protein.

Topics: Adenocarcinoma; Aged; Amyloidosis; Androgen Antagonists; Antineoplastic Agents, Hormonal; beta 2-Microglobulin; Biopsy; Drug Therapy, Combination; Epithelial Cells; Flutamide; Gonadotropin-Releasing Hormone; Humans; Immunoglobulin gamma-Chains; Immunoglobulin kappa-Chains; Immunohistochemistry; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Proteinuria; Seminal Vesicles; Serum Amyloid A Protein; Testicular Diseases

In order to improve the effect of hormone treatment for prostate cancer, a total of 17 such patients were treated with Enantone(chemical castration) from July 1990 to July 1992.. In the control group, 16 evaluable patients who were followed for 3 to 5 years, PSA was determined with ELISA. Commercial kit was used for determination of T, LH and FSH. Prostate lesion and metastasis and patient's status was eximination in the follow-up.. Enantone was ableto suppress plasma testosterone concentration to the condition of castration during treatment (P < 0.01). PSA and other markers also responded well. Significant improvement in performance status, micturition problems and general well-being was reported.. The once a-month administration of Enantone combined with flutamide is effective in the management of advanced prostate cancer with acceptable side-effects.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Follicle Stimulating Hormone; Follow-Up Studies; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

We describe a florid xanthomatous histiocytic reaction in the pelvic lymph nodes of a patient treated with androgen deprivation therapy prior to radical prostatectomy. The xanthomatous reaction was so marked that it nearly obscured the presence of metastatic carcinoma in the same lymph nodes. A similar histiocytic reaction was also present in association with carcinoma in the prostatectomy specimen, a finding that was not identified in pretreatment biopsy specimens. No other known cause of pronounced histiocytic lymph node proliferation was present in this patient. Only one brief description of a xanthomatous reaction in lymph nodes associated with this treatment has been previously recorded in the literature to our knowledge. Other patients from our institution who were treated similarly preoperatively all had lymph nodes negative for tumor, and none demonstrated a xanthomatous tissue reaction, suggesting that this reaction may be a marker for metastatic tumor in the same lymph node.

Topics: Adenocarcinoma; Adult; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Flutamide; Histiocytes; Histiocytosis; Humans; Leuprolide; Lymph Nodes; Lymphatic Diseases; Lymphatic Metastasis; Male; Pelvis; Prostatectomy; Prostatic Neoplasms; Xanthomatosis

Topics: Antineoplastic Agents, Hormonal; Diethylstilbestrol; Estradiol; Estrogens; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms

Topics: Aged; Alendronate; Animals; Antineoplastic Agents, Hormonal; Diphosphonates; Humans; Leuprolide; Male; Orchiectomy; Osteoporosis; Prostatic Neoplasms; Rats

Topics: Adenoma; Aged; Humans; Leuprolide; Luteinizing Hormone; Male; Pituitary Neoplasms; Prostatic Neoplasms

To determine whether there is a role for endorectal coil magnetic resonance imaging (erMRI) in the prediction of pathologic stage, margin status, and/or postoperative prostate-specific antigen (PSA) failure in patients with clinically organ-confined prostate cancer.. Using erMRI, the radiologic-pathologic correlation of extracapsular extension (ECE) and seminal vesicle invasion (SVI) was evaluated in 445 surgically managed patients. Logistic regression multivariable analysis was applied to the clinical stage, PSA, biopsy Gleason grade, and erMRI findings to assess the outcomes of ECE, SVI, positive surgical margins (PSM), and postoperative PSA failure.. The accuracy of erMRI to predict for ECE and SVI numerically decreased with both increasing PSA and biopsy Gleason score because of the increasing false-negative scans in cases of microscopic transcapsular or seminal vesicle disease. Of patients who could not be categorized into low or high risk for postoperative PSA failure on the basis of clinical stage, preoperative PSA, and biopsy Gleason score, a negative or positive erMRI for ECE or SVI stratified these patients into groups with a 78% versus 21% (P < .0001) 3-year rate of actuarial freedom from PSA failure. In this subgroup, the overall accuracy of the erMRI was 70% +/- 6% and 94% +/- 2% for ECE and SVI, respectively. The most significant predictor on multivariable analysis of PSM was the erMRI finding of ECE (P = .0001).. This initial report suggests that a preoperative erMRI can identify clinically organ-confined prostate cancer patients at high risk for having ECE, SVI, and PSM that otherwise would be missed on the basis of the clinical stage, preoperative PSA, and biopsy Gleason score. Confirmatory studies are needed.

Topics: Adenocarcinoma; Antineoplastic Agents, Hormonal; Biopsy; Combined Modality Therapy; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Predictive Value of Tests; Prognosis; Prostate; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Sensitivity and Specificity

The syndrome of pituitary apoplexy has been reported to occur after the administration of several different medications. We report a case in which pituitary apoplexy developed shortly after the administration of leuprolide in a patient with prostate cancer. Leuprolide is a potent gonadotrophin releasing hormone (GnRH) analogue used to suppress leuteotrophic hormone (LH) and testosterone levels in patients with metastatic prostate cancer. LH and testosterone levels actually rise in the first week after its administration before becoming suppressed. We suspect that this acute stimulating effect of leuprolide is linked to the acute onset of pituitary apoplexy in a patient with a possible gonadotrophoma.

Topics: Acute Disease; Aged; Antineoplastic Agents, Hormonal; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Pituitary Apoplexy; Pituitary Gland; Prostatic Neoplasms; Tomography, X-Ray Computed

Flutamide is a nonsteroidal antiandrogen commonly used in the treatment of prostate cancer. Hepatic toxicity associated with flutamide has been reported with an incidence from less than 1% to about 5%. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, has been widely used in the treatment of cholesterol gallstones and of several liver diseases, but few data are now available concerning its use in the management of drug-induced hepatitis. The case of a patient who presented severe hepatitis with jaundice following use of flutamide is reported. UDCA treatment was started on admission and, contemporaneously, flutamide was withdrawn. Clinical and biochemical improvement was progressively observed, and the patient was discharged six weeks after the admission. Since fatal flutamide-related hepatitis has been reported, monitoring of serum liver tests is advocated during flutamide administration, and the effectiveness of UDCA in the treatment of drug-induced hepatotoxicity requires further study.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Flutamide; Humans; Leuprolide; Male; Prostatic Neoplasms; Ursodeoxycholic Acid

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Biopsy; Combined Modality Therapy; Diagnostic Errors; Finasteride; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostate; Prostatectomy; Prostatic Neoplasms

An 89-year-old man with bilateral leg edema and a huge abdominal mass was admitted for further evaluation. CT scan showed a hugh prostatic mass which occupied the whole pelvis cavity accompanying multiple pelvic bone metastases. Suprapubic needle biopsy revealed that the mass was well differentiated adenocarcinoma of prostate origin. The treatment was initiated by 500 mg per day of estramustine phosphate combined with injectable LH-RH analogue 2 months later. The serum levels of tumor markers were markedly elevated at the first visit; PSA 210ng/ml, PAP 110ng/ml, gamma-Sm 800ng/ml. They became normalized 3 months after the initiation of the treatment, and the mass was reduced to 11.5% of the initial size, which lead to removal of indwelling urethral catheter. The patient and his family, however, refused further treatment and the patient died of disseminated disease 8 months later.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Bone Neoplasms; Estramustine; Humans; Leuprolide; Male; Prostatic Neoplasms

We report an unusual case of bilateral choroidal masses developing in a patient with metastatic prostate cancer. Visual symptoms resolved and ocular mass lesions regressed after initiating total androgen deprivation. The natural history and management of choroidal metastatis originating from prostate cancer is discussed.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Choroid Neoplasms; Flutamide; Humans; Leuprolide; Male; Prostatic Neoplasms

Topics: Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Controlled Clinical Trials as Topic; Flutamide; Goserelin; Humans; Leuprolide; Male; Nitriles; Prostatic Neoplasms; Tosyl Compounds

The introduction of the endorectal coil magnetic resonance imaging (MRI) technique has improved the accuracy of preoperative staging for prostate cancer. This study quantifies the improvement in the ability to identify clinically unsuspected extraprostatic disease with the use of the endorectal coil MRI.. A retrospective review of the pathologic findings of 347 patients with prostate cancer treated with a radical retropubic prostatectomy was performed. The preoperative clinical indicators including prostate specific antigen (PSA), clinical stage, Gleason score, and endorectal coil MRI data were employed in a multivariate analysis to identify patients who were at high risk for seminal vesicle invasion (SVI) or extracapsular extension (ECE). The sensitivity, specificity, and positive and negative predictive values for predicting SVI and ECE were calculated using the significant clinical indicators found on the multivariate analysis.. The clinical factors identified on multivariate analysis as significant predictors of SVI include the endorectal coil MRI data (P < 0.0001), PSA (P = 0.0096), and the Gleason score (P = 0.012). Endorectal coil MRI data (P < 0.0001), PSA (P = .0001), and Gleason score (P < .0001) were significant predictors of ECE. In the patient subgroup with PSA (> 10-20 ng/ml) and Gleason score of 5 to 7, the addition of the endorectal coil MRI data enabled an additional 71 and 27% of patients with SVI and ECE, respectively, to be correctly identified. These patients would have been missed based on the prediction obtained from the PSA and Gleason score alone.. The use of the endorectal coil magnetic resonance imaging data, in addition to prostate specific antigen and Gleason score, provides a more accurate prediction of the pathologic outcome of seminal vesicle invasion and extracapsular extension than the PSA and Gleason score alone for the patient subgroup with a PSA of greater than 10 to 20 ng/ml and Gleason score of 5 to 7.

Topics: Adenocarcinoma; Combined Modality Therapy; Forecasting; Genital Neoplasms, Male; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Multivariate Analysis; Neoplasm Invasiveness; Neoplasm Staging; Predictive Value of Tests; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Rectum; Retrospective Studies; Risk Factors; Seminal Vesicles; Sensitivity and Specificity

A Cox regression multivariate analysis was done to determine the clinical and pathological indicators that predict for prostate specific antigen (PSA) failure in 347 patients who underwent radical prostatectomy for clinically localized prostate cancer between 1989 and 1993. In the patient subgroups (PSA less than 20 ng./ml. and biopsy Gleason sum 5 to 7 or PSA more than 10 to 20 ng./ml. and biopsy Gleason sum 2 to 4) not classifiable into those at high and low risk for postoperative PSA failure using PSA and biopsy Gleason sum, the status of the seminal vesicles and prostatic capsule on endo-rectal coil magnetic resonance imaging (MRI) allowed for this categorization. Specifically, 2-year actuarial PSA failure rates were 84% versus 23% in patients with and without seminal vesicle invasion, respectively, on MRI (p < 0.0001) and 58% versus 21% in those with and without extracapsular extension, respectively (p = 0.0001). In patients with extracapsular extension but without pathological involvement of the seminal vesicle(s) or poorly differentiated tumors (pathological Gleason sum 8 to 10), the 2-year actuarial PSA failure rates were 50% (margin positive), 28% (margin negative with established extracapsular disease) and 9% (margin negative with focal microscopic extracapsular disease). Therefore, endo-rectal coil MRI showing seminal vesicle invasion or extracapsular extension when the PSA level is less than 20 ng./ml. and the biopsy Gleason sum is 5 to 7 or the PSA level is more than 10 but less than 20 ng./ml. and the biopsy Gleason sum is 2 to 4 predicted for PSA failure. In patients with extracapsular extension who had pathological Gleason sum less than 8 disease with uninvolved seminal vesicles, the margin status and extent of extracapsular disease predicted for PSA failure.

Topics: Actuarial Analysis; Adenocarcinoma; Biopsy; Chemotherapy, Adjuvant; Follow-Up Studies; Forecasting; Humans; Leuprolide; Magnetic Resonance Imaging; Male; Multivariate Analysis; Neoplasm Invasiveness; Neoplasm Staging; Preoperative Care; Prognosis; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Risk Factors; Seminal Vesicles; Treatment Failure

To evaluate the efficacy of combined radiation and hormonal therapy in patients with prostate cancer metastatic to the pelvic lymph nodes.. Fifty consecutive patients with node-positive prostate cancer were evaluated by the Departments of Urology and Radiation Oncology at the University of Pennsylvania and offered combined hormonal and radiation therapy. All patients received pelvic radiation to 45 Gy, with a boost dose to the prostate to 65 to 71 gy. Forty-five of the patients were treated with concurrent hormonal therapy consisting of diethylstilbestrol (2 patients), orchiectomy (18 patients), leuprolide (5 patients), or combined androgen blockade (20 patients); the other 5 patients declined hormonal therapy. Patients represented a group with locally advanced disease with a high incidence of T3 tumors (66%), high grade (74%; Gleason score more than 7), high prostate-specific antigen (PSA) (40%; more than 30.0 ng/mL), and a high incidence of gross (36%) or bilateral (30%) adenopathy and a high incidence of multiply involved lymph nodes (62%).. Median follow-up of patients is 42 months (range, 10 to 102). All 5 patients declining hormonal therapy relapsed within 18 months and only 1 patient survived longer than 3 years. Among patients treated with combined hormonal and radiation therapy, the 6-year survival rate is 82%, the clinical disease-free survival at 6 years is 71%, and the probability of survival free of recurrence, with a PSA less than 0.2 ng/mL, is 62%. Only two PSA recurrences occurred, both in patients who elected to discontinue hormone therapy. There was no synergistic toxicity observed as a result of combined therapy.. Combined hormonal and radiation therapy offers the potential for extended disease-free survival and may represent an effective treatment option for patients with locally advanced prostate cancer.

Topics: Adenocarcinoma; Aged; Combined Modality Therapy; Diethylstilbestrol; Disease-Free Survival; Flutamide; Follow-Up Studies; Humans; Leuprolide; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy Dosage; Time Factors

The effect of [D-Leu6,des-Gly-NH2(10),Proethylamide9]-GnRH, leuprolide, was determined for the human primary prostate tumor cell line ALVA-31 by in vitro mitogenic assays. Prostate tumor cell proliferation was inhibited up to 50% by leuprolide. Inhibition was not observed in parallel cultures treated with other low molecular weight bioactive peptides. The incorporation and metabolic reduction of testosterone was not affected by concentrations of leuprolide that were inhibitory in the mitogenic assay. Specific high-affinity binding of 125I-labeled leuprolide was also demonstrated on intact tumor cells with an estimated effective median dose (ED50) of < 1 x 10(-9)M. Inhibition of prostate tumor growth was further demonstrated in Balb/c athymic intact and castrate male mice bearing ALVA-31 tumor xenografts following chronic administration of leuprolide. These data clearly demonstrate that leuprolide can inhibit the growth of a human prostate carcinoma cell line. Studies conducted in castrate animals further suggest an alternative mechanism of growth inhibition that appears to be independent of the suppression of steroid hormone biosynthesis by LHRH analogues.

Topics: Animals; Cell Division; Humans; Leuprolide; Male; Mice; Mice, Inbred BALB C; Prostatic Neoplasms; Testosterone; Tumor Cells, Cultured

To evaluate the clinical usefulness of the kinetic analysis of prostatic volume in the prognosis of patients with Stage D prostatic cancer treated using luteinizing hormone-releasing hormone (LHRH) analogues.. The reduction of prostatic volume was monitored in 12 patients with Stage D prostatic cancer using transrectal ultrasonography (TRUS) after treatment with LHRH analogues. Data obtained from the kinetic analysis of prostatic volume were compared with the prognosis.. All the patients having a reduction time, tau (derived from the kinetic analysis of prostatic volume change with time), of less than 41 days had neither clinical progression within 15 months nor death caused by prostatic cancer during the 5-year follow-up, while the disease-specific 5-year survival rate in patients having a tau of greater than 42 days was as low as 17%. The difference in both the progression and disease-specific survival between these groups was statistically significant (P < 0.05) despite the limited number of patients. In contrast, conventional prognostic parameters showed no significant predictability for prognosis with the exception of prostatic acid phosphatase, which correlated strongly with the occurrence of progression within 15 months.. The kinetic analysis of the change of prostatic volume using TRUS shows promise in the prognosis of the patients with Stage D prostatic cancer.

Topics: Aged; Aged, 80 and over; Buserelin; Disease Progression; Follicle Stimulating Hormone; Humans; Kinetics; Leuprolide; Luteinizing Hormone; Male; Predictive Value of Tests; Prognosis; Prostate; Prostatic Neoplasms; Survival Analysis

We report a primary squamous cell carcinoma of the prostate that developed in a 57-year-old man, 3 years after treatment with leuprolide and flutamide for Stage D1 adenocarcinoma of the prostate. This is the first case that describes this transformation from adenocarcinoma to squamous cell carcinoma following the use of luteinizing hormone agonists.

Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Flutamide; Humans; Leuprolide; Male; Middle Aged; Neoplasms, Second Primary; Prostatic Neoplasms

Eighteen previously untreated patients with metastatic carcinoma of the prostate were treated with LHRH analogue. They were divided into 3 groups according to the degree of glandular differentiation. In all groups, a transient rise of PAP and PSA was observed after the LH and testosterone surge. However, relative values of LH, testosterone, PAP and PSA did not differ significantly among the 3 groups. These facts suggest that a transient rise of PAP and PSA is caused by testosterone surge independently from the degree of glandular differentiation after LHRH analogue administration in patients with advanced prostatic cancer.

Topics: Acid Phosphatase; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Prognosis; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

A massive, locally extensive adenocarcinoma of the prostate (2,246 ccm) presenting as constipation and a palpable abdominal mass, was treated with androgen deprivation resulting in a 94 percent reduction in tumor size, and relief of symptoms. Serum prostate-specific antigen was reduced from 4,029 to 0.4 ng/mL, after hormonal therapy was combined with radiation treatments for local disease control.

Topics: Adenocarcinoma; Aged; Combined Modality Therapy; Constipation; Flutamide; Humans; Leuprolide; Male; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Radiotherapy Dosage

To determine whether hormonal therapy prior to radical prostatectomy (neoadjuvant hormonal therapy) leads to improved results in patients with stage C prostate cancer.. Thirty patients received neoadjuvant hormonal therapy for stage C carcinoma of the prostate. Eighteen patients who responded to treatment subsequently underwent extirpative surgery.. Fourteen of the 30 patients (47%) were diagnosed as being downstaged to clinical stage B disease following therapy. No major complications occurred. Pathology staging revealed only three patients (10%) to have organ-confined disease after radical prostatectomy.. Neoadjuvant hormonal therapy prior to radical prostatectomy offers little probability of rendering patients with clinical stage C carcinoma of the prostate free of disease. Further investigation of the efficacy of this treatment should be accomplished in randomized trials.

Topics: Adenocarcinoma; Aged; Chemotherapy, Adjuvant; Diethylstilbestrol; Flutamide; Humans; Leuprolide; Male; Middle Aged; Prostatectomy; Prostatic Neoplasms

The use of suramin, a polysulfonated naphthylurea, in the treatment of advanced prostate cancer currently is being investigated. A 52-year-old man developed acute renal dysfunction after receiving nine doses of suramin. His suramin therapy was discontinued, but his serum creatinine level continued to rise to 10.8 mg/dl during the next 6 days. The patient was not rechallenged with suramin, and his renal function returned to baseline within the next 3 weeks. Future investigators of this drug should be aware of the possibility of such a reaction with parenteral administration.

Topics: Acute Kidney Injury; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Combined Modality Therapy; Creatinine; Flutamide; Humans; Hydrocortisone; Kidney; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Suramin

Treatment of patients with prostate carcinoma using drugs with antiandrogenic effects is increasingly common. One of the most popular agents is leuprolide (with or without flutamide), an agonist of luteinizing hormone-releasing hormone (LH-RH). Prostates exposed to antiandrogenic agents develop distinctive pathologic changes. The ability of a group of 18 pathologists to recognize these LH-RH effects on prostate cancers and to distinguish them from poor tumor differentiation was tested using a Delphi technique.. The Delphi method maximizes the opportunity for individual contributions by eliminating opportunities for group dynamics and confrontational interaction. In this study, participants were provided with a set of duplicate transparencies and a list of written definitions of both poor tumor differentiation and LH-RH effect. They were instructed to examine the cases privately using the definitions provided and to distinguish poor tumor differentiation from LH-RH effect. Responses of the participants were shared anonymously, and each was asked to reexamine the cases in light of this knowledge.. After a learning experience accomplished by one round of examination and feedback, LH-RH effect could be correctly distinguished from poor tumor differentiation in greater than 90% of cases by 83% of the participants. A small percentage of cases confounded complete consensus, although every case was correctly identified by most participants.. The pathologic effects associated with androgen deprivation with leuprolide (plus flutamide) are sufficiently distinctive to be recognized by knowledgeable pathologists. In most cases, the tissue shrinkage representing a favorable response to the drug can be distinguished from solid or infiltrating patterns of poorly differentiated carcinoma.

Topics: Cell Differentiation; Clinical Competence; Delphi Technique; Flutamide; Humans; Leuprolide; Luteinizing Hormone; Male; Pathology; Prostate; Prostatic Neoplasms

Metastases to the meninges from prostatic cancer are rare, accounting for less than 0.5% of all solid tumor cases. Management for patients with leptomeningeal metastases of various histologic types includes intrathecal chemotherapy and radiation therapy, but the prognosis is poor. Therefore, the identification of selected patients for whom effective therapy exists is of paramount importance.. A patient with adenocarcinoma of the prostate presented with leptomeningeal metastases as his first manifestation of metastatic disease.. Androgen blockade was initiated with flutamide and ketoconazole. After 5 days of therapy, leuprolide acetate depot was substituted for ketoconazole. The patient responded to therapy and remained asymptomatic with a normal serum prostate-specific antigen levels at 16-plus months with no further evidence of malignant cells in spinal fluid from repeated lumbar punctures.. Patients with hormone-naive metastatic prostatic carcinoma manifested as carcinomatous meningitis should be considered for hormonal ablative therapy. This is preferred to the use of intrathecal chemotherapy, which has limited efficacy.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Flutamide; Follow-Up Studies; Humans; Ketoconazole; Leuprolide; Male; Meningeal Neoplasms; Meningitis; Prostatic Neoplasms

Luteinizing hormone releasing hormone agonists have been shown to reduce the levels of androgens in the peripheral circulation and to reduce prostate volume. The objective of this study was to quantify testicular function in patients with metastatic carcinoma of the prostate treated with a luteinizing hormone releasing hormone agonist, leuprolide, by analysis of spermatic vein blood for testosterone and androstenedione, and by determination of the maximum velocity of the 17 beta-hydroxysteroid oxidoreductase enzyme in testicular tissue in vitro. A chemical analysis of the spermatic vein blood of 19 patients with a median age of 78 years revealed the presence of significantly high levels of testosterone and androstenedione, 20.7 +/- 1.9 micrograms % and 6.7 +/- 0.7 micrograms %, respectively. These androgens could not be detected in patients treated with leuprolide before orchiectomy. Patients treated with leuprolide for several months followed by a period of no treatment before orchiectomy secreted testosterone and androstenedione levels comparable to the control group. The maximum velocity of the 17 beta-hydroxysteroid oxidoreductase enzyme in vitro in the testes of the leuprolide treated patients was significantly inhibited. Enzyme activity returned to normal levels when leuprolide treatment was followed by a recovery period of no treatment before orchiectomy.

Topics: 17-Hydroxysteroid Dehydrogenases; Aged; Aged, 80 and over; Androgens; Androstenedione; Humans; Leuprolide; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Testis; Testosterone

To assess whether the 'oestrogen effect' of vacuolation in treated prostatic cancer cells is seen after luteinizing hormone releasing hormone (LHRH) analogue therapy.. Eight patients with locally advanced prostate cancer were treated with the LHRH analogue, leuprorelin acetate. Biopsies taken pretreatment and after 3 months were assessed for the presence or absence of microscopic vacuolation.. Seven out of eight patients had evidence of vacuolation induced or accentuated by treatment.. Recent research suggests that both stilboestrol and LHRH analogues have a direct cytotoxic effect on prostate cell lines in vitro, which appears to be supported by these findings. Vacuolation seems to be a normal consequence of treatment with LHRH analogues.

Topics: Biopsy; Humans; Leuprolide; Male; Prospective Studies; Prostate; Prostatic Neoplasms; Vacuoles

A 73-year-old man presented with dyspnea, right-sided pleural effusion, and bilateral pulmonary infiltrates. The pleural fluid revealed adenocarcinoma cells that stained positively for prostatic specific antigen (PSA), which confirmed this uncommon metastatic involvement from prostate cancer. The dyspnea, effusion, and infiltrates disappeared after therapy with flutamide and leuprolide was started. This report demonstrates both the usefulness of immunocytochemical staining for PSA in ascertaining the origin of malignant pleural effusion in men and the effectiveness of the aforementioned endocrine therapy in such setting.

Topics: Adenocarcinoma; Aged; Flutamide; Humans; Leuprolide; Male; Pleural Effusion, Malignant; Pleural Neoplasms; Prostatic Neoplasms

Transforming growth factor beta-1 (TGF-beta 1) has been proposed as a mediator of tumour growth in a number of tumours and cell lines including prostate, and in a recent study was shown to be up-regulated in the stroma of breast cancer tissue following treatment with the anti-oestrogen tamoxifen. Immunolocalisation of the intracellular form of TGF-beta 1 confirmed that the source of the stromal TGF-beta 1 was the peritumoral fibroblasts. We present here the results of a study in which five patients with hormonally unresponsive prostatic carcinoma and seven patients responding to a luteinising hormone-releasing hormone analogue had prostate biopsies taken before and during treatment. These were stained for TGF-beta expression prior to treatment and at either relapse or 3 months later respectively. Six of seven clinically responding tumours and three of five relapsed tumours showed up-regulation of extracellular TGF-beta 1, again primarily in the stroma, with no apparent up-regulation of intracellular TGF-beta 1, TGF-beta 2 or TGF-beta 3. These data illustrate that the epithelial growth inhibitor TGF-beta 1 can be induced by hormonal manipulation in prostate cancer in vivo, and may continue to be up-regulated even after relapse. This suggests that relapse of hormonally treated prostate cancer may be associated with a failure of the epithelium to respond to stromal TGF-beta 1.

Topics: Androgens; Biopsy; Diethylstilbestrol; Extracellular Space; Humans; Immunohistochemistry; Leuprolide; Male; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Transforming Growth Factor beta; Up-Regulation

A total of 22 patients with locally advanced prostate cancer (stage B2 to C) was entered into a protocol for 3 months of preoperative hormonal deprivation. Of the patients 8 were judged to have clinical stage B2 and 14 to have stage C disease. The protocol regimen consisted of daily administration of flutamide (250 mg. orally 3 times per day) and leuprolide injection (7.5 mg. intramuscularly) every month. Patients with objective evidence of downstaging by prostate specific antigen (PSA) levels and transrectal ultrasound were offered surgical therapy. Of the 22 patients 20 have completed the protocol and are evaluable, and 2 of them did not show significant downstaging and elected radiotherapy. Preoperative hormonal therapy produced an average 33% downsizing of the prostate gland as determined by transrectal ultrasound volumetrics. Decreases in serum PSA values were demonstrated from a pre-hormonal average of 30 micrograms./l. (range 0.7 to 97.7) to an average of 0.53 micrograms./l. (range 0.2 to 5.7) after hormonal therapy. Of the 18 patients who underwent an operation after demonstrating significant downsizing 7 had pathologically confirmed stage B disease, 7 had stage C cancer and 4 had positive pelvic lymph nodes. Of the 8 clinical stage B2 cancer patients 3 had pathological stage B2 disease following the protocol. Of the 12 clinical stage C cancer patients 3 had pathological stage B disease, 4 had positive pelvic lymph nodes and the remainder had pathological stage C cancer. Thus, only 3 of 20 patients (15%) demonstrated pathological downstaging from the clinical stage. Downsizing the prostate volume and PSA changes with hormonal therapy were not predictive of patient outcome either alone or in combination. Preoperative hormonal therapy did not appear to facilitate the surgical procedure. Patients completing neoadjuvant hormonal therapy had an average estimated blood loss of 1,238 ml. and an average operating time of 183 minutes. A group of 20 consecutive patients with stage B2 prostate cancer who underwent radical prostatectomy without preoperative hormone therapy had an average estimated blood loss of 1,296 ml. and an average operating time of 171 minutes.

Topics: Administration, Oral; Aged; Drug Therapy, Combination; Flutamide; Humans; Injections, Intramuscular; Leuprolide; Male; Middle Aged; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms

Adrenal androgens contribute 40% of total androgens in adult men. The inactive precursor steroids dehydroepiandrosterone (DHEA) and DHEA-sulfate are secreted in large amounts by the adrenals and reach the prostate and other peripheral target tissues, where they are transformed into the potent androgen dihydrotestosterone (DHT). We have cloned and sequenced the cDNAs and/or genes which encode the enzymes responsible for the transformation of DHEA into DHT, namely 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase, 17 beta-hydroxysteroid dehydrogenase and 5 alpha-reductase. Blockade of DHT synthesized by these enzymes, with a pure antiandrogen of the class of flutamide, prolongs life in advanced prostate cancer, the effect being much more important when a small number of metastases is present. Most importantly, 3-month combination therapy reduces cancer-positive margins at radical prostatectomy, from 38.5% in control patients to only 13% in those who received combination therapy. Combined with an efficient strategy for detection of early-stage prostate cancer, the present approach could offer the possibility of a cure to more than 80% of prostate cancer patients, compared with the present situation where a cure can be offered to less than 20% of patients, since the first diagnosis of prostate cancer is usually made at a late stage of the disease.

Topics: Adrenal Glands; Androgen Antagonists; Androgens; Flutamide; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Orchiectomy; Prostate; Prostatic Neoplasms

The maximum horizontal area (MHA) of the seminal vesicles was measured in 20 prostatic cancer patients by means of transrectal sonography (TRS) after LHRH analog treatment. MHA of the seminal vesicles changed in parallel to the serum testosterone (T) level and decreased by 11-62%, compared with the baseline after LHRH analog treatment for 4 months. Two different patterns were observed for the change of MHA. In 9 cases, MHA of the seminal vesicles increased transiently and then decreased gradually, while in the other 11 cases, MHA decreased continuously from the beginning with no significant increase. Thus, the direct and dynamic response of the seminal vesicles to the change of serum T level was clarified.

Topics: Aged; Aged, 80 and over; Buserelin; Follicle Stimulating Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Prostate; Prostatic Neoplasms; Seminal Vesicles; Testosterone

To determine the effects of clonidine, a centrally acting adrenergic agonist, in abating symptoms of hot flashes in men receiving either leuprolide or goserelin for prostate cancer.. Patients were administered transdermal or oral clonidine 0.1-0.2 mg/d. Dosages were increased in increments of 0.1-0.3 mg/d every two to four weeks if symptoms persisted or until adverse effects developed.. Medical oncology clinic at the University of Illinois and the hypertension clinic at the Veterans Affairs West Side Medical Center.. Consenting male patients were eligible for the study if they were receiving leuprolide or goserelin for prostate cancer and were experiencing hot flashes. Exclusion criteria included diastolic blood pressure of 75 mm Hg or below or a history of adverse reactions to clonidine.. Effectiveness of clonidine was determined by questioning patients about frequency, severity, and duration of hot flashes at baseline and at two- to four-week intervals.. All four patients receiving clonidine experienced a partial response within two weeks of starting treatment. No dose-dependent response was observed. Adverse effects were noted in one patient but did not result in discontinuation.. Our results document the first report of the use of clonidine to treat hot flashes secondary to leuprolide or goserelin therapy. Symptomatic improvement was noted in all four patients. Further evaluation of clonidine as well as other centrally acting adrenergic agonists is needed.

Topics: Climacteric; Clonidine; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Time Factors

Topics: Humans; Leuprolide; Male; Palliative Care; Prostatic Neoplasms

The prognostic value was determined of prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) measured before and after endocrine treatment in 57 patients with newly diagnosed Stage D2 prostatic cancer.. Therapy included orchiectomy or administration of luteinizing hormone releasing hormone analogues or an antiandrogen.. The absolute pretreatment PSA (elevated in 100% of patients) but not PAP (abnormal in 93%) predicted disease progression (P < 0.0011), i.e., a poor response to therapy. Fifty-three patients responded to androgen deprivation with a decrease in PSA level. This declined to normal at 3 and 6 months in 25% of patients. Forty-nine percent had a greater than 90% decrease in their PSA level. By 1 year, 58% of patients had progressive disease. Both the nadir PSA level and the percent decline from the pretreatment level at 3 and 6 months predicted the progression-free interval (P < 0.001). Patients with a 90% or greater decline in PSA had a prolonged progression-free survival. Serial PAP levels were similarly prognostic.. It was concluded that PSA was better than PAP in evaluating patients before and after androgen-deprivation therapy. The nadir level of both markers was an important tool to predict progression-free survival in patients with metastatic prostatic cancer.

Topics: Acid Phosphatase; Aged; Aged, 80 and over; Androgen Antagonists; Biomarkers, Tumor; Follow-Up Studies; Goserelin; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Orchiectomy; Prognosis; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Remission Induction; Time Factors

The results of long-term administration of leuprorelin acetate depot (TAP-144-SR), a sustained-release preparation of luteinising hormone-releasing hormone (LH-RH) agonist, to 40 stage D prostate cancer patients who had had no previous hormonal therapy, have been analyzed. The drug was administered by subcutaneous injection once every four weeks at a dose of 3.75 or 7.5 mg. The mean duration of treatment was 480 (141-1,266) days, and treatment continued for more than one year for 60% of the 40 patients. Objective response was evaluated in accordance with Japanese Response Criteria. The best objective response in the overall evaluation was a partial response in 68.6% of the total patient group (3.75 mg, 64.3%; 7.5 mg, 71.4%). During the administration period, 21 patients were diagnosed as having progressive disease (PD), and the mean time to onset of PD was 308 days. The earliest diagnoses of PD were made on bone metastases (17 cases) and prostatic acid phosphatase levels (12 cases). The survival rate, as determined by Kaplan-Meier's method, was 81.2% (3.75 mg, 80.5%; 7.5 mg, 81.3%) two years after starting the regimen and 66.0% (3.75 mg, 65.1%; 7.5 mg, 66.0%) after three years. There was no dose dependency between either of the two drug doses, which we adopted as functions of the objective response rate, and patients' survival. Serum levels of testosterone, LH and follicle-stimulating hormone (FSH) were monitored from the first-dose until the 148th week of administration. In all patients receiving the drug as scheduled, the testosterone level was maintained at less than 1 ng/ml, and the LH and FSH levels were maintained at levels lower than their respective upper normal limits. There were no particular adverse reactions specific to the long-term administration subsequent to the foregoing 12-week administration study. In conclusion, LH-RH analogue treatment is thought to be a long-lasting, effective, palliative measure for patients with previously-untreated, advanced, prostatic cancer.

Topics: Aged; Aged, 80 and over; Delayed-Action Preparations; Follicle Stimulating Hormone; Follow-Up Studies; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Neoplasm Staging; Prostatic Neoplasms; Remission Induction; Survival Rate; Testosterone

Leuprorelin acetate, a highly potent gonadotrophin-releasing hormone agonist, was originally launched in the USA as a daily injection for the treatment of metastatic prostatic cancer. A once-monthly injectable depot form was subsequently developed. Biodegradable copoly(DL-lactic/glycolic) acid was chosen as the release-controlling polymer, and microspheres containing leuprorelin acetate were prepared by the in-water drying method. Results of studies in rats showed that a copolymer with a molecular weight of 14,000 and a lactic/glycolic acid ratio of 75/25 had the most satisfactory release-controlling properties. Microspheres given once monthly reduced serum testosterone levels in male rats. Microspheres also reduced serum oestradiol levels and caused a marked regression in experimental endometriosis in female rats. In clinical studies of prostatic cancer, use of the depot formulation has effectively reduced the dose required to as low as one-eighth of that needed for administration by daily injection. A sophisticated manufacturing system has now been developed and products now available have many advantages.

Topics: Animals; Chemistry, Pharmaceutical; Delayed-Action Preparations; Endometriosis; Female; Humans; Injections, Intramuscular; Injections, Subcutaneous; Leuprolide; Male; Microspheres; Prostatic Neoplasms; Rats; Testosterone

Topics: Adult; Aged; Combined Modality Therapy; Flutamide; Humans; Leuprolide; Male; Middle Aged; Orchiectomy; Prostatic Neoplasms

Retrospective evaluation of the efficacy of complete androgenic blockade started by Labrie et al. using therapy with leuprolide acetate in monthly dosage of 7.5 mg i.m. associated to flutamide at the usual dosage in 35 patients with prostate adenocarcinoma in C-D1-D2 stages, who had not been given prior anti-neoplastic therapy. Clinical and analytical control studies were carried out during therapy follow-up for a maximum time of 36 months. The objective response of adverse events that can be superimposed to previous studies carried out with analogs on daily administration was assessed. Castration levels achieved were maintained for the length of the study below 50 ng/dl. Correlation between tissue type, rated according to the Mostofi classification, evolution or degree of response obtained and preserved increase of tumour markers (PSA, PAP, LDH, Prolactin) was evaluated; the evolution observed in patients who maintained high values of markers was worse with the referred treatment.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Flutamide; Follow-Up Studies; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prostatic Neoplasms; Retrospective Studies; Testosterone

Topics: Humans; Leuprolide; Male; Prostatic Neoplasms

Topics: Antineoplastic Agents; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms

Topics: Antineoplastic Agents; Delayed-Action Preparations; Drug Administration Schedule; Humans; Injections, Subcutaneous; Leuprolide; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Testosterone

Topics: Antineoplastic Agents; Delayed-Action Preparations; Drug Administration Schedule; Humans; Injections, Subcutaneous; Leuprolide; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms

Gonadotropin-releasing hormone (GnRH), a decapeptide synthesized and released by the hypothalamus, regulates production and release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the adenohypophysis. Parenterally administered GnRH was initially used diagnostically as a test of adenohypophyseal reserve of LH and FSH. Subsequently, native GnRH was used therapeutically to treat hypothalamic hypogonadal and infertility states in both men and women. Because of the low potency and short half-life of native GnRH, long-acting, potent analogs have been developed that suppress secretion of native pituitary gonadotropins, resulting in medical gonadectomy. When administered parenterally and, more recently, intranasally, these compounds are useful in the management of prostate and breast carcinoma, endometriosis and uterine leiomyomata, precocious puberty and nontumorous ovarian hyperandrogenic syndromes.

Topics: Endometriosis; Female; Gonadotropin-Releasing Hormone; Humans; Infertility, Female; Leuprolide; Male; Nafarelin; Prostatic Neoplasms

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

In conclusion, the intergroup study in the US, as well as preliminary results of the Anandron and leuprolide study, would support the view that combined androgen blockade is better than monotherapy in achieving clinical responses, prolonging the time to progression, and improving the survival rate. This improvement in survival rate is not a huge advance but is a step in the right direction. Future clinical trials are needed to evaluate newer methods to improve survival rates. The results also open up the possibility of employing this combined androgen blockade in earlier stages of prostate cancer in order to delay progression of the cancer and perhaps improve patient survival. Only carefully constructed clinical trials will be able to answer these questions.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents; Flutamide; Gonadotropin-Releasing Hormone; Humans; Imidazoles; Imidazolidines; Leuprolide; Male; Middle Aged; Orchiectomy; Prostatic Neoplasms

Prostate glands exposed to androgen deprivation with leuprolide +/- flutamide were evaluated for pathologic changes which might be related to therapy. Comparing pretreatment and posttreatment tissue by visual discrimination using light microscopic study revealed treatment-related alterations in the size and distribution of neoplastic glands in 60% of cases. Quantitative measurements documented glandular changes in an even greater percentage of cases. Although distinctive, the histologic pattern was not specific for leuprolide/flutamide. The absence of appreciable degeneration and necrosis in tumor cells suggests that this type of androgen deprivation may act through suppression rather than ablation of prostatic cancers. The relationship between treatment-related histologic effects and initial tumor grade and clinical stage as well as expression of prostate-specific antigen was studied. Accurate histologic assessment of leuprolide/flutamide-treated prostate glands should not be a problem so long as specimens are thoroughly examined and drug-related variations in tumor morphologic features are appreciated.

Topics: Aged; Androgens; Antineoplastic Agents; Carcinoma; Combined Modality Therapy; Drug Therapy, Combination; Flutamide; Gonadotropin-Releasing Hormone; Humans; Immunoenzyme Techniques; Leuprolide; Male; Middle Aged; Prostatectomy; Prostatic Neoplasms

A sensitive method for the determination of leuprorelin (TAP-144), a luteinizing hormone-releasing hormone analogue, and its C-terminal metabolite, M-I, in serum and urine has been developed. Leuprorelin and M-I were extracted from serum or urine samples with Sep-Pak C18 cartridges, and separated completely by high-performance liquid chromatography and determined by radioimmunoassay using [125I]leuprorelin as the labelled antigen. The detection limit of the method was 0.05 ng/ml for leuprorelin and M-I, and the recovery of the compounds added to serum and urine was over 88% with a coefficient of variation (within-assay) of less than 5%. The method was applied to the determination of leuprorelin and M-I-like immunoreactivity in serum or urine after administration of once-a-month injectable microspheres of leuprorelin acetate (TAP-144-SR) to patients with prostate cancer.

Topics: Amino Acid Sequence; Antineoplastic Agents; Chromatography, High Pressure Liquid; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Microspheres; Molecular Sequence Data; Prostatic Neoplasms; Radioimmunoassay

The prognostic value of prostate specific antigen was evaluated to predict disease progression after endocrine therapy in patients with prostatic cancer. A total of 73 patients was studied (6 with stage B2, 16 with stage C, 9 with stage D1 and 42 with stage D2 disease). Endocrine therapy included bilateral orchiectomy, diethylstilbestrol diphosphate and luteinizing hormone-releasing hormone analogue. Pre-treatment serum prostate specific antigen levels were determined in all patients with an enzyme immunoassay kit. During a followup of 4 to 68 months (average 24 months) clinical disease progression occurred in 24 of the 73 patients. The pre-treatment prostate specific antigen level by itself did not predict disease progression. Changes in prostate specific antigen level with treatment were correlated with the interval to disease progression in the 44 patients who had prostate specific antigen determinations at regular intervals after endocrine therapy and whose initial level was greater than 10 ng./ml. Patients who had a decrease in the prostate specific antigen levels of 80% or more within 1 month after the beginning of therapy survived significantly longer free of disease progression (p less than 0.001). Patients whose prostate specific antigen level remained elevated for more than 3 months had a high risk of disease progression within 2 years. Our study suggests that patients with the more favorable prognosis can be identified early, after 1 to 3 months of endocrine therapy, by the rapid decrease in the prostate specific antigen levels.

Topics: Antigens, Neoplasm; Antineoplastic Agents; Biomarkers, Tumor; Combined Modality Therapy; Diethylstilbestrol; Follow-Up Studies; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Orchiectomy; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Factors; Time Factors

Common manifestations of metastatic carcinoma of the prostate are bone pain, spinal cord compression, and disseminated intravascular coagulation. Prostate-specific antigen represents a useful marker to monitor tumor progression and response to therapy. Until recently, no therapy was available to prolong survival in these patients. Now, the use of a luteinizing hormone-releasing hormone agonist (leuprolide acetate [Lupron]) plus an antiandrogen (flutamide [Eulexin]) to provide total androgen blockade has demonstrated a 25% increase in survival time.

Topics: Antigens, Neoplasm; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Disseminated Intravascular Coagulation; Flutamide; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Pain; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Spinal Cord Compression

Topics: Antineoplastic Agents; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms

Topics: Anilides; Antineoplastic Agents; Drug Therapy, Combination; Flutamide; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms

The scintigraphic "flare" phenomenon on bone imaging refers to an increase in intensity of tracer uptake in sites of bone metastases and/or the appearance of "new" lesions, which occur shortly after commencement of hormonal therapy or chemotherapy for breast, prostate, or lung cancer. In this study, we observed that scintigraphic flare can occur in patients with prostate cancer following treatment with the "hormone-like" luteinizing hormone releasing hormone analog, leuprolide acetate. Twenty-six patients with prostate cancer being treated with leuprolide acetate underwent serial bone scans at three-month intervals. Five (19.2%) of the 26 patients had findings consistent with a scintigraphic flare on bone scans obtained between three and six months after initiation of therapy. These scan findings should not be confused with progression of skeletal metastases.

Topics: Antineoplastic Agents; Bone Neoplasms; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms; Radionuclide Imaging; Technetium Tc 99m Medronate

TAP-144-SR is a sustained release formulation of an LH-RH agonist, leuprorelin acetate (TAP-144), that has been newly developed in Japan. As a phase I study, a single subcutaneous dose of TAP-144-SR was given to 15 patients with prostatic cancer to investigate the safety, endocrinological effects, and serum levels of the drug. The patients were divided into four groups according to the dosage levels of 1.88 mg, 3.75mg, 7.5 mg and 15 mg. No serious side effects were noted in any of the patients treated with any dose. No patients exhibited signs of a local reaction at the site of injection. In two patients transient exacerbation of clinical symptoms owing to "flare up" was observed. Serum testosterone levels decreased to the castration level (less than 1.0 ng/ml) in all of the patients, although the time required to attain the castration level tended to be longer in the patients receiving 1.88 mg. Serum TAP-144 levels increased on the first day and gradually decreased thereafter. In the groups of patients that received 3.75 mg or more of TAP-144-SR, TAP-144 was detected in the serum up to 4 weeks after administration. Based on the results of the phase I study, 3.75 mg and 7.5 mg of TAP-144-SR were selected as the doses for the phase II study. The phase II study was carried out as a multi-center open trial. Patients with stage B-D prostatic cancer received subcutaneously either 3.75 mg (3.75 mg group) or 7.5 mg (7.5 mg group) of TAP-144-SR once every 4 weeks for a total of 3 doses over a period of 12 weeks. TAP-144-SR 3.75 mg was administered to 51 patients and 7.5 mg to 50 patients. Both of these doses were adequate to suppress serum LH and FSH levels. Serum testosterone was decreased to the castration level within 22 days after the first dose, and this suppression was maintained throughout the treatment period. Clinical response rate (CR + PR) was 21% in the 3.75 mg group and 22-24% in the 7.5 mg group according to the Criteria for Evaluating the Direct Response to Chemotherapy in Solid Carcinomas and NPCP criteria. The response rate by the criteria of Japanese Prostatic Cancer Study Group was 51% in the 3.75 mg group and 62% in the 7.5 mg group. Adverse reactions were noted in 26% of patients in the 3.75 mg group and 34% in the 7.5 mg group.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Delayed-Action Preparations; Dogs; Drug Evaluation; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Mice; Middle Aged; Prostatic Neoplasms; Testosterone

Topics: Antineoplastic Agents; Breast Neoplasms; Female; Humans; Leuprolide; Libido; Male; Prostatic Neoplasms

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Delayed-Action Preparations; Humans; Leuprolide; Male; Middle Aged; Neoplasm Staging; Prostatic Neoplasms

Topics: Follicle Stimulating Hormone; Humans; Kinetics; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms

A case of prostatic cancer treated with an LH-RH analogue depo-preparation was found to have a mediastinal thymoma which was later removed by surgery. The association of thymoma and prostatic cancer has not been documented in the world literature, and it remains to be elucidated whether the occurrence of the both tumors is a coincidence or etiologically inter-related.

Topics: Adenocarcinoma; Aged; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Neoplasms, Multiple Primary; Prostatic Neoplasms; Remission Induction; Thymoma; Thymus Neoplasms

Twenty-two patients with advanced prostatic cancer and one with benign prostatic hypertrophy were given the GnRH analogue leuprolide in the form of a slow-release depot formulation by subcutaneous injection at doses of 3.75, 7.5, 15 or 30 mg. Following the first dose, drug levels were measured by a double-antibody RIA over an observation period of 5 weeks. Thereafter patients continued long-term subcutaneous treatment at the same dose every 4 weeks. Serum levels of leuprolide showed a rapid increase immediately after injection, reaching a peak proportional to dose within 3 h (range of mean values 13.1-54.5 ng/ml). Subsequently, mean drug levels declined to a plateau proportional to dose (0.49-1.99 ng/ml at 5 weeks). A significant dose-dependent increase in the area under the serum concentration-time curve from zero to 35 days (AUC0-35 days) from 541.7 to 1653.9 ng/ml.h was also noted (p less than 0.01). With all doses there was an initial rise in serum LH and FSH, followed by a rise in testosterone and dihydrotestosterone, then a sharp decrease within 3 weeks. FSH inhibition was achieved in all the 20 evaluable patients and was maintained in 17 of them (85%) over 5 weeks. Fifteen subjects (75%) had marked suppression of LH levels. In 13 of them (65%) this condition continued for the entire observation time. Castration levels of serum testosterone and dihydrotestosterone, however, were maintained in all patients for up to 5 weeks. Two of the 21 evaluable patients (10%) had a complete response; 15 a partial response (71%) and 3 stable disease (14%). No significant differences were observed in relation to dose. Clinical improvement and serum hormonal changes support this as a new and superior method of administration of leuprolide at a dose as low as 3.75 mg.

Topics: Aged; Antineoplastic Agents; Delayed-Action Preparations; Dihydrotestosterone; Dose-Response Relationship, Drug; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Models, Theoretical; Prostatic Neoplasms; Radioimmunoassay; Testosterone

Six patients with advanced prostatic cancer who had been treated by long-term administration of LH-RH agonistic preparations (Buserelin or Leupron) were tested for their pituitary-testicular endocrine functions. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), prolactin (PRL), estradiol (E2) and dihydrotestosterone (DHT) were measured consecutively. In all medically castrated patients, serum levels of LH, FSH, T, DHT and E2 were suppressed and particularly serum T levels were below the castration level of 1.0 ng/ml. On the other hand, serum PRL levels were unchanged after the long-term treatment with the agonists. Serum LH and FSH levels failed to respond to LH-RH stimulation after the treatment, whereas serum T responded to stimulation by human chorionic gonadotropin (hCG) to various degrees. It was remarkable that, in 4 out of 6 medically castrated patients treated up to more than 3 years, serum T response levels above 1.0 ng/ml were noted. It is suggested that testicular endocrine function to secrete T and DHT in patients under treatment with long-term LH-RH agonist administration are still preserved in response to hCG stimulation.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Buserelin; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Testis; Testosterone

Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Flutamide; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Prostatic Neoplasms

Topics: Antineoplastic Agents; Delayed-Action Preparations; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Prostatic Neoplasms; United States; United States Food and Drug Administration

A luteinizing hormone-releasing hormone (LH-RH) analogue was administered for 3 to 32 months to 15 prostatic cancer patients in stage B-D (B:3, C:8, D:4). Intratesticular, intratubular and prostatic androgen levels were measured by radioimmunoassay before and after LH-RH analogue therapy. The measurement of serum prostatic acid phosphatase (PAP) and prostatic specific antigen (PA) levels was also conducted. Thereafter, we assessed the effect of the LH-RH analogue on androgen levels and the relation of prostatic tissue 5 alpha-dihydrotestosterone (DHT) level to the clinical response. The results were as follows: 1) Johnsen's mean germinal epithelium count was significantly decreased from 7.7 +/- 2.1 (mean +/- S.D.) to 4.3 +/- 2.3, and the wall thickness of seminiferous tubules was increased from 5.93 +/- 1.31 to 11.9 +/- 3.64 microns. 2) Plasma testosterone (T), intratesticular and intratubular androgen levels were significantly decreased (plasma T: from 4.40 +/- 1.84 to 0.61 +/- 0.32 ng/ml, intratesticular T: from 335.3 +/- 170.3 to 4.6 +/- 3.8 ng/g.t.w., DHT: from 25.3 +/- 11.7 to 3.7 +/- 2.7 ng/g.t.w., intratubular T: from 50.8 +/- 36.6 to 0.10 +/- 0.99 ng/g.t.w. and DHT: 7.54 +/- 3.20 to 0.63 +/- 0.90 ng/g.t.w.). 3) Crude nuclear DHT levels in prostatic tissue fell from 15.3 +/- 9.3 (N = 8) to 0.37 +/- 0.54 pg/mg protein (N = 3) and the level was non-detectable in 5 of 8 cases. 4) Complete remission was achieved in 1 patient, partial response in 5, objective stable in 8, and objective progression in 1 patient, according to Shimazaki's criteria.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgens; Antineoplastic Agents; Buserelin; Dihydrotestosterone; Drug Evaluation; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Middle Aged; Prostatic Neoplasms; Remission Induction; Testosterone

Serial measurements of urinary hydroxyproline excretion were performed in 16 patients with stage D2 prostatic cancer to evaluate its role as a marker for following disease course. Patients were defined as having stable or progressive disease by the criteria of the National Prostatic Cancer Project. For patients with stable disease and those with disease progression excretion of hydroxyproline did not correlate with the clinical course. We did not find that hydroxyproline was a useful marker in the clinical setting to follow patients with prostatic cancer.

Topics: Bone Neoplasms; Buserelin; Creatinine; Flutamide; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Hydroxyproline; Leuprolide; Male; Prostatic Neoplasms

A slow-release formulation of the luteinizing hormone releasing hormone (LH-RH)analog(TAP-144-SR) was administered in 6 cases of prostatic cancer. Five were untreated cases, 3 of moderately-differentiated and 2 of poorly-differentiated cancers (four D2 and one C, NX), the other (D2) was under control by another LH-RH analog. The plasma level of luteinizing hormone and follicle stimulating hormone fell below normal, and the plasma testosterone was less than 1 ng/ml by four weeks after start of treatment. According to the National Prostatic Cancer Project Criteria, 2 of the untreated cases showed a partial response and 3 of the untreated ones showed a stable response, one of which underwent transurethral resection later. The pretreated case still continued controlled more than 4 months. No side effect was noticed.

Topics: Acid Phosphatase; Aged; Aged, 80 and over; Antineoplastic Agents; Delayed-Action Preparations; Drug Evaluation; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Prostate; Prostatic Neoplasms; Remission Induction; Testosterone

The R-3327 prostatic tumor implanted in the male Copenhagen x Fischer F1 rat continues to grow because androgen is being supplied from an endogenous source. It follows that regimens which decrease the availability of androgen will retard the growth rate of the tumor. These experiments showed that castration, the antiandrogen flutamide, and the luteinizing hormone-releasing hormone (LHRH) agonist leuprolide inhibited tumor growth. Adrenalectomy alone had no significant effect on tumor size and did not further retard the growth of the tumor in castrated rats. Further, under the conditions of this study, there was no significant difference in tumor growth rates between the groups of rats treated with either flutamide alone or flutamide combined with leuprolide. Total ablation of androgen may not be needed for maximal inhibition of tumor growth.

Topics: Adenocarcinoma; Adrenalectomy; Anilides; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Drug Evaluation, Preclinical; Flutamide; Gonadotropin-Releasing Hormone; Leuprolide; Male; Neoplasm Transplantation; Orchiectomy; Prostatic Neoplasms; Rats; Rats, Inbred F344; Time Factors

Leuprolide, a synthetic LHRH analog, inhibited growth of the Dunning R 3327 androgen-sensitive rat prostatic tumor and induced weight loss in male accessory sex organs. The relationship between the mode of administration and efficiency of the treatment was examined. Maintenance of the drug level in vivo seemed to be one of the important factors in the suppression of tumor growth, while a decrease in the weight of the accessory sex organs was mainly dependent on the dose administered. No treatment with leuprolide surpassed the effect caused by castration. Cytosolic androgen receptor and acid phosphatase activity in the tumor tissues were not changed significantly after treatment with leuprolide.

Topics: Acid Phosphatase; Animals; Cytosol; Genitalia, Male; Gonadotropin-Releasing Hormone; Leuprolide; Male; Neoplasm Transplantation; Orchiectomy; Organ Size; Prostatic Neoplasms; Rats; Rats, Inbred Strains; Receptors, Androgen; Testis; Testosterone

Endocrine therapy for urological tumor includes estrogen therapy for prostatic carcinoma. This endocrine therapy is one of the most firmly established therapeutic methods in the field of clinical oncology. However, confusion exists about how long this treatment remains effective and whether it prolongs survival, since estrogen can create cardiovascular complications in patients with prostatic carcinoma. Recently, new endocrine agents have been developed to compensate for the problems of estrogen therapy and to make treatment more effective. Estramustine sodium phosphate is medicine for internal use prepared by combining estradiol with nitrogen mustard. This hormonal chemotherapeutic agent has proved effective in 98% of treated patients. Most of the side effects of this agent have been observed in the digestive organs. Chlormadinone acetate, a progestational agent, has proved more effective against early prostatic carcinoma than against late-stage disease. LHRH analogue, which is now drawing much attention as a "chemical castration" agent for prostatic cancer patients, exerts an effectiveness equal to medium-dose estrogen treatment. The above three agents for the treatment of prostatic carcinoma should become increasingly popular in the future.

Topics: Buserelin; Chlormadinone Acetate; Estramustine; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Nitrogen Mustard Compounds; Prostatic Neoplasms

The chronic effect of long-term injections of leuprolide on the hypothalamic, pituitary and gonadal axes have been studied in men with advanced prostatic cancer. The possibility of transient acute changes in luteinizing hormone, follicle-stimulating hormone and testosterone after each daily injection was studied in 31 patients treated for more than 1 year. No evidence of escape from daily 1.0 mg. doses was noted. No pituitary responsiveness was observed at any time point examined. Thus, daily administration of 1.0 mg. leuprolide acetate subcutaneously produces durable, complete suppression of gonadotropins and testosterone for prolonged periods.

Topics: Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Orchiectomy; Prostatic Neoplasms; Testosterone; Time Factors

Topics: Administration, Intranasal; Aged; Aged, 80 and over; Biodegradation, Environmental; Gonadotropin-Releasing Hormone; Hormones; Humans; Injections, Subcutaneous; Leuprolide; Male; Prostatic Neoplasms

Topics: Animals; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms; Rats; Rats, Inbred Strains; Testis; Testosterone

Topics: Androgen Antagonists; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Buserelin; Carcinoma; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms; Triptorelin Pamoate

Luteinizing hormone-releasing hormone (LH X RH) agonist can be administered daily to patients with prostatic cancer with resulting clinical efficacy. A sustained drug release formulation of an LH X RH agonist, (D-Leu6)-des Gly-NH2(10)-LH X RH ethylamide (leuprolide)-vinyl polymer composite, was prepared by means of radiation-induced polymerization under a supercooled state. The sustained release of leuprolide from subcutaneously implanted leuprolide-vinyl polymer composite (14 mm in diameter and 4 mm in thickness) was obtained over a period of several months in five patients with prostatic cancer. Serum testosterone levels began to decrease on the tenth day, fell below 1 ng/ml after three weeks of implantation, and thereafter remained at the castration level until removal of the polymer composite. Clinical improvement was associated with serum hormonal changes, and support this as a novel and superior method of administration of LH X RH agonist.

Topics: Aged; Antineoplastic Agents; Delayed-Action Preparations; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Luteinizing Hormone; Male; Polymers; Prostatic Neoplasms; Testosterone

From June 1982 to February 1985, 53 patients with stage D2 carcinoma of the prostate confirmed by tissue biopsy, elevated prostatic acid phosphatase and a positive bone scan were initiated on androgen deprivation therapy. Before commencement of treatment all patients underwent determination of serum testosterone levels at 8 a.m. Of the patients 23 received 200 mcg. buserelin per day, 17 received 1 mg. diethylstilbestrol 3 times daily, 6 received 40 mg. megestrol acetate 4 times daily, 2 received 1 mg. leuprolide per day and 5 underwent bilateral orchiectomy. Evaluation of the best response in each patient revealed 3 (6 per cent) complete and 17 (32 per cent) partial responses, while 22 patients (41 per cent) remained stable and 11 (21 per cent) had progression. Pre-treatment serum testosterone levels ranged from 150 to 879 ng. per dl. The mean serum testosterone level in patients having a complete response was 524 +/- 18.04 ng. per dl. The mean in the progression group was 279.4 +/- 110.1 ng. per dl. This difference was not statistically significant owing to the large standard deviation in the progression group. However, of the 15 patients who had a pre-treatment serum testosterone level of more than 500 ng. per dl. only 1 (7 per cent) had progression. None of the patients whose pre-treatment testosterone level was less than 200 ng. per dl. had objective tumor regression. Our study suggests that pre-treatment serum testosterone levels may predict the probability of a satisfactory response to androgen deprivation therapy.

Topics: Aged; Aged, 80 and over; Buserelin; Carcinoma; Diethylstilbestrol; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Megestrol; Megestrol Acetate; Middle Aged; Orchiectomy; Prostatic Neoplasms; Testosterone

The hormonal and clinical efficacy of (D-Leu6)-des Gly-NH2(10)-LH.RH ethylamide (Leuprolide, TAP 144) was investigated with 12 prostatic cancer patients. The hormonal studies were performed in 8 patients who were not previously treated by any hormonal therapies including estrogen, castration and others. Serum level of LH and FSH was apparently decreased at the end of 2 weeks after the starting of leuprolide (1 mg/day) subcutaneous injection. At the same time, testosterone level was decreased to the castration level. Clinical efficacy of 1 mg/day of leuprolide was evaluated in 7 patients who were not previously treated. Three of the 4 patients with stage B2 cancer showed a partial response and 1 patient a stable response; and 1 of the 3 patients with stage D2 cancer showed a partial response and patients stable a response. No significant side effects were observed in these 12 patients. These results show that 1 mg/day of leuprolide has the same degree of potency in decreasing the serum testosterone as 20 mg/day.

Topics: Aged; Antineoplastic Agents; Dehydroepiandrosterone; Drug Administration Schedule; Estradiol; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Prostatic Neoplasms; Testosterone

Twenty-two patients with prostatic cancer were treated for 12 to 52 weeks with the luteinizing hormone-releasing hormone agonist, (D-Leu6)-des Gly-NH2 10-LHRH ethylamide (leuprolide). The clinical efficacy of leuprolide was evaluated at 12 weeks according to NPCP criteria. All seven patients with Stage B and C disease demonstrated a partial objective regression. The objective response rate in 12 previously untreated Stage D patients was 92% (partial regression: 5; stable disease: 6). In three relapsing Stage D patients, one demonstrated stable disease and two failed to respond to leuprolide therapy. Even though the dose of leuprolide used in this study was high, no serious side effects were observed in any patients. There was a large increase in serum FSH and LH levels during the first few days of treatment, but serum FSH and LH levels fell below the initial levels by 1 and 2 weeks, respectively. Serum testosterone fell to less than 1 ng/ml within 3 weeks, and at 12 weeks it was 7.99% of the initial level. The present study shows that chronic administration of leuprolide in high doses can safely and effectively reduce the level of serum testosterone in patients with prostatic cancer.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Biopsy; Bone Neoplasms; Carcinoma; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Prostatic Neoplasms; Testosterone; Time Factors

Leuprolide (Lupron, TAP Pharmaceuticals), a potent agonist analogue of GnRH, has been shown to suppress testicular androgen production in animals. In order to determine the potential of leuprolide as an alternative to surgical castration in human males with prostatic cancer, this agent was administered to castrate and noncastrate males with carcinoma of the prostate. Baseline and treatment levels of LH, FSH, testosterone and dihydrotestosterone were determined serially. Leuprolide suppressed pituitary production of LH and FSH and, consequently, testicular production of testosterone and dihydrotestosterone. This agent simulates the results achieved with surgical castration.

Topics: Adenocarcinoma; Antineoplastic Agents; Castration; Dihydrotestosterone; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Luteinizing Hormone; Male; Prostatic Neoplasms; Testis; Testosterone

Current management techniques for metastatic prostatic cancer have given rise to controversies regarding the optimal timing, form, and degree of androgen deprivation. Low-dose diethylstilbestrol (DES) or orchiectomy decrease serum testosterone levels while posing less cardiovascular risk than high-dose DES. LH-RH analogues, such as leuprolide or buserelin, also inhibit testosterone production. Some studies suggest that some tumor cells may be relatively, rather than absolutely, androgen dependent. This has been the rationale for the combined use of a pure antiandrogen and an LH-RH agonist. Unfortunately, while this combination has been found effective in previously untreated patients, it has not been equally effective in those who have undergone prior therapy and demonstrated disease progression.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Buserelin; Castration; Cyclophosphamide; Diethylstilbestrol; Estramustine; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Neoplasm Metastasis; Prostatic Neoplasms

Bilateral orchiectomy was performed as secondary endocrine treatment in 12 patients with prostatic cancer who were treated initially with a gonadotropin-releasing hormone analogue. Compared to a control group of prostatic cancer patients undergoing orchiectomy as primary therapy, the testes in the hormonally treated group showed marked spermatogenic suppression, peritubular membrane thickening and decreased numbers of Leydig cells. The degree of fibrosis and the damage seen in these testes imply that the spermatogenic suppression seen after prolonged gonadotropin-releasing hormone analogue administration may not be as reversible as previously suggested.

Topics: Aged; Antineoplastic Agents; Carcinoma; Castration; Combined Modality Therapy; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Leydig Cells; Male; Middle Aged; Prostatic Neoplasms; Spermatogenesis; Testis; Time Factors

Topics: Animals; Antineoplastic Agents; Castration; Diethylstilbestrol; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Prostatic Neoplasms

Luteinizing hormone releasing hormone (LHRH) analogs have been shown to be an effective alternative endocrine treatment of metastatic prostatic carcinoma. After a transient stimulation of testosterone (T) and dihydrotestosterone (DHT) during the first week of therapy, continued administration of LHRH analogs has reliably suppressed serum androgens to castrate levels. About 10 per cent of previously untreated patients begun on LHRH therapy will experience transient worsening of disease symptoms corresponding to the initial rise in androgen levels. In an attempt to eliminate the early rise of T and DHT, 9 patients with metastatic prostatic carcinoma were pretreated with diethylstilbestrol (DES), 3 mg/day, for one week prior to the initiation of LHRH therapy. Following this, both DES and LHRH were given concomitantly for a week, after which DES was discontinued. LHRH was then continued as long as patients experienced clinical benefit. T and DHT levels were performed pre-study and on days 4, 8-11, 13, 15, and 29 of study. Results indicate that pretreatment with DES did not completely prevent the rise in T and DHT seen during the first week of LHRH therapy, although T and DHT levels rose to only slightly above baseline during the first four days. T and DHT levels then markedly decreased, and castrate levels were achieved by day 29 of treatment.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Diethylstilbestrol; Drug Administration Schedule; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Prostatic Neoplasms; Testosterone; Time Factors

The chemical structure of luteinizing-hormone-releasing hormone (LHRH) was discovered in 1971 after more than a decade of intensive effort. Subsequent physiologic studies in primates and humans showed that the biologic activity of LHRH depends on the way in which the hormone is administered. Pulsatile administration of LHRH, which mimics the natural secretory pattern, causes sustained secretion of the gonadotrophins. This method of administration has been used to induce ovulation in women with hypothalamic amenorrhea and to induce puberty and spermatogenesis in men with hypogonadotrophic hypogonadism. Continuous infusion, however, produces only transient stimulation of gonadotrophin secretion, followed by a "desensitization" response in which gonadotrophin secretion is inhibited. Thus, LHRH can either augment or inhibit gonadotrophin secretion depending on the mode of administration. Recently, long-acting synthetic analogs of LHRH have been shown to desensitize the pituitary gland and inhibit gonadotrophin release when administered as a single daily subcutaneous injection. These LHRH analogs have proved highly effective in the treatment of prostatic carcinoma and central precocious puberty. They are also being studied as a new approach to contraception and to the treatment of endometriosis and polycystic ovary syndrome.

Topics: Animals; Child; Contraceptive Agents, Male; Endometriosis; Estrogens; Female; Follicle Stimulating Hormone; Genital Diseases, Female; Genital Diseases, Male; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Hypothalamic Diseases; Infertility; Leuprolide; Luteinizing Hormone; Male; Neoplasms, Hormone-Dependent; Ovulation Induction; Polycystic Ovary Syndrome; Prostatic Neoplasms; Puberty, Precocious; Spermatogenesis; Time Factors; Triptorelin Pamoate

Topics: Animals; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Luteinizing Hormone; Male; Neoplasms, Experimental; Prostatic Neoplasms; Rats; Testosterone

Topics: Antineoplastic Agents; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Neoplasm Metastasis; Prostatic Neoplasms

Topics: Animals; Diethylstilbestrol; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Prostatic Neoplasms

Topics: Acid Phosphatase; Aged; Diethylstilbestrol; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prospective Studies; Prostatic Neoplasms; Random Allocation; Testosterone

Topics: Androgen Antagonists; Antineoplastic Agents; Buserelin; Combined Modality Therapy; Estradiol Congeners; Estramustine; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Lymphatic Metastasis; Male; Neoplasm Staging; Orchiectomy; Prognosis; Prostate; Prostatectomy; Prostatic Neoplasms

Ketoconazole is a potent inhibitor of the P450 series of enzymes that are essential for the production of androgens. In order to determine the effects of ketoconazole on androgen production and androgen dependent tissues in the rat, adult male rats were administered varying doses of ketoconazole every 12 hours. Serum testosterone declined to unmeasurable levels at ketoconazole doses of greater than 4 mg. This dose was sufficient to completely inhibit the testosterone surge induced by the administration of a potent luteinizing releasing hormone agonist. The ventral prostate weight of normal rats and the volume of the Dunning R3327H androgen dependent prostatic cancer declined at the same rate in animals treated with ketoconazole or castration. Ketoconazole may be an effective agent to treat androgen dependent diseases.

Topics: Adenocarcinoma; Animals; Castration; Depression, Chemical; Gonadotropin-Releasing Hormone; Half-Life; Ketoconazole; Leuprolide; Male; Neoplasms, Hormone-Dependent; Organ Size; Prostate; Prostatic Neoplasms; Rats; Rats, Inbred Strains; Testosterone

Administration of the superagonist analog of GnRH, D-Leu6-GnRH proethylamide, profoundly reduced plasma LH, FSH, testosterone, and dihydrotestosterone levels when given for 6-11 weeks to adult men with prostatic carcinoma. Since patients with prostatic carcinoma can be expected to receive this analog for as long as 3-4 yr, we questioned whether the same degree of reduction could be maintained during chronic administration. In 22 men who had received D-Leu6-GnRH proethylamide for at least 1 yr, LH and testosterone remained at the initial low levels. Plasma dihydrotestosterone concentrations, on the other hand, gradually fell further with long term administration. FSH levels reached a nadir of 5.7 +/- 0.94 (+/- SEM) mIU/ml at 10-11 weeks. Unexpectedly, the plasma levels of this gonadotropin then gradually increased, and between 25 and 97 weeks were approximately 10-15 mIU/ml. This pattern occurred identically in patients receiving either 1 or 10 mg D-Leu6-GnRH proethylamide daily. These data indicate persistent suppression of LH and androgen levels during prolonged therapy and suggest that D-Leu6-GnRH-induced "medical castration" can be maintained with chronic administration.

Topics: Aged; Dihydrotestosterone; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Prostatic Neoplasms; Testosterone; Time Factors

The synthetic gonadotropin releasing hormone agonist [D-leu6, desgly-NH2(10), proethylamide9]-GnRH (leuprolide) was tested for its ability to inhibit androgen-sensitive R3327-G rat prostatic tumor growth in Copenhagen X Fischer F1 male rats. The chronic administration of leuprolide at 50 micrograms per kg. body weight or 1000 micrograms per kg. body weight significantly reduced serum testosterone levels and testis weights. Only chronic leuprolide administration at high concentration (1000 micrograms per kg.) compared with orchiectomy in reducing the rate of tumor growth, prolonging survival, and affecting changes in DNA content per cell as quantitated by flow cytometry. The DNA content changes and cell kinetic responses of R3327-G tumors to these treatments were related to the extent to which serum testosterone levels were reduced. The data suggest that for some prostatic cancers gonadotropin releasing hormone agonist administration must reduce serum testosterone levels to those achieved by orchiectomy for maximal growth rate inhibition.

Topics: Animals; Castration; Diploidy; Flow Cytometry; Gonadotropin-Releasing Hormone; Karyotyping; Leuprolide; Male; Neoplasm Transplantation; Prostatic Neoplasms; Rats; Testosterone; Time Factors

Leuprolide is a new, potent analogue of gonadotropin releasing hormone, which lowers serum gonadotropins and testosterone with chronic administration. Thirty patients with metastatic carcinoma of the prostate have undergone primary endocrine treatment with leuprolide. Subjective and objective response rates appear to be equal to alternative endocrine therapy, although the mean response duration has not been defined to date. Since castration and the side effects of oral estrogens are avoided leuprolide may prove to be the preferred initial hormonal therapy for selected patients with metastatic prostatic cancer.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents; Carcinoma; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Pituitary Hormone-Releasing Hormones; Prostatic Neoplasms

Twenty-nine subjects with metastatic carcinoma of the prostate received daily subcutaneous injections of leuprolide, a luteinizing hormone-releasing hormone analog. After transient gonadotropin and androgen stimulation, leuprolide induced long-term suppression of serum testosterone and gonadotropins production. In 25 subjects there was objective disease stabilization or tumor regression. Eleven subjects subsequently relapsed (median = 10 mo) after initiation of treatment. Except for vasomotor hot flashes, leuprolide appears to be well tolerated by patients with advanced prostatic cancer.

Topics: Aged; Drug Evaluation; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Luteinizing Hormone; Male; Middle Aged; Prostatic Neoplasms; Testosterone

The clinical efficacy of (D-Leu6)-des Gly-NH2(10)-LH X RH ethylamide (Leuprolide) against prostatic cancer was evaluated at the end of twelve weeks of administration of a daily dose of 20 mg subcutaneous injection to 22 patients with prostatic cancer. Of these 22 patients, 19 were previously non-treated and 3 had reactivated cancer. Complete regression was obtained in all patients with stage B or C cancer. Also, in 5 out of 12 previously non-treated patients with stage D cancer, Leuprolide administration proved to be effective for controlling prostatic cancer. However, Leuprolide therapy produced only stable effects at best in 3 patients who had reactivated cancer. It has no side effect and should be recommended as a drug of first choice in the treatment of previously non-treated prostatic cancer. It can be assumed from the present studies that the efficacy of this agent against prostatic cancer is mainly the result of its inhibitory effect on hypothalamo-pituitary testicular system, i.e., a medical castration effect.

Topics: Aged; Antineoplastic Agents; Drug Evaluation; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Male; Middle Aged; Prostatic Neoplasms

The histologic appearance of the testes of men exposed to chronic gonadotropin-releasing hormone agonist (GnRH-A) therapy has not been previously documented. Herein, we report on the histologic features of the testes of four patients with disseminated prostatic carcinoma who received at least 1 year of daily treatment with (D-Leu6, des-Gly-NH2(10), proethylamide9)-GnRH (leuprolide, Abbott Laboratories, North Chicago, IL) for their disease, and subsequently underwent bilateral orchiectomy. In marked contrast to the testes from five control patients, the testes of these agonist-treated patients demonstrated absence of spermatogenesis, Leydig cell hypoplasia, and Leydig cell inactivity. These data provide direct histologic evidence that the chronic administration of GnRH agonists may be suitable as a potential male contraceptive.

Topics: Aged; Antineoplastic Agents; Carcinoma; Contraceptive Agents, Male; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Leydig Cells; Luteinizing Hormone; Male; Microscopy, Electron; Middle Aged; Prostatic Neoplasms; Spermatogenesis; Testis; Testosterone; Time Factors

Topics: Antineoplastic Agents; Diethylstilbestrol; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Male; Prostatic Neoplasms

At least 80 per cent of prostatic tumors exhibit some degree of hormone responsiveness. The preferred method of hormonal alteration has yet to be determined because new agents are currently undergoing clinical trials. The compounds tested have included cyproterone acetate, a progestational agent; flutamide, an antiandrogen that blocks the DHT-receptor complex in the tumor cell; and aminoglutethimide, which inhibits adrenal steroid production and, therefore, might further lower the level of circulating androgen following bilateral orchiectomy. The introduction of potent, synthetic analogues of gonadotropin-releasing hormone (GnRH) has provided another method of reducing the level of circulating androgen. A recent report on the efficacy of one of these analogues--leuprolide--in men with newly diagnosed metastatic prostatic cancer has revealed an initial response rate of 76 per cent (4% complete remissions, 32% partial remissions, and 40% stable) using National Prostatic Cancer Project criteria.

Topics: Adenocarcinoma; Aminoglutethimide; Androgen Antagonists; Bone Neoplasms; Buserelin; Flutamide; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Megestrol; Megestrol Acetate; Pituitary Hormone-Releasing Hormones; Prostatic Neoplasms

Metastatic prostatic cancer generally is treated by either castration or the administration of exogenous estrogens, both of which have significant clinical disadvantages. Luteinizing hormone releasing hormone analogues have been shown to suppress gonadal steroidogenesis in animals and humans. To assess the effect of the administration of a potent luteinizing hormone releasing hormone analogue, (D-Leu-6)luteinizing hormone releasing hormone (1-9) nonapeptide ethylamide, 9 patients with previously untreated stage D2 prostatic cancer were treated with this agent for 3 to 8 months. By 3 months of treatment all patients demonstrated a significant decrease in serum testosterone and a decreased peak serum luteinizing hormone and testosterone response to the acute administration of the analogue, with no change in baseline serum luteinizing hormone or prolactin. These data suggest that this analogue acts by decreasing the pituitary release of luteinizing hormone. No major adverse effects were noted with this treatment modality, and all patients were symptomatically improved and demonstrated a decrease or stabilization in tumor activity as measured by prostatic computerized tomography or ultrasound scan, prostatic acid phosphatase and bone scan. A representative case is presented. Luteinizing hormone releasing hormone analogues may prove to be valuable new agents in the treatment of advanced prostatic cancer.

Topics: Aged; Bone Neoplasms; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Lymphatic Metastasis; Male; Middle Aged; Prostatic Neoplasms; Tomography, X-Ray Computed

Topics: Antineoplastic Agents; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prostatic Neoplasms