histrelin and Prostatic-Neoplasms

Histrelin is a gonadotropin-releasing hormone agonist available in a diffusion-controlled reservoir drug delivery system for subcutaneous implantation. The subcutaneous histrelin implant provided sustained suppression of serum testosterone, luteinizing hormone (LH) and prostate-specific antigen levels for up to 1 year in patients with advanced prostate cancer in two phase II or III trials. In the noncomparative, multicentre, phase III study, serum testosterone was suppressed to castrate levels (i.e. < or =50 ng/dL) within 4 weeks in all patients who received a histrelin acetate 50 mg implant, with 99-100% of histrelin implant recipients maintaining castrate levels for the remainder of the 1-year treatment period. Such efficacy was provided irrespective of patient age or stage of disease. Although a transient surge in serum testosterone levels occurred after placement of the initial histrelin implant, no acute elevations in testosterone or LH levels were observed in patients whose implant was replaced after 1 year of therapy and suppression of these hormones continued to be maintained. The histrelin implant was generally well tolerated in patients with advanced prostate cancer in the phase III trial and in a pooled analysis. No patients prematurely discontinued treatment because of adverse events, most of which were the consequence of hormone suppression.

Topics: Animals; Antineoplastic Agents, Hormonal; Drug Delivery Systems; Drug Implants; Evidence-Based Medicine; Gonadotropin-Releasing Hormone; Humans; Male; Neoplasm Staging; Prostatic Neoplasms; Treatment Outcome

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Clinical Trials as Topic; Drug Implants; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Prostatic Neoplasms; Treatment Outcome

Topics: Absorption; Antineoplastic Agents, Hormonal; Biological Availability; Delayed-Action Preparations; Drug Administration Schedule; Drug Implants; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Prostatic Neoplasms; Testosterone

Valera Pharmaceuticals, formerly Hydro Med Sciences, is developing a once-yearly Histrelin Hydrogel Implant [Histrelin implant, LHRH-Hydrogel implant, RL 0903, SPD 424, Vantas], a subcutaneous (s.c.) reservoir device capable of long-term delivery of histrelin at constant release rates for the treatment of prostate cancer. Histrelin is a luteinising hormone-releasing hormone agonist (LHRH). A different formulation of the LHRH implant is currently in development for the treatment of central precocious puberty (CPP). On 4 September 2003, Hydro Med Sciences announced that it had changed its name to Valera Pharmaceuticals. Shire Pharmaceuticals had an option to market and distribute the histrelin implant outside the US, but in a realigned agreement announced in January 2002, Shire stated that HydroMed (now Valera) would be responsible for concluding the phase III studies, filing for regulatory approval and producing the implant, while also gaining marketing rights in the US. Shire has no further involvement in development, but retains an option to market and distribute the product outside the US. The product is available for rest-of-the-world licensing through Valera Pharmaceuticals' business development division. Paladin Labs has received the exclusive rights for the sale and marketing of histrelin hydrogel implant in Canada. Valera Pharmaceuticals will have the responsibility for manufacturing and completing development of the product. In July 2004, Paladin announced it had filed for regulatory approval with Health Canada for the treatment of prostate cancer. Phase III trials have been conducted and initially involved two open-labelled, randomised, parallel studies that compared the hydrogel implant with the active comparators, leuprorelin acetate 22.5 mg depot (TAP Pharmaceutical's Lupron Depot) and a 3-month implant of goserelin acetate (Astra Zeneca's Zoladex). However, because of financial constraints, HydroMed discontinued recruitment in a phase II European study and could not rationalise keeping the comparator arm of the phase III study. The US FDA then gave permission to continue the US part of the programme without the comparator arm, but with appropriate increases in the patient sample size. Patient enrolment in the phase III trial (US and Canada) was completed in July 2002. Valera Pharmaceuticals believes the product may have advantages over standard prostate cancer treatments including reduced costly surgical procedures, lower dosing, increased pa

Topics: Antineoplastic Agents; Drug Implants; Female; Gonadotropin-Releasing Hormone; Humans; Hydrogels; Injections, Subcutaneous; Male; Prostatic Neoplasms; Puberty, Precocious

Use of gonadotropin-releasing hormone (GnRH) agonists produces a transient increase and subsequent long-term reduction in concentrations of pituitary hormones, resulting in gonadal hormone suppression. This reversible suppression is useful in treating diseases dependent on these hormones. GnRH agonists have been approved for use in patients with endometriosis, advanced prostate cancer, and precocious puberty. As research continues, GnRH agonists are expected to change the clinical approach to the treatment of many other reproductive and nonreproductive diseases.

Topics: Endometriosis; Female; Gonadotropin-Releasing Hormone; Humans; Male; Prostatic Neoplasms; Puberty, Precocious

To evaluate the efficacy and tolerability of a once-yearly histrelin implant during an open-label extension of a pivotal study.. Men with advanced prostate cancer and a clinical response to 52 weeks of treatment with the histrelin implant. Implants were placed annually. The primary efficacy variable was achievement of serum testosterone levels of ≤50 ng/dL. Secondary efficacy variables were disease progression, analgesia use, performance status and tolerability of therapy.. Of 104 patients enrolled, over 70% received three consecutive histrelin implants, and the longest, single treatment period was greater than 4 years. Serum testosterone was consistently suppressed below 50 ng/dL in all patients and mean testosterone levels were 13.1, 14.8 and 10.8 ng/dL after 104 weeks (year 2), 156 weeks (year 3) and 208 weeks (year 4) of treatment, respectively. Most patients showed no clinical worsening of their disease, were able to continue normal daily activities, and did not require analgesic medication during the extension period. Mean (SD) time to place the histrelin implant was 4.5 (6.2) min, with only three patients having insertions that were considered difficult. Adverse events were reported in 100 (96.2%) patients. The eight deaths and 28 (26.9%) serious adverse events were judged as unrelated to the study drug. The most commonly reported drug-related adverse events was hot flashes in 67 (64.4%) patients. Most of these cases was judged as mild or moderate.. The once-yearly histrelin implant maintained testosterone suppression for repeated treatment cycles and was generally well tolerated. The histrelin implant provides a clinically attractive option for long-term androgen deprivation therapy in patients with advanced prostate cancer seeking fewer office visits and repeated injections.

Topics: Aged; Disease Progression; Drug Implants; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Male; Palliative Care; Prostatic Neoplasms; Testosterone; Treatment Outcome

This open label, multicenter study was done to evaluate the efficacy and safety of the gonadotropin hormone-releasing hormone agonist histrelin acetate administered as a 50 mg subdermal implant in men with advanced prostatic cancer.. The 3 cm x 3.5 mm histrelin implant was surgically inserted in the inner aspect of the upper nondominant arm of eligible patients under local anesthesia. Patients were evaluated weekly for the first 2 weeks after implant insertion and monthly thereafter. At week 52 the implant was removed and in most cases a new implant was inserted. Patient observation for safety and efficacy continued to week 60. Efficacy was determined by the proportion of patients who attained chemical castration (serum testosterone 50 ng/dl or less) at weeks 4 through 52.. Of the 134 patients with week 4 testosterone levels available 100% achieved chemical castration. Testosterone suppression was maintained throughout the 52 weeks after implantation in more than 99% of patients. Significant LH and PSA suppression was also observed. By week 16 PSA had decreased an average of 90% from a baseline of 83.6 ng/ml (p = 0.0001). By week 60, 79% of patients had a complete PSA response (p <0.0175). No testosterone or LH surge was observed with reimplantation. Additionally, the implant was safe and well tolerated.. The gonadotropin hormone-releasing hormone agonist histrelin acetate provided in a unique implant delivery device is effective for treating men with advanced prostate cancer, as demonstrated by the suppression of testosterone and LH to castrate levels at 4 weeks and the maintenance of these levels during 52 weeks. PSA, a secondary end point for effectiveness, was also suppressed significantly from baseline.

Topics: Adenocarcinoma; Administration, Cutaneous; Aged; Aged, 80 and over; Disease Progression; Drug Implants; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Prostatic Neoplasms; Safety

Seventeen patients with advanced prostate cancer were studied to evaluate the pharmacokinetics and pharmacodynamics of a hydrogel implant designed to deliver histrelin at a constant rate (50 microg/d) for 1 year. Serum histrelin levels were collected during the 52-week implantation period and after a second implant. Testosterone suppression was the primary pharmacodynamic endpoint, with treatment success defined as serum testosterone less than 50 ng/dL. The histrelin subdermal implant delivered constant histrelin levels, with mean serum histrelin of approximately 0.265 ng/mL over 52 weeks. At the end of 52 weeks, mean histrelin concentrations were 0.128 +/- 0.0652 ng/mL. Patients achieved chemical castration (testosterone less than 50 ng/mL) by week 4. In patients who had the first implant removed and received a new implant at the end of the first 52 weeks, testosterone suppression was not interrupted. The hydrogel implant provided consistent delivery of histrelin over 1 year and effectively suppressed testosterone in men with prostate cancer.

Topics: Aged; Aged, 80 and over; Drug Implants; Gonadotropin-Releasing Hormone; Humans; Hydrogels; Luteinizing Hormone; Male; Prostatic Neoplasms; Testosterone

To evaluate the effectiveness of a hydrogel implant containing the gonadotropin-releasing hormone (GnRH) agonist histrelin in suppressing testosterone production in men with prostate cancer and to determine the effective dose (one, two, or four implants).. Forty-two men with prostate cancer and indications for androgen ablation were treated with one, two, or four implants. In two of the clinics, comprising 27 subjects, the treatment period was 12 months, with replacement with the same number of implants at 12-month intervals. In a third clinic, which treated 15 subjects, the implants were left in place for up to 30 months. The total experience was 605 treatment months.. The histrelin levels were detected in serum proportional to the number of implants placed. The response, however, was similar among all three dose levels, with testosterone and luteinizing hormone essentially completely suppressed. Serum testosterone levels decreased from 21.9 +/- 17.6 nmol/L to 0.93 +/- 1.57 nmol/L within 1 month and were maintained at 0.55 +/- 0.24 nmol/L at 6 months and 0.60 +/- 0.28 nmol/L after 12 months of treatment. Of the 38 assessable patients, 35 (92%) had castrate levels of testosterone within 4 weeks of the initial implant placement. All patients followed for up for 12 months after placement of the initial set of implants maintained suppression of testosterone production while the implant was in place.. The histrelin hydrogel implant provided adequate and reliable delivery of the potent GnRH agonist histrelin during at least 1 year using a single implant in men with prostate cancer. No apparent advantages were found in using more than one implant, and the question of the possible effectiveness of even lower doses remains open. This treatment modality appears to be both safe and effective.

Topics: Aged; Aged, 80 and over; Drug Implants; Follicle Stimulating Hormone; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Hydrogels; Luteinizing Hormone; Male; Middle Aged; Neoplasm Staging; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

The administration of gonadotropin hormone-releasing hormone agonists is well established for treating metastatic prostate cancer. In an ongoing study we evaluated the effect of a long acting implant that releases the gonadotropin hormone-releasing hormone agonist histrelin ([ImBzl]D-His6,Pro9-Net) in 15 patients with disseminated prostate cancer.. The 2.6 cm. implant releasing 60 microg. histrelin daily is inserted subcutaneously into the upper arm using local anesthesia. Of the patients 8 received 1 and the remainder received 2 implants. Treatment with the antiandrogen flutamide or cyproterone acetate began 2 weeks before implant insertion and continued for up to 12 weeks. Testosterone, luteinizing hormone (LH) and prostate specific antigen were determined monthly, and a metastatic evaluation was performed every 6 months.. LH and testosterone increased after flutamide administration and decreased after implant insertion. By day 28 LH and testosterone were completely suppressed. LH and testosterone decreased immediately after cyproterone acetate administration. Prostate specific antigen began to decrease during antiandrogen therapy and decreased further after implant insertion. One patient requested implant removal after 1 year for personal reasons and 1 died of an unrelated cause 18 months after insertion. Escape was demonstrated in 4 cases at 5, 10, 12 and 19 months, although LH and testosterone remained suppressed. Duration of treatment in the remaining 9 patients was between 21 and 30 months. LH and testosterone remained completely suppressed and prostate specific antigen levels were in the normal range. The clinical and biochemical response was identical in those who received 1 or 2 implants. At 12 months 8 patients were challenged at intermittent intervals for up to 24 months with a bolus of 100 microg. gonadotropin hormone-releasing hormone followed by 2 weeks of flutamide. The response was compared with that in untreated controls recently diagnosed with prostate cancer. Unlike controls there was complete LH suppression in the 8 challenged patients.. A histrelin implant suppresses LH and testosterone in prostate cancer for up to 30 months. This finding represents a significant improvement over existing preparations, which must be administered at 1 to 3-month intervals.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Drug Implants; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Time Factors

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

Medical castration with long-acting GnRH-agonist (GnRHa) is a well-established treatment for metastatic prostate cancer. Our aim was to explore the relationships between FSH, inhibin B, anti-Mullerian hormone (AMH), and testosterone during treatment with an implant releasing GnRHa.. Analysis of hormone levels in frozen serum samples.. Ten patients aged 77+/-7 (means+/-S.E.M.) years with prostate cancer were treated with the GnRHa histrelin for at least a year. Two weeks prior to insertion and for 3-4 months following removal the patients were treated with the antiandrogen flutamide. Serum inhibin B, FSH, testosterone, and AMH levels were measured retrospectively.. FSH, inhibin B, and testosterone increased during antiandrogen administration and levels fell after implant insertion. Four weeks post insertion, FSH gradually increased while inhibin B and testosterone remained fully suppressed. AMH levels did not change during antiandrogen treatment, but increased following implant insertion and remained elevated for the duration of implant use. Following removal, FSH and testosterone increased, inhibin B remained low, while AMH decreased.. The secondary increase in FSH following initial suppression with the implant is probably related to impaired inhibin B secretion. The lack of inhibin B response to the secondary increase in FSH suggests that long-term exposure of Sertoli-cells to GnRHa impairs their function. This effect appears to be selective since unlike inhibin B, AMH increased. In the absence of testosterone, FSH has a role in AMH regulation.

Topics: Aged; Aged, 80 and over; Anti-Mullerian Hormone; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Inhibins; Long-Term Care; Male; Prostatic Neoplasms; Retrospective Studies; Testosterone; Time Factors

Androgen deprivation therapy (ADT) is the standard care in men with advanced prostate cancer. Continuous testosterone suppression is essential to treatment efficacy. Recently a 1 year depot compound, histrelin, (VANTAS: Orion Pharmaceuticals, Finland; Endo Pharmaceuticals, USA), a gonadotropin-releasing hormone (GnRH) analog, was approved for hormone therapy of prostate cancer. In the present study the therapeutic efficacy of this compound was investigated, in addition to its impact on testosterone values and velocity as well as PSA.. One hundred thirty-one patients with histologically confirmed prostate cancer and normal testosterone levels were prospectively evaluated over 1 year. Androgen deprivation therapy was performed using a once yearly implant of the GnRH agonist histrelin. Testosterone and PSA levels, and histrelin serum profile were measured prospectively every month for 1 year. In addition, patients were stratified according to their PSA results and D'Amico risk profile.. Testosterone suppression (testosterone < or = 50 ng/dL) was measured in all patients between weeks 4 and 52; 88% of patients had a continuous testosterone level under 20 ng/dL. The PSA level in the total population decreased significantly within the first 2 weeks compared with baseline, and after 52 weeks the median PSA level of the total population was 0.2 ng/mL. PSA responses were grouped into three typical therapeutic outcomes and correlated with the clinical risk distribution, and levels were lowered in all three risk groups.. The GnRH agonist histrelin successfully suppressed testosterone over the entire study period. This effect was measured across a number of different clinical definitions of PSA response and clinical risk. The GnRH agonist therefore offers an effective therapy option in hormone treatment of prostate cancer.

Topics: Aged; Gonadotropin-Releasing Hormone; Humans; Male; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone

We present a case report of a patient with prostate cancer who failed to demonstrate consistent testosterone suppression to castration levels and incomplete suppression of serum prostate-specific antigen, although treated with gonadotropin releasing hormone agonists for 48 months. Serum dehydroepiandrosterone, dehydroepiandrosterone sulphate, as well as the androgen metabolite, androsterone glucuronide, were elevated compared to the other patients. The present data suggest that those prostate cancer patients who have even marginally elevated adrenal androgens may especially benefit from combined androgen blockade.

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Androgens; Anilides; Buserelin; Diarrhea; Flutamide; Gastrectomy; Glaucoma; Gonadotropin-Releasing Hormone; Hernia, Hiatal; Humans; Luteinizing Hormone; Male; Nitriles; Peptic Ulcer; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone; Tosyl Compounds

We determined the duration of testosterone suppression and recovery in patients with prostate cancer treated with a hydrogel implant releasing the gonadotropin releasing hormone (GnRH) agonist histrelin or treated with a depot GnRH agonist.. Luteinizing hormone (LH) and testosterone (T) responses were monitored in 3 groups. Group 1 comprised 7 patients treated with histrelin implant, which is inserted into the arm of the patient while under local anesthesia, and suppresses LH and testosterone. Following implant removal antiandrogens (flutamide or bicalutamide) were administered. Group 2 comprised 8 patients treated with long-term depot GnRH super agonists which were later withheld and patients were given bicalutamide. Group 3 consisted of 7 patients treated with bicalutamide.. In group 1 LH and T were in the castration range while implants were in place. LH increased 1 to 6 weeks after implant removal followed by an increase in T. In 7 of 8 patients in group 2, LH, T and prostate specific antigen remained suppressed for 9 months. In 6 of 7 group 3 patients LH and T increased with a decrease in prostate specific antigen.. Despite continuous prolonged T suppression for up to 3 years due to histrelin implant, LH and T increased rapidly following implant removal, indicating that suppression is reversible. In view of the 9-month suppression of LH and T after the last depot GnRH injection in 7 of 8 patients, it is possible to space GnRH agonist administration at longer intervals. However, T must be monitored to determine that suppression is maintained.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Antineoplastic Agents; Flutamide; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Middle Aged; Nitriles; Prostatic Neoplasms; Testosterone; Tosyl Compounds

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Cyproterone Acetate; Drug Implants; Drug Therapy, Combination; Flutamide; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Testosterone