Leuprolide is an established luteinizing hormone–releasing hormone (LHRH) agonist used as first-line treatment in advanced prostate cancer. As different formulations and dosing schedules are likely to have economic implications, we aimed to evaluate their efficacy, safety, and costs in nine European countries: Austria, Belgium, Czech Republic, Hungary, Italy, Latvia, Netherlands, Poland, and Portugal.
Database searches identified 13 clinical trials of leuprolide 1- (1 M), 3- (3 M) and 6-monthly (6 M). Only data on leuprolide with Atrigel were compared for all three formulations, which had the same efficacy, safety, and adherence. Cost-minimization analysis accounting for cost of Eligard®, specialist consultations, and diagnostics during up to 12 months follow-up was conducted. The perspective was that of public payers.
No significant differences were observed in the percentages of intention-to-treat patients achieving testosterone levels ≤ 50 ng/dL following treatment with Eligard® 1 M (93.3%), 3 M (98.3%), and 6 M (97.3%) (P > 0.05), and adverse event profiles of the three formulations were comparable. Overall, 6 M was the least expensive, with average total annual costs from €788 (Belgium) to €1839 (Portugal). The 3 M option was between 2.5% (Hungary) and 37.6% (Belgium) more expensive than 6 M; 1 M formulation was the most expensive, with costs 15.5% and 151.6% more expensive than 6 M for those countries, respectively. The 3 M option was 11.2%–45.3% less expensive than 1 M. Total costs were associated with frequency of visits for injection and monitoring. The 1 M required twelve visits, 3 M 4.4–4.8 visits, and 6 M 2.1–2.3 visits. Up to 50% additional visits could be funded with the savings resulting from switching eligible patients from 1 M and 3 M to 6 M. Results were stable in univariate and probabilistic sensitivity analyses.
Eligard® formulations offer comparable efficacy and safety, but different dosing schedules require different number of visits. The 6 M formulation offers the greatest cost savings and should be considered the treatment of choice in eligible patients in Europe.
prostate; cancer; androgen; leuprolide; Eligard; cost-effectiveness
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.
leuprolide acetate; gonadotropin-releasing hormone analog; testosterone; PSA; LH-RH
Two different 6-month GnRH agonist depot formulations approved for palliative treatment of advanced and metastatic prostate cancer in the United States – leuprolide acetate 45 mg and triptorelin pamoate 22.5 mg – provide patients with efficacy and safety comparable to those of existing 1-, 3-, and 4-month GnRH agonist depots. However, the 6-month formulations can increase patient convenience, comfort, and compliance by reducing the number of physician visits and injections required. At the conclusion of their pivotal trials, the 6-month formulations demonstrated efficacy rates in achieving chemical castration (serum testosterone ≤50 ng/dL) that ranged between 93% and 99%. As with existing GnRH agonist depot formulations, hot flashes represented the most common adverse event reported in trials of 6-month leuprolide acetate or triptorelin. As such, these products may prove useful not only for their labeled indication, but also as adjuncts to other treatments such as radical prostatectomy, radiotherapy, and chemotherapy. We recommend further research, including head-to-head trials between the 6-month GnRH depots, to refine our understanding of these products.
prostate cancer; leuprorelin; leuprolide; triptorelin; 6-month depot; testosterone
The primary objective of this study was to evaluate the effect of drug loading on the release of leuprolide acetate from an injectable polymeric implant, formed in situ, and efficacy of the released drug in suppressing serum testosterone levels in dogs for at least 90 days. An additional objective was to compare the optimum implant formulation with commercial microsphere product. Evaluated implant formulations contained 45% w/w 75/25 poly (DL-lactide-coglycolide) polymer having an intrinsic viscosity of 0.20 dL/g, dissolved in N-methyl-2-pyrrolidone. Irradiated polymer solution was mixed with leuprolide at different drug loads (3%, 4.5% and 6% w/w) prior to subcutaneous administration to dogs. Dog serum was analyzed for testosterone (RIA) and leuprolide (LC/MS/MS) levels and comparisons within the three implant formulation groups were made. Varying the drug load did not significantly affect the release of leuprolide or efficacy of the implant formulation. Thus, the 6% w/w formulation with the smaller injection volume was selected for comparison with the commercial LUPRON® Depot product, which was administered intramuscularly at a similar dosage. These comparisons of serum testosterone and leuprolide levels showed no significant difference in the pharmacologic efficacy even though drug levels were different at a number of points. This was mainly due to associated high standard deviations. Based on these studies, the 6% w/w leuprolide implant formulation was considered to be a suitable candidate for further development. Additional benefits of this system include its simple manufacturing and lower costs.
Polymeric Implant; Leuprolide Acetate; Dog; Sustained Release; Testosterone Suppression
Degarelix is a gonadotropin-releasing hormone (GnRH) antagonist for the treatment of patients with prostate cancer in whom hormonal therapy is indicated. Two phase II trials and one phase III have been published as full papers in the literature. In the dose-finding phase II studies an initial dose of 240 mg degarelix sc followed by a monthly injection of 80 mg or 160 mg degarelix sc was sufficient to keep testosterone levels ≤ 0.5 ng/ml. In a phase III trial it was demonstrated that degarelix was not inferior (in terms of testosterone suppression and prostate-specific antigen [PSA] decline) compared to standard hormonal therapy, ie, a GnRH agonist such as leuprolide. In fact, degarelix was associated with a faster testosterone suppression and PSA decline than leuprolide. Adverse events such as injection site reactions (40% vs <1%) and chills (4% vs 0%) were more commonly associated with degarelix. Also, degarelix is currently only available as one-month depot whereas in daily practice three-month depots (of GnRH agonists) are the preferred regimen. However, degarelix was recently approved by the US Food and Drug Administration for the treatment of advanced prostate cancer.
prostate cancer; hormonal therapy; GnRH antagonist; degarelix; testosterone; flare
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 ± 1ng/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.
We evaluated rapid androgen cycling in combination with docetaxel for men with progressive non-castrate prostate cancers.
Non-castrate patients with ≤ 6 months of hormones were eligible. Cohort 1 (63 patients ) received 6 28-day cycles of docetaxel (75 mg/m2), leuprolide and 7 days of topical testosterone. Cohort 2 (39 patients) received 9 21-day cycles of docetaxel (70 mg/m2), leuprolide and 3 days of testosterone. The primary endpoint was the proportion of patients at 18 months who achieved non -castrate testosterone levels (>150 ng/dl) and an undetectable PSA (≤ 0.05, ≤0.5, or ≤2.0 ng/ml with prior prostatectomy, radiotherapy, or no definitive therapy, respectively). Cytochrome P450 3A4 (CYP3A4) activity and docetaxel pharmacokinetics were evaluated.
A higher proportion of patients achieved the undetectable PSA outcome at 18 months in cohort 2 relative to cohort 1 (13% vs. 0%). The 16% incidence of febrile neutropenia was higher than observed in patients was castration-resistant disease, which may have been related to a 50% reduction in overall docetaxel clearance in the non-castrate group. There was no alteration in CYP3A4 activity (P=0.87) or docetaxel clearance (P=0.88) between cycles.
The undetectable PSA endpoint allows for a rapid screening of interventions for further study. Increasing the number of docetaxel cycles following a shorter period of testosterone repletion, and a longer duration of testosterone depletion, increased the proportion of men who achieved an undetectable PSA. The higher-than-expected incidence of febrile neutropenia may have been related to the reduced overall docetaxel clearance in patients with non-castrate vs castrate testosterone levels.
Degarelix is a gonadotrophin-releasing hormone (GnRH) antagonist for the first-line treatment of androgen-dependent advanced prostate cancer. It has a direct mechanism of action that blocks the action of GnRH on the pituitary with no initial surge in gonadotrophin or testosterone levels. Degarelix is the most extensively studied and widely available GnRH antagonist worldwide. Clinical studies have demonstrated similar efficacy to the GnRH agonist leuprolide in achieving testosterone suppression in patients with prostate cancer. However, degarelix produces a faster suppression of testosterone and prostate-specific antigen (PSA), with no testosterone surge or microsurges, thus preventing the risk of clinical flare in advanced disease. Clinical trials have demonstrated that degarelix can offer improved disease control when compared with a GnRH agonist in terms of superior PSA progression-free survival (suggesting that degarelix likely delays progression to castration-resistant disease), and a more significant impact on bone serum alkaline phosphatase and follicle-stimulating hormone. Degarelix is generally well tolerated, with no reports of systemic allergic reactions in any clinical studies. In conclusion, degarelix offers clinicians a rational first-line hormonal monotherapy option for the management of advanced prostate cancer.
degarelix; GnRH agonist; GnRH antagonist; prostate cancer
Leuprolide acetate is a synthetic analog of gonadotropin-releasing hormone used for the treatment of prostate cancer. Its side effects are hot flashes, nausea, and fatigue. We report a case of a patient with proximal inflammatory myopathy accompanied by severe rhabdomyolysis and renal failure following the second application of leuprolide acetate. Drug withdrawal and steroid therapy resulted in remission within six weeks of the diagnosis. To the best of our knowledge, our case report describes the second case of leuprolide acetate-induced inflammatory myopathy and the first case of severe leuprolide acetate-induced rhabdomyolysis and renal failure in the literature.
A 64-year-old Swiss Caucasian man was admitted to the hospital because of progressive proximal muscle weakness, dyspnea, and oliguria. He had been treated twice with leuprolide acetate in monthly doses. We performed a muscle biopsy, which excluded other causes of myopathy. The patient's renal failure and rhabdomyolysis were treated with rehydration and steroid therapy.
The aim of our case report is to highlight the rare but severe side effects associated with leuprolide acetate therapy used to treat patients with inflammatory myopathy: severe rhabdomyolysis and renal failure.
A biodegradable polymeric system is proposed for formulating peptides and proteins. The systems were assembled through the adsorption of biodegradable polymeric nanoparticles onto porous, biodegradable microspheres by an adsorption/infiltration process with the use of an immersion method. The peptide drug is not involved in the manufacturing of the nanoparticles or in obtaining the microspheres; thus, contact with the organic solvent, interfaces, and shear forces required for the process are prevented during drug loading. Leuprolide acetate was used as the model peptide, and poly(d,l-lactide-co-glycolide) (PLGA) was used as the biodegradable polymer. Leuprolide was adsorbed onto different amounts of PLGA nanoparticles (25 mg/mL, 50 mg/mL, 75 mg/mL, and 100 mg/mL) in a first stage; then, these were infiltrated into porous PLGA microspheres (100 mg) by dipping the structures into a microsphere suspension. In this way, the leuprolide was adsorbed onto both surfaces (ie, nanoparticles and microspheres). Scanning electron microscopy studies revealed the formation of a nanoparticle film on the porous microsphere surface that becomes more continuous as the amount of infiltrated nanoparticles increases. The adsorption efficiency and release rate are dependent on the amount of adsorbed nanoparticles. As expected, a greater adsorption efficiency (~95%) and a slower release rate were seen (~20% of released leuprolide in 12 hours) when a larger amount of nanoparticles was adsorbed (100 mg/mL of nanoparticles). Leuprolide acetate begins to be released immediately when there are no infiltrated nanoparticles, and 90% of the peptide is released in the first 12 hours. In contrast, the systems assembled in this study released less than 44% of the loaded drug during the same period of time. The observed release profiles denoted a Fickian diffusion that fit Higuchi’s model (t1/2). The manufacturing process presented here may be useful as a potential alternative for formulating injectable depots for sensitive hydrophilic drugs such as peptides and proteins, among others.
adsorption; biodegradable polymers; controlled release; nanoparticles; porous microspheres; peptide delivery
To evaluate whether occlusive salpingitis isthmica nodosa associated with endometriosis can be diagnosed by microlaparoscopy and managed with medical therapy using leuprolide acetate.
This was a prospective, nonrandomized study conducted at a university hospital and a private community hospital. It included women with occlusive salpingitis isthmica nodosa associated with endometriosis. Diagnosis of salpingitis isthmica nodosa was made via microlaparoscopy with chromotubation. Patients with occlusive salpingitis isthmica nodosa were treated with leuprolide acetate 3.75 mg administered monthly for 6 months.
Tubal patency in occlusive salpingitis isthmica nodosa following medical therapy with leuprolide acetate was evaluated. Thirteen of 16 (81.3%) women with bilateral salpingitis isthmica nodosa achieved patency of both fallopian tubes following treatment with leuprolide acetate; 3 of 16 (18.8%) developed patency in one of the fallopian tubes. All 5 women with unilateral SIN demonstrated bilateral patency following medical therapy.
Diagnosis of occlusive salpingitis isthmica nodosa can be made by microlaparoscopy. These preliminary results suggest that medical therapy with leuprolide acetate may be the first-line treatment modality for women with occlusive salpingitis isthmica nodosa associated with endometriosis, possibly avoiding a more invasive surgical procedure.
Microlaparoscopy; Endometriosis; Salpingitis isthmica nodosa; Infertility; GnRH agonist; Leuprolide acetate
Results of a phase II clinical trial of leuprolide administered before conditioning chemotherapy in hematopoietic stem cell transplantation patients to reduce the incidence of premature ovarian failure are presented. Leuprolide did not preserve ovarian function in patients who underwent hematopoietic stem cell transplantation using either myeloablative or nonmyeloablative regimens.
Premature ovarian failure occurs in 40%–70% of patients who receive conventional chemotherapy alone. However, the incidence is higher, 70%–100%, in patients who undergo myeloablative chemotherapy with hematopoietic stem cell transplantation (HSCT). Gonadotropin-releasing hormone (GnRH) analogs, such as leuprolide, in a continuous-release formulation, may protect the ovaries from the gonadotoxic effects of chemotherapy. In non-HSCT settings, GnRH analogs have reduced the risk for premature ovarian failure to <10%. We conducted a phase II clinical trial based on the hypothesis that giving leuprolide before conditioning chemotherapy in HSCT patients reduces premature ovarian failure incidence.
Patients and Methods.
Eligible patients were women aged ≤40 years who were HSCT candidates, were premenopausal, and had both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels ≤20 IU/L. Two 22.5-mg leuprolide doses were delivered in 3-month depot i.m. injections, the first within 2 months before HSCT. Patients were monitored for menstruation return, and ovarian function tests (FSH, LH, and estradiol) were done every 2 months starting 90 days after the last leuprolide dose.
Sixty eligible patients were enrolled, 59 underwent HSCT, and 44 were evaluable (median age, 25 years; median follow-up, 355 days). Only seven of 44 patients (16%) regained ovarian function. Of the 33 who received myeloablative regimens, six (18%) regained ovarian function. However, among the 11 who received nonmyeloablative regimens, only one (9%) regained ovarian function (p = .66).
Leuprolide did not preserve ovarian function in patients who underwent HSCT using either myeloablative or nonmyeloablative regimens. Other measures that protect ovarian function need to be investigated.
Gonadotropin-releasing hormone analog; Premature ovarian failure; Ovarian function preservation; Hematopoietic stem cell transplantation
Hormone therapy is well established for treating patients with prostate cancer and remains the mainstay of the treatment of metastatic and locally advanced disease, this article reviews the rationale for its use, its different forms, and complications and controversies still surrounding some of its modalities. Availability of long-acting synthetic luteinizing hormone-releasing hormone (LHRH) agonists revolutionized the hormonal treatment of prostate cancer, and helped to avoid the emotional and psychological effects related to surgical castration. The depot formula has gained wide acceptance from both patients and physicians. This review emphasizes the newer, long-acting formula, leuprorelin (leuprolide acetate), especially the 6-month formula, its advantage over over shorter-acting depot products, and its potential to become a standard of care for patients eligible for androgen deprivation therapy.
prostate cancer; androgen deprivation therapy (adt); leuprorelin
D17DT consists of the GnRH decapeptide linked to diphtheria toxoid. The aim of this pilot study was to assess the tolerance of D17DT and the production of anti-GnRH antibodies from two doses, 30 and 100 μg, in patients with locally advanced prostate cancer. Twelve patients with histologically proven prostate cancer in whom hormonal therapy was indicated were recruited. Patients received either 30 or 100 μg given intramuscularly on three separate occasions over six weeks. Patients were followed up and blood was taken for estimation of serum testosterone, PSA and anti-GnRH antibody titre. Overall the drug was well tolerated. In 5 patients a significant reduction in serum testosterone and PSA was seen. Castrate levels of testosterone were achieved in 4 and maintained for up to 9 months. Patients with the highest antibody titre had the best response in terms of testosterone suppression. This study shows that it is possible to immunize a patient with prostate cancer against GnRH to induce castrate levels of testosterone. This state appears to be reversible. This novel form of immunotherapy may have advantages over conventional forms of hormonal therapy and further studies are warranted in order to try and increase the proportion of responders. © 2000 Cancer Research Campaign
prostate cancer; hormonal therapy; anti-GnRH antibodies
To determine whether insulin sensitizers lower androgen levels and whether androgen suppression improves insulin resistance in non-diabetic postmenopausal women.
Randomized, double-blind, placebo-controlled study
Clinical and Translational Research Center of a university hospital
Thirty-five postmenopausal women aged 50-79 yr with insulin resistance and higher testosterone levels
Subjects were randomized to metformin plus leuprolide placebo (LP), leuprolide plus metformin placebo (MP), or LP plus MP in a 1:1:1 fashion over a 12 week period.
Main Outcome Measures
Insulin sensitivity (M) assessed by euglycemic-hyperinsulinemic clamp and free testosterone by equilibrium dialysis.
In those randomized to metformin, free testosterone decreased by 19% (p=0.02) compared to placebo, along with an expected improvement in M. Total testosterone also decreased significantly (p=0.001) whereas sex hormone binding globulin (SHBG) did not change. In those randomized to leuprolide, the percent change in M was not different from placebo (p=0.56), despite a 48% relative decrease in free testosterone levels (p<0.001).
These data are the first to establish a causal link between insulin resistance and testosterone in postmenopausal women. They confirm that treatment of insulin resistance decreases testosterone production in this population and demonstrate that pharmacologic lowering of testosterone does not affect insulin resistance.
Testosterone; insulin resistance; polycystic ovary syndrome; metabolic syndrome; aging; elderly; women
Gonadotropin-releasing hormone analogs (GnRHa) are the treatment of choice for CPP. We investigated growth in GnRHa-naïve subjects, treated with leuprolide acetate 1-month depot for CPP.
This prospective, open-label study had a long-term, observational, follow-up period. Forty-nine females and 6 males were enrolled. Leuprolide acetate depot was administered intramuscularly every 28 days. Height and growth rate during and after treatment until adulthood were measured.
Among 30 of 49 females having an adult height (AH) measurement, 29 had target heights available (mean = 163.8 cm) and 27 had pretreatment predicted adult heights (PAHs; mean = 157.4 cm). After treatment, the mean AH at mean age 21.8 years [range 13.7-26.7 years] was 162.5 cm, a mean height gain over baseline PAH of 4.0 cm. The mean height standard deviation score was -0.1 at AH.
Treatment of CPP with leuprolide acetate 1-month depot had beneficial effects on growth rate and preservation of AH.
Methods. This prospective US multicenter trial of leuprolide acetate 1-month depot (7.5–15 mg) for central precocious puberty utilized an open-label treatment period, long-term follow-up, and adult callback. Forty-nine females <9 years old with Tanner breast stage ≥2 before 8 years and 6 males <10 years old with Tanner genital stage ≥2 before 9 years with stimulated LH ≥10 IU/L and bone age advance ≥1 year were enrolled. Results. Subjects were treated for 3.9 ± 2.0 years. Mean peak GnRH-stimulated LH and FSH were prepubertal after the first dose and remained suppressed throughout treatment. During treatment, mean estradiol decreased to the limit of detection and mean testosterone decreased but remained above prepubertal norms. During posttreatment follow-up (3.5 ± 2.2 years), all patients achieved a pubertal hormonal response within 1 year and menses were reported in all females ≥12 years old. No impairment of reproductive function was observed at adulthood (mean age: 24.8 years).
Despite observations of age-dependent sexual dimorphisms in hypothalamic-pituitary-adrenal (HPA) axis activity, the role of androgens in the regulation of HPA axis activity in men has not been examined. We assessed this role by performing CRH stimulation tests in ten men (ages 18–45) during gonadal suppression with leuprolide acetate and during testosterone addition to leuprolide. CRH-stimulated cortisol levels as well as peak cortisol and greatest cortisol excursion were significantly lower (p < .05, .005, and .01, respectively) during testosterone replacement compared with the induced hypogonadal condition (leuprolide plus placebo); cortisol area under the curve was lower at a trend level (p < .1). Paradoxically, CRH-stimulated ACTH was increased significantly during testosterone replacement (p < .05). The cortisol:ACTH ratio, a measure of adrenal sensitivity, was lower during testosterone replacement (p < .1). A mixed effects regression model showed that testosterone but not estradiol or CBG significantly contributed to the variance of cortisol. These data demonstrate that testosterone regulates CRH-stimulated HPA axis activity in men, with the divergent effects on ACTH and cortisol suggesting a peripheral (adrenal) locus for the suppressive effects on cortisol. Our results further demonstrate that the enhanced stimulated HPA axis activity previously described in young men compared with young women cannot be ascribed to an activational upregulation of the axis by testosterone.
testosterone; cortisol; HPA axis; ACTH; CRH; men
To describe provocative testing and alternative imaging strategies used to localize an androgen-producing tumor in a 58 year old woman with severe hirsutism.
Clinical Research Center.
A 58 year old woman who presented for evaluation of severe hirsutism.
Serum androgens were drawn at baseline, 4 hours after administration of 2000 IU of hCG and 11 days following administration of 3.75 mg of leuprolide. MRI and FDG-PET/CT were performed.
Main Outcome Measure(s):
Description of pre-operative provocative testing and imaging.
In response to hCG, testosterone rose from 243 to 288 ng/dL then decreased to 233 ng/dL following leuprolide administration. FDG-PET/CT scan demonstrated focal hypermetabolism in the right pelvis, corresponding to a soft tissue density on the non-contrast CT. MRI images were correlated with the PET/CT and the right ovary was identified. Right salpingo-oophorectomy was performed and final pathology revealed a hilar cell tumor with ovarian cortical hyperplasia.
This case demonstrates the utility of provocative testing in the evaluation of a patient with severe hirsutism and illustrates the value of FDG-PET/CT when traditional imaging is non-diagnostic.
hirsutism; testosterone; hilar cell tumor; FDG-PET/CT
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.
Patients and Methods
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 ≥ 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 (≤ 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 ≤ 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.
A poly (lactide-co-glycolide) (PLGA) implant was used to control the release profile of leuprolide acetate (LA) drug. The system is an in-situ polymeric precipitation system. And the formulation consisted of PLGA polymer, LA drug and N-methyl-2-pyrrolidon solvent with no additives. First, the formulation was injected into PBS solution for in-vitro studies and then it was administered to the animal models (female rats) for in-vivo release studies. The release profiles of leuprolide acetate were measured by UV spectrophotometry for a period of 28 days. The initial burst release of LA was 14% in in-vitro whereas it was 7% in in-vivo. In-vitro and in-vivo release profiles of LA had similar trends after 72 hours. However, the rate of LA release was slower in-vivo. This might be attributed to the limited diffusion process of solvent and the drug molecules. This could be due to presence of an additional pressure caused by the surrounding tissue and also the presence of small amount of water between cells in the subcutaneous site. Cross-section and surface of the implants were studied via scanning electron microscopy. Morphology of both in-vitro and in-vivo implants confirmed the release behaviours. No toxicity effects were reported in the histopathological assay. Furthermore, the pharmacological analysis showed more inactive ovaries due to release of LA.
Drug delivery system; In-vitro; In-vivo; Biodegradable polymer; Rat; Poly (lactide-co-glycolide) (PLGA)
Androgen deprivation therapy remains the mainstay of medical treatment for advanced prostate cancer. Commonly, this is achieved with medical androgen deprivation rather than surgical intervention as the permanence and psychological effects of the latter are unacceptable for most patients. Degarelix is a third generation antagonist of luteinizing hormone-releasing hormone (LHRH, also termed gonadotropin-releasing hormone) for the first-line treatment of androgen-dependent advanced prostate cancer. Degarelix acts directly on the pituitary receptors for LHRH, blocking the action of endogenous LHRH. The use of degarelix eliminates the initial undesirable surge in gonadotropin and testosterone levels, which is produced by agonists of LHRH. Degarelix is the most comprehensively studied and widely available LHRH antagonist worldwide. Clinical trials have demonstrated that degarelix has a long-term efficacy similar to the LHRH agonist leuprolide in achieving testosterone suppression in patients with prostate cancer. Degarelix, however, produces a faster suppression of testosterone and prostate-specific antigen (PSA), with no testosterone surges or microsurges, and thus prevents the risk of clinical flare in advanced disease. Recent clinical trials demonstrated that treatment with degarelix results in improved disease control when compared with an LHRH agonist in terms of superior PSA progression-free survival, suggesting that degarelix likely delays progression to castration-resistant disease and has a more significant impact on bone serum alkaline phosphatase and follicle-stimulating hormone. Degarelix is usually well tolerated, with limited toxicity and no evidence of systemic allergic reactions in clinical studies. Degarelix thus represents an important addition to the hormonal armamentarium for therapy of advanced androgen-dependent prostate cancer.
degarelix; GnRH; LHRH; metastatic prostate cancer; androgen-dependent prostate cancer; hormonal therapy
Approximately 60–70 percent of women with premenstrual dysphoric disorder (PMDD) show symptomatic improvement in response to the GnRH agonist leuprolide acetate, which suppresses ovarian function. However, it has been very difficult to either predict or understand why some women respond, while others do not. We applied several complementary statistical methods to the dynamics of pre-treatment mood rating data to determine possible predictors of response for women with PMDD. We compared responders (n = 33) to nonresponders (n = 12) in clinical trials of leuprolide (three months in duration) as a treatment for PMDD, on the basis of pre-trial daily self-ratings of sadness, anxiety, and irritability. We analyzed both sequential irregularity (approximate entropy, ApEn) and a quantification of spikiness of these series, as well as a composite measure that equally weighted these two statistics. Both ApEn and Spikiness were significantly smaller for responders than nonresponders (P ≤ 0.005); the composite measure was smaller for responders compared with nonresponders (P ≤ 0.002) and discriminated between the subgroups with high sensitivity and specificity. In contrast, mean symptom levels were indistinct between the subgroups. Relatively regular and non-spiky pre-trial dynamics of mood ratings predict a positive response to leuprolide by women with PMDD with high probability, moreover based on typically less than 3 months of daily records. The statistical measures may have broad and direct applicability to behavioral studies for many psychiatric disorders, facilitating both accurate diagnosis and the prediction of response to treatment.
Mood disorders; Premenstrual dysphoric disorder; Response to therapy; Approximate entropy; Cyclicity
For advanced prostate cancer, the main hormone treatment against which other treatments are assessed is surgical castration. It is simple, safe and effective, however it is not acceptable to all patients. Medical castration by means of luteinizing hormone-releasing hormone (LH-RH) analogues such as goserelin acetate provides an alternative to surgical castration. Diethylstilboestrol, previously the only non-surgical alternative to orchidectomy, is no longer routinely used. Castration reduces serum testosterone by around 90%, but does not affect androgen biosynthesis in the adrenal glands. Addition of an anti-androgen to medical or surgical castration blocks the effect of remaining testosterone on prostate cells and is termed combined androgen blockade (CAB). CAB has now been compared with castration alone (medical and surgical) in numerous clinical trials. Some trials show advantage of CAB over castration, whereas others report no significant difference. The author favours the view that CAB has an advantage over castration. No study has reported that CAB is less effective than castration. Of the anti-androgens which are available for use in CAB, bicalutamide may be associated with a lower incidence of side-effects compared with the other non-steroidal anti-androgens and, in common with nilutamide, has the advantage of once-daily dosing. Only one study has compared anti-androgens within CAB: bicalutamide plus LH-RH analogue and flutamide plus LH-RH analogue. At 160-week follow-up, the groups were equivalent in terms of survival and time to progression. However, bicalutamide caused significantly less diarrhoea than flutamide. Withdrawal and intermittent therapy with anti-androgens extend the range of treatment options. © 1999 Cancer Research Campaign
hormonal therapy; advanced prostate cancer; combined androgen blockade; luteinizing hormone-releasing hormone analogues; surgical castration; anti-androgens
The purpose of this study was to assess whether male rats whose testosterone levels were suppressed to castration levels (<0.5 ng/mL) for a 1-year period by the sustained delivery of orntide acetate, a GnRH antagonist, would return to fertility (ie, produce offspring) after serum testosterone returned to control levels. Male rats comprising a treatment group (orntide microspheres, dose=27 mg/kg/y), a vehicle control group, and a control group of proven male breeders were used. For the treatment and vehicle control groups, serum orntide and testosterone levels were monitored at periodic intervals for 14 months from the initiation of treatment. After serum testosterone levels returned to vehicle control levels and orntide serum levels were no longer discernible for the treated group, each of the animals was housed with 2 drug-naive, female, proven breeders. All the breeder females produced offspring with the exception of 1 female housed with a male rat from the treatment group and the 2 females housed with a single male rat from the vehicle control group. The mean size and weight of the litters from each group were not statistically different. Further, fertility of the offspring from each group was assessed. The male and female offspring studied were all shown to be fertile. The results suggest that lack of fertility due to testosterone suppression in male rats is reversible after cessation of treatment with the GnRH analog, orntide.
orntide acetate; PLA microspheres; return to fertility; chemical castration; GnRH antagonist