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Leuprorelin Acetate in Prostate Cancer: a European Update
International Journal of Clinical Practice
Abstract
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.
... [9][10][11][12][13] The mean value of serum testosterone after surgical castration, as determined by current analytical methods, is 15 ng/dL (0.5 nmol/L), 14 and the most recent 2015 European Association of Urology guidelines now suggest <20 ng/dL is a more appropriate target castrate level rather than the original <50 ng/dL threshold. 5 Leuprolide acetate (LA) is the most widely used GnRH agonist 15 and is available in depot formulations allowing for administration every 1, 3, 4, or 6 months, depending on the formulation and/or dose. 10,15 These depot formulations are of two types: intramuscularly-administered LA-containing microspheres 16 and a subcutaneouslyadministered biodegradable LA-containing polymer solid. ...
... 5 Leuprolide acetate (LA) is the most widely used GnRH agonist 15 and is available in depot formulations allowing for administration every 1, 3, 4, or 6 months, depending on the formulation and/or dose. 10,15 These depot formulations are of two types: intramuscularly-administered LA-containing microspheres 16 and a subcutaneouslyadministered biodegradable LA-containing polymer solid. 17 Both microsphere- [18][19][20][21] and solid polymer-based LA [22][23][24] have been approved by the US Food and Drug Administration for treating prostate cancer based on successful suppression of testosterone levels in randomized clinical trials to the <50 ng/dL castrate threshold. ...
Introduction
Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) analogs is a standard treatment for advanced prostate cancer. GnRH analog therapy can reduce testosterone to “castrate” levels, historically defined as <50 ng/dL. With the advent of newer assays, a lower threshold of <20 ng/dL has recently been proposed. We report the results of a retrospective analysis of two Phase III trials of 4- and 6-month depot microsphere formulations of leuprolide acetate (LA), a GnRH agonist that has previously demonstrated efficacy in testosterone suppression to <50 ng/dL in patients on ADT. This analysis investigates the ability of these LA formulations to suppress to ≤20 ng/dL levels.
Methods
In two of five AbbVie/Abbott clinical trials of microsphere formulations of LA for ADT, analytic technology permitting testosterone detection as low as 3 ng/dL was used and thus was selected for this analysis. Both trials were open-label, fixed-dose studies in prostate cancer patients, naïve to ADT. Patients received either 30 mg (4-month formulation; n=49) or 45 mg (6-month formulation; n=151) depot injections of LA microspheres. Treatment duration was up to 32 weeks for the 4-month formulation and 48 weeks for the 6-month formulation. The proportion of patients achieving the 20 ng/dL threshold was determined every 4 weeks.
Results
Pooled analysis showed that 152 of 193 (79%) of patients achieved serum testosterone levels of ≤20 ng/dL at 4 weeks, and sustained the improvement at week 24 (169/189, 89%). Additionally, in the 6-month study, 127/135 (94.1%) patients were suppressed to ≤20 ng/dL at 48 weeks.
Conclusion
Both 4- and 6-month intramuscular depot formulations of LA achieved and maintained mean serum testosterone levels ≤20 ng/dL in the vast majority of patients as early as 4 weeks following treatment initiation. Additional research on the clinical relevance of this lower testosterone threshold is warranted.
... Leuprorelin acetate, a synthetic analogue of LHRH, is the most widely prescribed compound of its class (1)(2)(3)(4) . Two unique slow-release pharmaceutical forms of leuprorelin acetate (Leuprorelin Sandoz®, Leuprone® HEXAL®; 1-month and 3-month implant) were first approved in 2007 (5) . ...
Androgen deprivation therapy (ADT) in men with prostate cancer (PCa) is associated with significant side effects. With the transition of PCa from a foudroyant course to a chronic disease, managing these side effects has become increasingly important. There is growing evidence that nutritional changes and physical activity are beneficial in these patients. Here we examine the impact of written patient information on the physical activity and dietary habits of PCa patients receiving ADT, and behaviour changes between baseline and 1 year, in the open-label, non-interventional LEAN study. In total, 959 patients with advanced hormone-sensitive PCa requiring ADT with the Leuprorelin Sandoz® implant were included from January 2014 to July 2015 and followed for ≥12 months. At the start of the study, urologists received a questionnaire concerning the written information provided to patients regarding their disease, patient advocacy groups, diet and physical activity. Patients received a questionnaire on their dietary habits and physical activity at the start and end of the study. Urologists from 147 study centres and 540 patients responded to the questionnaires. While 69% of these patients received disease-specific information, only 27% and 16% received information regarding nutrition and physical activity, respectively. The majority of urologists estimate that their patients rarely or never follow guidance on nutrition or physical activity, yet >90% of patients indicate they would make use of this information, if provided. Few patients showed behavioural changes between baseline and 1 year without evident differences between patients that received information and those that did not.
... Leuprorelin acetate was the first LHRH agonist to be synthesized and used for the treatment of PCa for over 30 years; its convenience and flexibility of administration are constantly improving [32]. ...
Introduction:
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.
Areas covered:
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.
Expert opinion:
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.
... Leuprorelin acetate (leuprorelin), an LH-RH agonist, is available as depot formulations for subcutaneous administration every 1 or 3 months for the treatment of hormoneresponsive cancers, such as prostate cancer [19] and premenopausal breast cancer [20][21][22][23]. ...
Background:
Previously, we conducted the 5-year open-label, randomized controlled trial (RCT) of leuprorelin adjuvant therapy in post-operative premenopausal patients with endocrine-responsive breast cancer, which was a pilot study to investigate the optimal duration of leuprorelin treatment. Since, however, long-term outcomes became required for the adjuvant endocrine therapy, we performed this follow-up observation study.
Methods:
Follow-up observation study was performed up to 10th year after randomization, continuing RCT to evaluate the efficacy and safety of leuprorelin every 3 months for ≥ 3 versus 2 years, with daily tamoxifen for 5 years. Primary endpoints were disease-free survival (DFS) and 2-year landmark DFS.
Results:
Eligible patients (N = 222) were randomly assigned to receive leuprorelin for either 2 years (N = 112) or ≥ 3 years (N = 110) with tamoxifen. Leuprorelin treatment for ≥ 3 years versus 2 years provided no significant difference in DFS (HR 0.944, 95% CI 0.486-1.8392) or 2-year landmark DFS (N = 99 and 102 in 2-year and ≥ 3-year groups, HR 0.834, 0.397-1.753). In small, higher-risk subgroup (n = 17); however, 2-year landmark DFS in ≥ 3-year group was significantly longer (HR 0.095, 0.011-0.850) than that in 2-year group. The incidence of bone-related adverse events was around 5% in both groups.
Conclusions:
Adjuvant leuprorelin treatment for ≥ 3 years with tamoxifen only showed similar efficacy and safety profiles to those for 2 years in analyses among all patients but suggested greater benefit in higher-risk patients. No new safety signal was identified for long-term leuprorelin treatment.
Trial registration number:
Not applicable. This was an observational study.
... Leuprorelin acetate, a synthetic analogue of LHRH, is the most widely prescribed drug of its class [1,3,5]. Two unique slow-release pharmaceutical forms of leuprorelin acetate (Leuprorelin Sandoz ® and Leuprone ® HEXAL ® ; 1-month and 3-month implant 1 ) were first approved in 2007 [6]. ...
Background:
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.
Objectives:
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.
Methods:
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.
Results:
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%.
Conclusions:
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.
... Изучена роль лейпрорелина при применении как в постоянном, так и в интермиттирующем режиме, а также в неоадъювантном режиме для уменьшения размеров простаты и опухоли перед лучевой терапией. Шестимесячная форма введения была разработана с целью повышения надежного подавления Т, поддержания клинической эффективности, а также для удобства врачей и пациентов, что может существенно улучшить качество жизни больных РПЖ [31]. ...
This review is dedicated to the impact of modern achievements on the definition and diagnostics of castration-resistant prostate cancer (PCa) (CRPC), prognostic factors for its progression, and treatment strategies.
It was proven with new sensitive methods of diagnostics that surgical castration (CS) decreases serum testosterone (T) levels to < 20 ng/dL, while achieving T < 20 ng/dL improves outcomes and delays the development of CRPC. Regular assessment of the T level makes it possible to understand whether this androgen is adequately suppressed in the setting of potential progression of CRPC, given that late dosing may lead to an increase in T level. Improved imaging techniques and biomarker analysis enable early detection of disease progression. Prognostically significant risk factors for CRPC progression include Gleason score, the extent of metastatic spread, hereditary characteristics such as gene mutations affecting androgen receptor (AR) amplification or DNA repair deficiency mutations, prostate-specific antigen (PSA) kinetics, and biomarker levels. Today, treatment options for CRPC have gone beyond androgen deprivation therapy (ADT) to include therapy that blocks T-synthesis and/or suppresses its activity through various mechanisms. Future directions include therapies using new biological targets, drug combinations and personalized therapies. It is necessary to assess the possible reasons for the difference in the pharmacodynamics and pharmacokinetics of androgendeprivation drugs, to study the features of the processes of destruction of drugs under the action of endogenous enzymes and resorption in the subcutaneous or muscle depot, which may cause the resistance to therapy.
The aim of improved treatment and diagnostic options for PCa is to delay its progression to CRPC and to prolong patient survival. Rethinking of the castration concept and advances in understanding the biology of disease progression make it necessary to revise diagnostic and treatment strategies. ADT is a fundamental vector of treatment, and it should be continued even if some new ways of treatment for CRPC are introduced.
... Leuprolide acetate is a GnRH agonist that has been used successfully to induce reproduction in a number of frog species (Byrne & Silla, 2010;Trumbo, 2015, Clulow et al., 2018. Leuprolide acetate is the medical compound in the drugs Lupron (Tap Pharmaceuticals) and Lucrin (Abbott), which are used in treating prostate cancer and endometriosis, and for in vitro fertilisation in humans (Chetkowski et al., 1989;Dlugi et al., 1990;Persad, 2002). ...
Procuring offspring from captive animals can be important for research and conservation efforts. Yet, reliable methods for obtaining fertilised eggs are unavailable for many species. In this study, we examined the efficacy of one drug, leuprolide acetate, to induce reproduction (i.e. egg production, tadpole hatching) in the northern leopard frog, Rana pipiens. We found that leuprolide acetate successfully induced breeding and larval development in animals that were overwintered in the lab, but not in animals caught during the breeding season. These results indicate that leuprolide acetate can be successful in inducing breeding and fertilisation of frog eggs, but that its effectiveness might be contingent upon length of time in captivity and the animals having undergone an artificial overwintering period in the laboratory prior to induction. Artificial breeding success is species and context dependent; therefore, identifying additional methods effective across taxa will help support species in need of management intervention.
... Leuprolide acetate is a therapeutic peptide that is used to treat cancer such as prostate cancer and breast cancer [67]. Leuprolide acetate is available as depot formulations for subcutaneous administration every month or three months requiring daily injections [68]. However, it exhibits low drug bioavailability when administered to the nasal cavity resulting from low membrane permeability, mucociliary clearance due to short residence time and high enzymatic reaction in the epithelium [67]. ...
Nanogels are drug delivery systems that can bypass the blood-brain barrier and deliver drugs to the desired site when administered intranasally. They have been used as a drug delivery platform for the management of brain diseases such as Alzheimer disease, migraine, schizophrenia and depression. nanogels have also been developed as vaccine carriers for the protection of bacterial infections such as influenza, meningitis, pneumonia and as veterinary vaccine carriers for the protection of animals from encephalomyelitis and mouth to foot disease. It has been developed as vaccine carriers for the prevention of lifestyle disease such as obesity. Intranasal administration of therapeutics using nanogels for the management of brain diseases revealed that the drug transportation was via the olfactory nerve pathway resulting in rapid drug delivery to the brain with excellent neuroprotective effect. The application of nanogels as vaccine carriers also induced significant responses associated with protective immunity against selected bacterial and viral infections. This review provides a detailed information on the enhanced therapeutic effects, mechanisms and biological efficacy of nanogels for intranasal administration.
... However, chronic exposure to synthetic peptides that mimic natural luteinizing hormone-releasing hormone (LH-RH) also decrease T production via a negative feedback loop. 3 T suppression equivalent to orchiectomy is the objective 4 and although a T level of <50 ng/dl has historically been the target for suppression, this was based on sensitivity of available assays at the Pharmacokinetic and pharmacodynamic comparison of subcutaneous versus intramuscular leuprolide acetate formulations in male subjects time. 5 Assay advancements now permit detection of T as low as 0.1 ng/ml 6 and evidence suggests that lower T levels may lead to clinical benefits. ...
Background:
The aim of this study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of two distinct formulations of leuprolide acetate (LA); subcutaneous (SC) injection and intramuscular (IM) injection.
Methods:
A total of 32 healthy men were randomized to receive a single 7.5 mg injection of SC-LA (n = 16) or IM-LA (n = 16) in this phase I, open-label, parallel-group study. PK was assessed via LA concentrations, and PD via serum luteinizing hormone (LH) and testosterone (T) concentrations.
Results:
The initial surge of LA was higher for IM-LA than SC-LA (Cmax 27 ± 4.9 versus 19 ± 8.0 ng/ml, respectively), with a shorter tmax (1.0 ± 0.4 versus 2.1 ± 0.8 h). The duration of quantifiable LA concentration was longer for SC-LA (up to 56 versus 42 days for SC-LA and IM-LA, respectively). Median LH concentrations in both groups rapidly increased, followed by gradual decrease. However, SC-LA demonstrated a longer duration of LH suppression, with median levels remaining below 1.0 IU/l through Day 56 compared with IM-LA where LH started to rise by Day 35. Consequently, serum T began to increase by Day 42 in the IM-LA group, with only four subjects maintaining levels ⩽50 ng/dl, compared with 14 subjects in the SC-LA group. By Day 56, 13 SC-LA subjects maintained serum T levels ⩽50 ng/dl. Both SC-LA and IM-LA were well tolerated.
Conclusions:
Both formulations demonstrated consistent delivery of drug over 1 month; however, SC-LA provided a longer duration of action than expected based on the dosing interval. This profile suggests that SC-LA will provide effective suppression of T over a longer period of time, permitting greater injection scheduling flexibility.
... Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. [118] 3-month depot injection differs from the 1-month depot injection by replacement of PLGA copolymer with PLA as the vehicle and this product does not contain gelatin [16,17]. Leuprorelin one-month depot formulation (3.75 mg) resulted in peak serum levels within 1 h, followed by a rapid fall over the next 24 h. ...
... Surgical castration has been, for the most part, replaced with the use of drugs that suppress the secretion of androgens and inhibit the action of circulating androgens. The most common form of ADT utilized worldwide is the use of synthetic peptides that mimic natural luteinizing hormonereleasing hormone (LH-RH) [3]. The aim of this review is to describe and discuss the available long-acting therapies, the levels of T suppression achieved by different methods of long-acting release, and potential impact on clinical outcomes in light of recent advancements in the field. ...
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.
... Leuprorelin acetate (leuprorelin), an LH-RH agonist, is available as depot formulations for subcutaneous administration every 1-or 3-months. It is used worldwide for the treatment of hormone-responsive cancers, such as prostate cancer [16] and premenopausal breast cancer [17][18][19][20], as well as estrogen-dependent conditions such as endometriosis and uterine fibroids. In premenopausal patients with ER-positive, node-positive breast cancer, leuprorelin administered every-3-months depot showed a non-inferior effect to chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF), and was well tolerated [21]. ...
Luteinizing hormone-releasing hormone (LH-RH) agonists provide effective adjuvant treatment for premenopausal women with endocrine-responsive breast cancer. Here, we investigated appropriate treatment durations of an LH-RH agonist, leuprorelin.
We conducted an open-label, randomized controlled pilot study to evaluate the safety and efficacy of leuprorelin subcutaneously administered every-3-months for 2 versus 3 or more, up to 5 years, together with daily tamoxifen for 5 years in premenopausal endocrine-responsive breast cancer patients. Primary endpoints were disease-free survival (DFS) and safety.
Eligible patients (N = 222) were randomly assigned to receive leuprorelin for either 2 years (N = 112) or 3 or more years (N = 110) with tamoxifen for 5 years after surgery. Leuprorelin treatment for 3 or more years provided no significant difference in DFS rate over 2 years: 94.1 versus 91.8 % at 144 weeks (3 years) after the second year (week 96) and 90.8 versus 90.4 % at the fifth year (week 240). The overall survival rate was 100 % for both groups during the third through fifth year study period. There were no significant differences in the incidence of adverse events (AEs) between the 2 groups: most AEs were rated grade 1 or 2.
Adjuvant leuprorelin treatment for 3 or more years with tamoxifen showed a survival benefit and safety profile similar to that for 2 years in premenopausal endocrine-responsive breast cancer patients. No new safety signal was identified for long-term leuprorelin treatment. Longer follow-up observation is needed to determine the optimal duration of leuprorelin treatment.
... that the agent was active in baboons and affected the same hormonal pathways [18,19]. Serum testosterone then decreased below the level of chemical castration (50 μg/mL) within the first two weeks, where levels remained for 3 months. ...
... Although the mechanism of action of LA is well understood, 11 certain aspects of its pharmacology should be noted. The competitive occupation of LH receptors by LA in the anterior pituitary gland leads to their reactive downregulation, which results in the cessation of sex steroid production in the gonads after an initial flare effect. ...
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.
... 5,32,33,46,47,[60][61][62] Regarding potential indications for 6-month GnRH agonist depots, research has evaluated shorter-duration GnRH agonists as adjuvant and neoadjuvant treatments for patients undergoing radical prostatectomy and radiation therapy. 53,63,64 One reviewer predicts that 6-month triptorelin pamoate will prove a valuable adjunct to radiation therapy and chemotherapy because it possesses similar efficacy, but fewer side effects, than adjunctive therapies now commonly available. 65 Moreover, two clinical trials have shown that depot products often suppress testosterone for longer than the labeled interval. ...
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.
... In this respect, the DL-polylactic/glycolic acid (PLGA) microspheres have had success because of the experience provided in terms of safety and biodegradability. Currently marketed products include microspheres, wafers, and polymer solutions that solidify at the injection site, while semi-solid materials and thermally gelling liquid formulations are currently under development (Zentner et al., 2001; Ravivarapu et al., 2000; Barr et al., 2002; Westphal et al., 2003; Persad, 2002). The examples of formulations of PLGA microspheres in the market are: Lupron Depot ® , Enantone Depot ® , Decapeptil ® , and Pariodel LA ® . ...
In this investigation, poly(lactide-co-glycolide) (PLGA) gel implants and microspheric depot systems of bleomycin (BLM) were formulated and evaluated in vivo in mice bearing transplantable solid tumor (fibrosarcoma). The pharmacodynamic studies showed that both the formulations retarded tumor growth significantly (p<0.05) when compared to the control animals (without any drug treatment). Preliminary pharmacokinetic studies illustrated controlled release of the drug into the systemic circulation to elicit the anti-neoplastic action. The gel implants showed better release characteristics and greater pharmacodynamic action when compared to the microspheres, thus demonstrating the feasibility of employing biodegradable depot polymer gel matrix for chronic cancer therapy.
... Of all these materials, PLA / PLGA is the most popular and w idely used in the research and developm ent of p rotein or pep tide drug delivery system. Successful examp les include leup rorelin depot for the delivery of leup rolide acetate for 1 or 3 months [ 1 ] , and nutrop in depot for sustained delivery of human grow th hormone for 1 month [ 2 ] . O ther p rotein or pep tide drugs studied include nerve grow th factor, recombinant hum an erythropoietin, interferon, as well as vaccines, antigens and so on. ...
Sustained release drug delivery from microparticles is an excellent alternative for daily protein/peptide drug administration protocol. Poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) are the most commonly used polymer carriers in the development of protein/peptide microspheres. Basically there are three preparation methods for PLA/PLGA microspheres: the solvent extraction/evaporation based multiple emulsion (W/O/W emulsion) method, the phase separation method and the spray drying method. The stability of the protein/pipetide loaded, encapsulation efficiency, and the burst effect of the microspheres are key problems usually met in the preparation of microspheres. In this review the preparation techniques and progress in the development of protein/pipetide microspheres which aimed to stabilize protein/peptide structural integrity, keep the bioactivity of drugs, increase the encapsulation efficiency and improve the release profile were summarized and evaluated.
Leuprolide acetate (LA) is a gonadotropin‐releasing hormone agonist used as androgen deprivation therapy for advanced prostate cancer. LA is available in formulations intended for intramuscular (IM‐LA) or subcutaneous (SC‐LA) administration. Post‐marketing reports have noted handling errors associated with the preparation and administration of SC‐LA. This study gathered real‐world evidence on administration and management of IM‐LA and SC‐LA in large, urology‐ or oncology‐based practices. Over 200 staff were invited; 151 participated in an online survey. Main outcomes were time for each step of the ordering, inventory, mixing and administration processes. Mean values and standard errors are reported for continuous variables, and frequency and percentage are reported for categorical variables. Comparisons between groups were made with t tests and chi‐square tests as appropriate. For IM‐LA and SC‐LA, ease of ordering and time to place an order (10.8 ± 1.3 vs. 10.6 ± 1.4 min, respectively) were similar. IM‐LA was associated with a shorter time to complete preparation (2.5 ± 0.2 vs. 6.1 ± 0.6 min, P < 0.001) compared with SC‐LA. This difference of 3.6 min per preparation could result in substantial time savings annually ranging from 120 h per year to 240 h per year in clinical practices administering 2000 injections per year or 4000 injections per year, respectively. For IM‐LA vs. SC‐LA, greater ease of preparation was reported by 64% vs. 43% of respondents, respectively. Over 15% of respondents used injection sites inconsistent with prescribing information, regardless of the type of injection. This study found that it takes a significantly shorter time to prepare and administer IM‐LA than SC‐LA in large urology‐ and oncology‐based practices. The time saved could be utilized for other tasks such as seeing additional patients. Use of injection sites inconsistent with prescribing information suggests a need for more training of nursing staff in the proper administration of these drugs to ensure adequate testosterone suppression and patient safety.
Introduction:
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.
Continuous advances in androgen deprivation therapy (ADT) are made in terms of convenience and flexibility of administration, and in the incorporation of newer ADT into novel treatment regimens. Monotherapy is advocated in men with minimal tumour burden and offered similar efficacy as complete androgen blockade in certain cases. Intermittent ADT reduces treatment-associated side effects and offers comparable progression free and overall survival when compared to continuous ADT. Secondary hormonal manipulation provides an effective short term option in men who failed primary hormonal therapy. ADT is associated with significant side effects that interfere with patient's quality of life. Longer term adverse outcomes include accelerated bone loss, development of osteoporosis and subsequent potential risk of fractures, as well as induction of sarcopenic obesity with insulin resistance and alteration in lipid metabolism, resulting in an increased risk of cardiovascular morbidity and mortality. In the current world of consumerism, quality-of-life outcomes, costs, and treatment flexibility may predominate in patients' and urologists' treatment decisions. Several pertinent factors in patient consideration include perceived side effects of the types of ADT, pain from frequent depot injections, flexibility and convenience of a particular ADT. From the clinician's perspective, compliance to treatment and monitoring and managing the side effects of hypogonadism are paramount importance to minimise patient morbidity and mortality from both the hormonal treatment and prostate cancer.
Total prostatectomy remains the main treatment for intermediate risk prostate cancer with a life expectancy greater than 10 years. In other cases non-surgical treatments can be proposed: external radiotherapy (exclusive or combined anti-androgen therapy), brachytherapy with permanent implants, high frequency ultrasounds (HIFU, Ablatherm), cryotherapy or exclusive hormonal treatment. For such patients in case of biological recurrence, prostate biopsies are usually performed in order to affirm the local recurrence. The histological confirmation of persistent tumor is usually required before any treatment: salvage surgery, cryotherapy, and brachytherapy or high intensity focused ultrasound (HIFU). Pathologists must be aware of the histological modifications induced by these different treatments in order to ensure an optimal interpretation of the biopsies. In this review, we describe the modifications observed in the normal prostate and in cancers after these various therapeutic methods, and also after alpha reductase inhibitors proposed as treatment of benign prostate hypertrophy and prostate cancer chemoprevention.
Goserelin acetate (Gos) is a luteinizing hormone-releasing hormone agonist, used in treatment of prostate cancer in which desired concentration of Gos in blood is maintained for longer duration. The aim of this study is to improve the efficacy of Gos targeted at the site of action and eliminate the need for frequent administration. Gos-encapsulated nanoparticles were fabricated by double emulsification process. The physicochemical traits of the nanoparticles including morphology, particle size, zeta-potential, entrapment efficiency, and in-vitro release profile were studied. The in-vitro cytotoxicity of the blank nanoparticles and Gos-loaded nanoparticles were also evaluated on LNCaP cell line by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Blank methoxy PEG-poly(ϵ-caprolactone) (mPEG-PCL) nanoparticles exhibited low cytotoxicity, which increased with increase in concentration of Gos-loaded nanoparticles. Serum Gos and testosterone levels were analyzed after subcutaneous administration in Wistar rats. In-vivo study showed that a sustained serum level of Gos successfully suppressed the plasma testosterone concentration to castration level. So, it can be concluded that mPEG-PCL nanoparticles might prove to be useful for site specific and sustain protein delivery.
To compare 1-month and 3-month depot formulations of leuprolide acetate (DL), a gonadotropin-releasing hormone analog, in the treatment of central precocious puberty (CPP).
Subjects with CPP naïve to therapy were randomized to 7.5 mg of 1-month DL, 11.25 mg of 3-month DL, or 22.5 mg of 3-month DL. Stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and estradiol levels, growth velocity, and bone age progression were examined in a 2-year period.
Forty-nine female and 5 male subjects with CPP were randomized. Mean stimulated LH and FSH levels during treatment were higher in the low-dose 11.25-mg 3-month DL group, and more LH levels >4 IU/L were observed, in comparison with the other two dose groups. Mean LH and FSH levels in the 22.5-mg 3-month group were not different from the monthly DL. No differences in estradiol levels, growth velocity, or bone age progression were observed in dosing groups.
All DL doses resulted in prompt and effective suppression of puberty, but higher LH and FSH levels were seen with the 11.25-mg 3-month DL dose. Multi-monthly DL is effective in treating CPP, but higher dosing may be required in some circumstances.
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, <or=0.5 ng/mL) at day 28 and maintenance of clinical castration until study completion (day 168). The frequency of patients with testosterone concentrations <or=0.2 ng/mL was also studied.
The study included 160 patients with a mean (SD) age of 71.6 (9.2) years, weight of 83.7 (15.5) kg, and predominantly white race (87.5% [140/160]). All 160 patients received at least one dose of study drug; 157 of them were fully evaluable, and 152 completed the study. The proportion of successful patients over the total number of evaluable patients was 96.8% (152/157; 95% CI,92.7%-99.0%). Five of the 157 evaluable patients (3.2%) did not achieve the primary end point of testosterone concentration <or=0.5 ng/mL by day 28. Of the evaluable patients, 78.7% (122/155) achieved testosterone suppression by day 21. By day 28, 96.8% (151/156) of the evaluable patients had achieved castrate levels, and 73.1% (114/156) achieved testosterone concentrations <0.2 ng/mL. At study end, 100% (152/152) of the patients completing the study maintained castrate levels, and 92.8% (141/152) had testosterone concentrations <or=0.2 ng/mL. The pharmacokinetic profile of leuprolide during the first 3 months of treatment, evaluated in a subset of the study population (n = 12), showed sustained release of leuprolide from the formulation. Values for AUC(0-t) calculated from day 0 to day 28, days 28 to 56, and days 56 to 84 were 25,976.5 (7892.0), 30,685.5 (9348.4), and 31,030.9 (10,745.0) pg/mL per day, respectively. The most common treatment-related adverse event was hot flashes (45.0% [72/160]). Fatigue, hyperhidrosis, night sweats, and headache each occurred in <or=6.3% (10/160) of the patients. The most frequently reported local adverse reaction was pain at the injection site, experienced by 8.1% (13/160) of the patients.
Leuprolide acetate 3.75-mg depot was effective in achieving and maintaining testosterone suppression and was well tolerated throughout the study in this cohort of patients with prostate cancer. ClinicalTrials.gov identifier: NCT00128531.
To assess patient rationale in selecting androgen deprivation, structured telephone interviews were conducted on consecutive patients on androgen deprivation over a 17-year period. The majority of these patients have stable disease that require long-term follow-up with 6-monthly PSA estimations. Synchronous PSA check with depot injections are preferred by majority of patients and longer intervals between the depot administrations are preferable due to perceived less needle pain. This study highlights for the first time patients' preferences for synchronous PSA check with their depot injections and a longer interval between the depot administrations due to perceived less needle pain.
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.
Prostate cancer is being diagnosed at an earlier age and earlier disease stage than previously and increasing numbers of relatively young men are receiving potentially curative radical prostatectomy or radiotherapy for early prostate cancer. Although many of these men have an excellent outcome, a significant proportion subsequently experience disease recurrence or cancer-related death. Men with unfavorable tumor characteristics at the time of radical prostatectomy or radiotherapy are particularly at high risk of experiencing disease recurrence. One strategy to improve outcome for these men is adjuvant hormone therapy (hormone therapy administered immediately after therapy of primary curative intent). Surgical castration (bilateral orchiectomy), medical castration using the luteinizing hormone-releasing hormone (LHRH) agonist goserelin, and antiandrogen monotherapy have been investigated as adjuvant hormone therapy to radical prostatectomy and radiotherapy, and each therapy has demonstrated clinical benefits because of a significant improvement in disease-free survival. Furthermore, data are available to indicate that adjuvant hormone therapy achieved by goserelin or bilateral orchiectomy improves overall survival, particularly in men at high risk of progression. Because the effects of LHRH agonists are reversible, they provide a more acceptable method of adjuvant therapy compared to bilateral orchiectomy, particularly in the adjuvant setting, and are preferred by patients. However, the adverse effects on quality of life, in particular on sexual interest and function and bone mineral density, may limit the use of LHRH agonists in some patients. However, these parameters are maintained with nonsteroidal antiandrogens. The first data from the Early Prostate Cancer program indicate that adjuvant bicalutamide 150 mg is associated with a significant improvement in progression-free survival after radical prostatectomy or radiotherapy. Gynecomastia and breast pain are the most common side effects associated with bicalutamide therapy. Medical or surgical castration in combination with an antiandrogen (combined androgen blockade) is another option for use as an adjuvant hormone therapy. However, no study has reported on the use of combined androgen blockade in this setting. Adjuvant hormone therapy provides clinicians with another treatment option for patients with early prostate cancer and unfavorable tumor characteristics.
Despite the fact that they have been used for a century to treat several kinds of diseases, peptides and short proteins are now considered the new generation of biologically active tools. Indeed, recent findings suggest a wide range of novel applications in medicine, biotechnology, and surgery. The efficacy of native peptides has been greatly enhanced by introducing structural modifications in the original sequences, giving rise to the class of peptidomimetics. This review gives an overview of both classical applications and promising new categories of biologically active peptides and analogs. Besides the new entries in well known peptide families, such as antibiotic macrocyclic peptides, integrin inhibitors, as well as immunoactive, anticancer, neuromodulator, opioid, and hormone peptides, a number of novel applications have been recently reported. Outstanding examples include peptide-derived semi-synthetic vaccines, drug delivery systems, radiolabeled peptides, self-assembling peptides, which can serve as biomaterials in tissue engineering for creating cartilage, blood vessels, and other tissues, or as substrates for neurite outgrowth and synapse formation, immobilized peptides, and proteins. Finally, peptide-based biomaterials can find applications in bio-nanotechnology for bio-microchips, peptide nanorods and nanotubes, bio-sensors, bio-electronic devices, and peptide-metal wires.
Leuprolide acetate (LA) is a synthetic analog of gonadotropin releasing hormone. It is effective in prostate cancer treatment only when its desired concentration in blood is maintained for longer duration. Therefore, the purpose of this study was to investigate the in vitro release, biocompatibility, and in vivo absorption of LA from phase-sensitive polymer delivery systems capable of delivering it at a controlled rate for longer duration. Phase-sensitive formulations were prepared by dissolving dl-polylactic acid (dl-PLA) in a mixture of organic solvents, benzyl benzoate (BB) and benzyl alcohol (BA). LA was incorporated into the polymer solution by homogenization. In vitro release was studied into 15 ml of releasing media contained in a vial which was maintained at 37 degrees C in a reciprocal shaking water bath. The amount of LA in the released samples was analyzed by stability indicating HPLC method. The biocompatibility of polymer formulations was investigated by in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In vivo absorption of LA from delivery systems was studied in rabbits. Blood samples were analyzed for LA and testosterone contents by commercially available immunoassay kits. In vitro release studies showed a greater release of LA from formulations containing a greater proportion of BA (hydrophilic fraction) in the solvent mixture. In vitro biocompatibility study showed significantly (p<0.05) higher cell viability in growth media diluted with polymer extract than the control. In vivo absorption of LA and its effect on testosterone level in rabbits from the delivery system showed a sustained plasma level of LA up to 12 weeks which suppressed the testosterone plasma concentration to castration level beginning from 14th day until 90 days. Thus, phase-sensitive polymer delivery systems of LA were biocompatible and delivered LA at a controlled rate both in vitro and in vivo to keep testosterone plasma concentration at a castration level up to 3 months.
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.
Hormonal deprivation before radical prostatectomy remains controversial. The main purpose is to achieve downstaging, downgrading, improvement of the surgical results and increased survival. Experience with the last 100 patients who underwent radical prostatectomy, in whom 40 patients received complete preoperative androgen blockade (luteinizing-hormone- releasing hormone agonist and flutamide) prior to radical surgery, has shown a definitive decrease in volume of 40-50%). The significant reduction of volume seemed to facilitate the dissection of the prostate from closely vulnerable structures. Clinical downstaging was observed in one third of the patients, but the final pathological staging did not confirm the clinical impression and shows that it is difficult to solve this issue. There was one PT(0) patient. Histological changes are observed in both the nonneoplastic tissue as well as in the prostatic carcinoma with more marked effects on the latter. Downgrading was not observed, but this is even more difficult to assess since biopsies cannot be considered as representative of the entire heterogeneous tumor. Prostate-specific antigen (PSA) dropped to undetectable levels in 59% of the patients 3 months after hormonal suppression. Among these, 80% had PT(2) and only 13% had PT(3) tumor. PSA, 3 months after neoadjuvant hormonal treatment, might have a useful predictive value in patient selection for radical surgery since 86% with undetectable PSA had tumors confined to the gland (PT(2)/B(2)). On the other hand, patients who still had PSA >4 ng/ml after neoadjuvant therapy had all stage PT(3)-PT(4) disease. The true influence on the local control, time to progression and overall survival needs to be addressed by large prospective randomized studies comparing radical prostatectomy versus radical prostatectomy with neoadjuvant complete androgen deprivation in locally advanced (T(2)-T(3) N(0) M(0)) prostatic carcinoma.
The present practice of preceding radical prostatectomy by a 3-month androgen-deprivation treatment does not as a rule endanger the patient. In view of the low proliferation rate of 2.4%, progression of the tumour in this time interval is not to be expected. While histopathological downstaging is probably seen in only a very small percentage of the cases, the observed reduction in the rate of positive resection margins offers hope that the neoadjuvant androgen-deprivation therapy improves the curability of the operative procedure. Data available to date show that preoperative drug treatment - usually limited to 3 month - administered prior to radical prostatectomy, is clearly of benefit. The neoadjuvant preoperative treatment, in particular in the case of cT2 tumours, would appear to make good therapeutic sense. So far, data on the influence of this neoadjuvant treatment on the overall survival rate have been lacking. Current publications (Schulman, 1996) indicate an advantage in terms of the progression-free survival associated with the hormonal treatment. However, conclusions should not be drawn prematurely, and the future course of events must be awaited.
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.
Objective To compare the effect on the course of advanced prostate cancer of hormone treatment commenced on diagnosis with that deferred until clinically significant progression occurs.
Patients and methods Nine hundred and thirty-eight patients with locally advanced or asymptomatic metastatic prostate cancer were randomized either to immediate treatment (orchidectomy or luteinizing hormone-releasing hormone analogue) or to the same treatment deferred until an indication occurred. Follow-up and management were otherwise according to the participating clinician's normal practice. Information was collected annually on survival, local and distant progression, and major complications (pathological fracture, spinal cord compression, ureteric obstruction and extra-skeletal metastases).
Results Follow-up data were returned on 934 patients; 51 deferred patients died from causes other than prostate cancer before treatment was started (but only five of these presented at age <70 years) and 29 died from prostate cancer before treatment could be started. Treatment was commenced for local progression almost as frequently as for metastatic disease. Progression from M0 to M1 disease (P<0.001, two-tailed) and development of metastatic pain occurred more rapidly in deferred patients; 141 deferred patients needed transurethral resection for local progression compared with 65 treated immediately (P<0.001, two-tailed). Pathological fracture, spinal cord compression, ureteric obstruction and development of extra-skeletal metastases were twice as common in deferred patients. Of the patients who died, 67% did so from prostate cancer; 361 patients died in the deferred arm compared with 328 in the immediate arm (P=0.02, two-tailed), where 257 and 203 were deaths from prostate cancer, respectively (P=0.001 two-tailed). This difference was seen largely in M0 patients, with 119 and 81 deaths from prostate cancer, respectively (P<0.001 two-tailed).
Conclusions The results consistently favour immediate treatment, although some of the data, especially on M0 patients, are immature. The implications for management of advanced prostate cancer are discussed.
Purpose: To compare luteinizing hormone-releasing hormone (LHRH) agonists with orchiectomy or diethylstilbestrol, and to compare antiandrogens with any of these three alternatives. Data Sources: A search of the MEDLINE, Cancerlit, EMBASE, and Cochrane Library databases from 1966 to March 1998 and Current Contents to 24 August 1998 for articles comparing the outcomes of the specified treatments. The search was limited to studies on prostatic neoplasms in humans. Total yield was 1477 studies. Study Selection: Reports of efficacy outcomes were limited to randomized, controlled trials. Twenty-four trials involving more than 6600 patients, phase II studies that reported on withdrawals from therapy (the most reliable indicator of adverse effects), and all studies reporting on quality of life were abstracted. Data Extraction: Two independent reviewers abstracted each article by following a prospectively designed protocol. The meta-analysis combined data on 2-year overall survival by using a random-effects model and reported results as a hazard ratio relative to orchiectomy. Data Synthesis: Ten trials of LHRH agonists involving 1908 patients reported no significant difference in overall survival. The hazard ratio showed LHRH agonists to be essentially equivalent to orchiectomy (hazard ratio, 1.262 [95% Cl, 0.915 to 1.386]). There was no evidence of difference in overall survival among the LHRH agonists, although Cls were wider for leuprolide (hazard ratio, 1.0994 [Cl, 0.207 to 5.835]) and buserelin (hazard ratio, 1.1315 [Cl, 0.533 to 2.404]) than for goserelin (hazard ratio, 1.1172 [Cl, 0.898 to 1.390]). Evidence from 8 trials involving 2717 patients suggests that nonsteroidal antiandrogens were associated with lower overall survival. The Cl for the hazard ratio approached statistical significance (hazard ratio, 1.2158 [Cl, 0.988 to 1.496]). Treatment withdrawals were less frequent with LHRH agonists (0% to 4%) than with nonsteroidal antiandrogens (4% to 10%). Conclusions: Survival after therapy with an LHRH agonist was equivalent to that after orchiectomy. No evidence shows a difference in effectiveness among the LHRH agonists. Survival rates may be somewhat lower if a nonsteroidal antiandrogen is used as monotherapy.
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 retrieval by preventing premature luteinisation. While some studies demonstrate an improvement in intermediate end-points such as increased number of mature oocytes retrieved and embryos available for transfer, a significant effect has not been demonstrated on the rate of live births per stimulated cycle.(ABSTRACT TRUNCATED AT 400 WORDS)
Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.
Leuprorelin has demonstrated effectiveness comparable to orchiectomy and oral diethylstilboestrol for the palliation of advanced prostate cancer. Unlike orchiectomy, leuprorelin's effects are reversible; also leuprorelin is not associated with the cardiovascular or thromboembolic adverse effects of oestrogens. For these reasons, leuprorelin has been widely used as an alternative to surgical castration or to oestrogens in the treatment of metastatic prostate cancer. Sustained-release leuprorelin microsphere formulations have been developed which exhibit zero order release of active drug from the injection site, such that in the United States the 7.5 mg dosage strength is recommended to be administered once a month and the 22.5 mg dosage strength once every three months. Although most patients will have suppressed release of pituitary luteinizing hormone by the third or fourth week after the first dose of depot leuprorelin, 4–5% of treated patients have been reported to have delayed responses, taking many more weeks or months to respond. A transient biochemical hormone escape has also been reported, although worsening of clinical symptoms has not accompanied the elevation of serum testosterone levels during treatment. Usually, leuprorelin is initiated as monotherapy when patients with advanced prostate cancer become symptomatic. However, newer studies of combination therapy of luteinizing hormone releasing hormone analogs with antiandrogens suggest that early initiation of therapy, at the time of diagnosis of advanced disease, may be beneficial, particularly in a subgroup of patients with small volume disease and good performance status. Leuprorelin is also undergoing evaluation as neoadjuvant therapy prior to radical prostatectomy for localized prostate cancer. Preliminary studies suggest that neoadjuvant leuprorelin in combination with an antiandrogen may be effective in downstaging prostate tumours. Leuprorelin commonly produces several adverse effects: hot flashes, decreased libido and impotence, and tumour flare.
One hundred and ninety-nine patients with clinical stage D2 prostate cancer who had not received previous endocrine therapy or chemotherapy were treated with the combination therapy using the pure antiandrogen Flutamide and the LHRH agonist [D-Trp6]LHRH ethylamide for an average of 26 months (3–59 months). The objective response to the treatment was assessed according to the criteria of the U.S. NPCP. There was a 5.7-fold increase (26.3 vs 4.6%) in the percentage of patients who achieved a complete response compared with the results obtained in five recent studies limited to removal (orchiectomy) or blockade (DES or Leuprolide) of testicular androgens. Only 12 of the 186 evaluable patients (6.5%) did not show an objective positive response at the start of the combination therapy compared with an average of 18% in the same five studies using monotherapy. The duration of response was also significantly improved in the patients who received the combination therapy while the death rate was decreased by approximately two-fold during the first 4 yr of treatment. In fact, while an approximately 50% death rate is observed at 2 yr in all studies using monotherapy, the same 50% death rate is delayed by 2 yr in the present study. It should be mentioned that at the time of relapse under combination therapy, the treatment is continued and, in addition, further blockade of adrenal androgen secretion is achieved with aminoglutethimide. The marked (5.7-fold) improvement in the rate of complete objective responses coupled with the three-fold decrease in the number of non-responders, the increased duration of the positive responses and the two-fold decrease in the death rate during the first 4 yr of treatment are obtained with the combination therapy using Flutamide and castration, thus improving the quality and duration of life with no or minimal side-effects. By blocking the androgen receptors in the prostatic cancer tissue, the antiandrogen decreases the action of the androgens of adrenal origin and thus inhibits the growth of a large number of tumors which, otherwise, would continue to be stimulated by the adrenal androgens left after medical or surgical castration.
The incidence of prostate cancer is rising in the West, but information about developing treatment options and nursing care is limited. The author examines early disease detection and treatment, and discusses care for patients with locally advanced disease. The need for emotional support for sufferers and their families is stressed, and the importance of good patient education is highlighted.
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.
Une étude entreprise sur 470 malades souffrant d'adénocarcinome métastatique de la prostate a confirmé l'efficacité de Facétate de leuproréline sous forme retard%aG la dose de 3,75 mg administré par injection sous-cutanée une fois par mois. Les douleurs osseuses ont rapidement régressé et l'état générale des malades et les signes urinaires se sont améliorés. Une activité sexuelle s'est vue maintenue chez ces malades (50%). Après un traitement de 3 mois, il n'a pas été noté de progression de la tumeur chez 95 % des patients, une régression complète a été observée chez 39 % des malades, une régression partielle chez 49 % des malades, et une stabilisation de la maladie a été notée dans 17 % des cas. L'amélioration des signes cliniques a été directement mise en relation avec une diminution du nombre des antigènes spécifiquesà la prostate et des concentrations sanguines en testostérone 3 à 4 semaine après le démarrage du traitement. L'acétate de leuproréline retard a été bien toléré et il s'est avéré d'utilisation aisées.
Uno studio condotto su 470 pazienti affetti da adenocarcinoma metas-tatizzato delia prostata ha confermato l'efficacia di 3,75 mg di leuprorelin acetato, in preparazione “ritardo”, somministrato per via sottocutanea una volta al mese. E’ stata riscontrata una rapida remissione del dolore osseo ed un miglioramento delie condizioni generali del paziente e delia minzione. L'attività sessuale è stata conservata dal 50% dei pazienti. Dopo un trattamento di 3 mesi, non è stato registrate alcun peggioramento nel 95% dei pazienti, una completa remissione nel 39% ed una parziale remissione nel 49%, il 17% dei casi si è stabilizzato. II miglioramento dei parametri clinici è stato posto in diretta correlazione con il decremento delia quantità di antigene specifico prostatico ed è stato associato con un decremento delie concentrazioni seriche di testosterone entro 3–4 settimane dall'inizio del trattamento. Il leuprorelin acetato, in preparazione “ritardo”, è stato ben tollerato ed è risultato di facile impiego e conservazione.
The quality of life (QOL) was studied on 31 prostatic cancer (PC) patients, being followed at our out-patient-clinic during a relapse-free period. Fifteen of them were under treatment with a slow releasing LH-RH analogue (TAP-144 SR Depot) (TAP) and the other 16 prostatic cancer patients with synthetic estrogen (Honvan) (DES). The QOL of 37 benign prostatic hyperplasia (BPH) patients on conservative treatment was also studied. Concerning their general feeling of health, the prostatic cancer patients on TAP treatment felt subjectively better than those on DES. The social life of the patients on TAP or those who had BPH was less affected than that of those on DES. The quality of sexual life was worse for the prostatic cancer patients on both TAP and DES treatment than for the BPH patients.
Leuprorelin (leuprolide acetate) is a synthetic analogue of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH)] which initially stimulates luteinising hormone (LH) and hence testicular androgen release; continuous administration then results in profound suppression of these hormones. Testosterone levels associated with castration are attained within 3 to 4 weeks. A biodegradable subcutaneous or intramuscular depot formulation of leuprorelin 3.75 or 7.5 mg, which releases the drug at a constant rate over 28 days, is available and may be preferred over daily subcutaneous injections. The progression of previously untreated advanced prostatic cancer is delayed in 70 to 90% of men receiving leuprorelin, with median survival of approximately 2 years. The efficacy of leuprorelin is equivalent to that of estrogen therapy, but the tolerability of the GnRH analogue is far better. In contrast to most other studies of GnRH agonists, a slight survival advantage has been reported for combined treatment with leuprorelin and the antiandrogen flutamide. Small noncomparative trials reveal that leuprorelin also causes regression of benign hyperplastic prostate tissue with corresponding relief of obstructive, but not irritative, symptoms although continuous treatment is necessary to maintain remission. Impotence and flushing occur in most leuprorelin recipients but, unlike diethylstilbestrol (stilboestrol), cardiovascular toxicity and gynaecomastia are not significant problems. Symptom flare, usually manifested as bone pain in prostate cancer patients and exacerbation of obstructive symptoms in those with benign prostatic hypertrophy, can occur in 4 to 29% at the beginning of treatment. Leuprorelin treatment is therefore an established effective palliative measure in men with previously untreated advanced prostatic cancer, and may have a role in those with benign hypertrophy who are unfit for surgery.
Histomorphometric measurements of tumour-free bone have been undertaken in a closely matched group of patients with metastatic prostate cancer treated either by subcapsular orchidectomy (SCO) or luteinising hormone-releasing hormone (LHRH) agonists. Age, fasting morning urine hydroxyproline/creatinine ratios, alkaline and acid phosphatase levels and elapsed time after hormonal manipulation were similar in those receiving SCO (n = 8) as compared to LHRH therapy (n = 8). Results indicated that osteoid surface and mineralisation rate were significantly reduced in the SCO group (p less than 0.05); other indices were also lower in the SCO patients but failed to reach statistical significance. These changes, possibly due to increased adrenal cortical stimulation secondary to elevated gonadotrophin levels following orchidectomy suggest that medical castration by gonadotrophin inhibition may avoid unnecessary morbidity due to treatment-induced bone dysfunction.
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.
The clinical efficacy and safety of 3.75 or 7.5 mg leuprorelin acetate depot given subcutaneously once every 4 weeks was evaluated in a collaborative study of 81 patients with untreated prostatic cancer. Efficacy of treatment was assessed using criteria based on a meeting of the Prostatic Cancer Study Group funded by the Japanese Ministry of Health and Welfare and using National Prostatic Cancer Project criteria. Japanese criteria enabled evaluation of individual parameters, unlike the National Prostatic Cancer Project System which classified a patient as unevaluable if one evaluation parameter was unavailable. Leuprorelin acetate depot suppressed serum luteinizing hormone, follicle stimulating hormone and testosterone concentrations. Objective response rates of the prostate, bone mtastases, serum prostatic acid phosphatase and soft tissue metastases, and subjective dysuria and pain responses were comparable to those found with conventional hormone therapy. Leuprorelin acetate depot was well tolerated, with no significant differences in response to the two doses.
L'efficacité clinique de l'acétate de leuproréline sous forme retard à la dose de 3,75 ou 7,5 mg administré par voie sous-cutanée une fois toutes les 4 semaines a été évaluée dans le cadre d'une étude, portant sur 81 malades souffrant d'un cancer prostatique. L'efficacité du traitement a été évaluée en faisant appel à des critères déterminés par le Prostatic Cancer Study Group (Groupe d'Etudes sur le Cancer Prostatique) fondé par le Ministère de la Santé du Japon et le National Prostatic Cancer Project (Projet National sur le Cancer Prostatique). Les critères janonais ont rendus possibles l'évaluation de paramètres individuels à l'encontre du système adopté par le Projet National sur le Cancer Prostatique qui a classé un malade comme étant non évaluable dès que l'obtention d'un paramètre d'évaluation n'était pas possible. L'acétate de leuproréline retard induit la réduction des concentrations plasmatiques en hormones lutéinisantes, en hormones de stimulation des follicules (FSH) et en testérone. Les taux objectifs d'amélioration de la prostate, des métastases des tissus mous et des taux plasmatiques de phosphatase acide prostatique, de la dysurie subjective et des degrés de douleurs étaient comparables aux hormonothérapies conventionnelles. L'acétate de leuproréline retard a été bien toléré, et n'a pas induit de différences significatives dans la réponse obtenue aux deux doses administrées.
L'efficacia clínica di 3,75 o 7,5 mg di leuprorelin acetato, in preparazione “ritardo”, somministrato per via sottocutanea ogni 4 settimane è stata valutata nel corso di uno studio collaborativo condotto su 81 pazienti ammalati di cancro alla prostata. L'efficacia del trattamento è stata valutata adottando dei criteri scaturiti da una riunione del Gruppo di Studio sul Cancro della Prostata, fondato dal Ministero della Sanit à giapponese, nonchè dei criteri stabiliti dal “National Prostatic Cancer Project”. I criteri elaborad in Giappone hanno consentito la valutazione dei singoli paramtri a differenza del sistema del “National Prostatic Cancer Project”, nell'ambito del quale un paziente veniva classificato corne non valutabile nel caso che uno dei parametri necessari alla valutazione non fosse disponibile. Il leuprorelin acetato, in preparazione “ritardo”, ha soppresso le concentrazioni seriche di ormone luteinizzante, ormone follicolostimolante e testosterone. I tassi di risposta oggettivi, relativi alle metastasi prostatiche, ossee, alla concentrazione serica di fosfatasi acida prostatica ed alle metastasi dei tessuti molli, nonchè le risposte soggettive relative alla disuria ed al dolore, sono risultati comparabili a quelli ottenuti con una convenzionale terapia ormonale. Il leuprorelin acetato, in preparazione “ritardo”, è stato ben tollerato, senza significative differenze nella risposta alle due dosi.
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.
Quarante malades au total souffrant de cancer prostatique de stade A2 à C ont été traités par l'acétate de leuproréline sous forme retard une fois par mois pendant 2 mois avant d'être soumis à une irradiation pelvienne ou à une prostatectomie radicale. Sur les 32 malades évalués, sept (22%) ont été classés comme manifestant une légère amélioration suite à un traitement par leuproréline et 23 (72%) comme présentant une amélioration considérable suite à un examen rectal. Les concentrations en antigènes spécifiques à la prostate sont également revenues à la normale (5 ng/ml) chez 26/31 (84%) des malades. L'acétate de leuproréline retard a diminué les concentrations plasmatiques en testérone pour les amener à des valeurs de castration durant le traitement, les concentrations sont toutefois revenues à la normale 2 mois après la fin du traitement. Suite à un traitement radical, on a déploré trois décès – un décès post-opératif et deux autres dûs à une récidive de la maladie – on n'a toutefois pas noté de rechute locale isolée. On en a conclu que le protocole avait bien été toléré du point de vue local et que ce médicament était efficace dans le traitement des cancers prostatiques de stades B2 et C.
Un totale di 40 pazienti affetti da cancro prostatico, in stadi di sviluppo da A2 a C, sono stati trattati con leuprorelin acetato, in preparazione “ritardo”, somministrato una volta al mese, per un periodo di 2 mesi, prima di essere sottoposti ad irradiazione pelvica od a prostatectomia radicale. Dei 32 pazienti valutabili, in seguito alla valutazione mediante esame rettale, sette (22%) sono stati classificati come soggetti dalla risposta minima al trattamento con leuprorelin e 23 (72%) sono stati classificati come soggetti dalla risposta maggiore. Inoltre, gli antigeni prostato–specifici sono ritornati alle normali concentrazioni (5 ng/ml) in 26/31 pazienti (84%). II leuprorelin acetato, in preparazione “ritardo”, ha soppresso le concentrazioni plasmatiche di testosterone a valori analoghi a quelli ottenuti mediante castrazione, nel corso del trattamento; tuttavia, tali concentrazioni sono ritornate ai valori normali entro 2 mesi dal termine del trattamento. A seguito del trattamento radicale, si sono verificad tre decessi – uno postoperatorio e due dovuti a malattia recidiva – tuttavia non si è verificato alcun caso isolato di recidivit à localizzata. Se ne desume che la terapia è stata ben tollerata a livello locale ed è risultata efficace nel trattamento dei pazienti affetti da cancro prostatico negli stadi B2 e C.
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 leveis; luteinizing hormone levels were also suppressed. The incidence of progressive disease was low and partial reponse 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.
Dans le cadre d'une étude clinique multicentrique préliminaire portant sur l'acétate de leuproréline retard à une dose de 3,75 mg, on a administré le médicament à 18 malades atteints d'un cancer prostatique métastatique non traité au préalable, et ce sous forme d'injection sous-cutanée une fois toutes les quatre semaines pendant 28 semaines. On a également prescrit aux malades 100 mg de nilutamide qui a été ingérée par voie orale trois fois par jour pendant les 14 premiers jours du traitement en vue d'empêcher un réveil de la tumeur. L'acétate de leuproréline a réduit la concentration plasmatique de testostérone jusqu’ à des taux de castration; les taux d'hormones lutéinisantes ont également été réduits. L'incidence de progression de la maladie a été basse et une réponse partielle a été observée chez cinq patients sous le traitement. Aucun effet secondaire n'a été associé à la période de réveil de la tumeur. On en a conclu que l'acétate de leuproréline retard était un traitement sûr et efficace du cancer prostatique métastatique.
In uno studio preliminare policentrico delia terapia a base di 3,75 mg di leuprorelin acetato, in preparazione “ritardo”, a 18 pazienti affetti da cancro prostatico metastatico, che non erano stati trattati in pre-cedenza, è stata somministrata la suddetta dose di farmaco, in preparazione “ritardo” per via sottocutanea, una volta ogni 4 settimane, per 28 settimane. Ai pazienti sono stati somministrati anche 100 mg di nilutamide, per via orale, tre volte al giorno, per i primi 14 giorni di trattamento, al fine di impedire l'aggravamento. Il leuprorelin acetato ha soppresso la concentrazione serica di testosterone a livelli da castrazione; anche i livelli di ormone luteinizzante sono stati soppressi. L'incidenza dei casi di malattia progressiva è stata bassa ed in cinque pazienti si è rilevata una risposta parziale, dopo il trattamento. Nessun effetto collatérale è stato attribuito al periodo di aggravamento. Se ne desume che il leuprorelin acetato, in preparazione “ritardo” costituisce un trattamento sicuro ed efficace per il cancro della prostata metastatico.
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.
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 < 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 dihydro-testosterone 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.
On a administré à un total de 21 malades souffrant du cancer prostatique et à un malade atteint d'une hypertrophie bénigne de ou 15 mg d'acétate de leuproréline retard par injection sous-cutanée une fois toutes les 4 semaines. Les concentrations plasmatiques de leuproréline ont augmenté immédiatement après l'injection, atteignant un pic sérique (plage de 13,1 à 54,5 ng/ml), qui était directement proportionnel à la dose, en 3 heures. Les taux moyens du médicament ont ultérieurement diminué pour se stabiliser à la cinquième semaine à un plateau directement proportionnel à la dose administrée. On a noté une augmentation significative, dépendante de la dose administrée (P < 0,01), de la zone se trouvant sous la courbe durée – concentration pendant la période 0 à 35 jours. Les concentrations plasmatiques en hormones lutéinisantes et en hormones de stimulation des follicules (FSH) ont initialement augmenté à toutes les doses et ont été suivis par une augmentation des concentrations plasmatiques en testo-stérone et en dihydrotestostérone qui sont ensuite soudainement retombées au bout de trois semaines. Un taux réduit de FSH a ensuite été noté chez les 20 patients évalués, ce taux s'étant maintenu chez 17 malades pendant plus de 5 semaines. On a également observé une réduction initiale marquée des taux d'hormones lutéinisantes chez 15 malades et chez 13 d'entre eux, cette réduction s'est poursuivie. Les taux de castration de la tétostérone et de la dihydrotestostérone se sont maintenus chez tous les patients pendant une période allant jusqu’ à 5 semaines. Une amélioration de la condition a été notée chez deux malades, une amélioration partielle chez 14 malades et chez trois patients une stabilisation de la maladie pratiquement analogue aux diverses doses administrées. L'amélioration clinique et les changements plasmatiques hormonaux suggèrent que l'acétate de leuproréline retard est efficace à une dose aussi basse que 3,75 mg lorsqu'il est administré une fois toutes les 4 semaines.
Un totale di 21 pazienti affetti da cancro prostatico in fase avanzata ed un paziente affetto da ipertrofia prostatica benigna hanno ricevuto una dose di 3,75, 7,5 o 15 mg di leuprorelin acetato, in preparazione “ritardo”, somministrata per via sottocutanea una volta ogni 4 settimane. Le concentrazioni seriche di leuprorelin sono aumentate immediatamente dopo l'iniezione, raggiungendo, entro 3 ore, una concentrazione massima (nella gamma da 13,1 a 54,5 ng/ml) direttamente proporzionale alla dose somministrata. I livelli medi di concentrazione del farmaco sono, successivamente, scesi ad un valore costante direttamente proporzionale alla dose a 5 settimane. E’ stato riscon-trato, inoltre, un significativo incremento (P < 0,01), dipendente dal dosaggio, nell'area sotto la concentrazione – curva temporale per 0–35 giorni. Le concentrazioni seriche di ormone luteinizzante e di ormone follicolostimolante sono aumentate, inizialmente, con tutte le dosi, seguite da un incremento nelle concentrazioni seriche di testosterone e diidrotestosterone, che, successivamente, sono diminuite rapidamente, entro 3 settimane. Un ridotto livello di ormone follicolostimolante è stato, successivamente, rilevato in tutti i 20 pazienti valutabili ed in 17 pazienti è rimasto costante per oltre 5 settimane.
Inoltre, in 15 pazienti è stata rilevata anche una marcata soppressione iniziale dei livelli di ormone luteinizzante ed in 13 di tali pazienti questa soppressione è risultata continua. I livelli da castrazione del testosterone e del diidrotestosterone sono stati mantenuti in tutti i pazienti per un periodo fino a 5 settimane. In due pazienti si è riscon-trata una risposta completa, in 14 una risposta parziale ed in tre la malattia si è stabilizzata, senza alcuna differenza significativa in re-lazione al dosaggio. Il miglioramento clinico e le variazioni ormonali a livello serico suggeriscono che il leuprorelin acetato, nella preparazione “ritardo”, è efficace anche ad un dosaggio minimo di 3,75 mg, se viene somministrato una volta ogni 4 settimane.
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 còuld 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.
Dans une importante étude multicentrique, la dose d'l mg/jour de leuproréline administrée par voie sous-cutanée s'est avérée aussi efficace que le diéthylstilboestrol dans le traitement du cancer de la prostate, avec toutefois une incidence plus basse d'effets secondaires, bien que la leuproréline pouvait induire un réveil de la tumeur. Une réduction totale des androgènes engendrée par l'association de leuproréline et de flutamide antiandrogène non-stéroide s'est avérée plus efficace dans le traitement du cancer prostatique que l'orchidestomie ou le diéthylstilboestrol. On a comparé l'efficacité d'une dose d'1 mg/ jour de leuproréline administrée par injection sous-cutanée avec 250 mg de flutamide trois fois par jour à une association de leuproréline et de placébo confirmée dans une étude double-aveugle randomisée portant sur 603 malades. La survie globale et la durée de la période durant laquelle aucune détérioration n'a été notée ont été prolongées et le réveil de la tumeur et autres effets secondaires ont été réduits chez les malades souffrant d'un cancer prostatique avancé non traité et ceux souffrant d'une maladie mineure.
In un'estesa sperimentazione policentrica, 1 mg di leuprorelin al giorno, somministrato per via sottocutanea, è risultato efficace quanto il dietilstilbestrolo nel trattamento del cancro prostatico, tuttavia con una minore incidenza di effetti collaterali, sebbene il leuprorelin possa indurre un possa indurre un fiare up. La totale ablazione androgena, impiegando una combinazione di leuprorelin e dell'anti-androgeno, non steroideo, flutamide, nel trattamento del cancro prostatico, è risultata più efficace dell'orchiectomia o del dietilstilbestrolo. L'efficacia di 1 mg al giorno di leuprorelin, somministrato per via sottocutanea, più 250 mg di flutamide tre volte al giorno, confrontata con la somministrazione di leuprorelin più un placebo, è stata confermata in uno studio randomizzato, a ‘doppio cieco’, su 603 pazienti. Si è riscontrato un prolungamento dei periodi di stabilizzazione delia malattia e delia sopravvivenza in generale e l'aggravamento tumorale e gli altri effetti collaterali sono stati ridotti nei pazienti affetti da cancro prostatico in fase avanzata, non trattato, ed in quelli affetti da una forma leggera delia malattia.
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.
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 anti-androgen or cytostatic therapy. The two doses and the different routes of administration did not have any significant effects on serum testo-sterone, 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.
Patients (190) souffrant d'un cancer prostatique ont été évalués dans le cadre d'une étude multicentrique, non comparative de phase III se poursuivant encore à ce jour, lors de laquelle il leur a été administré 3,75 ou 7,5 mg d'acétate de leuproréline sous forme retard par injection sous-cutanée ou intramusculaire une fois par mois avec ou sans traitement cytostatique ou antiandrogène concomitant. Les deux posologies et voies d'administration différentes n'ont pas eu d'effet significatif sur les concentrations plasmatiques en hormones lutéinisantes, en hormones de stimulation des follicules, en dihydrotestostrone et en testostérone sur l'activité de la tumeur ou la tolérance clinique. Par l'utilisation de l'une ou de l'autre posologie, le taux de ‘non-progression’ (rémission totale, plus rémission partielle, plus stabilisation de la maladie) était globalement de 88.5% et de 88.2% dans une maladie au stade T1-T2 et de 82.5% dans une maladie au stade T3-T4 après 12 mois de traitement. II en a été conclu que la formulation d'acétate de leuproréline retard représentait une alternative à considérer dans le traitement du cancer avancé de la prostate.
In uno studio ancord in corso, non comparativo, aperto, policentrico, fase III, 190 pazienti con cancro prostatico avanzate sono stati trattati con 3,75 o 7,5 mg di leuprorelin acetato, in preparazione ‘ritardo’, somministrato per via sottocutanea od intramuscolare, una volta al mese, con o senza concomitante terapia antiandrogena o citostatica. I due dosaggi e le differenti vie di somministrazione non hanno avuto alcun effetto significativo sulle concentrazioni seriche di testosterone, diidrotestosterone, ormone follicolostimolante ed ormone luteinizzante, sull'attivit à tumorale o sulla tolleranza clinica. Adottando l'uno o l'altro dosaggio, la percentuale di casi di ‘non peggioramento’ (completa remissione, più parziale remissione, più stabilizzazione delia malattia) è risultata pari ad 88.5% complessiva ed è stata di 88.2% negli stadi T1-T2 e di 82.5% negli stadi T3-T4, dopo un trattamento di 12 mesi. Si conclude che la formulazione ‘ritardo’ del leuprorelin acetato costituisce un'importante alternativa nel trattamento del cancro prostatico in fase avanzata.
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.
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.
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)
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 leveis in rats, dogs and man. In clinicai 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.
L'acétate de leuproréline, un très puissant agoniste des hormones lutéinisantes, a été lancé à l'origine aux Etats-Unis en vue d'être administré une fois par jour par injection dans le traitement du cancer prostatique métastatique. L'acétate de leuproréline sous présentation retard, injectable par voie sous-cutanée ou intramusculaire une fois par mois, a ainsi été développé. Le copolymère biodégradable (acide lactique-DL/acide glycolique-DL) a été choisi comme polymère de contrôle de libération et les microgélules contenant l'acétate de leuproréline ont été préparées par la méthode de séchage dans l'eau. Les résultats de l'étude chez les rats ont mis en évidence qu'un copolymère d'un poids moléculaire de 14 000 et d'un rapport acide lactique/acide glycolique de 75/25 présentait les propriétés de libération les plus satisfaisantes. Les microcapsules administrées une fois par mois ont diminué les taux sériques de la téstostérone chez le rat, le chien et l'homme. Dans les études cliniques, la préparation retard a diminué considérablement la dose d'acétate de leuproréline requise d'un huitième de ce qui était nécessaire lors d'une injection journalière. Un système de fabrication sophistiqué a maintenant été développé et un produit de libération contrôlée très fiable et présentant de nombreux avantages est maintenant disponible.
Il leuprorelin acetato, un agonista del LHRH di elevata potenza è stato lanciato, originariamente, negli USA, in preparato per auto-iniezione da somministrare una volta al giorno, per il trattamento del cancro alla prostata metastatico. Successivamente, è stata messa a punto una forma ‘ritardo’ di leuprorelin acetato, iniettabile per via sottocutanea od intramuscolare, una volta al mese. Un copolimero biodegradabile (DL-acido lattico/acido glicolico) è stato scelto come polimero di contrallo del rilascio e le microcapsule contenenti il leuprorelin acetato sono state preparate con un metodo di essiccamento in acqua. I risultati degli studi condotti sui ratti hanno evidenziato che un copolimero con un peso molecolare di 14 000 ed un rapporto acido lattico/ acido glicolico pari a 75/25 presenta le più soddisfacenti propriet à di rilascio. Le microcapsule somministrate una volta al mese hanno ridotto i livelli serichi di testosterone nei ratti, nei cani e negli uomini. Negli studi clinici condotti, la preparazione ‘ritardo’ ha efficacemente ridotto la dose di leuprorelin acetato necessaria fino ad un ottavo di quella necessaria in caso di somministrazione giornsliera. Oggi, è, stato realizzato un sofisticate impianto produttivo ed è disponibile un prodotto nella formulazione ‘ritardo’, estremamente affidabile e dai molteplici vantaggi.
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.
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.
Given the current preference of many patients for an active role in decision-making regarding their care, the feasibility of patients making their own treatment choices was investigated, and the reasons for their selections were studied. Subjects comprised previously untreated Stage D prostate cancer patients for whom hormonal therapy was indicated. Thirteen institutions entered 159 patients into the study. After discussing treatment choices with their physicians, the patients took home a two-page letter explaining two options: surgical castration and therapy with Zoladex (goserelin acetate), a depot luteinizing hormone-releasing hormone (LHRH) analogue injected subcutaneously every twenty-eight days. Patients were encouraged to discuss the treatment choices with their families. After selecting a treatment approach, patients completed a "decision questionnaire" and then treatment was initiated. Of the 147 patients who completed baseline questionnaires, 78 percent selected Zoladex and 22 percent selected orchiectomy. The primary reason for selecting Zoladex included avoidance of surgery (36%), success of treatment (18%), convenience of the drug (10%), and physician's advice (10%). Patients chose surgery primarily because of convenience (32%) and success of treatment (29%). Three months later, patients and their wives completed another questionnaire, which assessed their satisfaction with their treatment choices. Ninety-three percent of patients and 91 percent of patients' wives indicated that they would select the same treatment again.
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.
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.
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.
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.
A series of peptide analogs of luteinizing hormone releasing hormone (LH-RH), altered at position 6 and 10, was synthesized and evaluated for the ability to induce ovulation in the diestrous rat and for ability to release pituitary luteinizing hormone and follicle stimulating hormone. All the analogs with D-amino acid substitutions at position 6, even those with large bulky side chain, exhibited an amazingly high potency compared with the parent hormone, LH-RH. On the basis of the biological activities, structure-activity relationships in the central part of this molecule were discussed in detail.
LH-releasing hormone (LH-RH) was obtained in apparently a homogeneous state from extracts of pig hypothalami. The LH-RH preparation isolated has FSH-releasing hormone (FSH-RH) activity, which appears to be intrinsic to LH-RH. The amino acid composition of LH-RH/FSH-RH as determined on acid hydrolysates is: His 1, Arg 1, Ser 1, Glu 1, Pro 1, Gly 2, Leu 1 and Tyr 1. The hormone isolated stimulates the release of FSH and LH and in doses of a few nanograms. This polypeptide appears to represent the hypothalamic hormone which controls the secretion of both LH and FSH from the pituitary.
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.
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.
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.
Hormonal deprivation by combination therapy before radical prostatectomy has been recently introduced. The main purpose of such treatment is to achieve downstaging, downgrading, improvement of surgical results, and prolonged survival. Our experience with the last 100 patients who underwent radical prostatectomy at our hospital, of whom 40 received complete androgen blockade (luteinizing hormone-releasing hormone (LHRH) superagonist and flutamide) before radical surgery, has shown a definitive decrease in prostatic volume of 40-50%. Of these 40 patients, 25 were clinical stage T2 and 15 stage T3 at diagnosis. The reduction in volume facilitates dissection of the prostate from close vulnerable structures, resulting in reduced blood loss and operating time. Also, return of urinary continence is more rapid. Combination therapy resulted in clinical downstaging in one third of the patients; at histopathology, upstaging occurred in 12.5% (5 of 40) of patients, compared with the expected 30-50% upstaging in patients untreated before surgery. Serum prostate specific antigen (PSA) dropped to undetectable levels in 59% of the patients 3 months after hormonal suppression. Among these, 80% had PT2, and only 13% had PT3, tumor; one patient had a PT0 tumor. On the other hand, all patients who still had PSA > 4 ng/ml after neoadjuvant combination therapy had stage PT3-PT4 disease. Histological changes were observed in both the non-neoplastic tissue and the prostatic carcinoma, with more marked effects in the latter. The surgical margins were positive in 32% of the treated patients, compared with 57% in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)
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 retrieval by preventing premature luteinisation. While some studies demonstrate an improvement in intermediate end-points such as increased number of mature oocytes retrieved and embryos available for transfer, a significant effect has not been demonstrated on the rate of live births per stimulated cycle.(ABSTRACT TRUNCATED AT 400 WORDS)
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.
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.
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.
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.
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.