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      Efficacy of Testosterone Suppression with Sustained-Release Triptorelin in Advanced Prostate Cancer

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          Abstract

          Introduction

          Androgen deprivation therapy (ADT) is a mainstay of treatment against advanced prostate cancer (PC). As a treatment goal, suppression of plasma testosterone levels to <50 ng/dl has been established over decades. Evidence is growing though that suppression to even lower levels may add further clinical benefit. Therefore, we undertook a pooled retrospective analysis on the efficacy of 1-, 3-, and 6-month sustained-release (SR) formulations of the gonadotropin-releasing hormone (GnRH) agonist triptorelin to suppress serum testosterone concentrations beyond current standards.

          Methods

          Data of 920 male patients with PC enrolled in 9 prospective studies using testosterone serum concentrations as primary endpoint were pooled. Patients aged 42–96 years had to be eligible for ADT and to be either naïve to hormonal treatment or have undergone appropriate washout prior to enrolment. Patients were treated with triptorelin SR formulations for 2–12 months. Primary endpoints of this analysis were serum testosterone concentrations under treatment and success rates overall and per formulation, based on a testosterone target threshold of 20 ng/dl.

          Results

          After 1, 3, 6, 9, and 12 months of treatment, 79%, 92%, 93%, 90%, and 91% of patients reached testosterone levels <20 ng/dl, respectively. For the 1-, 3-, and 6-month formulations success rates ranged from 80–92%, from 83–93%, and from 65–97% with median (interquartile range) serum testosterone values of 2.9 (2.9–6.5), 5.0 (2.9–8.7), and 8.7 (5.8–14.1) ng/dl at study end, respectively.

          Conclusion

          In the large majority of patients, triptorelin SR formulations suppressed serum testosterone concentrations to even <20 ng/dl. Testosterone should be routinely monitored in PC patients on ADT although further studies on the clinical benefit of very low testosterone levels and the target concentrations are still warranted.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s12325-016-0466-7) contains supplementary material, which is available to authorized users.

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          Most cited references20

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          Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry.

          The diagnosis of male hypogonadism requires the demonstration of a low serum testosterone (T) level. We examined serum T levels in pedigreed samples taken from 62 eugonadal and 60 hypogonadal males by four commonly used automated immunoassay instruments (Roche Elecsys, Bayer Centaur, Ortho Vitros ECi and DPC Immulite 2000) and two manual immunoassay methods (DPC-RIA, a coated tube commercial kit, and HUMC-RIA, a research laboratory assay) and compared results with measurements performed by liquid chromatography-tandem mass spectrometry (LC-MSMS). Deming's regression analyses comparing each of the test results with LC-MSMS showed slopes that were between 0.881 and 1.217. The interclass correlation coefficients were between 0.92 and 0.97 for all methods. Compared with the serum T concentrations measured by LC-MSMS, the DPC Immulite results were biased toward lower values (mean difference, -90 +/- 9 ng/dl) whereas the Bayer Centaur data were biased toward higher values (mean difference, +99 +/- 11 ng/dl) over a wide range of serum T levels. At low serum T concentrations (<100 ng/dl or 3.47 nmol/liter), HUMC-RIA overestimated serum T, Ortho Vitros ECi underestimated the serum T concentration, whereas the other two methods (DPC-RIA and Roche Elecsys) showed differences in both directions compared with LC-MSMS. Over 60% of the samples (with T levels within the adult male range) measured by most automated and manual methods were within +/- 20% of those reported by LC-MSMS. These immunoassays are capable of distinguishing eugonadal from hypogonadal males if adult male reference ranges have been established in each individual laboratory. The lack of precision and accuracy, together with bias of the immunoassay methods at low serum T concentrations, suggests that the current methods cannot be used to accurately measure T in females or serum from prepubertal subjects.
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            Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis.

            To compare luteinizing hormone-releasing hormone (LHRH) agonists with orchiectomy or diethylstilbestrol, and to compare antiandrogens with any of these three alternatives. 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. 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. 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. 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, 1.1262 [corrected] [95% CI, 0.915 to 1.386]). There was no evidence of difference in overall survival among the LHRH agonists, although CIs were wider for leuprolide (hazard ratio, 1.0994 [CI, 0.207 to 5.835]) and buserelin (hazard ratio, 1.1315 [CI, 0.533 to 2.404]) than for goserelin (hazard ratio, 1.1172 [CI, 0.898 to 1.390]). Evidence from 8 trials involving 2717 patients suggests that nonsteroidal antiandrogens were associated with lower overall survival. The CI for the hazard ratio approached statistical significance (hazard ratio, 1.2158 [CI, 0.988 to 1.496]). Treatment withdrawals were less frequent with LHRH agonists (0% to 4%) than with nonsteroidal antiandrogens (4% to 10%). 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.
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              Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy.

              We determined the testosterone castration level with clinical relevance in patients with prostate cancer on continuous androgen deprivation therapy. Secondary objectives were to analyze the role of associated bicalutamide in breakthrough increases of serum testosterone in these patients and the possible benefit of maximal androgen blockade. Serum testosterone was determined 3 times (in 6 months) in 73 patients with nonmetastatic prostate cancer treated with medical castration, 28 (38.4%) of whom also received bicalutamide (maximal androgen blockade). During a mean followup of 51 months (range 12 to 240) 41 (67.1%) events of androgen independent progression were identified, and correlated with breakthrough testosterone increases of 50 ng/dl (classic level) and 20 ng/dl (surgical castration level). Testosterone was less than 20 ng/dl in all determinations in 32 patients (43.6%). Breakthrough increases between 20 and 50 ng/dl were observed in 23 patients (31.5%), and increases greater than 50 ng/dl were observed in the remaining 18 (24.7%). The lowest testosterone level with a significant impact on survival free of androgen independent progression was 32 ng/dl. Mean survival free of androgen independent progression in patients with breakthrough increases greater than 32 ng/dl was 88 months (95% CI 55-121) while it was 137 months (95% CI 104-170) in those without breakthrough increases (p <0.03). Patients on maximal androgen blockade had an incidence of testosterone increase similar to those receiving monotherapy. However, maximal androgen blockade provided a significantly longer survival free of androgen independent progression in those with breakthrough increases greater than 50 ng/dl. In the current report the lowest testosterone castration level with clinical relevance in medically castrated patients with prostate cancer was 32 ng/dl. Breakthrough increases greater than this threshold predicted a lower survival free of androgen independent progression. Maximal androgen blockade might benefit medically castrated cases of prostate cancer with breakthrough increases of more than 50 ng/dl.
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                Author and article information

                Contributors
                eija.lundstrom@debiopharm.com
                Journal
                Adv Ther
                Adv Ther
                Advances in Therapy
                Springer Healthcare (Cheshire )
                0741-238X
                1865-8652
                27 December 2016
                27 December 2016
                2017
                : 34
                : 2
                : 513-523
                Affiliations
                [1 ]Loretto Hospital, Freiburg, Germany
                [2 ]Debiopharm International SA, Lausanne, Switzerland
                [3 ]ISNI 0000 0001 1957 4504, GRID grid.476474.2, , Ipsen, ; Boulogne-Billancourt, Paris, France
                [4 ]Premier Medical Group of the Hudson Valley, Poughkeepsie, NY USA
                Article
                466
                10.1007/s12325-016-0466-7
                5331090
                28028737
                00497cfe-8363-43d8-b941-bb38ba76202a
                © The Author(s) 2016
                History
                : 17 October 2016
                Funding
                Funded by: Debiopharm International
                Funded by: Ipsen Pharma
                Categories
                Original Research
                Custom metadata
                © Springer Healthcare 2017

                advanced prostate cancer,castration limits,hormonal therapy,testosterone suppression,triptorelin

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