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Testosterone Recovery in the Off-Treatment Time in Prostate Cancer Patients Undergoing Intermittent Androgen Deprivation Therapy

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Testosterone Recovery in the Off-Treatment Time in Prostate Cancer Patients Undergoing Intermittent Androgen Deprivation Therapy Prostate Cancer and Prostatic Diseases (2012) 15, 296 -- 302 & 2012 Macmillan Publishers Limited All rights reserved 1365-7852/12 www.nature.com/pcan ORIGINAL ARTICLE Testosterone recovery in the off-treatment time in prostate cancer patients undergoing intermittent androgen deprivation therapy UW Tunn1, G Canepa2, A Kochanowsky3 and E Kienle4 BACKGROUND: Intermittent androgen deprivation (IAD) for prostate cancer was studied with the objective of reducing the side effects of treatment and potentially delaying the development of hormone resistance. There also appears to be a quality of life benefit during off-treatment intervals owing to the recovery of serum testosterone levels. METHODS: In this multicentre European prospective randomised phase III trial EC507, testosterone serum concentrations were analysed in prostate cancer patients with PSA progression after radical prostatectomy. Patients were randomised to a continuous androgen deprivation (CAD) and IAD therapy using a 3-month depot with 11.25 mg leuprorelin acetate as microcapsule formulation. A complete IAD cycle comprises both a 6-month androgen deprivation therapy plus the off-treatment time (OTT). RESULTS: Serum testosterone recovery was recorded in 109 patients during OTT in the IAD group. Testosterone recovery to baseline values was achieved in 79.3% during the first and in 64.9% during the second IAD cycle, respectively. Median time to testosterone normalisation was 100 days in the first and 115 days in the second cycle, respectively. No significant difference was observed up to 1000 days between IAD and CAD with regard to time to androgen-independent progression. This is the first prospective study of leuprorelin acetate 11.25 mg demonstrating normalisation of testosterone levels in the off-treatment period in patients undergoing IAD. CONCLUSIONS: The prerequisite of an IAD treatment is the testosterone recovery during off-treatment periods. In this study, in patients with PSA relapse after radical prostatectomy, a real achievement of intermittent castration with normalisation of testosterone levels during off-treatment periods could be confirmed. Prostate Cancer and Prostatic Diseases (2012) 15, 296--302; doi:10.1038/pcan.2012.12; published online 26 June 2012 Keywords: intermittent androgen deprivation; leuprorelin acetate; testosterone recovery INTRODUCTION Guidelines issued in 2009 also proposed IAD for prostate cancer The European Association of Urology Guidelines issued in 2010 patients, stating that they must be well-informed of the lack of 7 state that for patients with pTxpN1 disease who have PSA only long-term clinical data. recurrence following radical prostatectomy, androgen deprivation A prerequisite for an effective IAD strategy is the recovery of therapy (ADT) may help to delay progression and possibly achieve testosterone serum levels during off-treatment periods. There are 1 a survival benefit. However, the advantages and disadvantages of a few publications available that show broad variations in continuous ADT need to be carefully balanced. One approach that percentage of patients achieving normalisation of testosterone aims to minimise the negative effects of therapy and maximise the and time to normalisation of testosterone concentrations in the benefits is an intermittent androgen deprivation (IAD) approach. off-treatment period.8--11 Furthermore, different definitions of IAD was initiated in prostate cancer patients after preclinical testosterone normalisation, different testosterone baseline values, evidence showing that the use of hormonal therapy on an varying lengths of hormone deprivation and different hormonal intermittent basis might delay hormonal resistance.2,3 Phase II doses were applied giving major problems for a clear-cut studies have also indicated that IAD does provide a quality of life definition of testosterone recovery in the off-treatment periods. benefit during off-treatment intervals owing to the recovery of This is the first report of an European multicentre, prospective serum testosterone levels.4,5 A number of multi-institutional phase III trial in patients with PSA progression after radical randomised trials on IAD are now ongoing and these should prostatectomy where serial serum testosterone concentrations provide information on overall survival, time to develop androgen were analysed to confirm that the dosage of 11.25 mg leuprorelin independence, quality of life benefits and reduction in the acetate microencapsulated as a 3-month depot (Trenantone, incidence of adverse effects.4--6 The current European Association Enantone 11.25) results in a real intermittent castration with of Urology Guidelines state that IAD should no longer be regarded recovery and normalisation of testosterone serum levels in the off- as investigational.1 It has to be acknowledged that IAD should treatment periods. Reported are the time to androgen-independent only be recommended for patients with PSA normalisation after a progression as well as the different patterns of testosterone 6--9 month period of initial hormone deprivation. The German S3 recovery during the off-treatment periods in the IAD group. Quality 1Facharztzentrum in den Akademischen Sta¨dtischen Kliniken Offenbach, Offenbach, Germany; 2Ospedali Galliera, Department of Urology, Genova, Italy; 3Urological Practice, Offenbach, Germany and 4Medical Consultant, Stolberg, Germany. Correspondence: Professor UW Tunn, Facharztzentrum in den Akademischen Sta¨dtischen Kliniken, Starkenburgring 50, 63069 Offenbach, Germany. E-mail: [email protected] or [email protected] Received 12 July 2011; revised 2 March 2012; accepted 13 March 2012; published online 26 June 2012 Testosterone recovery in IAD-treated prostate cancer patients UW Tunn et al 297 PSA < 0.5 ng/ml after RP Observation until PSA . 1 ng/ml Study inclusion 6M AD leuprorelin 3M depot + 1M CPA PSA No Not randomised < 0.5 ng/ml Study termination Yes Randomisation Intermittent treatment Continuous treatment (Arm IAD) (Arm CAD) AD stopped AD continued 3M controls of PSA/testosterone Monthly controls of PSA/testosterone No PSA . 3 ng/ml Yes PSA No . 3 ng/ml Study termination Yes AD for 6M PSA Yes < 0.5 ng/ml No PSA No AD for 3M . 3 ng/ml Yes No PSA Yes Study termination < 0.5 ng/ml Figure 1. Study design flow chart. AD, androgen deprivation; CAD, continuous androgen deprivation; CPA, cyproterone acetate; IAD, inter- mittent androgen deprivation; RP, radical prostatectomy. of life, clinical and safety aspects of the continuous androgen which commenced in January 1998 and had been completed in February deprivation- (CAD) and IAD-treated patients have been previously 2005 (final report 2007). Included were men with systemic PSA progression 12--14 reported. (defined as a PSA level X1ngmlÀ1) following an initial fall to o0.5 ng mlÀ1 within 3 months of radical prostatectomy. Men were required to have a testosterone value X100 ng dlÀ1 in order to rule out those with substantial MATERIALS AND METHODS hypogonadism and to allow for the effects of therapy on testosterone The study was a prospective, randomised, comparative, multicentre phase levels to be observed. At screening, all patients underwent mandatory III clinical trial involving 86 centres in Germany and 12 centres in Italy, clinical investigations comprising digital rectal examination, abdominal & 2012 Macmillan Publishers Limited Prostate Cancer and Prostatic Diseases (2012), 296 -- 302 Testosterone recovery in IAD-treated prostate cancer patients UW Tunn et al 298 Table 1. Demographic baseline data and tumour characteristics 1.0 0.9 CAD arm (n ¼ 92) IAD arm (n ¼ 109) 0.8 Arithmetic 0.7 CAD (n = 92) Demographic mean±s.d. data (median) P value 0.6 IAD (n = 109) Age (years) 67.5±5.9 (68.0), 67.3±5.8 (69.0), 0.877 (n.s.) 0.5 n ¼ 92 n ¼ 109 Height (cm) 173.7±6.1 (174.0), 173.7±6.3 (173.0), 0.964 (n.s.) Cumulative probability 0.4 n ¼ 91 n ¼ 107 0.3 Weight (kg) 79.9±9.9 (80.0), 80.2±10.0 (79.8), 0.827 (n.s.) n ¼ 92 n ¼ 108 0 90 180 270 360 450 540 630 720 810 900 9901080 BMI (kg mÀ2) 26.5±2.9 (26.1), 26.6±2.6 (26.1), 0.781 (n.s.) Days n ¼ 91 n ¼ 107 Patients at risk: CAD 92 92 89 89 87 86 85 84 83 80 63 18 Diagnosis/findings at baseline IAD 109 109 109 106 99 94 93 89 87 80 68 39 Testosterone 4.504±1.615 4.156±1.615 0.132 (n.s.) Figure 2. Kaplan--Meier curves for time to androgen-independent at baseline (4.400), n ¼ 91 (3.950), n ¼ 106 À1 progression in patients with intermittent androgen deprivation (ng ml ) (IAD) and continuous androgen deprivation (CAD). Intention to treat population. The number of patients in each arm at day 1000 was 16 Cytology/histology grading [WHO (MOSTOFI)] patients on CAD and 37 patients on IAD. G1 15 (16.3%) 10 (9.2%) 0.277 (n.s.) G2 57 (62.0%) 76 (69.7%) Diagnostico Italiano, Italian centres) (Appendix). Serum testosterone levels G3 20 (21.7%) 23 (21.1%) were determined using commercially available test kits; CHIRON/DIAG- pT /pT 31 (33.7%) 40 (36.7%) 0.767 (n.s.) 1 2 NOSTICS ACS: 180 in Germany and ARCHITECT Testosterone, Abbott pT3/pT4 61 (66.3%) 69 (63.3%) pN0/pNX 77 (83.7%) 105 (96.3%) 0.003 (sig.) diagnostics in Italy. Both test kits are based on an immunoassay pN1/pN2 15 (16.3%) 4 (3.7%) chemiluminescence technology. The comercially available E.I.A. Hybritech pM0/pMX 91 (98.9%) 108 (99.1%) 1.000 (n.s.) test kit was used for PSA measurements. pM1/pM1a 1 (1.1%) 1 (0.9%) The primary confirmatory target variable of the study was androgen- independent tumour progression within 2 years. To calculate the time until Time between 706.2±559.1 661.7±578.8 0.582 (n.s.) RPV and first (504.0), n ¼ 92 (524.0), n ¼ 109 androgen-independent progression, the log-rank test on non-inferiority PSA increase was applied.
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