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

Home , Leuprorelin

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

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, intermittent 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. The statistical analyses and generation of tables and (days) patient data listings were performed using the statistical software package SAS version 8.2 at the computer facilities of Omnicare, CRO, Cologne, Abbreviations: BMI, body mass index; CAD, continuous androgen deprivation; IAD, intermittent androgen deprivation; ns, not significant; Germany. RPV, radical prostatectomy; sig., significant P values based on two-sided t-test or Fisher’s exact test (two-sided), respectively. RESULTS ultrasound, bone scintigram, as well as the optional examinations of liver Of the 244 patients enrolled in the study, 201 patients were ultrasound and chest X-ray. Staging was performed according to the randomised to treatment with IAD (n ¼ 109) and CAD (n ¼ 92) Tumour Node Metastasis classification.15 respectively; 33 patients did not meet the criterion for randomisa- The overall study design is shown in Figure 1. Patients underwent a tion and 10 patients withdrew prematurely. At baseline, demo- 6-month androgen deprivation induction phase during which they received graphic data and tumour characteristics were well-balanced leuprorelin acetate as an 11.25 mg 3-month depot either by subcutaneous between treatment groups (Table 1). or intramuscular injection. Cyproterone acetate 200 mg per day orally was The median time for androgen-independent tumour progres- administered for the first 4 weeks to prevent tumour flare. Patients who sion (set at 2 years, primary efficacy parameter) was not reached at achieved a PSA level o0.5 ng mlÀ1 at the end of the induction phase were study end. At day 1000, there were 16 patients in the CAD arm and randomised to one of the two arms: an IAD arm and a CAD arm. Patients in 37 in the IAD arm who were at risk of progression. The mean (s.d.) the CAD arm received CAD with leuprorelin acetate 11.25 mg 3-month time until androgen-independent progression showed no sig- depot until androgen-independent progression was observed. Androgen- nificant differences between treatment groups; 986 (10.0) and 976 independent progression was defined as a PSA level of X3ngmlÀ1 on two (14.0) days in the CAD arm and the IAD arm, respectively consecutive months during a 6-month testosterone suppression despite ((P ¼ 0.853) using the log-rank test, intent to treat analysis set, castration levels of testosterone p50 ng dlÀ1. This level was chosen based secondary efficacy parameter). The Kaplan--Meier analysis of time on empirical evidence from phase II studies.16 In the IAD, arm treatment was until androgen-independent progression is shown in Figure 2. The discontinued again if the PSA level fell to o0.5 ng mlÀ1 and there were no time until PSA progression was defined as the time between date signs of clinical progression. A minimum of 6 months of treatment was of visit 0 and date of onset of PSA-progression (for cases with PSA required despite a quicker drop in PSA serum levels in order to regain progression), and date of last observation (for cases without PSA apoptotic responsiveness. If after 6 months of treatment the PSA level was progression) respectively. 40.5 ng mlÀ1 but p3ngmlÀ1, then the treatment was continued for The individual testosterone courses were analysed in the 109 another 3 months. If after a 9-month treatment period the PSA level was still patients on IAD therapy. In all 109 patients, castration testosterone 40.5 ng/ml, then the patient’s participation in the study was terminated. levels were achieved after 6 months of treatment involving two Serum PSA levels were measured at 3-month intervals in patients in the subcutaneous injections of the 3-month depot. A cycle was CAD arm and at 3-month intervals in patients in the IAD arm during the defined as the 6 months of ADT plus the off-treatment time (OTT). on-treatment phase and monthly during the off-treatment interval. PSA Patients with long IAD cycles X20 months showed, in most and testosterone measurements were performed in a central laboratory in of clinical parameters, a statistically significant better outcome Leverkusen (Prof. G. Horpacsy, German centres) and Milano (CDI Centro in comparison with those patients with a cycle length of p15

Prostate Cancer and Prostatic Diseases (2012), 296 -- 302 & 2012 Macmillan Publishers Limited Testosterone recovery in IAD-treated prostate cancer patients UW Tunn et al 299 months (Table 2). Achievement of testosterone baseline levels of testosterone to X2.3 ng mlÀ1 was 100 days in the first and 115 or lack thereof showed a trend for better outcome in time days in the second cycle respectively (Figure 3a). Figure 3b for clinical/PSA progression and time to PSA increase in those illustrates testosterone recovery during OTT in cycles 1 and 2 by achieving baseline testosterone levels but reached no statistical means of median values of testosterone concentrations of all significance. patients. In patients with low normal-testosterone baseline values Of the 82 patients completing cycle 1, normalisation of (2.3 to 4 ng mlÀ1), time for recovery was prolonged in comparison testosterone to X2.3 ng mlÀ1 was reported in 92.7% and among with those having high (44ngmlÀ1) normal testosterone values the 37 patients completing cycle 2, the equivalent proportion was (Figure 4). An overview of summary statistics of the outcome in 81.1%. Of note is that, a statistically significant correlation of the IAD patients is provided in Table 4. testosterone normalisation could be shown in relation to the baseline testosterone levels in cycle 1 and 2, whereas age and body mass index seemed to be of no importance (Table 3). Baseline testosterone levels were again reached in 79.3 and 64.9% of patients during OTT in those completing cycles 1 and 2, respectively. No baseline values were recorded in cycle 1 for three a 1.0 patients (3.7%). 0.9 OTP per cycle Cycle 1 In the first cycle, testosterone doubling time during OTT was 0.8 Cycle 2 13--56 days with a more pronounced testosterone increase in the 0.7 first month after stopping ADT. The median time for normalisation 0.6 0.5 0.4 Table 2. Clinical outcome in IAD patients on intermittent androgen 0.3 deprivation therapy in relation to cycle length during off-treatment 0.2 Cumulative probability period in cycle 1 (intention to treat analysis) 0.1 0.0 0 60 90 120 150 180 210 240 270 Length of ADT Length of ADT cycle less or cycle greater or Time to normalization (days) equal 15 equal 20 Patients at risk: months (n ¼ 49) months (n ¼ 32) Cycle 1 84 76 60 30 15 8 6 4 Mean±s.e. P value Cycle 2 37 33 25 18 10 6 3 1 ± ± Time to clinical 932 32.1 977 n.e. 0.039 (sig.) b Cycle 1 progression 5.0 (days) 4.5 Cycle 2 Time to PSA 932±32.1 977±n.e. 0.039 (sig.) 4.0 progression 3.5 (days) 3.0 Patients with PSA 6 (12.2%) 1 (3.1%) 0.235 (n.s.) 2.5 progression (number 2.0 (percent) of 1.5

patients) Testosterone (ng/ml) 1.0 Time to PSA 170±8.5 306±20.5 o 0.001 (sig.) 0.5 increase (days) 0 1 2 3 4 5 6 7 8 9 Abbreviations: ADT, androgen deprivation therapy; IAD, intermittent androgen deprivation; n.e., not estimable; n.s., not signiﬁcant; Months sig., signiﬁcant. Figure 3. Median time to testosterone normalisation (a) and (b) Mean calculated according to Kaplan-Meier. P values based on two-sided testosterone recovery during off-treatment phases of cycles 1 and 2 log-rank test or Fisher’s exact test (two-sided), respectively. for all patients.

Table 3. Testosterone normalization during off-treatment periods in cycles 1 and 2 in relation to age, body mass index and testosterone baseline values (intention to treat analysis)

Normalised at least once during Never normalised during P value cycle 1 (n ¼ 76) cycle 1 (n ¼ 6) Arithmetic mean±s.d. (median)

Age (years) 66.1±5.8 (67.0), n ¼ 76 66.2±4.6 (66.0), n ¼ 6 0.987 (n.s.) BMI (kg m-2) 26.3±2.3 (25.9), n ¼ 74 29.1±3.5 (29.0), n ¼ 6 0.116 (n.s.) Testosterone at baseline (ng ml-1) 4.221±1.478 (3.900), n ¼ 75 1.650±0.806 (1.900), n ¼ 4 0.004 (sig.) Normalised at least once during cycle 2, n ¼ 30 Never normalised during cycle 2, (n ¼ 7) Age (years) 66.4±5.3 (68.0), n ¼ 30 62.7±5.9 (66.0), n ¼ 7 0.167 (n.s.) BMI (kg m-2) 26.4±2.6 (26.0), n ¼ 30 27.7±3.7 (26.5), n ¼ 7 0.390 (n.s.) Testosterone at baseline (ng ml-1) 4.437±1.668 (3.950), n ¼ 30 2.729±1.283 (3.100), n ¼ 7 0.012 (sig.) Abbreviations: BMI, body mass index; n.s., not signiﬁcant; sig., signiﬁcant. Pvalues based on two-sided t-test.

& 2012 Macmillan Publishers Limited Prostate Cancer and Prostatic Diseases (2012), 296 -- 302 Testosterone recovery in IAD-treated prostate cancer patients UW Tunn et al 300 1.0 Baseline testosterone isation was prolonged in comparison with those with normal 2.3–4 ng/ml (n = 49) testosterone baseline values. These data are in accordance with 0.9 > 4ng/ml (n = 51) the findings of Gulley and coworkers, who showed that after 6 0.8 months of ADT with a gonadotropin-releasing hormone agonist P value log rank test: 0.246 the median time until testosterone normalisation was 16.6 weeks 0.7 and could be achieved in more than 80% of the patients.9,10 In all 10,18,19 0.6 the three studies by Gulley, Figg and Oefelein, the higher dosage of leuprorelin acetate registered in the United States 0.5 (3-month depot 22.5 mg) was administered whereas the time of androgen withdrawal with 3 months was different.10,19 Cumulative probability 0.4 IAD seems to be an option to balance benefits and 0.3 disadvantages of ADT but should not interfere with the incidence 0 60 90 120 150 180 210 240 270 of progression and mortality.5,6,20,21 In a recently published study, Time to normalization (days) 1386 patients with PSA progression after radical radiotherapy with Figure 4. Relation between testosterone baseline level and time to no evidence of distant metastases were randomised to one of the normalization of testosterone during off-treatment period. two treatment arms, IAD (n ¼ 690) or CAD (n ¼ 696) with a luteinis- ing hormone-releasing hormone agonist plus an anti-androgen.21 The IAD arm comprised an 8 months on-treatment period, which Table 4. Summary statistics of results from the intermittent androgen was reinstituted during the off-treatment interval if PSA levels À1 deprivation arm of the study (intention to treat analysis) reached 410 ng ml . The primary endpoint of the study was overall survival and the secondary endpoints included time to IAD arm hormone refractory state. The median follow-up of the study was (n ¼ 109) 6.9 years. Median overall survival was 8.8 versus 9.1 years on IAD and CAD arms, respectively (hazard ratio 1.02; 95% confidence Number of patients at risk after 1000 days 37 (33.9%) interval (CI): 0.86--1.21; P for non-inferiority (IAD versus CAD Number of patients with androgen independent 8 (7.3%) X1.25) ¼ 0.009). The IAD arm had more disease-related deaths but progression after 1000 days fewer unrelated deaths. Time to hormone refractory state was Mean time to androgen independent progression 976±14 a statistically significantly improved in the IAD arm (hazard ratio (days) 0.80; 95% CI: 0.67--0.98; P 0.024). The study showed that in men Mean time to PSA increase (days)a 234±11 ¼ Time between RPV and first PSA increase (days)b 662±579 (524) with PSA recurrence after radical radiotherapy, IAD was non-inferior n 109 to CAD with respect to the overall survival. To date, phase III studies ¼ 11,21 Number of patients with normalization of 76 (92.7%) have shown that IAD is non-inferior to continuous AD. testosterone in the first cyclec The current report in IAD is the first on testosterone recovery after Number of patients with normalization of 30 (81.1%) a 6-month IAD treatment with the 11.25 mg 3-month depot testosterone in the second cyclec microcapsule formulation of leuprorelin acetate. After ADT and Number of patients with achievement of baseline 65 (79.3%) c induction of testosterone castration levels, median time to testosterone in the first cycle testosterone normalisation during OTT was 100 days in the first Number of patients with achievement of baseline 24 (64.9%) c and 115 days in the second cycle. Normalisation of testosterone testosterone in the second cycle Median time to testosterone normalization in the 100 levels were achieved in 92.7 and 81.1% of patients in the first and first cycle (days) second cycle, respectively. These findings indicate that a real Median time to testosterone normalization in the 115 intermittent castration was achieved with temporary suppression second cycle (days) of the hypothalamic-pituitary-gonadal axis and reversibility during OTT with normalisation of testosterone values. The mean (s.d.) time Abbreviations: IAD, intermittent androgen deprivation; RPV, radical until androgen-independent progression showed no significant prostatectomy. aMean±s.e. according to Kaplan--Meier. differences between treatment groups with 986 (10.0 days) and bMean±s.d. (median). 976 (14.0 days) days in the CAD and IAD arm, respectively. cPercentage based on the number of patients who completed the Our study confirms that the IAD resulted in recovery of respective cycle. testosterone during the OTT, which is the prerequisite for the reversal of the adverse events due to CAD. Based on our findings, the individual testosterone baseline values were considered to be DISCUSSION important and should be determined before IAD treatment starts ADT fails to eliminate the entire malignant-cell population and and during OTT to estimate testosterone recovery. after a variable period of time the tumour relapses into an androgen-independent state of growth. Animal experimental data indicate that cyclical AD would delay the emergence of androgen- CONCLUSION independence.2 Therefore, IAD holds the potential of minimizing This study with the 3-month 11.25 mg depot microcapsule adverse events and improving the quality of life during OTT, while formulation of leuprorelin acetate shows a real achievement of maintaining clinical anti-tumour effects and improving time to intermittent castration with normalisation of testosterone levels hormone refractory state. A key issue in this scenario is that the during off-treatment periods. It is assumed that the recovery of serum testosterone levels should recover during OTT to normal testosterone in IAD patients will balance the benefits of long-term values with IAD leading to a real intermittent ‘castration’ (not just androgen withdrawal and reduce ADT- related side effects. IAD an intermittent treatment delivery). seems to be a feasible option in selected well-informed and Testosterone recovery after 6 months of IAD has been reported compliant patients who need long-term hormonal deprivation. in a phase III clinical trial.17,18 Median baseline value of testosterone was 3.11 ng mlÀ1 and time for recovery of testosterone was 15.4 and 18.3 weeks in the first and second IAD CONFLICT OF INTEREST cycles, respectively. As in the current study, among patients with Professor Ulf Tunn is consultant and lecturer for Abbott, Astellas, Bayer Health, low testosterone baseline-values time to testosterone normal- Novartis, Sanofi-Aventis and Takeda. Dr Giorgio Canepa and Dr Andreas

Prostate Cancer and Prostatic Diseases (2012), 296 -- 302 & 2012 Macmillan Publishers Limited Testosterone recovery in IAD-treated prostate cancer patients UW Tunn et al 301 Kochanowsky declare no potential conflict of interest. Dr Erika Kienle is consultant 10 Gulley JL, Aragon-Ching JB, Steinberg SM, Hussain MH, Sartor O, Higano CS et al. and lecturer for Abbott and Takeda. Kinetics of serum androgen normalization and factors associated with testosterone reserve after limited androgen deprivation therapy for non- ACKNOWLEDGEMENTS metastatic prostate cancer. J Urol 2008; 180: 1432--1436. This study was sponsored by Takeda Pharma GmbH Germany and Takeda Italia 11 Gleave M, Klotz L, Taneja SS. The continued debate: intermittent vs continuous Farmaceutici SPA. hormonal ablation for metastatic prostate cancer. Urol Oncol 2009; 27: 81--86. 12 Tunn UW. Can intermittent hormone therapy fulfill its promise? Eur Urol 2008; (Suppl 7): 752--757. REFERENCES 13 Tunn UW, Canepa G, Hillger H, Fuchs W. Intermittent androgen deprivation in 1 Heidenreich A, Bolla M, Joniau S, Van der Kwast JH, Matveev VB, Mason MD et al. patients with PSA relapse after radical prostatectomy-final result of a european Guidelines on prostate cancer. Eur Assoc Urol 2010. http://www.uroweb.org/gls/ randomized prospective phase-III clinical trial AUO study AP 06/95, ED 507. J Urol pdf/Prostate%20Cancer%202010%20June%2017th.pdf. 2007; 177: 201 (abstr. 600). 2 Akakura K, Bruchovsky N, Goldenberg SL, Rennie PS, Buckley AR, Sullivan LD. 14 Tunn UW. The current status of intermittent androgen deprivation (IAD) therapy Effects of intermittent androgen suppression on androgen-dependent tumors. for prostate cancer: putting IAD under the spotlight. BJU Int 2007; 99: 19--22. Apoptosis and serum prostate-specific antigen. Cancer 1993; 71: 2782--2790. 15 Bostwick DG. Staging prostate cancer---1997: current methods and limitations. Eur 3 Wright JL, Higano CS, Lin DW. Intermittent androgen deprivation: clinical Urol 1997; 32(Suppl 3): 2--14. experience and practical applications. Urol Clin North Am 2006; 33: 167--179. 16 Tunn UW. Intermittent endocrine therapy of prostate cancer. Eur Urol 1996; 30 4 Boccon-Gibod L, Hammerer P, Madersbacher S, Mottet N, Prayer-Galetti T, Tunn U. (Suppl 1): 22--25. The role of intermittent androgen deprivation in prostate cancer. BJU Int 2007; 17 Figg WD, Dahut W, Duray P, Hamilton M, Tompkins A, Steinber SM et al. A 100: 738--743. randomized phase II trial of thalidomide an angiogenesis inhibitor in 5 Spry NA, Galvaõ DA, Davies R, La Bianca S, Joseph D, Davidson A et al. Long-term patients with androgen-independent prostate cancer. Clin Cancer Res 2001; 7: effects of intermittent androgen suppression on testosterone recovery and bone 1888--1983. mineral density: results of a 33-month observational study. BJU Int 2009; 104: 18 Figg WD, Hussain MH, Gulley JL, Arien PM, Aragon-Ching JB, Petrylak DP et al. A 806--812. double-blind randomized crossover study of oral Thalidomide versus placebo for 6 Calais da Silva FC, Bono AV, Whelan P, Brausi M, Queimadelos AM, Martin JAP androgen dependent prostate cancer treated with intermittent androgen et al. Intermittent androgen deprivation for locally advanced and metastatic ablation. J Urol 2009; 181: 1104--1113. prostate cancer: Results from a randomised phase III study of the South European 19 Oefelein M. Serum testosterone-based luteinizing hormone-releasing hormone Uroncological Group. Eur Urol 2009; 55: 1269--1277. agonist redosing schedule for chronic androgen ablation: a phase I assessment. 7 German Society of Urology. Interdisciplinary S3 guideline of quality for early Urology 1999; 54: 694--699. detection, diagnosis and treatment of various stages of prostate cancer. 2009. 20 Spry NA, Kristjanson L, Hooton B, Hayden L, Neerhut G, Gurney H et al. Adverse http//www.uro-freiburg.de/S3-Leitlinie-Prostatakarzinom-2009,102.html. effects to quality of life arising from treatment can recover with intermittent 8 Bong GW, Clarke Jr HS, Hancock WC, Keane TE. Serum testosterone recovery after androgen suppression in men with prostate cancer. Eur J Cancer 2006; 42: cessation of long-term luteinizing hormone-releasing hormone agonist in 1083--1092. patients with prostate cancer. Urology 2007; 71: 1177--1180. 21 Klotz L, O’Callaghan CJ, Ding K, Dearnaley DP, Higano CS, Horwitz EM et al. A 9 Gulley JL, Figg WD, Steinberg SM, Carter J, Hussain MH, Dahut WL. A prospective phase III randomized trial comparing intermittent versus continuous androgen analysis of the time to normalization of serum androgens following 6 months of suppression for patients with PSA progression after radical therapy: NCIC CTG androgen deprivation therapy in patients on a randomized phase III clinical trial PR.7/SWOG JPR.7/CTSU JPR.7/UK Intercontinental Trial CRUKE/01/013. J Clin Oncol using limited hormonal therapy. J Urol 2005; 173: 1567--1571. 2011; 29(Suppl 7): (abstr 3).

APPENDIX

Study investigators involved from Italian and German centres (Continued )

Italian German Italian German

Alphabetical Alphabetical Dr Alcini Dr Adamczyk Dr Gleißner Prof. Bartoletti Dr Altenburg Dr Griesbaum Prof. Belgrano Dr Arnhold Fr. Dr Grunwald Prof. Campo Dr Bannermann Dr Hahn Dr Canepa Dr Bartels Dr Haider Prof. Di Silverio Dr Bauer Dr Hammerer Dr Favro Prof. Becker Dr Heinrich Prof. Ferrari Dr Becker-Dexl Dr Herrmann Prof. Mandressi Dr Behling Dr Herting Prof. Manganelli Dr Benusch Dr Hess Dr Marconi Dr Bingold Dr Hettmer Prof. Martorana Dr Blu¨ mlein Dr Hirnstedt Prof. Selvaggi Dr Boehm Dr Hofmann Dr Tellarini Dr Bo¨ mke Dr Holzknecht Dr Zucconelli Dr Bothor Dr Hudemann Dr Bremer Dr Jaspers Dr Breu Dr Keipert Dr Cappell Dr Koch Dr Charisius Dr Ko¨ ttig Dr Denninger Dr Kowalik Dr Dietrichs Dr Krain Dr Drost Dr Kruse Dr Frankenau Dr Lahm Dr Frehse Dr Lange Dr Frerk Dr Lehmann Dr Galamb Dr Lehmkuhl Dr Gienewinkel Dr Lux

& 2012 Macmillan Publishers Limited Prostate Cancer and Prostatic Diseases (2012), 296 -- 302 Testosterone recovery in IAD-treated prostate cancer patients UW Tunn et al 302 (Continued )

Italian German

Alphabetical Dr Maßek Dr Meier- Mouhanna Dr Meyer Dr Michel Dr Molz Dr Mumperow Dr Mu¨ nch Dr Naus Dr Neumann Dr Plate Prof. Pohl Dr Pokupic Dr Prosinger Dr Reineke Dr Rincker Dr Ro¨ ßler Dr Rulf Dr Ruppert Dr Ru¨ ssel, C. Dr Samberger Dr Schmitt Dr Schraub Dr Schulten Fr. Dr Simson Prof. Sinagowitz Dr Spiegelhalder Dr Stryer Dr Theermann Dr Timpe Prof. Tunn Dr Vogel Dr Vogt Dr Walter Dr Warnack Dr Wicklein Dr Wiegel Dr Woschick Dr Zemke

Prostate Cancer and Prostatic Diseases (2012), 296 -- 302 & 2012 Macmillan Publishers Limited