Comparative Effect of Finasteride and Dutasteride on Chromogranin A Levels

Transcription

1 Comparative Effect of Finasteride and Dutasteride on Chromogranin A Levels ALESSANDRO SCIARRA 1, STEFANO SALCICCIA 1, GIANLUCA NESI 2, SUSANNA CATTARINO 1, ANDREA ALFARONE 1, ALESSANDRO GENTILUCCI 1 and VINCENZO GENTILE 1 1 Department of Urology, University Sapienza of Rome, Italy; 2 Department of Urology, San Andrea Hospital, Rome, Italy Abstract. The aim of this study was to verify and to compare in benign prostatic hyperplasia (BPH) patients, the effect of finasteride versus dutasteride therapy on chromogranin A (CgA) serum levels, as a marker of neuroendocrine (NE) differentiation. Patients and Methods: This was a prospective randomised study in which 60 consecutive men with clinical diagnosis of BPH were randomised to a 6-month period of finasteride 5 mg/day versus dutasteride 4 mg/day versus control (no therapy). Total prostate-specific antigen (PSA), testosterone and CgA were analysed at randomisation and thereafter at one-, three- and six-month intervals. Results: In both Group A (finasteride) and Group B (dutasteride), but not in Group C (no therapy), a statistically significant increase (p<0.05) in serum CgA levels was found at the three- and six-month intervals of therapy when compared with the start. Comparing the three groups, at three- and six-month intervals, serum CgA was significantly (p<0.05) higher in Group A and B than in Group C. At each interval, no significant (p>0.05) difference between Group A and B was found. Conclusion: In this population, 5- alpha reductase inhibitors, with no difference between finasteride and dutasteride, produced a significant increase in serum CgA levels, probably related to NE activation. Androgens play a crucial role in prostatic development, growth and function, and prostate diseases such as benign prostatic hyperplasia (BPH) and prostate cancer (PC) are also influenced by androgens (1). Several data from randomised clinical trials have demonstrated the efficacy and safety of 5- alpha reductase inhibitors (5-ARI) in the medical treatment of BPH (1). Finasteride is a type-2 ARI whereas dutasteride is a dual 5-ARI, both approved for the treatment of BPH (2). Correspondence to: Professor Alessandro Sciarra, U Bracci Department of Urology, University Sapienza of Rome, Viale Policlinico 155, Rome, Italy. Tel: , sciarra.md@libero.it Key Words: Neuroendocrine (NE) differentiation, benign prostatic hyperplasia, finasteride, dutasteride, chromogranin A. The effect of 5-ARI on androgen levels is mainly represented by a reduction (over 90% for dutasteride and over 70% for finasteride) in dihydrotestosterone (DHT) and a slight increase in testosterone levels (3). The Prostate Cancer Prevention Trial (PCPT) and Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial (4, 5) have both shown that 5-ARIs are an agent class proven to be effective in preventing PC. PCPT demonstrated that finasteride significantly reduced the risk of developing PC by 24.8% versus placebo over a seven-year period (an increased incidence of carcinomas with Gleason score 7-10 was observed in the finasteride group, suggesting a causal bias for the observation) (5). The REDUCE trial indicated that dutasteride produced a 23% reduction in the risk of PC versus placebo over a four-year period (no statistically significant increase in high grade disease) (6). Neuroendocrine cells (NE) represent the third epithelial cell type of normal prostate tissue (7). NE cell hyperactivation within the prostate has been recognised as a risk factor for developing aggressive PC and hormone-refractory prostate cancer (HRPC) (7). NE cells in normal and neoplastic prostates are androgen-insensitive and they do not express PSA (8). Serum levels of NE markers, particularly Cromogranin A (CgA), might reflect the NE activity of prostate carcinoma and have been used as serum prognostic marker of NE differentiation in PC in several trials (9, 10). There is evidence that androgen deprivation in PC increases NE differentiation and tissue CgA expression in human prostate tissue (7). The aim of the present study was to verify and to compare in BPH patients, the effect of finasteride versus dutasteride therapy on CgA serum levels, as a possible marker of NE differentiation and activity in the prostate gland. Patients and Methods This is a prospective randomized study. Between June 2009 and December 2009, 60 consecutive men with clinical diagnosis of BPH referred to our U. Bracci Department of Urology, were randomized to a 6-month period of finasteride 5 mg/day versus dutasteride 4 mg/day versus control (no therapy) strategy /2010 $

2 Figure 1. Study design. Population. Inclusion in this study was based on the following criteria: clinical diagnosis of lower urinary tract symptoms (LUTS) related to BPH; prostate volume >30 ml; no previous medical therapies for prostate disease or other therapies that may influence the prostate gland and hormones; no history of other disorders or therapies or conditions known to interfere with CgA levels or NE systems as defined in previous studies (11); no previous surgery or radiation therapy on the prostate gland; no histological evidence or clinical suspicious of PC (normal digital rectal examination (DRE) and total PSA <2.5 ng/ml); no active prostate inflammation or urinary infection and no contraindication for 5-ARI treatment. Consent for the treatment and study analyses was obtained from each patient at baseline in the trial. All 60 patients included in the study were referred to the host clinic for LUTS. Table I shows the clinical characteristics of the study population at baseline. Methods. At baseline, LUTS were analysed by the International Prostate Symptom Score (IPSS) and the clinical diagnosis of prostate enlargement was based on DRE. Prostate volume was calculated at the transrectal ultrasonography using the ellipsoid method. Serum total PSA was measured by RIA (Hybritech, Inc., San Diego, California, USA). Serum CgA was evaluated by RIA using a commercial Kit (CIS International, Bagnols-sur-Ceze, France). The normal range for CgA reported by the kit was 0-90 ng/ml. Serum testosterone was measured by RIA (normal range ng/ml). Study design. At baseline all 60 cases were evaluated for inclusion and exclusion criteria and therefore randomized (1:1:1) for a 6- month period of finasteride 5 mg daily (Group A) versus dutasteride Table I. Clinical characteristics of the study population. Number of cases, mean±sd, median (range) are shown. Number of cases 60 Age (years) 64.7±3.9;65 (57-72) Prostate volume (ml) 44.5±7.0;43.5 ( ) IPSS 15.8±2.8; 15.5 (10-21) PSA (ng/ml) 1.7±0.4;1.8 ( ) CgA (ng/ml) 28.1±6.9;27.0 ( ) Testosterone (ng/ml) 3.2±0.8;3.0 ( ) 4 mg daily (Group B) versus control who received no medical therapy (Group C) (Figure 1). Using the same serum sample, total PSA, testosterone and CgA were analysed in all cases at randomisation and thereafter at one-, three- and six-month intervals in each of the three groups. Prostate volume was evaluated at baseline and at the six-month interval during randomisation. Statistical analysis. All statistical analyses were conducted using SigmaStat and SigmaPlot 9.0 programs (Point Richmond, CA, USA). PSA, CgA and testosterone variations in each group of randomization were analysed using the Mann-Whitney test. A oneway analysis of variance (ANOVA) model was also used. PSA, CgA and testosterone were always analyzed as continuous variables. All statistical tests were two-sided and statistical significance was set at p<0.05. Spearman correlation coefficients were calculated to measure the association among serum CgA, PSA and testosterone variations. 4738

3 Sciarra et al: Effect of 5α-Reductase Inhibitors on CgA Levels Table II. Variation in serum PSA, CgA and testosterone levels in the three groups during the 6-month period of treatment (age and prostate volume are also reported). Parameter Group A Group B Group C P-value Finasteride Dutasteride Control Visit 0 (Randomisation) Age (years) 63.9±4.4; 65.0 (57-72) 64.5±4.0; 65.0 (58-70) 65.6±3.4; 65.0 (60-72) 1= = = IPSS 15.6±3.0; 15.0 (10-21) 16.0±2.6; 16.0 (12-21) 15.7±2.9; 15.5 (10-21) 1= = = Prostate volume (ml) 45.4±7.3; 45.0 ( ) 44.5±6.9; 44.5 ( ) 43.6±6.8; 41.0 ( ) 1= = = PSA (ng/ml) 1.8±0.5; 1.7 ( ) 1.7±0.4; 1.7 ( ) 1.7±0.5; 1.8 ( ) 1= = = CgA (ng/ml) 29.5±9.2; 26.0 ( ) 27.3±5.2; 27.5 ( ) 28.6±5.6; 28.5 ( ) 1= = = Testosterone (ng/ml) 3.2±0.8; 3.0 ( ) 3.3±0.8; 3.0 ( ) 3.2±0.7; 3.0 ( ) 1= = = Visit 1 (1st month) PSA (ng/ml) 1.6±0.4; 1.5 ( ) 1.5±0.4; 1.5 ( ) 1.5±0.4; 1.6 ( ) 1= = = CgA (ng/ml) 30.6±8.5; 29.0 ( ) 30.7±9.0; 30.0 ( ) 32.5±7.8; 31.0 ( ) 1= = = Testosterone (ng/ml) 3.2±0.7; 3.1 ( ) 3.5±0.9; 3.3 ( ) 3.2±0.6; 3.2 ( ) 1= = = Visit 2 (3rd month) PSA (ng/ml) 1.3±0.4; 1.4 ( ) 1.2±0.3; 1.0 ( ) 1.6±0.4; 1.5 ( ) 1= = = CgA (ng/ml) 43.4±23.5; 38.5 ( ) 43.6±25.0; 37.0 ( ) 31.5±7.4; 30.0 ( ) 1= = = Testosterone (ng/ml) 3.8±1.2; 3.5 ( ) 4.1±1.2; 4.1 ( ) 3.3±0.7; 3.0 ( ) 1= = = Visit 3 (6th month) Prostate volume (ml) 35.8±7.0; 35.0 ( ) 35.2±5.6; 34.0 ( ) 46.1±6.9; 44.0 ( ) 1< < = PSA (ng/ml) 0.9±0.3; 0.9 ( ) 0.9±0.2; 0.8 ( ) 1.8±0.4; 1.8 ( ) 1< < = CgA (ng/ml) 53.6±31.1; 46.0 ( ) 51.7±29.2; 47.0 ( ) 32.4±6.3; 32.0 ( ) 1= = = Testosterone (ng/ml) 4.9±2.4; 4.5 ( ) 5.0±2.0; 4.9 ( ) 3.4±0.6; 3.3 ( ) 1=0.0112; 2= = Values expressed as mean±sd; median (range). P-values: 1=A vs. C, 2=B vs. C, 3=A vs. B. Results At randomisation, no statistically significant (p>0.05) difference in terms of patient age, prostate volume, IPSS, serum PSA, CgA and testosterone levels among the three groups (Group A, B and C) was found (Table II). In both Group A and B, at the six-month interval, a statistically significant reduction (p<0.05) in prostate volume (Group A: 22.3% and Group B: 23.6%) was found, whereas in Group C no statistically significant variation (+6.9%; p>0.05) was reported (Table II). Serum PSA. In both Group A (finasteride) and Group B (dutasteride), a statistically significant decrease (p<0.05) in total serum PSA levels was found at the three-month and sixmonth intervals of therapy when compared to visit 0 (Figure 2). No statistically significant (p>0.05) variation in PSA levels was found in Group C (control) (Figure 2). Comparing the three groups (Table II), either at the three-month or at six-month interval, serum PSA was significantly (p<0.05) lower in Group A and Group B than in Group C. These data were also confirmed at ANOVA analysis (F ratio=3.45; p=0.001). No significant difference (p>0.05) between Group A and B was found at any time. Serum CgA. In both Group A (finasteride) and Group B (dutasteride), a statistically significant increase (p<0.05) in serum CgA levels was found at the three-month and sixmonth interval of therapy when compared with visit 0 (Figure 2). No statistically significant (p>0.05) variation in CgA levels was found in Group C (control) (Figure 2). Comparing the three groups (Table II), either at the three-month or at the six-month interval, serum CgA was significantly (p<0.05) higher in Group A and Group B than in Group C. These data were also confirmed at ANOVA analysis (F ratio=3.27, p=0.01). At each interval, no significant (p>0.05) difference between Group A and Group B was found. Considering the normal range value for CgA (0-90 ng/ml) reported by the kit, Table III shows the percentage of cases with elevated serum CgA levels in the three groups at the different intervals. Serum testosterone. In both Group A (finasteride) and Group B (dutasteride), an increase in testosterone serum levels was observed at the six-month interval of therapy when compared with visit 0, but in all cases, testosterone levels remained within the normal range (Figure 2). In Group C, no statistically significant (p>0.05) variation in testosterone levels was found at any interval (Figure 2). 4739

4 Table III. Number (%) of cases with elevated CgA serum levels (>90 ng/ml) in Group A (finasteride), Group B (dutasteride) and Group C (control). Variable CgA >90 ng/ml n, % Group A (baseline) 0 (0) B (baseline) 0 (0) C (baseline) 0 (0) Group A (1-month) 0 (0) B (1-month) 0 (0) C (1-month) 0 (0) Group A (3-month) 3 (15) B (3-month) 3 (15) C (3-month) 0 (0) Group A (6-month) 3 (15) B (6-month) 3 (15) C (6-month) 0 (0) Comparing the three groups (Table II), in particular at the six-month interval, serum testosterone was significantly (p<0.05) higher in Group A and Group B than in Group C. These data were also confirmed at ANOVA analysis (F ratio=2.75; p=0.04). Correlation among PSA, CgA and testosterone. Using the Spearman correlation coefficients, no significant correlation among PSA, CgA and testosterone variations during treatment (Group A and B) or among the different groups of treatment was found (p>0.05; r<0.085). In particular, CgA levels did not significantly correlate with PSA or testosterone level variation in each group (p>0.05; r<0.070). Discussion Figure 2. Variation in serum CgA (a), testosterone (b) and PSA (c) levels during 6 months treatment with finasteride (Group A), dutasteride (Group B) and controls (Group C). Mean±SD values. Statistically significant variation from baseline: *p<0.05, **p<0.001, ***p< This is the first published comparative trial showing that both finasteride and dutasteride treatment similarly produce an increase in CgA serum levels in patients with BPH. CgA is currently considered to be the best marker for NE activity in the prostate gland (9, 12). In patients with PC, a significant correlation between serum CgA and prostate tissue expression of CgA with reverse transcriptase-polymerase chain reaction has been shown in some studies (7, 9). NE cells are represented in normal, BPH and PC tissue, and both serum and tissue expression of CgA has been shown not only in PC but also in BPH cases (12). Prostatic NE cells can have a role in the growth and differentiation of the prostate gland and PC displaying NE differentiation or higher CgA levels tends to be more aggressive (9, 10, 13, 14). More convincing data have been reported in advanced and HR PC, where NE activity is one of the possible factors involved in castration resistance (15). However, there is evidence of a 4740

5 Sciarra et al: Effect of 5α-Reductase Inhibitors on CgA Levels sustained role of NE differentiation and for a prognostic value for CgA also in the non-metastatic stage of PC (10, 16). The College of the American Pathologist Consensus Statement (17) considered NE differentiation in PC as a category III factor for the prognostic value in patients. The EAU guidelines reported NE differentiation as a possible factor involved in the progression of PC (2), although the current published data are not considered sufficient to use NE markers in routine clinical practice for the evaluation of PC cases. NE cells in the prostate are androgen independent and do not express PSA, but hormone-therapy for PC is probably the main factor increasing NE activity in the prostate (18). Some studies have shown that the number of NE cells and CgA tissue and serum expression significantly increase with the continuous use of hormonal therapy for PC (19-21). Ahlgren et al. (22) showed that as early as 3 three months of hormonal treatment with luteinising hormonereleasing hormone (LHRH) analogue, the number of CgApositive NE cells and CgA expression significantly increase in PC cases. Some studies suggest that the type of hormone therapy may also differently condition NE differentiation and CgA levels in patients (23, 24). In particular, a continuous administration of LHRH analogue produces a significantly greater serum and tissue CgA expression when compared to an intermittent administration of the same therapy (23). Moreover, a non steroidal anti-androgen monotherapy showed less effect on CgA expression in PC than does castration with LHRH analogues (24). Recently Tarle et al. (25) analysed the effect of a continuous versus intermittent finasteride treatment versus control on serum CgA expression in BPH patients. The authors showed that the continuous administration of finasteride in BPH cases produces a statistically significant increase in CgA levels when compared to controls (elevated >90 ng/ml CgA levels: 13.6% in finasteride and 6.4% in controls) (25). They suggested that finasteride treatment reduces PC prevalence in cases free of NE activation but elevates the number of aggressive carcinomas in CgA-positive cases (25). The aim of the current study was to verify whether a 5- ARI continuously administered to BPH patients is able to increase CgA expression as a possible marker of NE activity in the prostate. Moreover, this study also verified whether a different 5-ARI enzyme inhibition (only type II with finasteride and dual type I-II with dutasteride) may produce different results. The rationale for this hypothesis and study design was based on the following facts: (i) NE cells and CgA are expressed also in BPH, and (ii) NE prostate cells are hormone independent but different androgen deprivation therapies produce a different but significant effect on NE and CgA activation in the prostate; only one previous study suggests an effect of finasteride on CgA in BPH cases. At baseline, the study population well represented the population of BPH patients commonly considered for 5-ARI. In particular, based on the results of international trials and on EAU guidelines (2), BPH patients with a prostate volume 30 cc were included in this study. All patients in this study had a baseline PSA level <2.5 ng/ml and no clinical suspicion of PC. Testosterone and CgA levels at inclusion were in the normal range for all patients (elevated >90 ng/ml CgA levels at randomisation=0%). Modifications in testosterone and PSA levels during treatment were in the range to be expected on the basis of previous evidences in the literature. This study showed a slight increase in testosterone levels (in all cases values remained in the normal range) and a statistically significant reduction in PSA levels after six months of treatment with 5-ARI, with no significant difference between finasteride and dutasteride. Although CgA levels were not significantly modified during the six-month period of only observation in Group C, starting at three months and confirmed after six months of therapy, this study showed that both finasteride and dutasteride treatment produce a statistically significant and progressive increase in CgA levels. The effect of a type II (finasteride) versus a dual (dutasteride) 5-AR seems not to be different in terms of CgA increase, and the percentage of cases with elevated (>90 ng/ml) CgA at the end of treatment (finasteride 15%; dutasteride 15%) was also not different between the finasteride and dutasteride group. As in previous studies in PC (10, 15), no significant correlation between CgA and PSA- testosterone variations was found. This confirms that CgA as shown in PC is independent of PSA response to therapy. The limits of this study must be noted. These results were obtained in a prospective randomised analysis from a limited population and larger studies should be undertaken to confirm the current results. There was also no opportunity to also analyse DHT and free/total PSA levels in the current patient population and it would be possible to obtain more data through such analysis. However, the DHT reduction expected during finasteride or dutasteride treatment is very stable and well reported in previous studies (3). It was not possible to match the clinical results from this study with histological results on prostate tissue expression of CgA. However, previous studies have shown a significant correlation between serum and tissue expression of CgA in prostate diseases (9). No cases in the current patient population had a history of other disorders, or therapies or conditions known to interfere with CgA levels and NE activity, as defined in previous studies (11). A control (no treatment) group was included in this study to support the relationship between CgA levels variation and NE activity in the prostate gland. The absence of significant variations in serum CgA levels reported in the control group strongly supports the hypothesis that serum CgA variations described during finasteride and dutasteride treatment were related to the effect of 5-ARI on prostatic CgA expression and NE activity. 4741

6 Conclusion In contrast to the study of Tarle et al. (25) the Authors do not believe that these results provide evidence of a relationship between 5-ARI treatments and the risk of aggressive PC development. This study showed that 5-ARIs produce a significant increase in serum CgA levels in the BPH population, probably related to NE activation in the prostate gland. References 1 Rittmaster RS: 5Alpha-reductase inhibitors in benign prostatic hyperplasia and prostate cancer risk reduction. Best Pract Res Clin Endocrinol Metab 22(2): , Emberton M: Medical treatment of benign prostatic hyperplasia: physician and patient preferences and satisfaction. Int J Clin Pract 64(10): , Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB and Hobbs S: Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5 alphareductase inhibitor. J Clin Endocrinol Metab 89(5): , Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ and Coltman CA Jr.: The influence of finasteride on the development of prostate cancer. N Engl J Med 349(3): , Andriole G, Bostwick D, Brawley O, Gomella L, Marberger M, Tindall D, Breed S, Somerville M, Rittmaster R; REDUCE Study Group: Chemoprevention of prostate cancer in men at high risk: rationale and design of the reduction by dutasteride of prostate cancer events (REDUCE) trial. J Urol 172(4 Pt 1): , Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, Pettaway CA, Tammela TL, Teloken C, Tindall DJ, Somerville MC, Wilson TH, Fowler IL, Rittmaster RS; REDUCE Study Group: Incidence of biopsy-detectable prostate cancer in the REduction of DUtasteride of Prostate Cancer Events (REDUCE) trial: blinded 2-year results [abstract 2207]. Presented at the Annual Meeting of the American Urological Association, April 25-30, 2009, Chicago, IL, USA. 7 Sciarra A, Mariotti G, Gentile V, Voria G, Pastore A, Monti S and Di Silverio F: Neuroendocrine differentiation in human prostate tissue: is it detectable and treatable? BJU Int 91(5): , Sciarra A, Cardi A, Dattilo C, Mariotti G, Di Monaco F and Di Silverio F: New perspective in the management of neuroendocrine differentiation in prostate adenocarcinoma. Int J Clin Pract 60(4): , Berruti A, Bollito E, Cracco CM, Volante M, Ciccone G, Porpiglia F, Papotti M, Scarpa RM and Dogliotti L: The prognostic role of immunohistochemical chromogranin a expression in prostate cancer patients is significantly modified by androgen-deprivation therapy. Prostate 70(7): , Alessandro S, Vincenzo G, Maria AG, Stefano S, Alessandro G, Salvatore M, Vincenzo T and Franco DS: Chromogranin A and biochemical progression-free serviva in prostate adenocarcinomas submitted to radical prostatectomy. Endocr Relat Cancer 14(3): , Sciarra A, Voria G, Monti S, Mazzone L, Mariotti G, Pozza M, D'Eramo G and Silverio FD: Clinical understaging in patients with prostate adenocarcinoma submitted to radical prostatectomy: predictive value of serum chromogranin A. Prostate 58(4): , Sciarra A, Gentile V, Monti S, Dattilo C, Gomez AA, Salciccia S, Pannunzi LP, Toscano V and Di Silverio F: Comparison of chromogranin A, insulin-like growth factor 1 and prostatespecific antigen serum markers in prostate adenocarcinoma and benign prostatic hyperplasia. Urol Int 80(1): 68-73, Di Sant Agnese I and Cickett AT: Neuroendocrine differentiation in prostatic malignancy. Cancer 78: , Abrahamsson PA: Neuroendocrine differentiation in prostate carcinoma. Prostate 39: , Berruti A, Mosca A, Tucci M, Terrone C, Torta M, Tarabuzzi R, Russo L, Cracco C, Bollito E, Scarpa RM, Angeli A and Dogliotti L: Independent prognostic role of circulating chromogranin A in prostate cancer patients with hormone-refractory disease. Endocrine-Related Cancer 12(1): , Ahlegren G, Pedersen K, Lundberg S, Aus G, Hugosson J and Abrahamsson P: Neuroendocrine differentiation is not prognostic of failure after radical prostatectomy dut correlates with tumour volume. Urology 56(6): , Bostwick DG, Grignon DJ, Hammond EH, Amin MB, Cohen M and Crawford D: Prognostic factors in prostate cancer: College of American Pathologists consensus statement Arch Pathol Lab Med 124: , Yuan TC, Veeramani S, Lin FF, Kondrikou D, Zelivianski S, Igawa T, Karan D, Batra SK and Lin MF: Androgen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells. Endocrine-Rel Cancer 13(1): , Jongsma J, Oomen MH, Noordzij MA, Romijn JC, van Der Kwast TH, Schröder FH and van Steenbrugge GJ: Androgenindependent growth is induced by neuropeptides in human prostate cancer cell lines. Prostate 42(1): 34-44, Kadmon D, Thompson TC, Lynch GR and Scardino PT: Elevated plasma chromogranin A concentrations in prostatic carcinoma. J Urol 146(2): , Krijnen JL, Bogdanowicz JF, Seldenrijk CA, Mulder PG and van der Kwast TH: The prognostic value of neuroendocrine differentiation in adenocarcinoma of the prostate in relation to progression of disease after endocrine therapy. J Urol 158(1): , Ahlgren G, Pedersen K, Lundberg S, Aus G, Hugosson J and Abrahamsson PA: Regressive changes and neuroendocrine differentiation in prostate cancer after neoadjuvant hormonal treatment. Prostate 42(4): , Sciarra A, Monti S, Gentile V, Mariotti G, Cardi A, Voria G, Lucera R and Di Silverio F: Variation in chromogranin A serum levels during intermittent versus continuous androgen deprivation therapy for prostate adenocarcinoma. Prostate 55(3): , Sciarra A and Di Silverio F: Effect of nonsteroidal antiandrogen monotherapy versus castration therapy on neuroendocrine differentiation in prostate cancer. Urology 63(3): , Tarle M, Spajic B, Kraljic I and Kusic Z: Continuous finasteride therapy for benign prostate hypertrophy upgrades both neuroendocrine differentiation and aggressive prostate cancer. Anticancer Res 29(5): , Received September 19, 2010 Revised October 12, 2010 Accepted October 14,