Vol 16 No 02 March-April 2019 157 UROLOGICAL ONCOLOGY Effect of Hormonal Therapy for Volume Reduction, Lower Urinary Tract Symptom Relief and Voiding Symptoms in Prostate Cancer: Leuprolide vs Goserelin Taha Numan Yıkılmaz1*, Erdem Öztürk1, Fatih Hızlı1, Nurullah Hamidi2, Halil Basar1 Purpose: The complaints of lower urinary tract symptoms in cases with prostate carcinoma (Pca) are associated with coexisting benign prostate hyperplasia or aging bladder. The aim of this study was to investigate and compare the effect of goserelin acetate with leuprolide acetate on total prostate volume (TPV), post voiding residue (PVR), International Prostate Symptom Score (IPSS) and maximum flow rate (Qmax) reduction in cases of advanced Pca. Materials and Methods: The study initially enrolled 71 patients who presented at our clinic for hormonotherapy because of advanced prostate carcinoma between May 2015 and August 2016. A total of 51 patients were found suitable for the study and were divided into two groups as Group 1 who received goserelin acetate (10.8 mg /3 months) and Group 2 who received leuprolide acetate (22.5 mg /3 months). Age, Gleason score, T stage, pre and post treatment Prostate specific antigen (PSA) and testesterone level, TPV, IPSS, PVR, and Qmax values were recorded retrospectively. Changes in parameters were assessed every 3 months. Results: Analysis was made on 51 patients in this study. No statistically significant difference was determined between the two groups in respect of the mean percentage decrease in PSA (98.7% and 98.4%, respectively; P = .9) and testosterone (92.9 % and 96.4 %, respectively; P = .15) from baseline to 6 months but TPV reduced by -20.2 % ± 4.8 and -15.6 % ± 1.04, the median total IPSS score decreased by -34.77 % ± 8.8 and -19.77 % ± 6.1, median Qmax increased by 45.34 % ± 10.16 and 23.21 % ± 6.93, and median PVR decreased by -31.54 % ± 8.4 and -19.23 % ± 5.5, respectively for the two groups (all parameters P < .05) Conclusion: In this study, the improvement observed in voiding parameters with the use of goserelin acetate was better than with leuprolide acetate. The superiority of the goserelin acetate group was determined in particular on the reduction of TPV, PVR and IPSS. Although the PSA follow-up time was short, no significant difference was determined between the groups in the early oncological outcomes. Keywords: androgen deprivation therapy; total prostate volume; post voiding residue; voiding symptoms; prostate carcinoma INTRODUCTION Prostate carcinoma (Pca) is one of the most common malignant cancers and the second greatest malig- nancy-related cause of death in males(1). In 2014, the prostate cancer incidence rate was reported as 35 cases per 100,000 in Turkey(2). Androgen deprivation therapy (ADT) is a main stage in the treatment of metastatic or advanced prostate cancer and has been shown to im- prove overall survival(3). Gonadotropin releasing hor- mone (GnRH) agonists remain the most widely used form of ADT. As 70% of prostate carcinomas originate from the pe- ripheral zone, they are frequently asymptomatic until growth is of a size that compresses the prostatic urethra, bladder neck or there is metastasis(4). Therefore, com- plaints of lower urinary tract symptoms (LUTS) in cases with Pca are associated with the coexistence of benign prostate hyperplasia (BPH) or aging bladder(5). In these cases, total prostate volume (TPV), post voiding resi- 1 Department of Urology, Ankara Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, Ankara 06200, Turkey. 2 Atatürk Training and Research Hospital, Ankara 06200, Department of Urology. *Correspondence: Department of Urology, Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, Yenimahalle, Anka- ra 06200, Turkey. Phone: +90 312 3360909. Fax: +90 312 3340352. E-mail: numanyikilmaz@gmail.com. Received November 2017 & Accepted March 2018 due (PVR), the International Prostate Symptom Score (IPSS) and maximum flow rate (Qmax) are important in the planning of the treatment. Published data show that ADT can reduce TPV ranges by 30 % to 55 %(6,7). Hormonal therapy reduces TPV as well as the tumor volume and this downsizing of the prostate gland has an effect on PVR, IPSS and Qmax values(8). However, to the best our knowledge, there are no published stud- ies that have investigated the effect of different GnRH agonists on LUTS. To adress this knowledge gap, the effect of goserelin and leuprolide acetate on LUTS of prostate cancer were investigated in this study. The aim of the study was to show that there may be regression of symptoms only with hormonotherapy in cases of pros- tate cancer with LUTS complaints. Urological Oncology 158 MATERIALS AND METHODS Study population and design A retrospective review was made of the data of 71 pa- tients who received ADT only for advanced prostate cancer between May 2015 and August 2016. Patients with an indwelling urinary catheter, treatment with 5 al- pha reductase inhibitors or alpha adrenoceptor blocker, had evident nervous system disorder or had undergone pelvic or urinary tract surgery were excluded from the study. After exclusion of these patients, the data of the remaining 51 patients were analyzed. Written informed consent was obtained from patients who participated in this study. All study procedures were applied in compli- ance with the Helsinki Declaration and the Good Clin- ical Practice Guidelines. Age, Gleason score, T stage, pre and post treatment prostate specific antigen (PSA) and testesterone level, TPV, IPSS, PVR, and Qmax values were recorded for each patient. In this study, patients with advanced prostate cancer received le- uprolide or goserelin acetate for at least 6 months at the discretion of the attending physician (T.N.Y. & E.Ö.). Three-month doses were applied to all cases. The cases were divided into 2 groups, as Group 1 patients who re- ceived goserelin acetate (10.8 mg/3 months) and Group 2 patients who received leuprolide acetate (22.5 mg/3 months). In all cases bicalutamide (50 mg once daily) was given for the first 10 days for flare protection and on the 10th day GnRH agents were inserted subcutane- ously into the abdominal wall. Blood samples were collected to analyse testosterone and PSA levels with a validated chemiluminescence method at the beginning of the ADT and the analyses were repeated at the 3rd and 6th month. Ultrasonogra- phy and uroflowmetry were also performed before ad- ministration of the drug and at each 3-monthly visit by the same urologist using the same equipment. Total prostate volume and PVR were calculated by an elliptical approximation (width x height x length x 0.5) with transrectal ultrasound (using a Sono Scape SSI- 5500BW ultrasound scanner, Shenzhen, China). Ultra- sound was performed on day 0 and repeated 3 and 6 months later to assess evaluate the change in volume due to ADT with the same equipment by the same urol- ogist. Ultrasound was also performed to measure PVR pre and post ADT. The changes were recorded. The IPSS questionnaire was completed by all the cases enrolled in the study. This score system is used to as- sess LUTS(9). It includes 7 symptoms of urinary tract: incomplete emptying, frequency, intermittency, urgen- cy, weak stream, straining and nocturia(8). Mild LUTS was defined as IPSS of 1-7, moderate LUTS as IPSS of 8-19 and severe as IPSS of 20-35(10). A clinically sig- nificant response was defined as a change of at least 3 points in IPSS(10). The IPSS form was administered to the patients at the beginning of the treatment and was repeated at the 3rd and 6th months. Statistical analysis SPSS version 19.0 software (SPSS Inc., Chicago, IL, USA) was used for statistically analysis. All values are presented as mean ± standard deviation. Values of the clinical factors were analyzed using the Mann Whitney U-test to determine the significance of differences be- tween groups, and Spearman rank correlation analysis was applied to evaluate the relationship between ADT and the IPSS score, Qmax, TPV and PVR. A value of P < .05 was considered to be statistically significant. RESULTS The mean age of the patients was 63.9 ± 4.2 years (range, 46-83 years). Group 1 (goserelin acetate) com- prised 24 patients and Group 2 (leuprolide acetate), 27 patients. Patient characteristics (age, stage, Gleason score, PSA variables, total testosterone, TPV, IPSS, Q max and PVR) are shown in Table 1. A statistically significant difference was found in mean age between the treatment groups (P = .035). Serum PSA, total testosterone, TPV, IPSS, Q max and PVR values were not statistically significant between the two groups (P = .09, P = .11, P = .06, P = .06, P = .11, P = .27, respectively) No statistically significant difference was determined between the groups in respect of mean percentage de- crease in PSA from baseline to month 6 (98.7 % and 98.4 %, respectively; P = .9). No significant difference was determined between the two groups in the chang- es of testosterone values in the 6th month of treatment compared with baseline values (92.9 % and 96.4 %, re- spectively; P = .15). Leuprolide vs goserelin on LUTS-Yikilmaz et al. Table 1. Demographic characteristics Baseline characteristics Goserelin acetate (10.8 mg) N=24 Leuprolide acetate (22.5 mg) N=27 P Age, years 67.4 (48-80) 64.25 (46-83) 0.035* Time from diagnosis to initial treatment 61 57 T stage T1 8 11 T2 12 10 T3/4 4 6 Gleason score ≤7 7 9 ≥8 17 18 TPV (mL) day of 0 64.12 (28-136) 81.18 (24-110) 0.06 IPSS day of 0 13.45 (4-29) 12.39 (6-26) 0.06 Qmax day of 0 12.4 (5-23) 12.19 (4-21) 0.11 PVR day of 0 73.02 (29-156) 75.9 (20-98) 0.27 PSA levels, ng/mL (mean) 25.6 (4-100) 30.45 (4-81) 0.09 Testosterone, ng/mL (mean) 2.77 (1.1-6.6) 2.98 (1.53-6.2) 0.11 Abbreviations: TPV: Total prostate volume, IPSS: International Prostate Symptom Score, Qmax: maximum flow rate, PVR: post voiding residue, PSA: Prostate specific antigen Vol 16 No 02 March-April 2019 159 Total prostate volume (TPV) was reduced significant- ly from baseline to month 6 in both groups with mean ±standard error percentage decreases of -20.2 % ± 4.8 and -15.6 % ± 1.04 for goserelin acetate and leuprolide acetate, respectively. Statistical evaluation showed that goserelin acetate was superior to leuprolide acetate (P = .02). From baseline to 6th month, the median total IPSS score decreased by -34.77 % ± 8.8 and -19.77 % ± 6.1, median Qmax increased by 45.34 % ± 10.16 and 23.21 % ± 6.93, median PVR decreased by -31.54 % ± 8.4 and -19.23 % ± 5.5, respectively in the two groups. Statistically significant Goserelin acetate was observed to be statistically significantly superior in all of these parameters (P < .05) (Table 2 and Figure 1). DISCUSSION Hormone therapy is the main treatment for locally ad- vanced and metastatic prostate carcinoma patients who are not eligible for radical treatment options. Gonado- tropin-releasing hormone (GnRH) receptor agonists are successful in obtaining the required therapeutic levels (serum testesterone < 0.5 ng/mL) in 90 % of patients(11). The first administration may create a sudden increase in serum T levels. Therefore, because of this effect, the patient is given antiandrogen treatment for 10 days before the first injection to prevent clinical symptoms such as flare phenomenon, spinal cord compresion, bone pain and urethral obstruction(1). Low urinary tract symptoms are one of the main con- cerns of prostate cancer patients. Although studies have indicated that endocrine treatments have a diminishing effect on LUTS complaints, there are no studies that have measured the efficacy of goserelin acetate and leuprolide acetate on the improvement on IPSS, TPV, PVR and Qmax(8,12,13). The results of the current study show that hormonal therapy has a positive effect on LUTS symptoms and prostate volume within 6 months. Prostate cancer frequently coexists with BPH, which can cause LUTS. Lehrer et al. reported that 55.6 % of PCa patients have mild LUTS, 37.1 % have moderate symptoms, and 7.3 % have severe symptoms(14). Ham- ilton et al. reported a significant improvement in LUTS complaints and reductions in PVR and TPV values after 12 months of hormonal therapy in patients with pros- tate cancer(4). In 2012, Klarskov et al. showed 50 % reduction in IPSS levels, 38 % increase of Qmax, 26 % decrease in PVR value and 37 % decrease in TPV lev- els within 12 months of hormone therapy(13). As a result of that study, the best improvement in these parameters was observed to be in the first month of the ADT. A few studies have detected the reduction in TPV to be in the range of 21 % to 48 % within 3.7 months as a result of ADT(15,16). In the current study, TPV reduction sec- ondary to hormone therapy was 20.2 % in the goserelin group, and 15.6 % in the leuprolide group in 6 months, which was similar to the findings of previous studies. The effects of testosterone suppression on bladder out- let obstruction have been determined in vitro and in vivo animal studies. Blockage of GnRH receptors in the prostate smooth muscle and epithelial cells allows the down-regulation of pro-inflammatory cytokines, growth factors and α1-adrenoreceptors involved in these cells. An improvement in LUTS and a decrease in TPV were accepted in this patient group with the pro- vided smooth muscle relaxation(10,17). It is believed that hormone therapy in the elderly bladder contributes to IPSS scores through the effect on prostate carcinoma. In a study that compared degarelix and goserelin acetate, it was observed that the improvement was better in cas- Table 2. Changes parameter from baseline to 6th month in patients treated with goserelin acetate and leuprolide acetate Goserelin acetate Leuprolide acetate p PSA (initial to 6th month) -98.7 % ±0.9 -98.4 % ±0.4 0.9 TT (initial to 6th month) -92.9 % ±5.8 -96.4 % ±6.9 0.15 TPV (initial to 6th month) -20.2 % ±4.8 -15.6 % ± 1.04 0.02* IPSS (initial to 6th month) -34.77 % ±8.8 -19.77 % ±6.1 0.001* Qmax (initial to 6th month) 45.34 % ± 10.16 23.21 % ± 6.93 0.001* PVR (initial to 6th month) -31.54 % ±8.4 -19.23 % ±5.5 0.01* Abbreviations: TPV: Total prostate volume, IPSS: International Prostate Symptom Score, Qmax: maximum flow rate, PVR: post voiding residue, PSA: Prostate specific antigen, TT: Total testesterone Figure 1. Voiding parameters and prostat size from initial to 6th month. Comparison chart of the effects of goserelin acetate and leupro- lide acetate on parameter (*p < 0.001, **p < 0.01, ***p < 0.02) Leuprolide vs goserelin on LUTS-Yikilmaz et al. Urological Oncology 160 es with low IPSS scores in the 3rd month and degare- lix was superior to goserelin acetate(10). In the current study, although IPSS scores were not divided into void- ing and storage scores, goserelin acetate was found to be statistically more significant in total score improve- ment (-34.77 % ±8.8 vs -19.77 % ± 6.1, respectively). The storage score of IPSS is associated with PVR while Qmax value is related to voiding scores. Improvement in IPSS has been similarly observed at Q max and PVR levels(13). In the results of the current study, the increase in maximum flow rate (45.34 % ± 10.16) and decrease in postvoid residual volume (-31.54 % ± 8.4) were sig- nificanty higher in the goserelin acetate group than in the leuprolide acetate group in the 6th month (P < .01). There are different opinions that assume the upper level of testosterone as 0.2 ng/mL or 0.5 ng/mL as the ide- al castration level. It is often accepted as adequate at 0.5 ng/mL as there has been seen to be no difference regarding the decrease in PSA and progression in the follow-up of patients(3). In terms of comparing GnRh agonists, some studies have shown no statistically sig- nificant difference between goserelin acetate and le- uprolid acetate(3). Goserelin groups have shown some superiority over leuprolide(18). In the current study, for castration level < 0.5 ng/mL of testesterone, there was no significant difference between the groups (P = .15). Similar results were observed in the changes in PSA level, with no statistically significant difference ob- served between the groups in respect of the PSA de- crease (P = .9). There were some limitations to this study. Although the number of patients was sufficient, the study was con- ducted at a single center. To the best of our knowledge, this is the first study to have compared the effect of gos- erelin acetate and leuprolide acetate on voiding param- eters and reduction of prostate volume and postvoiding residue. CONCLUSIONS The main goal of hormonal therapy is to treat patients with locally advanced and metastatic prostate carcino- ma who are not eligible for radical treatment options, and in the current study, the effect of ADT was ob- served on voiding symptoms and prostate volume. The improvement in voiding parameters of goserelin acetate was determined to be better than leuprolide acetate. In particular, the superiority of goserelin acetate was ob- served in the reduction of TPV, PVR and IPSS. CONFLICT OF INTEREST The authors report no conflict of interest. REFERENCES 1. Pourmand G, Safavi M, Ahmadi A et al. EPCA2.22: A Silver Lining for Early Diagnosis of Prostate Cancer. Urol J. 2016;13:2845-8. 2. Zorlu F, Zorlu R, Divrik RT, Eser S, Yorukoglu K. Prostate cancer incidence in Turkey: an epidemiological study. Asian Pac J Cancer Prev. 2014;15:9125-30. 3. Nguyen PL, Alibhai SM, Basaria S, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol. 2015;67:825-36. doi: 10.1016/j. eururo.2014.07.010. Epub 2014 Aug 2. 4. Hamilton W, Sharp D. Symptomatic diagnosis of prostate cancer in primary care: a structured review. Br J Gen Pract. 2004;54:617-21. 5. Andersson SO, Rashidkhani B, Karlberg L, Wolk A, Johansson JE. Prevalence of lower urinary tract symptoms in men aged 45-79 years: a population-based study of 40 000 Swedish men. BJU Int. 2004;94:327-31. 6. Soloway MS, Hachiya T, Civantos F, Murphy WM, Gomez CC, Ruiz HE. Androgen deprivation prior to radical prostatectomy for T2b and T3 prostate cancer. Urology. 1994;43:52-6. 7. Washino S, Hirai M, Saito K, Kobayashi Y, Arai Y, Miyagawa T. Impact of Androgen Deprivation Therapy on Volume Reduction and Lower Urinary Tract Symptoms in Patients with Prostate Cancer. Low Urin Tract Symptoms. 2016 Dec 12. doi: 10.1111/ luts.12142. [Epub ahead of print] 8. Sun S, Bai Y, Yang H, Yang HW. Investigation on lower urinary tract symptoms (LUTS) in elderly patients with prostate cancer (PC) received endocrine therapy. Arch Gerontol Geriatr. 2015;60:535-7. doi: 10.1016/j. archger.2014.10.014. 9. Stone NN, Marshall DT, Stone JJ, Cesaretti JA, Stock RG. Does neoadjuvant hormonal therapy improve urinary function when given to men with large prostates undergoing prostate brachytherapy? J Urol. 2010;183:634- 9. doi: 10.1016/j.juro.2009.09.084. 10. Axcrona K, Aaltomaa S, da Silva CM et al. Androgen deprivation therapy for volume reduction, lower urinary tract symptom relief and quality of life improvement in patients with prostate cancer: degarelix vs goserelin plus bicalutamide. BJU Int. 2012;110:1721-8. doi: 10.1111/j.1464-410X.2012.11107.x. 11. Lepor H. Comparison of single-agent androgen suppression for advanced prostate cancer. Rev Urol. 2005;7 Suppl 5:S3-S12. 12. Kucway R, Vicini F, Huang R, Stromberg J, Gonzalez J, Martinez A. Prostate volume reduction with androgen deprivation therapy before interstitial brachytherapy. J Urol. 2002;167:2443-7. 13. Klarskov LL, Klarskov P, Mommsen S, Svolgaard N. Effect of endocrine treatment on voiding and prostate size in men with prostate cancer: a long-term prospective study. Scand J Urol Nephrol. 2012;46:37-43. doi: 10.3109/00365599.2011.637953. 14. Lehrer S, Stone NN, Droller MJ, Stock RG. Association between American Urologic Association (AUA) urinary symptom score and disease stage in men with localized prostate cancer. Urol Oncol. 2002;7:73-6. 15. Pinault S, Têtu B, Gagnon J, Monfette G, Dupont A, Labrie F. Transrectal ultrasound Leuprolide vs goserelin on LUTS-Yikilmaz et al. Vol 16 No 02 March-April 2019 161 evaluation of local prostate cancer in patients treated with LHRH agonist and in combination with flutamide. Urology. 1992;39:254-61. 16. Whittington R, Broderick GA, Arger P et al. The effect of androgen deprivation on the early changes in prostate volume following transperineal ultrasound guided interstitial therapy for localized carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 1999;44:1107- 10. 17. Gallo CB, Miranda AF, Felix-Patricio B et al. Effects of castration and hormone replacement in the urinary bladder of rats: structural, ultrastructural, and biochemical analysis. J Androl. 2012;33:684-90. doi: 10.2164/ jandrol.111.014159. 18. Sarosdy MF, Schellhammer PF, Sharifi R et al. Comparison of goserelin and leuprolide in combined androgen blockade therapy. Urology. 1998;52:82-8. Leuprolide vs goserelin on LUTS-Yikilmaz et al.