ANTICANCER RESEARCH 34: 1983-1988 (2014) Oncological Outcomes of Hormonal Therapy with a Gonadotropin-releasing Hormone Agonist Combined with a Steroidal or Non-Steroidal Antiandrogen in Patients with Prostate Cancer TSUKASA IGAWA1, TOSHIFUMI TSURUSAKI2, KOICHIRO NOMATA3, MIKIO HAYASHI4, MASATAKA FURUKAWA5 and HIDEKI SAKAI1 1Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; 2Division of Urology, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan; 3Division of Urology, Nagasaki Municipal Hospital, Nagasaki, Japan; 4Division of Urology, Nagasaki Medical Center, Omura, Japan; 5Division of Urology, Sasebo General Hospital, Sasebo, Japan Abstract. Aim: To determine the treatment outcome of Androgen deprivation therapy (ADT) has been the mainstay combined androgen blockade (CAB) therapy using the non- of treatment for managing advanced prostate cancer. steroidal antiandrogen bicalutamide or the steroidal However, an increase in earlier diagnosis of this disease has antiandrogen chlormadinone in patients with prostate cancer. led to increasing ADT use in men with non-metastatic Patients and Methods: In total, 124 patients with prostate disease or with recurrence after definitive therapy, i.e. cancer enrolled in the present study were randomized to prostatectomy or radiation therapy. Thus, a significant receive CAB therapy using a gonadotropin-releasing hormone proportion of patients with prostate cancer have received (GnRH) agonist, combined with bicalutamide or ADT even in Western countries, and especially in Japan (1). chlormadinone. The survival of patients was analyzed. Results: Hence, the management of patients who have received ADT The 5-year cancer-specific survival for the bicalutamide- and is an important issue. One aspect of this issue is the chlormadinone-treated groups were 91.7% and 86.6%, management of adverse effects of ADT e.g. loss of libido, respectively, with no significant difference (p=0.39). Five-year increased cardiovascular disease risk, liver dysfunction, bone overall survival was significantly (p=0.029) better in the loss, and so forth (2, 3). Among these adverse events, hot bicalutamide-treated group. Moreover, M1 patients in the flashes have elicited concern as a factor that lowers patients’ chlormadinone group had significantly lower cancer-specific quality of life (QOL) (4, 5). In this regard, we previously and overall survival compared to those in the bicalutamide- conducted a randomized prospective study of hot flashes and treated group. However, in the case of M0 patients, no QOL during combined androgen blockade (CAB) therapy significant difference in cancer-specific nor in overall survival using the non-steroidal antiandrogen bicalutamide or the was observed. Conclusion: CAB therapy using chlormadinone steroidal antiandrogen chlormadinone, and found fewer and led to a significantly poorer survival outcome versus the use of less-distressing hot flashes in the group of patients using bicalutamide. However, because this survival trend was not chlormadinone (6). Interestingly, similar results have been observed in M0 cases, chlormadinone may still be an option reported from Western countries using the other steroidal for CAB therapy, depending on clinical stage and the severity antiandrogen, cyproterone acetate, with a lower incidence of of adverse effects, such as hot flashes. hot flashes compared to castration-alone or with castration- plus-placebo (7, 8). Thus, chlormadinone may have a positive impact on patient QOL regarding hot flashes. On the other hand, several clinical studies from Western countries Correspondence to: Tsukasa Igawa, Department of Nephro-urology, have reported delay in disease progression or conferring Nagasaki University Graduate School of Biomedical Sciences, 1-7- survival advantage in CAB therapy with a non-steroidal 1, Sakamoto, Nagasaki 852-8501, Japan. Tel: +81 958197340, Fax: antiandrogen compared to CAB with cyproterone acetate (9). +81 958197343, e-mail: [email protected] However, this finding in Japanese patients with prostate Key Words: Prostate cancer, combined androgen blockade, cancer has not been fully-investigated. Only a few reports are antiandrogen. available concerning the short-term outcome of CAB therapy 0250-7005/2014 $2.00+.40 1983 ANTICANCER RESEARCH 34: 1983-1988 (2014) using chlormadinone. One randomized prospective study Table I. Baseline characteristics of eligible patients from Japan showed similar short-term (24 weeks) objective responses between CAB with flutamide and CAB with Chlormadinone Bicalutamide p-Value (n=60) (n=64) chlormadinone (10). In our previous study, we also observed no significant difference between the two groups with respect Age (years) 0.88 to 2-year progression-free survival. Given this background, Median 74.2 75.7 aiming to confirm the oncological outcomes of CAB therapy Mean±SD 74.6±6.9 74.8±5.7 with bicalutamide or chlormadinone, we analyzed the longer- Performance status 0.60 0-1 59 (98.3) 62 (96.9) term survival status of the patients enrolled in our study. 2-3 1 (1.7) 2 (3.1) TNM classification 0.23 Patients and Methods T1-2N0M0 27 (45.0) 24 (37.5) T3-4N0M0 19 (31.7) 24 (37.5) The detailed design of the original prospective study was described N1M0 6 (10.0) 2 (3.1) previously (6). Briefly, in total, 151 patients with histologically- M1 8 (13.3) 14 (21.9) Histological grade 0.30 confirmed prostate cancer, including both localized and metastatic 1 15 (25.0) 10 (15.6) disease, were enrolled from May 2001 to June 2003. These patients 2 28 (46.7) 38 (59.4) were randomized to receive CAB therapy using a gonadotropin- 3-4 17(28.3) 16 (25.0) releasing hormone (GnRH) agonist (leuprorelin) combined with Serum PSA (ng/mL) bicalutamide or chlormadinone. A 3.75 mg depot of leuprorelin was Median 22.8 29.8 0.62 administered subcutaneously once every four weeks, and 100 mg Mean±SD 103.7±171.1 135.4±476.0 chlormadinone or 80 mg bicalutamide was given daily. The primary Comorbid disease end-points of the original study were the incidence, frequency, and Absent 39 (65.0) 47 (73.4) 0.31 severity of hot flashes and the QOL during treatment. After Present 21 (35.0) 17 (26.6) exclusion of ineligible patients, data were available for analysis from 124 patients (bicalutamide group: 64 patients, chlormadinone PSA: Prostate specific antigen. group: 60 patients). The observation period lasted for two years. After this period in the primary study, hormonal treatment continued in principle, but changes in treatment due to disease progression were determined at the attending urologist’s discretion. For the However, 5-year OS in all cases was significantly better current study, we conducted a cross-sectional analysis of patient (p=0.029) in the bicalutamide-treated group (91.7%) compared survival in 2011. Patients’ data on treatment outcome were collected to that in the chlormadinone-treated group (79.2%, Figure 1B). from each participating Institution, and overall survival (OS) and We subsequently analyzed the impact of several cancer-specific survival (CSS) of these patients were analyzed by Kaplan−Meier survival analysis with log-rank tests. The prognostic clinicopathological factors on the CSS and OS in these 124 significance of various factors was assessed using the Cox patients (Table II). Univariate analysis showed that proportional hazards regression model. The Clinical Trial Review histological grade, clinical stage, and presence of bone Committee of Nagasaki Prostate Cancer Research Group and the metastasis were significant predictors of CSS, while the institutional review board of each participating institution approved presence of bone metastasis was associated with OS. the study protocol (approval number: 10012250). Statistical analyses However, only the presence of bone metastasis appeared to were performed using the SPSS software ver. 20 (IBM Co., Ltd. have an independent impact on both CSS and OS. Although New York. United States), and p-values of less than 0.05 were considered to indicate statistical significance. the type of antiandrogen was not associated with patient survival, the chlormadinone-treated group showed a tendency Results for poorer OS. According to these predictors of survival, we analyzed the survival data of the sub-groups of patients with Patients’ characteristics from all 124 cases analyzed in a and without bone metastasis. As shown in Figure 2, patients previous study are presented in Table I. Between the two in the chlormadinone-treated group with distant metastasis groups, no statistically significant differences were found in the (M1) had significantly poorer CSS (p=0.019) and OS background variables. The median follow-up period of all 124 (p=0.007) versus the bicalutamide-treated group. On the other patients was 78.9±31.6 months. During follow-up, 22 (17.7%) hand, after excluding M1 cases, there was no significant patients died, including 8 due to prostate cancer (bicalutamide- difference in CSS or OS between the groups (Figure 3). treated group: 3 cases, chlormadinone-treated group: 5 cases) and 14 due to other causes (bicalutamide-treated group: 4 Discussion cases, chlormadinone-treated group: 10 cases). Overall, the 5- year CSS of the bicalutamide-treated and chlormadinone- In our original prospective study, we determined that fewer treated groups was 91.7% and 86.6%, respectively, with no and less-distressing hot flashes were induced by CAB using a significant differences between groups (p=0.39, Figure 1A). steroidal antiandrogen such as chlormadinone, rather than 1984 Igawa et al: Outcomes of CAB Therapy with Different Antiandrogens Table II. Univariate and multivariate analyses of the association between predictor variables and patient survival Variables Cancer-specific survival Overall survival Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis HR p-Value HR p-Value HR p-Value HR p-Value Age (years) (<75 vs. ≥75) 1.81 0.417 – – 1.58 0.289 – – PSA (ng/mL) (<20 vs. ≥20) 1.61 0.227 – – 1.492 0.125 – – Histological grade (1/2 vs. 3/4) 2.45 0.014 1.98 0.067 1.52 0.148 – – Clinical stage (N0M0 vs.