sign in sign up
<<
Home , Bicalutamide, Steroidal antiandrogen

ANTICANCER RESEARCH 34: 1983-1988 (2014)

Oncological Outcomes of Hormonal Therapy with a -releasing Combined with a Steroidal or Non-Steroidal in Patients with 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, ; 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 deprivation therapy (ADT) has been the mainstay combined androgen blockade (CAB) therapy using the non- of treatment for managing advanced . or the steroidal However, an increase in earlier diagnosis of this has antiandrogen 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 , respectively, with no significant difference (p=0.39). Five-year increased cardiovascular disease risk, 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, 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 (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 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 () 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 Review histological grade, clinical stage, and presence of bone Committee of Nagasaki Prostate Cancer Research Group and the 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. ), 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

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. N1/M1) 2.69 0.013 2.18 0.043 1.92 0.053 – – Bone metastasis (negative vs. positive) 3.39 0.009 2.57 0.028 2.86 0.032 1.69 0.127 Antiandrogen (bicalutamide vs. chlormadinone) 1.58 0.547 – – 2.33 0.039 1.57 0.145

HR: Hazard ratio; PSA: prostate specific antigen.

CAB with bicalutamide (6). Similar clinical advantages of the Besides cyproterone acetate, the other type of steroidal steroidal antiandrogen cyproterone acetate have been reported antiandrogen is chlormadinone, which was developed in from Western countries (7, 8). Several studies have shown Japan and has a long history of clinical use in this country. that cyproterone acetate treatment leads to lower incidence of The clinical efficacy of CAB using chlormadinone has been hot flashes and in patients with prostate cancer reported in a few studies in Japan. As mentioned previously, (4, 5). However, steroidal antiandrogens are associated with Ozono et al. reported no significant difference in the clinical disadvantages, such as liver dysfunction, loss of objective response to CAB with flutamide or with libido, and increased cardiovascular disease risk (11). chlormadinone in a prospective randomized study (10). To determine the type of antiandrogen for clinical use, we However, the mean follow-up period of this study was only need to consider both clinical advantages and disadvantages. 24 weeks, and the authors did not include patient survival Needless to say, the other priority in determining a method data. Another retrospective study with a mean follow-up of androgen deprivation therapy is efficacy of treatment, period of 5.4 years showed that the type of antiandrogen was especially in survival outcome. Currently, the usefulness of not a prognostic factor for patients with prostate cancer in CAB compared to castration monotherapy is still all clinical stages (17). Thus, the present study may be the controversial. However, several randomized studies and a first to have analyzed relatively long-term survival outcomes meta-analysis have shown survival advantages with CAB, using CAB with bicalutamide or chlormadinone, in a including for patients in Japan (12). Moreover, one prospective randomized design. Consequently, compared to prospective randomized study from Japan showed superior CAB with bicalutamide, CAB with chlormadinone led to antitumor efficacy of CAB using bicalutamide, compared significantly poorer CSS and OS in patients with distant with GnRH agonist monotherapy, in stage C and D1 cases metastasis of prostate cancer. The reason for this survival (13). Thus, at least the addition of antiandrogens could have difference between the two groups is currently unknown. positive effects on patient survival. Direct or indirect antitumor activity may differ between these The next question is the impact of the type of two types of antiandrogens, especially when applied to a antiandrogen on patient survival. In this regard, prospective large tumor burden, as in metastatic prostate cancer cases. clinical data are quite limited, especially for long-term Another possibility is restrictions for chlormadinone follow-up, over five years, both in Western countries and administration due to its adverse effects, especially liver Japan. One study that compared antiandrogen monotherapy dysfunction or cardiovascular events. In fact, the frequency using flutamide or cyproterone acetate in patients with of liver dysfunction in our study was significantly higher in metastatic prostate cancer showed no significant differences the chlormadinone-treated group (data not shown). in OS or CSS, with a median follow-up period of 8.6 years There are several limitations to the present study. Firstly, (14). Regarding CAB, two meta-analyses have shown a our case numbers and follow-up periods may not be enough survival advantage of CAB with non-steroidal antiandrogens to draw a firm conclusion regarding survival outcomes. compared to that with steroidal antiandrogens (15, 16). Secondly, because chlormadinone was developed as a However, to our knowledge, no study has been reported from therapeutic drug for prostate cancer in Japan, our data may Western countries to have directly compared the survival not be readily-applicable to the other type of steroidal outcome of CAB with non-steroidal antiandrogens and CAB antiandrogen, cyproterone acetate. However, as these with steroidal antiandrogens. steroidal antiandrogens exhibit similar biological behavior

1985 ANTICANCER RESEARCH 34: 1983-1988 (2014)

Figure 1. Cancer-specific survival (A) and overall survival (B) of all Figure 2. Cancer-specific survival (A) and overall survival (B) of M1 patients. The overall survival of the bicalutamide-treated group was patients (n=22). Both cancer-specific and overall survival of the significantly better. bicalutamide-treated group were significantly better.

and treatment outcomes when used with CAB, the potential strategy. It will be important to monitor clinical data on the advantage of non-steroidal antiandrogens on patient various types of antiandrogens, including MDV3100, and survival may be valuable, especially in advanced cases. to properly evaluate adverse events and treatment outcomes Recently, a new class of antiandrogen, which includes for each. Then it will be possible to choose the most MDV3100, has become available for clinical use. Thus, suitable antiandrogen as a treatment tool for each patient ADT will move to a new stage in prostate cancer treatment with prostate cancer.

1986 Igawa et al: Outcomes of CAB Therapy with Different Antiandrogens

was not observed in cases free of distant metastasis. Moreover, the results from our original study indicated that chlormadinone has a positive impact on patient QOL regarding hot flashes. Thus chlormadinone may still be of value in CAB therapy for selected cases, depending on cancer stage and the severity of adverse events, including hot flashes.

Conflicts of interest

All Authors declare that there is no conflict of interest in relation to this article and that there was no financial support for the present research.

References

1 Cancer Registration Committee of the Japanese Urological Association: Clinicopathological statistics on registered prostate cancer patients in Japan: 2000 report from the Japanese Urological Association. Int J Urol 12: 46-61, 2005. 2 Saylor PJ and Smith MR: Adverse effects of androgen deprivation therapy: Defining the problem and promoting health among men with prostate cancer. J Natl Compr Canc Netw 8: 211-223, 2010. 3 Cheung AS, Pattison D, Bretherton, Hoermann I, Joon LD, Ho E, Jenkins T, Hamilton EJ, Bate K, Chan I, Zajac JD and Grossmann M: Cardiovascular risk and bone loss in men undergoing androgen deprivation therapy for non-metastatic prostate cancer: implementation of standardized management guidelines. Andrology 1: 583-589, 2013. 4 Stearns V, Ullmer L, López JF, Smith Y, Isaacs C and Hayes D: Hot flushes. Lancet 360: 1851-1861, 2002. 5 Holzbeierlein JM, McLaughlin MD and Thrasher JB: Complications of androgen deprivation therapy for prostate cancer. Curr Opin Urol 14: 177-183, 2004. 6 Sakai H, Igawa T, Tsurusaki T, Yura M, Kusaba Y, Hayashi M, Iwasaki S, Hakariya H, Hara T and Kanetake H: Hot flashes during androgen deprivation therapy with - releasing hormone agonist combined with steroidal or antiandrogen for prostate cancer. Urology 73: 635- 640, 2009. 7 Barradell LB and Faulds D: Cyproterone. A review of its pharmacology and therapeutic efficacy in prostate cancer. Drugs Aging 5: 59-80, 1994. 8 Migliari R, Muscas G, Murru M, Verdacchi T, De Benedetto G and De Angelis M: Antiandrogens: a summary review of pharmacodynamic properties and tolerability in prostate cancer Figure 3. Cancer-specific survival (A) and overall survival (B) of M0 therapy. Arch Ital Urol Androl 71: 293-302,1999. patients (n=102). No significant survival differences were observed 9 Prostate Cancer Trialists’ Collaborative Group: Maximum between groups. androgen blockade in advanced prostate cancer: an overview of the randomised trials. Lancet 355: 1491-1498, 2000. 10 Ozono S, Okajima E, Yamaguchi A, Yoshikawa M, Iwai A, Conclusion Moriya A, Yoshida K, Samma S, Maruyama Y and Hirao Y: A prospective randomized multicenter study of versus flutamide in total androgen blockade for prostate Our results suggest that CAB therapy using chlormadinone cancer. Jpn J Clin Oncol 30: 389-396, 2000. leads to significantly poorer survival outcomes in patients 11 Gillatt D: Antiandrogen treatments in locally advanced prostate with advanced metastatic prostate cancer compared to CAB cancer: are they all of the same? J Cancer Res Clin Oncol therapy using bicalutamide. However, this survival trend 132(Suppl 1): S17-S26, 2000.

1987 ANTICANCER RESEARCH 34: 1983-1988 (2014)

12 Hinotsu S, Akaza H, Usami M, Ogawa O, Kagawa S, Kitamura 16 Samson DJ, Seidenfeld J, Schmitt B, Hasselblad V, Albertsen T, Tsukamoto T, Naito S, Namiki M, Hirao Y, Murai M and PC, Bennett CL, Wilt TJ and Aronson N: Systematic review and Yamanaka H: Current status of endocrine therapy for prostate meta-analysis of monotherapy compared to combined androgen cancer in Japan analysis of primary androgen deprivation therapy blockade for patients with advanced prostate carcinoma. Cancer on the basis of data collected by J-CaP. Jpn J Clin Oncol 37: 95: 361-376, 2002. 775-78, 2007. 17 Kobayashi M, Nukui A, Suzuki K, Kurokawa S and Morita T: 13 Akaza H, Hinotsu S, Usami M, Arai Y, Kanetake H, Naito S and Clinical efficacy of primary combined androgen blockade for Hirao Y: Combined androgen blockade with bicalutamide for Japanese men with clinically localized prostate cancer unsuitable advanced prostate cancer: long-term follow-up of a phase 3, double- for local definitive treatment: a single institution experience. Int blind, randomized study for survival. Cancer 115: 3437-3445, 2009. J Clin Oncol 16: 630-636, 2011. 14 Schröder FH, Whelan P, de Reijke TM, Kurth KH, Pavone- Macaluso M, Mattelaer J, van Velthoven RF, Debois M and Collette L: Metastatic prostate cancer treated by flutamide versus cyproterone acetate. Final analysis of the “European Organization for Research and Treatment of Cancer” (EORTC) Protocol 30892. Eur Urol 45: 457-464, 2004. 15 Thorpe SC, Azmatullah S, Fellows GJ, Gingell JC and O’Boyle PJ: A prospective, randomised study to compare acetate (Zoladex) versus cyproterone acetate (Cyprostat) versus Received January 10, 2014 a combination of the two in the treatment of metastatic prostatic Revised February 9, 2014 carcinoma. Eur Urol 29: 47-54, 1996. Accepted February 10, 2014

1988