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; 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

2Division

Abstract. Aim: To determine the treatment outcome of combined androgen blockade (CAB) therapy using the nonsteroidal antiandrogen bicalutamide or the steroidal antiandrogen chlormadinone in patients with prostate cancer. Patients and Methods: In total, 124 patients with prostate cancer enrolled in the present study were randomized to receive CAB therapy using a gonadotropin-releasing hormone (GnRH) agonist, combined with bicalutamide or chlormadinone. The survival of patients was analyzed. Results: The 5-year cancer-specific survival for the bicalutamide- and chlormadinone-treated groups were 91.7% and 86.6%, respectively, with no significant difference (p=0.39). Five-year overall survival was significantly (p=0.029) better in the bicalutamide-treated group. Moreover, M1 patients in the chlormadinone group had significantly lower cancer-specific and overall survival compared to those in the bicalutamidetreated group. However, in the case of M0 patients, no significant difference in cancer-specific nor in overall survival was observed. Conclusion: CAB therapy using chlormadinone led to a significantly poorer survival outcome versus the use of bicalutamide. However, because this survival trend was not observed in M0 cases, chlormadinone may still be an option for CAB therapy, depending on clinical stage and the severity of adverse effects, such as hot flashes.

Correspondence to: Tsukasa Igawa, Department of Nephro-urology, Nagasaki University Graduate School of Biomedical Sciences, 1-71, Sakamoto, Nagasaki 852-8501, Japan. Tel: +81 958197340, Fax: +81 958197343, e-mail: [email protected] Key Words: Prostate cancer, combined androgen blockade, antiandrogen.

0250-7005/2014 $2.00+.40

Androgen deprivation therapy (ADT) has been the mainstay of treatment for managing advanced prostate cancer. However, an increase in earlier diagnosis of this disease has led to increasing ADT use in men with non-metastatic disease or with recurrence after definitive therapy, i.e. prostatectomy or radiation therapy. Thus, a significant proportion of patients with prostate cancer have received ADT even in Western countries, and especially in Japan (1). Hence, the management of patients who have received ADT is an important issue. One aspect of this issue is the management of adverse effects of ADT e.g. loss of libido, increased cardiovascular disease risk, liver dysfunction, bone loss, and so forth (2, 3). Among these adverse events, hot flashes have elicited concern as a factor that lowers patients’ quality of life (QOL) (4, 5). In this regard, we previously conducted a randomized prospective study of hot flashes and QOL during combined androgen blockade (CAB) therapy using the non-steroidal antiandrogen bicalutamide or the steroidal antiandrogen chlormadinone, and found fewer and less-distressing hot flashes in the group of patients using chlormadinone (6). Interestingly, similar results have been reported from Western countries using the other steroidal antiandrogen, cyproterone acetate, with a lower incidence of hot flashes compared to castration-alone or with castrationplus-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 have reported delay in disease progression or conferring survival advantage in CAB therapy with a non-steroidal antiandrogen compared to CAB with cyproterone acetate (9). However, this finding in Japanese patients with prostate cancer has not been fully-investigated. Only a few reports are available concerning the short-term outcome of CAB therapy

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ANTICANCER RESEARCH 34: 1983-1988 (2014) using chlormadinone. One randomized prospective study from Japan showed similar short-term (24 weeks) objective responses between CAB with flutamide and CAB with chlormadinone (10). In our previous study, we also observed no significant difference between the two groups with respect to 2-year progression-free survival. Given this background, aiming to confirm the oncological outcomes of CAB therapy with bicalutamide or chlormadinone, we analyzed the longerterm survival status of the patients enrolled in our study.

Patients and Methods The detailed design of the original prospective study was described previously (6). Briefly, in total, 151 patients with histologicallyconfirmed prostate cancer, including both localized and metastatic disease, were enrolled from May 2001 to June 2003. These patients were randomized to receive CAB therapy using a gonadotropinreleasing hormone (GnRH) agonist (leuprorelin) combined with bicalutamide or chlormadinone. A 3.75 mg depot of leuprorelin was administered subcutaneously once every four weeks, and 100 mg chlormadinone or 80 mg bicalutamide was given daily. The primary end-points of the original study were the incidence, frequency, and severity of hot flashes and the QOL during treatment. After exclusion of ineligible patients, data were available for analysis from 124 patients (bicalutamide group: 64 patients, chlormadinone 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 current study, we conducted a cross-sectional analysis of patient survival in 2011. Patients’ data on treatment outcome were collected from each participating Institution, and overall survival (OS) and cancer-specific survival (CSS) of these patients were analyzed by Kaplan−Meier survival analysis with log-rank tests. The prognostic significance of various factors was assessed using the Cox proportional hazards regression model. The Clinical Trial Review Committee of Nagasaki Prostate Cancer Research Group and the institutional review board of each participating institution approved the study protocol (approval number: 10012250). Statistical analyses were performed using the SPSS software ver. 20 (IBM Co., Ltd. New York. United States), and p-values of less than 0.05 were considered to indicate statistical significance.

Results Patients’ characteristics from all 124 cases analyzed in a previous study are presented in Table I. Between the two groups, no statistically significant differences were found in the background variables. The median follow-up period of all 124 patients was 78.9±31.6 months. During follow-up, 22 (17.7%) patients died, including 8 due to prostate cancer (bicalutamidetreated group: 3 cases, chlormadinone-treated group: 5 cases) and 14 due to other causes (bicalutamide-treated group: 4 cases, chlormadinone-treated group: 10 cases). Overall, the 5year CSS of the bicalutamide-treated and chlormadinonetreated groups was 91.7% and 86.6%, respectively, with no significant differences between groups (p=0.39, Figure 1A).

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Table I. Baseline characteristics of eligible patients

Age (years) Median Mean±SD Performance status 0-1 2-3 TNM classification T1-2N0M0 T3-4N0M0 N1M0 M1 Histological grade 1 2 3-4 Serum PSA (ng/mL) Median Mean±SD Comorbid disease Absent Present

Chlormadinone (n=60)

Bicalutamide (n=64)

74.2 74.6±6.9

75.7 74.8±5.7

59 (98.3) 1 (1.7)

62 (96.9) 2 (3.1)

27 19 6 8

24 24 2 14

p-Value

0.88

0.60

0.23 (45.0) (31.7) (10.0) (13.3)

(37.5) (37.5) (3.1) (21.9) 0.30

15 (25.0) 28 (46.7) 17(28.3)

10 (15.6) 38 (59.4) 16 (25.0)

22.8 103.7±171.1

29.8 135.4±476.0

0.62

39 (65.0) 21 (35.0)

47 (73.4) 17 (26.6)

0.31

PSA: Prostate specific antigen.

However, 5-year OS in all cases was significantly better (p=0.029) in the bicalutamide-treated group (91.7%) compared to that in the chlormadinone-treated group (79.2%, Figure 1B). We subsequently analyzed the impact of several clinicopathological factors on the CSS and OS in these 124 patients (Table II). Univariate analysis showed that histological grade, clinical stage, and presence of bone metastasis were significant predictors of CSS, while the presence of bone metastasis was associated with OS. However, only the presence of bone metastasis appeared to have an independent impact on both CSS and OS. Although the type of antiandrogen was not associated with patient survival, the chlormadinone-treated group showed a tendency for poorer OS. According to these predictors of survival, we analyzed the survival data of the sub-groups of patients with and without bone metastasis. As shown in Figure 2, patients in the chlormadinone-treated group with distant metastasis (M1) had significantly poorer CSS (p=0.019) and OS (p=0.007) versus the bicalutamide-treated group. On the other hand, after excluding M1 cases, there was no significant difference in CSS or OS between the groups (Figure 3).

Discussion In our original prospective study, we determined that fewer and less-distressing hot flashes were induced by CAB using a steroidal antiandrogen such as chlormadinone, rather than

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 Univariate analysis

Age (years) (