Japanese Journal of Clinical Oncology 30:389-396 (2000)
© 2000 Foundation for Promotion of Cancer Research
A Prospective Randomized Multicenter Study of Chlormadinone Acetate versus Flutamide in Total Androgen Blockade for Prostate Cancer
+Department of Urology, Nara Medical University, Nara, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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Background: A randomized multicenter study was conducted to investigate the efficacy of total androgen blockade (TAB) for patients with previously untreated prostate cancer using the steroidal anti-androgen chlormadinone acetate (CMA) and the non-steroidal anti-androgen flutamide. We also compared the liver dysfunction in these two arms.
Methods: From November 1995 to October 1997, 71 patients were registered into this study and 70 of them were eligible.
Results: There was no significant difference in the efficacy of TAB between CMA and flutamide at 24 weeks. The testosterone and prostate-specific antigen (PSA) levels in patients administered flutamide (Group II) increased significantly 3 days after the first dose of LH-RH analog, whereas no such increase was observed in patients administered CMA (Group I), indicating that CMA prevented the flare-up. Parameters of liver function, serum GOT and GPT levels, which were normal at the baseline, became abnormal in 30.0% and 35.3%, respectively, of patients in Group II. These figures were significantly higher than the corresponding figures of 6.3% and 12.5%, respectively, in Group I. When the degree of change in each of these parameters was analyzed, both GOT and GPT levels showed a significantly greater increase in Group II than in Group I.
Conclusion: These results indicate that attention must be paid to changes in liver function during the administration of flutamide in patients with prostate cancer even if their baseline liver function is normal. It is also suggested that CMA may be better tolerated from the viewpoint of the drug effects on liver function.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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Hormone therapy for prostate cancer, an androgen-dependent tumor, has been a subject of research and practiced over the past half-century (1). Today, the mainstay of treatments for prostate cancer is total androgen blockade (TAB). This hormonal therapy is aimed at eliminating testis-derived testosterone and blocking the action of adrenal androgen. TAB consists of surgical castration or medical castration by a luteinizing hormone-releasing hormone (LH-RH) analog and the use of an anti-androgenic agent to inhibit the actions of adrenal androgen mediated via androgen receptors in prostate cells. In Japan, the anti-androgens available include the steroidal anti-androgen chlormadinone acetate (CMA) and the non-steroidal anti-androgens flutamide and bicalutamide. All of these are known to inhibit the binding of androgen to androgen receptors.
The present comparative study was conducted to investigate the endocrine profiles, tumor response and adverse events, particularly on liver function, of LH-RH analog therapy combined with CMA or flutamide in patients with previously untreated prostate cancer.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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The subjects were patients with previously untreated prostate cancer which was histopathologically diagnosed as stage B to D primary prostate adenocarcinoma, recruited from the Department of Urology, Nara Medical University and affiliated hospitals (Appendix 1) between November 1995 and October 1997.
The inclusion criteria were as follows: (1) previously untreated prostate cancer, Stage B, C or D; (2) histologically defined prostate cancer; (3) not feasible for radical prostatectomy; (4) presence of measurable or evaluable lesions; (5) prospect of at least 3 months survival; (6) grade 0–3 (including apparent grade 4 due to bone metastasis, etc.) of Eastern Cooperative Oncology Group performance status (P.S.); (7) age under 80 years. The exclusion criteria were as follows: (1) active double cancer; (2) baseline serum testosterone level of <1.0 ng/ml; (3) history of anti-androgen treatment for benign prostatic hyperplasia in the past year; (4) serious cardiac, hepatic or renal complications; (5) history of hypersensitivity to anti-androgens, synthetic LH-RH or LH-RH analogs; (6) unfit to participate in the study as judged by the physician-in-charge.
All eligible patients were informed of (1) the purpose and method of the study, (2) the possible beneficial and adverse effects, (3) availability and details of other treatments for the disease, (4) freedom to refuse to participate in the study, (5) freedom to withdraw consent at any time even if it has already been given and (6) relevant matters concerning personal rights. After obtaining informed consent, these patients were registered using a central facsimile system. The study was a multicenter study in which the patients were randomized into two groups: (1) LH-RH analog with CMA (50 mg twice daily) (Group I) or (2) LH-RH analog with flutamide (125 mg three times daily) (Group II). The endocrine profiles, tumor response and adverse events, in particular on the liver function, were investigated until the end-point of the study, i.e. 24 weeks after the beginning of treatment. The LH-RH analog used was leuprolide acetate (3.75 mg every 4 weeks) or goserelin acetate (3.6 mg every 4 weeks).
Among the items evaluated, the endocrine profile in terms of the luteinizing hormone (LH) and testosterone levels were determined before treatment and 3 days and 1, 4, 8, 12 and 24 weeks after the beginning of treatment. Tumor response was determined 12 and 24 weeks after the beginning of treatment in terms of changes in the extent of evaluable lesion, primary prostate lesion, bone metastases, prostate-specific antigen (PSA) and soft tissue metastases according to the Japanese Response Criteria for evaluation of clinical efficacy in prostate cancer. For investigation of the adverse events, the severity of the signs and symptoms of possible adverse events observed after the beginning of treatment were examined based on the criteria for evaluation of drug adverse reactions prescribed by the Japan Society of Clinical Oncology (JSCO). In particular, liver function parameters were determined before treatment and 4, 8, 12 and 24 weeks after the beginning of treatment. To preclude inter-facility differences, the levels of LH, testosterone and PSA were measured exclusively at the Special Reference Laboratory (SRL, Tokyo).
The validity of the above evaluations was reviewed for each individual case by the Protocol Committee of the TAB Study Group.
For statistical analysis, biases in the characteristics of the patients were tested by a two-sample t-test, Mann–Whitney test, Fisher’s exact test or chi-squared test according to the type of data. Changes in the clinical and laboratory parameters (comparison with the baseline or day 0) were analyzed by a paired t-test or Wilcoxon one-sample test and differences in the objective response between the two groups were analyzed by the Mann–Whitney test at a two-sided p value of 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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Seventy-one patients were registered, but one of them was subsequently excluded because of previous treatment; therefore, 70 patients were eligible comprising 34 in Group I and 36 in Group II. Table 1 shows the characteristics of these eligible patients. There were no significant differences in any item between the two groups. There were two cases of withdrawal due to adverse events and three drop-out cases in Group I and six cases of withdrawal due to adverse events and two drop-out cases in Group II. Therefore, the number of patients evaluated for tumor response was 29 in Group I and 28 in Group II. The safety of treatment was evaluated in 35 patients in Group I, including the patients excluded for the aforementioned reasons, and 36 patients in Group II.
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Absolute Values of Serum LH, Testosterone and PSA
Figure 1 shows a summary of serum LH, testosterone and PSA levels of the patients evaluated during the whole 24 weeks.
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The serum LH level increased significantly from 8.9 ± 9.1 mIU/ml on day 0 to 17.3 ± 16.3 mIU/ml on day 3 (p < 0.01) in Group I, but decreased thereafter. Similarly in Group II, the serum LH level significantly increased from 9.5 ± 9.2 mIU/ml on day 0 to 17.5 ± 12.5 mIU/ml on day 3 (p < 0.01), but decreased thereafter.
The serum testosterone levels on day 0 (495.1 ± 186.5 ng/dl) and day 3 (552.6 ± 181.4 ng/dl) were similar (p = 0.1209) in Group I, whereas there was a significant increase in this parameter (p < 0.01), from 506.0 ± 149.5 ng/dl on day 0 to 717.8 ± 242.7 ng/dl on day 3, in Group II. Serum testosterone decreased to castration levels in both groups at 4 weeks.
The PSA levels on day 0 (183.9 ± 105.2ng/ml) and day 3 (150.0 ± 80.8 ng/dl) were similar (p = 0.1882) in Group I, whereas there was a significant increase in this parameter (p < 0.05), from 182.8 ± 99.3 ng/dl on day 0 to 204.6 ± 123.1 ng/dl on day 3, in Group II and they decreased in both groups thereafter.
Tumor Response
Since the end-point of the present study was 24 weeks after the beginning of treatment, objective response was assessed at 12 weeks only in those subjects in whom any objective parameters were evaluated. As can be seen in Table 2, excluding the serum PSA response at 12 weeks, there was no significant difference between the two groups of patients with regard to the primary lesion, bone metastases, soft tissue metastases and PSA levels.
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The response rate (PR or better) on overall evaluation at 12 weeks was 90.0% in Group I and 78.9% in Group II and there was no significant difference in the response (p = 0.2223). The response rate at 24 weeks was 87.5 and 86.4% in groups I and II, respectively, which were not significantly different (p = 0.6726).
When the results of overall evaluation in the two groups were compared in relation to the grade of histological differentiation of the tumor, no difference was found at any time point of evaluation.
Adverse Events
Adverse events were seen in 12 (34.3%) of 35 patients in Group I and in 23 (63.9%) of 36 patients in Group II (p = 0.0126) during the treatment (Table 3). Attention was focused on the effects of the two treatments on the liver function in the present study and liver dysfunction was found frequently in both Group I (eight cases, 22.9%) and Group II (15 cases, 41.7%). Other significant adverse events including diarrhea (two cases) and hot flushes, specifically facial hot flushes (one case), profuse sweating (one case) and feeling of warmth (one case), were seen in Group II.
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Liver Function
The serum GOT, GPT, Al-P and total bilirubin levels were classified into grades 0–4 according to the JSCO criteria for the evaluation of adverse drug reaction. The proportion of patients with worsening to grade 1 or worse among those who were grade 0 on day 0 were compared between the two groups. These patients were not given any specific drugs to improve the liver function during the treatment period.
Worsening of serum GOT to grade 1 or worse was found in two (6.3%) of 32 patients in Group I and in 10 (30.3%) of 33 patients in Group II, the difference between the two groups being significant (p = 0.0125). Similarly, increased serum GPT was noted significantly more frequently in Group II (12/34, 35.3%) than in Group I (4/32, 12.5%) patients (p = 0.0308). There was no significant difference in the incidence of worsening of serum Al-P between Group I (8.7%) and Group II (10.0%). No worsening of serum total bilirubin to grade 1 or worse was found in any patient of either group. Grade 2 GPT was found in four patients and grade 2 Al-P in one patient in Group II, whereas no such cases were found in Group I (Table 4).
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Figure 2 shows the degree of changes in the serum GOT and GPT levels at each measurement point. Relative values were used for intergroup comparisons and absolute values were used for intragroup comparisons. To ensure precise observation of the time course of the changes, only patients in whom measurements could be performed almost completely consistent with the schedule were included in this analysis. Data from 32 and 30 patients in Groups I and II, respectively, were used for the analysis of GOT and those from 30 and 31 patients in Groups I and II for GPT. Patients with increased GOT levels were found in Group II at 8 and 12 weeks, whereas no patients with increased GOT were found in Group I. The GOT levels were significantly higher in Group II than in Group I at all the measurement points (p < 0.05). In addition, there was a significant increase in the serum GPT levels at 8, 12 and 24 weeks in Group II and at 8 and 12 weeks in Group I. The GPT levels were significantly higher in Group II than in Group I at 12 and 24 weeks (p = 0.0291, p = 0.0217).
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, p < 0.05; 
, p < 0.01 in the two-sample t-test (Group I vs II).There were two cases of withdrawal due to liver dysfunction in Group I and six cases in Group II, which were judged by the individual physicians. However liver functions were recovered and normalized within 2–4 weeks in all those cases.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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The present study was conducted to compare the effects of two regimens, LH-RH analog with CMA (Group I) and LH-RH analog with flutamide (Group II). In addition, special attention was paid to the possible adverse events on the liver function. The overall response at 24 weeks was 87.5% in Group I and 86.4% in Group II (Table 2). However, there were notable differences in the endocrine profiles in the initial stage of treatment between the two groups (Fig. 1). There was a significant increase in the testosterone level in Group II after 3 days of treatment, whereas no increase was seen in Group I. It is well known that initial administration of LH-RH analogs is associated with a flare-up along with a transient rise of the testosterone level.
CMA exerts a negative feedback action on the hypothalamus–pituitary system as well as having an anti-androgenic action, thus inhibiting the production of testosterone in the testis (2). Taking advantage of this inhibitory effect of CMA, Shimada et al. (3) and Yamamoto et al. (4) induced a decrease in serum testosterone levels by preadministration of CMA for 2–4 weeks and thereby prevented flare-up. However, in our present study, no increase in the levels of testosterone or PSA was found in Group I, despite not employing preadministration. This may be explained by the negative feedback regulation by CMA, which might have provided a mild inhibition of LH even in the situation of coadministration. With regard to the finding that CMA inhibited the biosynthesis of testosterone in male rat testes (2), further research is required to elucidate the mechanism of the inhibition.
The results of a number of large-scale, prospective randomized studies on the efficacy of TAB using flutamide have been reported. The 1998 final report of the European Organization for Research and Treatment of Cancer (EORTC) 30853 trial (5) documented that goserelin acetate with flutamide was significantly superior to surgical castration in patients with metastatic prostate cancer, in terms of the overall and progression-free survival. The Southwest Oncology Group (SWOG) (6) in 1989 also reported that leuprolide acetate with flutamide was significantly more effective than leuprolide acetate with a placebo, in terms of progression-free survival. However, the 1998 SWOG report (7) claimed that surgical castration with flutamide was not superior to surgical castration with placebo.
Thus, the efficacy of TAB remains controversial, and a meta-analysis of these studies has been published. The Prostate Cancer Trialists’ Collaborative Group (PCTCG) (8) analyzed the results of 22 trials and did not support the usefulness of TAB. However, Caubet et al. (9) carried out a meta-analysis of trials using non-steroidal anti-androgens alone and reported the significant usefulness of TAB. Thus, although no definite conclusion can be arrived at yet, it is likely that TAB using non-steroidal anti-androgens is useful.
In the present study, the PSA response at 12 weeks was significantly worse in Group I (p = 0.0416), whereas no significant difference was observed at 24 weeks. Horiguchi et al.(10) reported that PSA values at the early stage of hormone therapy provide important prognostic information, so that careful long-term follow-up should be required. On the other hand, Akaza et al. (11) reported data from a 2-year randomized study comparing leuprolide acetate monotherapy and leuprolide acetate with CMA in patients with non-metastatic prostate cancer. They found that leuprolide acetate with CMA was significantly more effective than leuprolide acetate monotherapy. Long-term data from the extended study have yet to be published. Unfortunately there was no investigation to compare the effects of CMA alone and LH-RH analog, but there has been a randomized study to compare goserelin acetate versus cyproterone acetate versus combination of the two drugs. In this study, Thorpe et al. (12) reported that there was no significant difference in terms of median time to progression between the TAB and either monotherapy, although there was a significant difference between goserelin acetate alone and cyproterone acetate alone, in favor of goserelin acetate.
A main purpose of the present study was to determine the effects of the two regimens on the liver function. Close observation of the liver function parameters revealed a high frequency of liver dysfunction, detected as adverse events, i.e. 22.9% in Group I and 41.7% in Group II. When patients who showed normal liver function parameters at the baseline were included in the analysis, the GOT and GPT levels were found to be increased to a significantly greater extent in Group II than in Group I. When the changes in these enzymes levels over the treatment period were analyzed in detail (Fig. 2), both GOT and GPT levels showed a significant increase in Group II. These results confirm that close monitoring of liver function is necessary during flutamide therapy even when the patient has normal baseline liver function. Recently, monthly check-up of liver function has been recommended for flutamide-administered patients. The cost of CMA is lower than that of flutamide, therefore CMA is superior to flutamide in cost-effectiveness with regard to liver function tests.
Since the daily dose of flutamide used in Japan (375 mg/day) is half of that used elsewhere (750 mg/day), diarrhea, which is an extremely frequent adverse event of flutamide overseas, is infrequent in Japan (13). This may indicate that using half the standard dose used overseas is of no consequence from the aspect of liver dysfunction, when comparing the numbers of deaths in the two areas based on the size of the patient population given flutamide therapy. In other words, it is possible that there are race-related differences in the toxicity of flutamide to liver cells.
Other adverse events noted in this study included hot flushes in two (5.6%) (facial hot flushes and feeling of warmth) in Group II, but none in Group I. While Buchholz et al. (14) indicated that hot flushes occur frequently after surgical castration, the hot flushes seen in our study seem to be attributable to the activity of the LH-RH analogs. In Japan, Kotake et al. (15) reported that hot flushes occurred in 43.3% of patients who received goserelin acetate combined with bicalutamide. Schellhammer et al. (16) reported that the incidence of hot flushes was more than 50% among 409 patients who received LH-RH analog with flutamide and among 404 patients who received LH-RH analog with bicalutamide. Hence hot flushes seem to be common also with LH-RH analog therapy administered with a non-steroidal anti-androgen.
However, Thorpe et al. (17) found in a randomized study that the incidence of hot flushes was significantly lower with goserelin acetate + cyproterone acetate than with goserelin acetate monotherapy. Kramer et al. (18) also reported a preventive or therapeutic effect of cyproterone acetate therapy in the incidence of hot flushes and/or profuse sweating. The underlying mechanism could be explained as follows: under the circumstances of decreased testosterone levels after castration, the steroidal anti-androgen acts to inhibit a decrease in the level of endogenous opioid peptides (EOP). In addition, the mechanism of hot flushes is considered to be induced by the actions of catecholamines, such as norepinephrine in the hypothalamus, on the thermoregulatory system. The intracranial concentration of catecholamines is controlled by EOP such as endorphins under normal conditions. When the amount of circulating steroids decreases, the production of EOP in the hypothalamus also decreases, resulting in increased concentrations of catecholamines (14,19). It is considered that the administration of CMA, like cyproterone acetate and megestrol acetate, inhibits this decrease in the amount of steroids as a steroidal hormone.
Although there is a modest difference in PS between two groups, in favor of flutamide, there was no significant difference in clinical effects. In addition, the use of CMA for TAB may lead to the prevention of hepatic dysfunction and hot flushes and may be beneficial to improving patients’ quality of life in the treatment of prostate cancer. These results indicate that liver function should be monitored carefully during the administration of flutamide in patients with prostate cancer even if their baseline liver function is normal.
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APPENDIX |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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The members of the Nara Medical University TAB Study Group were as follows: Eigoro Okajima (Chairman), Nara Medical University; Yoshihiko Hirao*, Nara Medical University; Seiichiro Ozono*, Nara Medical University; Yoshiteru Kaneko, Nara Prefectural Nara Hospital; Soichi Ohara, Nara Prefectural Mimuro Hospital; Shoichi Tabata, Nara Prefectural Gojo Hospital; Osamu Natsume, Nara National Hospital; Kojiro Yoshida, Yamatotakada City Hospital; Shuji Watanabe, Saiseikai Chuwa Hospital; Hideo Aoyama, Saiseikai Nara Hospital; Shoji Samma*, Kokuho Chuo Hospital; Noboru Morita, Takai Hospital; Kazuya Hirao, Hirao Hospital; Yoshio Maruyama*, Matsusaka Chuo Hospital; Motoyoshi Yoshikawa, Okanami General Hospital; Tadashi Hiramatsu, Nissei Hospital; Shoichiro Ikuma, Osaka Kaisei Hospital; Kaoru Yamada, Hoshigaoka Koseinenkin Hospital; Akira Moriya, Asakayama Hospital; Tsutomu Shiomi, Bobath Memorial Hospital; Yoshiki Hayashi, Tane General Hospital; Akio Iwai*, Ishinkai Yao General Hospital; and Masayasu Tokizane, Tokizane Clinic (*Protocol committee member).
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FOOTNOTES |
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+ For reprints and all correspondence: Seiichiro Ozono, Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan. E-mail: ozn-kkr@nmu-gw.naramed-u.ac.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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1 Ozono S, Hirao Y. Total androgen blockade. Concept, theory, method and clinical application. Nihonrinsyo 1998;56:2129–34 (in Japanese).
2 Honma S, Ugi S, Iizuka K, Kambegawa A. The effects anti-androgenic anents on metabolism and biosynthesis of testosterone (I): Testosterone metabolic regulation in the liver and the biosynthesis in the testes on rats treated with chlormadinone acetate. Nippon Naibunpi Gakkai Zasshi 1977;53:703–18 (in Japanese).[Medline]
3 Shimada M, Uchida H, Kasahara T, Fuji K, Ogawa Y, Yoshida H, et al. Clinical study on chlormadinone acetate alone followed by combination with LH-RH analog for prostatic cancer: effects on lipid metabolism. Hinyokika Kiyo 1998;44:525–32 (in Japanese).[Medline]
4 Yamamoto A, Sumiyoshi Y, Miyake N, Yokozeki H, Kanayama H, Kagawa S. Pretreatment with chlormadinone acetate in prostate cancer patients treated with a luteinizing hormone-releasing hormone analogue. Hinyokika Kiyo 1998;44:557–63 (in Japanese).[Medline]
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6 Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989;321:419–24.[Abstract]
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12 Thorpe SC, Azmatullah S, Fellows GJ, Gingell JC, O’Boyle PJ. A prospective, randomized study to compare goserelin acetate (Zoladex®) versus cyproterone acetate(Cyprostat®) versus a combination of the two in the treatment of metastatic prostatic carcinoma. Eur Urol 1996;29:47–54.[Web of Science][Medline]
13 Akaza H, Usami M, Kotake T, Koiso K, Aso Y, The Japan Flutamide Study Group. A randomized phase II trial of flutamide vs chlormadinone acetate in previously untreated advanced prostatic cancer. Jpn J Clin Oncol 1993;23:178–85.
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16 Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, et al. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology 1997;50:330–6.[Medline]
17 Thorpe SC, Azmatullah S, Fellows GJ, Gingell JC, Boyle PJO. A prospective, randomised study to compare goserelin acetate (Zoladex 8) versus a combination of the two in the treatment of metastatic prostatic carcinoma. Eur Urol 1996;29:47–54.
18 Krämer P, Andrzefak NN, Kallischnigg G, Neumann F. Prevention of hot flushes with CPA in the hormonal treatment of prostatic cancer: results of a placebo-controlled double-blind trial. In: Murphy G, Khoury S, Chatelain C, Denis L, editors. 3rd International Symposium on Recent Advances in Urological Cancer Diagnosis and Treatment. Proceedings. Paris: Scientific Communication International Ltd 1992;111–5.
19 Radlmaier A, Bormacher K, Neumann F. Hot flushes: mechanism and prevention. In: Schröder FH, editor. EORTC Genitourinary Group Monograph 8. Treatment of Prostatic Cancer – Facts and Controversies: New York: Wiley-Liss 1990;131–40.
Received April 19, 2000; accepted July 7, 2000.
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