Japanese Journal of Clinical Oncology 30:131-136 (2000)
© 2000 Foundation for Promotion of Cancer Research
Early Results of LH-RH Agonist Treatment with or without Chlormadinone Acetate for Hormone Therapy of Naive Localized or Locally Advanced Prostate Cancer: A Prospective and Randomized Study
Department of Urology, 1Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, 2The University of Tokyo, Tokyo, 3Nihon University, Tokyo, 4Toranomon Hospital, Tokyo, 5Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 6Nara Medical University, Kashiwara, Nara, 7Okayama University, Okayama, 8Department of Epidemiology and Biostatistics, School of Health Sciences and Nursing, The University of Tokyo, Tokyo and 9Fujieda Municipal General Hospital, Fujieda, Shizuoka, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Background: The majority of patients with localized and some cases of locally advanced prostate cancer undergo radical prostatectomy. However, radical prostatectomy cannot always be selected for those patients. In this situation, primary hormone therapy is an alternative treatment option. We have designed a prospective randomized study of the effects of primary hormone therapy for such patients.
Methods: A total of 151 patients with T1b, T1c, T2a, T2b or T3a prostate cancer who were not scheduled for radical prostatectomy were enrolled into this study. Patients were randomly allocated into two groups; Group I received luteinizing hormone-releasing hormone (LH-RH) agonist monotherapy (leuprorelin acetate depot, 3.75 mg monthly) and Group II received LH-RH agonist in combination with chlormadinone acetate (100 mg/day). Effects on serum prostate-specific antigen level, progression-free survival and survival were observed for 2 years.
Results: The reasons why radical prostatectomy was not scheduled were poor risk for surgery (38%), patient’s wish (32%) and physician’s recommendation (30%). After 12 weeks of treatment, 49% of the patients in both groups showed a complete response (CR). Of the patients showing a partial response (PR) after 12 weeks of treatment, 25% in Group I and 52% in Group II improved to CR 1 year later (p < 0.05). Group II showed a longer progression-free survival (p < 0.05). Progression-free survival rates were 62% (Group I) and 91% (Group II) in T2b patients and 43% (Group I) and 73% (Group II) in T3 patients. Only one patient in each group died from prostate cancer.
Conclusions: Early primary hormone therapy is a reasonable treatment option for localized or locally advanced prostate cancer patients if radical prostatectomy was not scheduled. Chlormadinone acetate showed an additive effect with LH-RH agonist, at least in 2 years’ observation.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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In recent years, the aging of the Japanese population and changes in the Japanese lifestyle have been associated with an increase in the number of patients with prostate cancer. At the same time, the development and wide use of diagnostic NStechnology including prostate-specific antigen (PSA), transrectal ultrasonography (TRUS) and systematic biopsy have led to an increase in the rate of early cancer diagnosis. Although radical prostatectomy is considered the ‘gold standard’ for the treatment of localized and some cases of locally advanced prostate cancer, there are instances in which radical prostatectomy is not an option, sometimes because the patient is a poor risk for surgery and sometimes owing to the wishes of the patient. In such cases, other treatment options include radiation therapy, hormone therapy, careful observation or combination therapy with these methods. Decisions regarding treatment must be made on an individual basis, with consideration for the patient’s life expectancy and quality of life (QOL), as well as the patient’s wishes.
Hormone therapy for prostate cancer generally involves monotherapy with luteinizing hormone-releasing hormone (LH-RH) agonist or a combination of LH-RH agonist and antiandrogen therapy, also termed maximum androgen blockade (MAB). Although a number of authors have reported on the effect of hormone therapy in advanced prostate cancer, few reports are available on the therapeutic effect of applying this treatment regimen to localized or locally advanced prostate cancer (1–7).
In 1993, we began a randomized controlled study comparing LH-RH agonist monotherapy with LH-RH agonist concomitant with the steroidal antiandrogenic agent chlormadinone acetate (CMA) on patients with prostate cancer who were not scheduled for radical prostatectomy for some reason. Our objective was to investigate the effect of hormone therapy on localized or locally advanced prostate cancer. We report here our data for the 2-year follow-up.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patient Enrollment
Patients with T1b, T1c, T2a, T2b or T3 prostate cancer who were not scheduled for radical prostatectomy were enrolled. Cancer stages were determined using biopsy, ultrasonography or computed tomography (CT) and bone scintigraphy or CT was performed to determine the absence of distant metastasis before enrollment. The pretreatment examinations confirmed a serum testosterone level of at least 1 ng/ml and a performance status of grade 0–3. Written consent to participate in this study program was obtained from all patients prior to initiation of the study.
Between February 1993 and March 1995, 178 patients were enrolled at the participating institutions. These patients were randomly allocated into two groups. Group I received LH-RH agonist monotherapy (leuprorelin acetate depot, 3.75 mg monthly). Group II was treated with LH-RH agonist in combination with CMA (100 mg/day). The dynamic balancing method was employed at the time of randomization to ensure an equal distribution of the cases between the two groups with regard to cancer stage and grade of histological differentiation.
Of the 90 patients allocated to Group I, four were ineligible (double enrollment in one case and a serum testosterone level <1 ng/ml in three cases) and there were 13 cases with a protocol violation (concomitant use of CMA in eight cases, discontinuation of administration at the first dose because of adverse reaction in one case, discontinuation of administration at the third dose due to stroke in one case and suspension of the treatment at the request of the patient in three cases). Of the 88 patients allocated to Group II, two were found to be ineligible (concurrent development of carcinoma of the sigmoid colon in one case and a serum testosterone level <1 ng/ml in one case) and there were eight cases of protocol violation (no concomitant use of CMA in two cases, discontinuation of administration at the first dose because of adverse reactions in two cases and suspension of the treatment at the request of the patient in four cases). Exclusion of these patients left 73 patients in Group I and 78 in Group II for analysis.
Laboratory Studies
The Delfia PSA test was used to measure serum PSA levels before the start of treatment, at 1, 2, 4, 8 and 12 weeks after the start of treatment and then at 3-month intervals after the twelfth week. Testosterone levels were measured, two-dimensional measurements using TRUS or CT were made of the primary prostate lesion and techniques such as radiography, bone scintigraphy or CT were used to determine distant metastasis. Serum PSA levels and testosterone levels were determined in batch measurements by SRL (Hachioji, Japan).
Antitumor Effects
Antitumor effects were evaluated according to the ‘General Rules for Clinical and Pathological Studies on Prostatic Cancer’ (2nd edition) (8). Criteria for PSA level were defined as below; complete response (CR), abnormal pretreatment PSA level returned to normal level (<1.98 ng/ml); partial response (PR), 
50% improvement of abnormal pretreatment PSA level, but not decreased to normal level; no change (NC), <50% improvement or <25% aggravation of abnormal pretreatment PSA level; and progressive disease (PD), 25% increase of abnormal pretreatment PSA level or normal pretreatment PSA level became abnormal level.
Recurrence
Image findings which confirmed distant metastasis, an increase in PSA level of at least 25% in comparison with nadir values over the course of observation or an increase over the course of observation of at least 25% in two-dimensional measurements of the primary prostate lesion in comparison with nadir values indicated recurrence.
Statistical Analysis
Patient characteristics between the groups were tested using the Student’s t-test or the Mann–Whitney U test, depending on the data type. The antitumor effects between the groups were tested using the Mann–Whitney U test. Analysis of survival and progression-free survival was performed using the Kaplan–Meier method and the results were tested using the log rank test and the generalized Wilcoxon test. The level of significance was set at 5%.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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The characteristics of the patients in the two study groups are shown in Table 1. The mean patient age was 76.1 years in Group I and 75.2 years in Group II. There were insignificant increases in the numbers of patients with stage T2b disease in Group I and in stage T3 patients in Group II and there were slightly more poorly differentiated tumors in Group II patients. Although the pretreatment PSA levels were lower in Group I patients, there was a wide range in PSA levels in Group II patients which gave a large standard deviation, negating any statistical analysis between the two groups. Also, approximately two-thirds of patients were enrolled into either group because they were either a poor risk for surgery or on the recommendation of their physicians (Table 2).
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After 12 weeks of treatment, CR according to PSA level was observed in 49.3 and 49.3% and PR in 50.7 and 49.3%, for Group I and II patients, respectively. There was no significant difference between the two groups. Among patients who had CR after 12 weeks of the treatment, the CR findings were sustained 1 year later in >80% of patients in either treatment group. However, of the patients showing PR after 12 weeks of the treatment, 25.7% in Group I and 52.9% in Group II improved to CR 1 year later (p < 0.05). Similarly, Group II patients with PR at 12 weeks of the treatment also showed a significantly higher rate of improvement to CR after 2 years (p < 0.05; Table 3).
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The progression-free survival after 2 years showed that there was a significantly lower rate of recurrence in Group II patients (Fig. 1). When the patient data were stratified by pretreatment clinical stage, the progression-free survival showed a significantly lower rate of recurrence in Group II for T2b patients. The 2 year progression-free survival rates in Group I and II were 87 and 87% for T1b,c, 66 and 57% for T2a, 62 and 91% for T2b and 43 and 70% for T3, respectively (Fig. 2).
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Five patients in Group I and seven patients in Group II died during the course of the study, but there was only one death in each group from prostate cancer, with no significant difference noted between the two groups with regard to cause-specific survival.
Twenty-three patients in Group I and 21 patients in Group II showed various adverse drug reactions such as an elevation of serum transaminase level, feeling hot or fatigue, but there were no severe adverse drug reactions.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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The results of studies on radical prostatectomy have shown a 10-year biochemical failure-free survival rate of 70% and a 15-year cause-specific survival rate of ~90% (9–11), and radical prostatectomy could be considered as the first-choice option for localized prostate cancer. However, in elderly patients whose expected lifespan is <10 years and in patients with elevated PSA levels, in whom suspected extracapsular invasion makes radical surgery problematic, other options are desirable.
In the present study, radical prostatectomy was not performed because ~40% of these subjects were considered a poor risk for surgery, while patient’s wishes and physician’s recommendations accounted for another 30% each. Concurrent with this study, we also undertook a trial involving preoperative androgen deprivation in radical prostatectomy at the same participating institutions (12,13). However, when we compared patients’ characteristics, we found that in the present study, the patients were on average 10 years older, T3 cases made up a larger proportion of the total study population and the PSA values were higher. An advanced patient age, with a relatively short remaining lifespan and the likelihood of advanced prostate cancer, were considered the major reasons for selecting hormone therapy by each physician.
In this study, no difference was noted between the two groups regarding the rate of PSA improvement after 12 weeks of treatment, but after 1 and 2 years, the CR rate was higher in Group II patients. These findings suggest that although treatment with the LH-RH agonist produced a rapid improvement in PSA level, this improvement was maximized relatively early with monotherapy, whereas long-term concomitant treatment with CMA yielded further PSA improvement. There were also significantly fewer recurrences in Group II patients, suggesting that the concomitant use of CMA and LH-RH agonist can satisfactorily provide local control of prostate cancer.
Stratification by clinical stage showed no significant difference between the two groups in progression-free survival for stages T1 or T2a, but the recurrence rate was significantly lower in Group II for stages T2b and T3a. However, the results of a postoperative histopathological diagnosis following radical prostatectomy in our other trial as described above showed that of patients with a preoperative diagnosis of T1c or T2N0, 47% were postoperatively found to be pT3 and 19% were pN+, while a postoperative diagnosis of pN+ was found in 61% of cases diagnosed preoperatively as T3N0. These findings indicate a high incidence of preoperative understaging (12). In the present study, it was assumed that there were also some latent cases of pN+. For such patients, we believe that LH-RH agonist-induced suppression of testicular androgen secretion is insufficient and that MAB with the concomitant use of an antiandrogenic agent is also required in order to suppress adrenal-derived androgen production. The efficacy of MAB applications using non-steroidal antiandrogenic agents such as flutamide, nilutamide or bicalutamide has been reported for the treatment of advanced prostate cancer (4–7). The steroidal anti-androgen agent CMA, which we used in the present study, did not provide obvious concomitant effects during the 12-week period of the treatment in combination with LH-RH agonist (14). However, the present study indicates that long-term concomitant treatment was effective. These findings suggest that further basic and clinical studies are needed. Our results showed slightly elevated serum transaminase levels in Group II patients, but the differences were slight and we detected no other safety concerns when administering the LH-RH agonist concomitantly with CMA.
Although the observation period of the present study was only 2 years and further observations are required, there were only two deaths from prostate cancer. A total of 10 deaths occurred in both groups from other causes during this same period. The patients were elderly with a mean age of 76 years, so the numerous deaths from other causes were attributed primarily to age.
Opinions differ on the appropriateness of hormone therapy for localized or locally advanced prostate cancer. In a questionnaire survey of urologists in the USA, the majority of respondents indicated that they selected hormone therapy without firm evidence for its efficacy (15). In western Europe, however, hormone therapy is not widely used, because of the impression that it is palliative therapy and it reduces quality of life, particularly with regard to sex life. For patients with early prostate cancer whose estimated remaining lifespan is <10 years, ‘watchful waiting’ and delayed hormone therapy are frequently selected since there are more chances for these patients to die from causes other than prostate cancer. Johansson et al. reported good results of this treatment both for 10-year cause-specific (at least 85%) and for progression-free (50%) survivals (16). However, dissenting opinions have also been raised (17), and further study will be required to determine whether ‘watchful waiting’ before hormone therapy is appropriate or not.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Participating institutes (with representative researchers) were as follows: Hokkaido University School of Medicine (Tomohiko Koyanagi), Sapporo Medical University School of Medicine (Yoshiaki Kumamoto, Taiji Tsukamoto), Hokkaido Memorial Hospital of Urology (Tadashi Matsuno), Jin-yukai Hospital (Akio Maru), Akita University School of Medicine (Tadashi Harada), Iwate Medical University (Takashi Kubo, Tomoaki Fujioka), Mito-Saiseikai General Hospital (Ryosuke Noguchi), Jichi Medical School (Akihiko Tokue, Yutaka Kobayashi), Dokkyo University School of Medicine (Etsuji Takasaki, Kenichiro Yoshida), Kimitsu Central Hospital (Kaoru Nagashima), Saitama Social Insurance Hospital (Yasunori Ishii), Saitama Medical Center of Saitama Medical School (Kenichiro Yoshida, Shinichi Takeuchi), Faculty of Medicine, University of Tokyo (Yoshio Aso, Kazuki Kawabe, Tadaichi Kitamura), School of Medicine, Keio University (Hiroshi Tazaki, Masaru Murai), Nihon University School of Medicine (Kiyoki Okada), Jikei University School of Medicine (Toyohei Machida, Yukihiko Ohishi), Jikei University, Aoto Hospital (Tetsuro Ohnishi), Nippon Medical School (Kazuhiro Yoshida), Toho University School of Medicine (Kazukiyo Miura), Tokyo Medical University (Makoto Miki), Tokyo Medical University Hachioji Medical Center (Tetsuo Matsumoto), Kyorin University School of Medicine (Ichiro Chino, Eiji Higashihara), Toranomon Hospital (Masao Yokoyama), St. Luke’s International Hospital (Shigehiro Okamoto, Junnosuke Fukui), Musashino Red Cross Hospital (Hiroshi Nito), Tokyo Seamen’s Insurance Hospital (Tadao Niijima, Kenkichi Kaiso), Federation of National Public Service and Affiliated Personnel Mutual Aid Associations Tachikawa Hospital (Toshio Fujioka), Yokohama City University School of Medicine (Masahiko Hosaka), St. Marianna University School of Medicine (Takao Osada, Teruaki Iwamoto), Kitasato University School of Medicine (Ken Koshiba, Shiro Baba), Kanto-Rosai Hospital (Yoshio Ishida), Labor Welfare Corporation Yokohama-Rosai Hospital (Kunio Yamaguchi), Niigata Cancer Center Hospital (Yasunosuke Sakata), Yamanashi Medical University (Akira Ueno), Hamamatsu University School of Medicine (Kazuki Kawabe, Kimio Fujita), Nagoya University School of Medicine (Koji Miyake), Nagoya Second Red Cross Hospital (Koji Obata), Faculty of Medicine, Mie University (Juichi Kawamura), Toyama Medical and Pharmaceutical University (Takashi Katayama, Hideki Fuse), Fukui Medical School (Kenichiro Okada), Osaka City University Medical School (Taketoshi Kishimoto), Kansai Medical University (Tadashi Matsuda), National Osaka Hospital (Minato Takaha), Osaka Prefectural General Hospital (Shiro Sagawa), Sumitomo Hospital (Hiroaki Itatani), Osaka-Rosai Hospital (Syutaro Mizutani), Nara Medical University (Eigoro Okajima, Yoshihiko Hinao), Nara Prefectural Nara Hospital (Yoshiteru Kaneko), Wakayama Medical College (Tadashi Ohkawa), Youka Hospital (Shoudou Wataru), Okayama University Medical School (Hiroyuki Ohmori, Hiromi Kumon), Okayama Red Cross Hospital (Katsuichi Nanba), Kawasaki Medical School (Hiroyoshi Tanaka), Fukuyama National Hospital (Satoru Matsuki), Yamaguchi University School of Medicine (Katsusuke Naito), Faculty of Medicine, Kagawa Medical University (Ikumasa Takenaka), School of Medicine, University of Tokushima (Susumu Kagawa), Ehime University School of Medicine (Masafumi Takeuchi), Matsuyama Red Cross Hospital (Tsuneo Shiraishi), National Shikoku Cancer Center Hospital (Yoshiteru Sumiyoshi), Kochi Municipal Hospital (Jiro Fujita), Faculty of Medicine, Kyushu University (Joichi Kumazawa, Seiji Naitoh), Kyushu Kosei-Nenkin Hospital (Tetsuo Omoto), Japan Red Cross Society, Nagasaki Atomic Bomb Hospital (Yasuyuki Kusaba), Nagasaki Municipal Hospital (Tanetoshi Hara) and Kumamoto University School of Medicine (Syoichi Ueda).
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FOOTNOTES |
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+ For reprints and all correspondence: Hideyuki Akaza, Department of Urology, Institute of Clinical Medicine, University of Tsukuba, 1–1–1 Tennoudai, Tsukuba, Ibaraki 305-0006, Japan. E-mail: akazah@md.tsukuba.ac.jpAbbreviations: LH-RH, luteinizing hormone-releasing hormone; PSA, prostate-specific antigen; CR, complete response; PR, partial response; TRUS, transrectal ultrasonography; QOL, quality of life; MAB, maximum androgen blockade; CT, computed tomography; CMA, chlormadinone acetate; NC, no change; PD, progressive disease
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Received October 25, 1999; accepted December 22, 1999.
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