Hideyuki Akaza, Department of Urology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba-city, Ibaraki 305–0006, Japan. e-mail: firstname.lastname@example.org
To evaluate the efficacy of primary hormone therapy for localized or locally advanced prostate cancer, by analysing the 10-year survival rates for men with localized or locally advanced prostate cancer treated with primary hormone therapy or prostatectomy.
PATIENTS AND METHODS
Between February 1993 and March 1995, men with T1b, T1c or T2-3 N0M0 prostate cancer were enrolled. In all, 176 men who had a prostatectomy were assigned to Study 1 and were given adjuvant luteinizing hormone-releasing hormone (LHRH) agonist; 151 men who did not have a prostatectomy were assigned to Study 2 and had LHRH agonist monotherapy or combined androgen blockade. They were followed until death, loss to follow-up, or until the end of the observation period (31 March 2004). We analysed all cases in each study as a single population, and compared Study 1 with Study 2.
The mean patient ages were 67.2 years in Study 1 and 75.7 years in Study 2. During a median of 10.4 years of follow-up, 20 men in Study 1 and 17 in Study 2 died from prostate cancer, and 21 men in Study 1 and 50 in Study 2 died from other causes. In Study 1, the 10-year overall survival rate was 73% and the 10-year cause-specific survival rate was 86%, vs 41% and 78% in Study 2. Overall survival curves were similar to expected survival curves in both studies. There was no significant difference between studies in cause-specific survival.
The progression of prostate cancer was retarded by primary hormone therapy in men with localized or locally advanced prostate cancer. With primary hormone therapy or prostatectomy, the men had a life-expectancy similar to that of the normal population.
Since Huggins and Hodges  reported that castration and oestrogen treatment were effective against advanced prostate cancer, hormone therapy has been a mainstay of treatment. In clinical guidelines implemented in the USA and Europe, primary hormone therapy is recommended as a front-line regimen for the treatment of advanced and some cases of locally advanced prostate cancer, although it is not recommended for men with localized prostate cancer [2,3]. However, in the surveillance study reported by the Japanese Urological Association, 45% of clinically T1c-T3 cases had had primary hormone therapy . In addition, the Cancer of the Prostate Strategic Urologic Research Endeavor report  indicated a rapid increase in the use of primary hormone therapy for localized prostate cancer in the USA. Moreover, in the Early Prostate Cancer Program, antiandrogen was found to be effective for treating localized or locally advanced prostate cancer [6,7]. There might thus be a radical change in the view of the role of primary hormone therapy in the treatment of prostate cancer.
Since 1993, we have been conducting two multicentre prospective, randomized comparative studies to evaluate the efficacy of hormone therapy for localized or locally advanced prostate cancer, and have reported the results of the 5-year follow-up [8–13]. In Study 1, the efficacy of neoadjuvant and adjuvant hormone therapy was investigated in men who had had a prostatectomy. In Study 2, the efficacy of primary hormone therapy was evaluated in men who for various reasons did not have a prostatectomy. Patients were not randomly allocated to Study 1 or Study 2, and comparison of Study 1 and Study 2 was not planned at the start of these studies. However, we considered that the results of the two studies could be compared, as they were conducted at the same institutions during similar periods. In the 5-year follow-up analysis, we compared survival rates in the two studies . The 5-year cause-specific survival rate was ≈ 90% in both studies, and the overall survival curve was similar to the expected curve in both studies. Although these findings indicate that primary hormone therapy is as effective as prostatectomy, the 5-year observations were insufficient for definitive conclusions about the efficacy of primary hormone therapy in treating localized or locally advanced prostate cancer. We continued the follow-up and now present the 10-year survival rates.
PATIENTS AND METHODS
The details of study design were described previously [9,10]. Between February 1993 and March 1995, untreated men with T1b, T1c or T2–3N0M0 (1997 TNM classification ) prostate cancer, whose baseline testosterone levels were >1.0 ng/mL, were enrolled at 104 sites in Japan. Men aged ≤ 80 years and those undergoing prostatectomy were assigned to Study 1, and those who for various reasons did not have a prostatectomy to Study 2. Indications for surgery were judged individually by the physician and/or patient. Before study enrolment, written informed consent was obtained from all patients. The study protocol was approved by the Institutional Review Board of each study site, and the study was conducted in accordance with the guidelines of the Declaration of Helsinki.
The men in Study 1 were randomly assigned to a 12-week preoperative combined androgen blockade (CAB) group or an immediate-prostatectomy group. After prostatectomy, men were treated with LHRH agonist for 2 years. The men in Study 2 were randomly assigned to a LHRH agonist monotherapy group or a CAB group. Dynamic balancing was used to an ensure equal distribution of clinical stage and histological classification in both studies. These treatments were administered continuously for 2 years. Leuprorelin acetate depot (Takeda Pharmaceutical Co., Ltd. Osaka, Japan) 3.75 mg was administered as the LHRH agonist at intervals of 28 days. For CAB therapy, leuprorelin acetate and a steroidal antiandrogen, chlormadinone acetate (Aska Pharmaceutical Co., Ltd, Tokyo, Japan) 100 mg/day, were administered . Treatment after the 2-year follow-up was left to the discretion of the physician or patient.
In both studies, the PSA level was monitored at the start of the protocol therapy and every 3 months thereafter, using the Delfia PSA-kit (Wallac Oy, Finland) for the first 2 years. After this, PSA levels were monitored at least every 3 months using a kit selected at each institution. The prostate size was determined by TRUS or CT, while distant metastasis was diagnosed by bone scintigraphy or CT. The men were followed until death, loss to follow-up, or until the end of the observation period (31 March 2004).
At the 5-year follow-up, we combined the two groups within each study and handled all cases enrolled in each study as a single population, as there were no significant differences in overall, cause-specific, or metastasis-free survival between the groups in either study, while the CAB group had a better outcome for progression-free survival (elevation of PSA level, increase in prostate size or metastasis was treated as the event) in Study 2 [11,13].
Adverse drug reactions were classified according to the common toxicity criteria of the Japan Society of Clinical Oncology, which are similar to the criteria of the National Cancer Institute. Overall, cause-specific and metastasis-free survival rates (95% CI) were estimated by the Kaplan–Meier method. Time zero was defined as the day of randomization. Death from any cause was considered an event in the analysis of overall survival. Only deaths due to prostate cancer were treated as events in the analysis of cause-specific survival; deaths from other causes were handled as censored cases. In analysis of metastasis-free survival, metastasis was treated as the event; deaths from other causes without metastasis were categorized as censored cases. The expected survival rates were estimated by the Ederer II method, a standard method for estimating expected survival rates in Japan, using the Japanese cohort survival table .
In a subgroup analysis, we classified patients into four groups on the basis of T classification, histological classification and initial PSA level, as follows: low-risk group, T1b-2a, well differentiated, and initial PSA level of ≤ 10 ng/mL; intermediate-risk group, T1b-2a, moderately differentiated or initial PSA level of 10–20 ng/mL; high-risk group, T2b, poorly differentiated or initial PSA level of >20 ng/mL; very high-risk group, T3. As there were few men classified in the low- and intermediate-risk groups, we combined these as a low-intermediate-risk group.
For comparison of patients’ characteristics between the studies, we used the two-sample t-test or Mann–Whitney U-test, depending on the raw data distribution. To compare survival rates, the log-rank test and generalized Wilcoxon test were used. A two-sided P < 0.05 was considered to indicate statistical significance.
Of 224 men in Study 1, 48 were excluded because of violation of inclusion criteria or refusal to undergo prostatectomy, leaving 176 for analysis . In Study 2, 27 of 178 men were excluded because of protocol violation or other reasons, leaving 151 for analysis ; Table 1 shows the patients’ characteristics. There were significant differences between studies in mean patient age, clinical T classification, and mean initial PSA levels. In Study 1, 63% of men were aged <70 years vs 21% in Study 2. In Study 2, 23% of men were aged >80 years, but none in Study 1 were. In Study 1, 48% of men were in the high-risk and 25% in the very high-risk group, vs 32% and 45% respectively in Study 2. The median (range) duration of hormone therapy (including men undergoing castration and men treated with antiandrogen or oestrogen agents after termination of leuprorelin administration) was 4.6 (0.3–11.0) years in Study 1 and 4.3 (0.1–11.0) years in Study 2.
Table 1. The patients’ characteristics and 10-year outcomes
By a median follow-up of 10.4 years, 20 men in Study 1 and 17 in Study 2 died from prostate cancer, and 21 men in Study 1 and 50 in Study 2 died from other causes (Table 1). In Study 1, the 10-year overall survival (95% CI) was 73 (66–80)%, and the 10-year cause-specific survival was 86 (81–92)%. In Study 2, the 10-year overall survival was 41 (31–52)%, and the 10-year cause-specific survival was 78 (67–88)%. The overall survival curves were similar to the expected survival curves in both studies (Fig. 1). In subgroup analyses, the overall survival curves were similar to expected curves in each risk group for both studies (Fig. 2).
In Study 1, the 10-year cause-specific survival rate was 97% in the low-intermediate-risk group, 88% in the high-risk group, and 73% in the very-high-risk group. In Study 2, the 10-year cause-specific survival was 86% in the low-intermediate-risk group, 91% in the high-risk group, and 69% in the very-high-risk group. There were no significant differences between the studies in the 10-year cause-specific survival stratified by risk group (Fig. 3, Table 2). The 10-year cause-specific survival was 85% for men aged <70 years and 89% for men aged ≥ 70 years in Study 1. In Study 2, the 10-year cause-specific survival was 73% for men aged <70 years and 79% for men aged ≥ 70 years. There were no significant differences between the studies in 10-year cause-specific survival stratified by patient age (Fig. 4; Table 2).
Table 2. Summary of the 5- and 10-year cause-specific survival rates
Cause-specific survival rates, % (95% CI)
Study 1 (176)
Study 2 (151)
Study 1 (47)
Study 2 (34)
Study 1 (85)
Study 2 (49)
Study 1 (44)
Study 2 (68)
Age < 70 years:
Study 1 (111)
Age ≥70 years:
Study 1 (65)
Study 2 (119)
Overall, 30 men developed metastasis in Study 1 and 34 in Study 2. In Study 1, the 10-year metastasis-free survival was 81 (75–88)%, and in Study 2 it was 58 (45–71)%. The 10-year metastasis-free survival stratified by risk group was 97 (92–100)% in the low-intermediate-risk group, 81 (72–90)% in the high-risk group, and 66 (51–82)% in the very-high-risk group in Study 1, and 83 (65–100)% in the low-intermediate-risk group, 68 (42–95)% in the high-risk group, and 44 (27–61)% in the very-high-risk group in Study 2. There were no significant differences in 10-year metastasis-free survival between the studies for any risk group (Fig. 5).
Adverse drug reactions were reported in 35 men in Study 1 (20%) and 35 in Study 2 (23%); the most frequently reported reactions were abnormal liver function tests, hot flashes and hyperglycaemia (Table 3). Except for two cases of dyspnoea and one of cerebral infarction reported as grade 3 or 4, all adverse reactions were grade 1 or 2. Initial treatment was discontinued due to adverse reactions in six men in Study 1 (arthralgia in two; dyspnoea, hot flashes, oedema, and asthenia in one man each) and four in Study 2 (arthralgia, cerebral infarction, injection site induration, and fatigue in one man each).
Table 3. Adverse drug reactions
Adverse event, n (%)
Number of patients
Injection site reactions
Abnormal liver function tests
Elevated blood urea nitrogen
Protein in urine
For treating localized prostate cancer, prostatectomy is considered the ‘gold standard’, while primary hormone therapy is considered palliative for men who are poor risks for surgery or who do not want radical treatment. However, in the USA, brachytherapy and primary hormone therapy have been used increasingly often for treating localized prostate cancer, indicating a greater need for less-invasive treatment . Labrie et al.  reported that the PSA relapse rate at 5 years after cessation of CAB was only 10% in men with localized prostate cancer who had CAB for >6.5 years. By contrast, the PSA relapse rate was 64% for men who had CAB for 3.5–6.5 years, suggesting that long-term primary hormone therapy might be curative for men with localized prostate cancer.
In the present study, we compared the 10-year survival rates in two studies that we have been conducting since 1993, to evaluate the efficacy of primary hormone therapy for men with localized or locally advanced prostate cancer. During a median of 10.4 years of follow-up, 20 men died from prostate cancer in Study 1 and 17 in Study 2. More men died from other causes in Study 2 than in Study 1 (50 vs 21). In Study 1, 63% of men were aged <70 years; by contrast, 56% were aged 70–80 years and 23% were >80 years old in Study 2. It is possible that there were more deaths from other causes in Study 2 than in Study 1 because older patients were enrolled in Study 2. In the present analysis, we compared overall survival with expected survival estimated from the cohort survival table for Japanese men as a control. Overall survival curves were almost the same as expected survival curves for both studies. When patients were stratified by risk group, there were no differences between overall survival and expected survival in any risk group in either study. In particular, the 10-year overall survival rate was very similar to the expected survival rate for men with T3 prostate cancer, who were expected to have a poorer life-expectancy than the general population due to a greater risk of death from cancer. These results suggested that men with localized or locally advanced prostate cancer and with prostatectomy or primary hormone therapy have a life-expectancy similar to that of the normal population.
However, it is difficult to clearly conclude that the life-expectancy of men with localized or locally advanced prostate cancer can be improved by primary hormone therapy, as no watchful-waiting group was included in the present study, and natural history data are not available for Japanese patients with prostate cancer. Bill-Axelson et al. reported that prostatectomy was significantly better than watchful-waiting in both 10-year cause-specific survival and overall survival. In the present analysis there was no significant difference in cause-specific survival rate between Study 1 and Study 2. Thus it is possible that prostate cancer progression is retarded by primary hormone therapy in men with localized or locally advanced prostate cancer, leading to improved life-expectancy.
The 10-year cause-specific survival rates were 86% in Study 1 and 78% in Study 2, with no significant difference between them, although the percentage of T3 cases in Study 2 was about twice that in Study 1 (45% vs 25%). In analyses stratified by risk group and patient age, there were no significant differences in cause-specific survival rates between the studies. In particular, the 10-year cause-specific survival rate was ≈ 90% for men with localized disease in both studies. There were no differences between the 5-year and 10-year cause-specific survival rate in the low-intermediate-risk and high-risk groups. This indicates that men with localized prostate cancer who do not die from prostate cancer within 5 years of treatment are likely not to die from prostate cancer in the subsequent 5 years, when treated with primary hormone therapy or prostatectomy. Albertsen et al.  reported 20-year outcomes after conservative management of localized prostate cancer. About half of the men in that study had hormone therapy as primary treatment. The 20-year prostate cancer-specific mortality rate was 29%, and few men died from prostate cancer among those with low-grade tumours; the present results are similar to theirs.
A major objective when treating localized or locally advanced prostate cancer is to minimize the incidence of distant metastasis, as quality of life will be greatly decreased by bone pain or spinal compression when metastasis, particularly bone metastasis, occurs. In the present study, 30 men developed metastasis in Study 1 and 34 in Study 2, and the 10-year metastasis-free survival rate was lower in Study 2 than in Study 1 (58% vs 81%). However, there were no significant differences in metastasis-free survival rates stratified by risk group between the studies, suggesting that the higher incidence of T3 prostate cancer in Study 2 might account for the significant differences in the 10-year metastasis-free survival rates.
There were no significant differences in cause-specific or metastasis-free survival rates between the studies in any risk group. However, patients were not randomly allocated to Study 1 or Study 2, and there was a significant difference in patient age between studies (67.2 vs 75.7 years, respectively). The incidence of prostate cancer death might have been relatively low in Study 2 because men with shorter life-expectancy were enrolled and more died from other causes than in Study 1. As men with a long life-expectancy have a high risk of progression from prostate cancer [18,20], it is not clear whether the present results are applicable to younger men.
Adverse drug reactions were reported in 20% of the present patients, and most were grade 1 or 2. The present results therefore indicate that long-term hormone therapy is well tolerated. However, the effect on bone density and quality of life, which we did not investigate, are also considered disadvantages of hormone therapy [18,21,22]. Primary hormone therapy for localized or locally advanced prostate cancer should be selective, considering toxicity and life-expectancy. As intermittent hormone therapy for advanced prostate cancer can minimize these adverse reactions while maintaining efficacy, it might be useful to evaluate intermittent hormone therapy in men with localized or locally advanced prostate cancer [23–25].
In the therapeutic guidelines for prostate cancer proposed in the USA and Europe, prostatectomy, radiation, and watchful-waiting are recommended for treating localized prostate cancer [2,3]. As we did not use randomized allocation to compare the efficacy of primary hormone therapy with prostatectomy in the present study, we are reluctant to conclude that we have enough evidence to recommend primary hormone therapy as an alternative to prostatectomy. However, primary hormone therapy has been administered to many men with localized or locally advanced prostate cancer, based on the clinical experience of the treating physicians. The results of the J-Cap surveillance, conducted to evaluate the trends and outcomes of hormone therapy in Japan, revealed that ≈ 40% of men undergoing primary hormone therapy had clinical stage II prostate cancer . The present results suggest that, at least for older men, primary hormone therapy is a valid therapeutic option for localized or locally advanced prostate cancer.
In the near future, randomized clinical studies should be conducted to compare primary hormone therapy with other curative treatments, e.g. radical prostatectomy, external beam radiotherapy, or watchful waiting, to establish its clinical efficacy and safety for localized or locally advanced prostate cancer.
The authors thank the physicians at the participating institutions in the Prostate Cancer Study Group, which made this work possible. The studies were financially supported by Takeda Pharmaceutical Company, Ltd. (Osaka, Japan).