Long-term survival following radical prostatectomy in Japanese men with clinically localized prostate cancer: A single institutional study

Authors


Takahiko Hachiya md, Department of Urology, Nihon University School of Medicine, 30-1 Oyaguchikamimachi Itabashi-ku, Tokyo 173-8610, Japan. Email: hachiya@med.nihon-u.ac.jp

Abstract

Background:  We evaluated the outcome of radical prostatectomy to provide information about long-term survival following this procedure.

Methods:  One hundred and twenty-three otherwise healthy Japanese patients with clinically localized tumors underwent radical prostatectomy. Treatment outcomes were measured in terms of clinical progression-free survival, prostate cancer-specific survival and overall survival. Overall survival was compared with expected survival of age-matched Japanese men.

Results:  For these 123 patients, clinical progression-free survival and prostate cancer-specific survival at 10 years were 72.5% and 86.4%, respectively. Results of Cox multivariate analysis showed that only pathological stage (P = 0.047) and tumor grade (P = 0.009) were independent predictors of clinical progression. Only tumor grade was a statistically significant independent predictor (P = 0.048) in terms of prostate cancer death. Both the 10 and 15-year overall survival rates for these 123 patients were 58.6%, whereas the expected survival of age-matched Japanese men was 65.0% at the 10-year follow up, and 43.8% at the 15-year follow up.

Conclusions:  The long-term overall survival in this surgically treated group is comparable to the expected survival rate of age-matched Japanese men. These results might be useful in counselling patients with clinically localized prostate cancer.

Introduction

Since the widespread use of prostate-specific antigen (PSA) for the detection of prostate cancer in Japan, the diagnosis of clinically localized prostate cancer is not as rare as before.1 This phenomenon led Japanese urologists to commonly use radical prostatectomy to treat otherwise healthy patients with localized prostate cancer.2 To date, radical prostatectomy is considered the preferred treatment for patients with localized disease and at least a 10-year life expectancy. Japanese men have the longest life expectancy in the world;3,4 however, the therapeutic benefit for radical prostatectomy remains uncertain in Japanese men. In order to understand the natural history after radical prostatectomy in Japanese men, we compared long-term survival following radical prostatectomy with the life expectancy of the general Japanese male population of the same age during the same period to speculate on the impact of radical prostatectomy in Japanese patients. We also evaluated the most important factors that influenced survival rate, in order to confirm risk factors of progression after radical prostatectomy.

Patients and methods

One hundred and twenty-three consecutive patients with previously untreated and histologically confirmed clinical T1b, T1c, T2a, and T2b tumors were included in this retrospective analysis (Table 1). These 123 patients underwent radical prostatectomy from February 1982 through February 2000 without receiving androgen deprivation before surgery.

Table 1.  Patient background and pathological outcome
 nPathological stageP-valueFinal tumor gradeP-value
pT2N0pT3N0pN1WellModeratelyPoorly
  1. χ2 tests were used to evaluate correlation of pathological background with clinical background. Moderately, moderately differentiated tumor; Poorly, poorly differentiated tumor; PSA, prostate-specific antigen; Well, well-differentiated tumor.

Age
<7084403014 26517 
≥70391226 1 0.003151770.134
Clinical stage
T1b3023 4 3 13143 
T1c331021 2 13164 
T2a2314 9 0  7151 
T2b37 52210<0.001 82360.415
Initial PSA (ng/mL)
<10.0462520 1 20242 
≥10.0421125 6 0.009 92670.032
Final tumor grade
Well412318 0     
Moderately68282812     
Poorly14 110 3 0.003    

Mean follow up was 51 months (range 3–186 months), 13 patients were followed for 10 years or more. The ages (age at surgery) of the patients ranged from 55 to 85 years with both the mean and median being 68 years. All 123 patients underwent radical retropubic prostatectomy (RRP) preceded by a bilateral pelvic lymph node dissection. One of the authors (Kiyoki Okada) performed RRP as either an operator or a supervising assistant on all patients.

Clinical staging before radical retropubic prostatectomy was determined in accordance with the unified tumor node metastasis (TNM),5 by digital rectal examination (DRE), transrectal ultrasonography (TRUS), endorectal magnetic resonance imaging (MRI), computer tomography (CT) and bone scan. Preoperative pathological diagnosis and tumor grading were made by transrectal biopsy before the initiation of any treatment in all patients. Finger-guided prostate biopsy was used until 1992. Subsequently, ultrasound-guided systematic biopsies were performed with a Brüel & Kjaer (Gentofte, Denmark) model 1846 scanner or a Mochida (Tokyo, Japan) Model MeU-1581 Sonovista EX. Biopsies were graded as well differentiated, moderately or poorly differentiated. Where a Gleason score was assigned, a score of 2–4 was grouped with the well-differentiated tumors, 5–7 was grouped with the moderately differentiated tumors and 8–10 with the poorly differentiated tumors. Whole mount paraffin sections were routinely used for pathological analysis. Each specimen was cut into slices 3–5 mm in thickness. Tumors contained within the prostatic capsule without penetration of the capsule were considered pT2N0. Specimens with prostatic carcinoma through the capsule and into the periprostatic fat, with or without seminal vesicle involvement, were designated as pT3N0 for statistical purposes. Positive regional lymph node metastasis with any pT was defined as pN1. Patients were seen every month during the first year postoperatively and every 3 months thereafter. Before the introduction and widespread use of serum PSA determination, patients were evaluated by periodic DRE, measurement of prostatic acid phosphatase and/or bone scan. Subsequently, determination of serum PSA levels, DRE and TRUS were the methods used in all patients. Serum PSA (Tosoh AIA-PACK PA) levels were determined every 3 months postoperatively.

Adjuvant hormonal therapy, consisting of surgical castration or an LHRH agonist was started within 1 month after surgery in 24 patients with pT3N0 and 15 patients with pN1. Postoperative external beam adjuvant therapy was not performed. Thirty-nine of these 123 received immediate adjuvant hormonal therapy, which probably rendered PSA follow-up data unreliable. Thirty-five patients, before the PSA era, did not have complete data available for statistical analysis of PSA failure-free survival.

Thus, the analysis of PSA failure-free survival as a surrogate end-point was carried out in the 64 patients who did not receive adjuvant therapy and received complete PSA follow up since initial diagnosis. PSA failure was defined as two consecutive detectable PSA levels (≥0.4 ng/mL). The patients in whom PSA failure was confirmed received salvage hormone therapy consisting of surgical castration or an LHRH agonist.

Clinical progression was seen as local tumor recurrence or distant metastasis by DRE, TRUS biopsy, or bone scan. A bone scan was performed every 6–12 months after PSA failure. We analyzed long-term clinical progression-free survival, prostate cancer-specific survival, and overall survival using the Kaplan–Meier method. In addition, we also analyzed PSA failure-free survival of patients that could be evaluated. Comparisons of survival curves were performed using the log-rank test. Overall survival was compared with expected survival of age-matched Japanese men using Japanese life tables.6

Univariate and multivariate analyses were performed using Cox proportional hazard analysis for the assessment of the prognostic significance of age, clinical stage, initial PSA, nerve-sparing status, pathological stage, tumor grade and adjuvant therapy, as well as for calculating the relative risk. The covariates, age (≥70 vs <70), nerve-sparing status (done vs not done), adjuvant therapy (done vs not done) were used as categorical variables. The covariate, initial PSA level, was used as the continuous numeric variable. The covariates, clinical stage (first, T1b and T1c; second, T2a; third, T2b), pathological stage (first, pT2N0; second, pT3N0; third, pN1) and tumor grade (first, well; second, moderately; third, poorly) were used as the ordinal numeric variables. A commercially available statistical package (SPSS Version 11) was used to conduct statistical analyses. Values of P < 0.05 were considered statistically significant.

Results

Details of the clinicopathological correlation

Details of the clinicopathological correlation in 123 consecutive patients with localized prostate cancer are shown in Table 1. There was an inherent bias between age and pathological stage in this retrospective analysis (P = 0.003). Patients with pT3N0 disease tended to be older than 70 years. Results of correlations were statistically significant between pathological stage and clinical stage (P < 0.001), and pathological stage and initial PSA (P = 0.009). Final tumor grade did not correlate with either age or clinical stage; however, it was significantly correlated with both initial PSA (P = 0.032) and pathological stage (P = 0.003).

PSA failure-free survival

Of the 64 patients that could be evaluated, nine patients showed PSA failure afterwards. These nine patients did not show local progression or distant metastasis over the follow-up period. PSA failure-free survival is demonstrated according to clinical variables in Table 2. The 26 patients with initial PSA equal to or more than 10.0 ng/mL tended to show statistically poor PSA failure-free survival compared to that of the 38 patients with initial PSA less than 10.0 ng/mL (P = 0.014). The 29 patients with pT3N0 tumors showed statistically poor PSA failure-free survival compared to that of the 35 patients with pT2N0 disease (P = 0.020). Of the 64 patients, 27, 33 and 4 had well-differentiated tumor, moderately differentiated tumor and poorly differentiated tumor, respectively. The patients with poorly differentiated tumor tended to show poor PSA failure-free survival, although it was not statistically significant (P = 0.158).

Table 2.  Prostate-specific antigen failure-free survival rate (n = 64)
 n5 years10 yearsP-value
  1. Data for PSA failure-free survival rate presented as mean ± SE (%). Moderately, moderately differentiated tumor; Poorly, poorly differentiated tumor; PSA, prostate-specific antigen; Well, well-differentiated tumor.

PSA failure-free survival6476.5 ± 9.376.5 ± 9.3
PSA failure-free survival according to initial PSA
 PSA < 10 ng/mL3894.5 ± 3.894.5 ± 3.8 
 PSA ≥ 10 ng/mL2647.3 ± 20.70.014
PSA failure-free survival according to pathological stage
 pT2N03585.0 ± 11.685.0 ± 11.6 
 pT3N02969.2 ± 10.90.020
PSA failure-free survival according to tumor grade
 Well2777.2 ± 14.777.2 ± 14.7 
 Moderately3386.9 ± 6.1 
 Poorly 437.5 ± 28.60.158

Clinical progression-free survival

Of the 123 patients, 14 patients showed clinical progression afterwards. Six and eight of these 14 patients had local progression and distant metastasis, respectively. Seven of these 14 patients died of prostate cancer afterwards. In six patients who had been diagnosed with local failure, three, one and two patients had pT2N0, pT3aN0 and pN1 disease, respectively. In the eight patients who had been diagnosed with distant metastasis, one had pT3aN0, one had pT3bN0 and six had pN1.

Long-term clinical progression-free survival is demonstrated according to clinical variables in Table 3. The patients with initial PSA equal to or more than 10.0 ng/mL tended to show poor clinical progression-free survival, although baseline PSA was assessed in only 88 patients, because PSA testing was not available in the 1980s. Pathologically advanced tumors showed statistically poor clinical progression-free survival (P < 0.001). Patients with higher tumor grades tended to show poor clinical progression-free survival, although a 10-year follow up was not completed in patients with poorly differentiated tumors.

Table 3.  Clinical progression-free survival rate (n = 123)
 n5 years10 yearsP-value
  • *

    Clinical progression-free survival rate calculated at 7 years. Data for clinical progression-free survival rate presented as mean ± SE (%). Moderately, moderately differentiated tumor; Poorly, poorly differentiated tumor; PSA, prostate-specific antigen; Well, well-differentiated tumor.

Clinical progression-free survival123 88.2 ± 4.1 72.5 ± 7.4
Clinical progression-free survival according to initial PSA 88   
 PSA < 10 ng/mL 46100100 
 PSA ≥ 10 ng/mL 42 95.7 ± 4.3 79.7 ± 15.0*Not generated
Clinical progression-free survival according to pathological stage
 pT2N0 52 95.7 ± 4.3 87.7 ± 8.6 
 pT3N0 56 86.5 ± 8.0 86.5 ± 8.0 
 pN1 15 72.0 ± 12.0 32.0 ± 16.0<0.001
Clinical progression-free survival according to tumor grade
 Well 41100100 
 Moderately 68 85.2 ± 6.6 68.5 ± 10.3 
 Poorly 14 72.7 ± 13.4 48.5 ± 21.7*Not generated

We evaluated the important factors that influence clinical progression-free survival using the Cox model (Table 4). Clinical variables, including age, clinical stage, initial PSA, nerve-sparing status, pathological stage, tumor grade, and adjuvant hormonal therapy were all assessed as dependent variables to evaluate the relative risk of clinical progression using univariate analysis. In this model, pathological stage (P = 0.002) and tumor grade (P < 0.001) were the significant risk factors of clinical progression of prostate cancer. Age, clinical stage, nerve-sparing status, PSA and additional adjuvant therapy were not factors that significantly influenced clinical progression in the 123 patients. Based on multivariate analysis, only pathological stage (P = 0.047) and tumor grade (P = 0.009) were the independent predictors of clinical progression.

Table 4.  Relative risk for clinical progression determined by Cox proportional hazard tests (n = 123)
VariablesUnivariate testMultivariate test
RR95% CIP-valueRR95% CIP-value
  1. 95% CI, 95% confidence interval; PSA, prostate-specific antigen; RR, relative risk.

Age (≥70/<70)0.940.29–3.05 0.914
Clinical stage1.570.83–2.94 0.164
Initial PSA (n = 88)1.020.99–1.11 0.101
Nerve-sparing status (Done/not done)0.740.23–2.44 0.625
Pathological stage3.421.57–7.42 0.0022.301.01–5.230.047
Tumor grade5.292.13–13.16<0.0013.621.37–9.520.009
Adjuvant therapy (Done/not done)0.500.15–1.68 0.249

Prostate cancer-specific survival

Long-term prostate cancer-specific survival is demonstrated according to clinical variables in Table 5. The trend was that patients with a higher pathological stage had a higher probability of cancer death. Higher tumor grade showed poor prostate cancer-specific survival; however, a 10-year follow up was not completed in patients with poorly differentiated tumors.

Table 5.  Prostate cancer-specific survival rate (n = 123)
 n5 years10 years15 yearsP-value
  1. Data for prostate cancer-specific survival rate presented as mean ± SE (%). †, Prostate cancer-specific survival rate calculated at 7 years. Moderately, moderately differentiated tumor; Poorly, poorly differentiated tumor; PSA, prostate-specific antigen; Well, well-differentiated tumor.

Prostate cancer-specific survival123 92.4 ± 3.3 86.4 ± 5.2 86.4 ± 5.2
Prostate cancer-specific survival according to initial PSA 88    
 PSA < 10 ng/mL 46100100Not generated
 PSA ≥ 10 ng/mL 42 94.1 ± 5.7 94.1 ± 5.7 
Prostate cancer-specific survival according to pathological stage
 pT2N0 52100100100 
 pT3N0 56 90.7 ± 6.3 75.6 ± 14.8Not generated
 pN1 15 80.0 ± 10.3 71.1 ± 12.4 
Prostate cancer-specific survival according to tumor grade
 Well 41100100 
 Moderately 68 95.1 ± 3.6 84.9 ± 7.6 84.9 ± 7.6Not generated
 Poorly 14 70.0 ± 14.5 70.0 ± 14.5* 

Factors that influenced prostate cancer-specific survival were evaluated using the Cox model (Table 6). Clinical variables, including age, clinical stage, initial PSA, nerve-sparing status, pathological stage, tumor grade, and adjuvant hormonal therapy status were all assessed as dependent variables to evaluate the relative risk for prostate cancer death using univariate analysis. In this model, pathological stage (P = 0.022) and tumor grade (P = 0.010) were the significant risk factors of prostate cancer death. Age, clinical stage, nerve-sparing status, PSA and additional adjuvant therapy were not factors that significantly influenced clinical progression in the 123 patients.

Table 6.  Relative risk for prostate cancer-specific death determined by Cox proportional hazard tests (n = 123)
VariablesUnivariate testMultivariate test
RR95% CIP-valueRR95% CIP-value
  1. 95% CI, 95% confidence interval; PSA, prostate-specific antigen; RR, relative risk.

Age (≥70/<70)1.550.35–6.940.567
Clinical stage1.360.59–3.120.475
Initial PSA (n = 88)1.050.90–1.160.362
Nerve-sparing status (Done/not done)0.830.16–4.340.830
Pathological stage3.841.22–12.110.0222.790.83–9.340.096
Tumor grade5.531.51–20.250.0103.981.01–15.610.048
Adjuvant therapy (Done/not done)0.940.21–4.260.937

Based on multivariate analysis, only tumor grade was a statistically significant independent predictor (P = 0.048) of prostate cancer death.

Overall survival

Both 10 and 15-year overall survival rate for these 123 patients with clinically localized disease was 58.6%, whereas the expected survival rates of age-matched Japanese men were 65.0% and 43.8%, respectively (Fig. 1). The long-term overall survival in this surgically treated group is comparable to the expected survival rate of age-matched Japanese men. Nineteen patients died within 10 years after surgery. Seven of the 19 died from prostate cancer. Twelve patients died from other causes, although these patients did not have any sign of concomitant disease at the time of surgery. The causes of death other than recurrent prostate cancer were cardiovascular in six patients, lung cancer in two patients, and pneumonia, alcoholism, cerebral infarction and dehydration in the remaining four patients. These 12 patients did not show either PSA failure or clinical progression in the follow-up period. Long-term overall survival curves of these 123 Japanese patients are displayed, according to clinical variables, in Table 7. Ten-year overall survival according to age approached a statistically statistical difference (P = 0.069). In 84 patients less than 70 years old, three died from prostate cancer and five died from concomitant disease. In 39 patients 70 or older, three died from prostate cancer and seven died from concomitant disease. The 10-year overall survival rates for 52 patients with pT2N0, 56 with pT3N0 and 15 patients with pN1 were 80.0%, 24.5% and 56.9%, respectively. In 52 patients with pT2N0, four patients died from diseases other than prostate cancer. No patients died from prostate cancer in these 52. In 56 patients with pT3N0, seven patients died from a disease other than prostate cancer and three patients died from prostate cancer. In 15 patients with pN1, one patient died from a disease other than prostate cancer and four patients died from prostate cancer. Although there was not a statistically significant difference between pT3 and pN1, overall survival of patients with pT3 was the worst, because seven of 53 patients with pT3N0 died from a disease other than prostate cancer. In terms of tumor grade, overall survival curves between tumor grade did not show a statistically significant difference (P = 0.173); however, poorly differentiated tumors tended to show poor overall survival.

Figure 1.

Long-term overall survival rate of the 123 Japanese patients, determined by the Kaplan–Meier method, and the expected survival rate of age-matched Japanese men. The solid line represents the mean overall survival, the dotted line is standard error and the solid black circle represents expected survival of age-matched Japanese men.

Table 7.   Overall survival rate (n = 123)
 n5 years10 years15 yearsP-value
  • *

    Overall survival rate calculated at 7 years. Data for overall survival rate presented as mean ± SE (%). Moderately, moderately differentiated tumor; Poorly, poorly differentiated tumor; PSA, prostate-specific antigen; Well, well-differentiated tumor.

Overall survival12383.5 ± 4.658.6 ± 8.258.6 ± 8.2
Overall survival according to age
 <70 8488.9 ± 4.869.8 ± 9.669.8 ± 9.6 
 ≥70 3973.8 ± 9.341.0 ± 13.30.069
Overall survival according to initial PSA 88    
 PSA < 10 ng/mL 4680.2 ± 10.866.9 ± 15.2 
 PSA ≥ 10 ng/mL 4285.6 ± 9.785.6 ± 9.7*0.291
Overall survival according to pathological stage
 pT2N0 5292.3 ± 5.280.0 ± 9.380.0 ± 9.3 
 pT3N0 5673.5 ± 9.624.5 ± 14.5 
 pN1 1580.0 ± 10.356.9 ± 16.10.041
Overall survival according to tumor grade
 Well 4187.0 ± 7.158.7 ± 14.3 
 Moderately 6889.4 ± 5.263.3 ± 10.763.3 ± 10.7 
 Poorly 1456.0 ± 17.156.1 ± 17.1*0.173

In the Cox univariate model, age (P = 0.077) and pathological stage (P = 0.089) approached statistical significance in the 123 patients (Table 8). Based on multivariate analysis, only age (P = 0.048) was proven to be a statistically significant independent predictor of overall death.

Table 8.   Relative risk for overall death determined by Cox proportional hazard test (n = 123)
VariablesUnivariate testMultivariate test
RR95% CIP-valueRR95% CIP-value
  1. 95% CI, 95% confidence interval; PSA, prostate-specific antigen; RR, relative risk.

Age (≥70/<70)2.260.92–5.560.0772.521.01–6.290.048
Clinical stage1.160.70–1.930.564
Initial PSA (n = 88)1.000.96–1.060.872
Nerve-sparing status (Done/not done)0.520.20–1.340.177
Pathological stage1.610.93–2.780.0891.630.86–3.060.132
Tumor grade1.530.74–3.200.2641.29059–2.820.517
Adjuvant therapy (Done/not done)0.570.22–1.510.259

Discussion

Although the natural history of prostate cancer and long-term results of radical prostatectomy in men with clinically localized prostate cancer have been reported elsewhere in western countries, the most fundamental question about the treatment of localized prostate cancer, namely whether or not early intervention with radical prostatectomy decreases morbidity and mortality rates and improves quality of life, remains unanswered.7–17 Until the results of well-controlled prospective randomized studies are available, continuing controversy will surround the choice of treatment for men with clinically localized prostate cancer.18 However, radical prostatectomy is considered the preferred treatment for patients with localized disease, and a 10-year life expectancy, in the western world.19,20

Relative to western countries, previous surveys of Japanese populations have shown that the prevalence of prostate cancer was low, and the number of patients with localized prostate cancer was limited in Japan. Therefore, the number of Japanese men who required radical prostatectomy was also relatively limited. However, with the widespread use of PSA for the detection of prostate cancer, the incidence of clinically localized prostate cancer in Japan has increased.1 This phenomenon led Japanese urologists to use radical prostatectomy quite commonly to treat otherwise healthy patients with localized prostate cancer.2

To decide on the most adequate treatment method for Japanese men with localized prostate cancer, among the available options, it is essential to know the natural history of Japanese men following radical prostatectomy for localized prostate cancer. However, in Japanese men, the natural history after radical prostatectomy has not been studied sufficiently and it is not as well understood as the equivalent history of western men.

Results from the present study compare favorably with previous western reports in terms of prostate cancer death, clinical progression-free survival, as well as risk factors of disease progression following radical prostatectomy.13,15,17,19,21,22 Indeed, the present study might indicate that prostate cancer-specific survival and risk factors of disease progression after radical prostatectomy in patients with localized prostate cancer are not that different between western men and Japanese men. Recent reports showed that the natural history of Japanese prostate carcinoma does not differ significantly from that of its western counterpart once it becomes clinically manifested,23 although the incidence and mortality of prostate carcinoma have been reported to vary widely in different parts of the world.

Japanese socio-economic standards are as high as their counterparts in the west. However, to properly examine the hypothesis that the risk factors of disease progression and natural history of prostate cancer after radical prostatectomy in Japanese men are not significantly different from those of western men, a variety of other variables should be carefully considered. Race and diet of Japanese men have traditionally been different from those of the West.24 Moreover, Japanese men have the longest life expectancy in the world.3,4,6 Therefore, it might not be true that the impact of radical prostatectomy on western men is the same as the impact of surgery on Japanese men. To examine this issue, we compared long-term survival following radical prostatectomy with the life expectancy of the general Japanese male population of the same age during the same period so that we could speculate on the impact of radical prostatectomy in Japanese patients. Our results showed that the long-term overall survival in this surgically treated group is comparable to the expected survival rate of age-matched Japanese men. These results support the speculation that radical prostatectomy is the preferable treatment option for Japanese patients with clinically localized prostate cancer. However, the likelihood of non-prostate cancer death after radical prostatectomy in the follow-up period in the present study was also comparable to a recent German report, which indicates that not only prostate cancer death but also death from concomitant disease affect overall survival rate.15 Whether more relevant patient selection for radical prostatectomy, taking into account risk factors, natural history, comorbidity, and life expectancy, will improve the overall survival after radical prostatectomy in Japanese men should be determined in a larger controlled study.

In summary, when deciding between treatment options for patients with clinically localized prostate cancer, physicians should incorporate information on all risk factors, including natural history, comorbidities and life expectancy. Results from the present study might be useful in counselling patients with clinically localized prostate cancer; however, caution is advised when comparing these results with similar studies because of the inherent potential biases in an uncontrolled single institutional study.

Ancillary