Japanese Journal of Clinical Oncology 33:574-579 (2003)
© 2003 Foundation for Promotion of Cancer Research
Radical Prostatectomy for Prostate Cancer Patients with Prostate-specific Antigen >20 ng/ml
1 Division of Urology, Department of Surgery and 3 Department of Pathology, Taichung Veterans General Hospital, National Yang-Ming University School of Medicine, Taichung and 2 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: Prostate cancer patients with prostate-specific antigen (PSA) >20 ng/ml are at high risk of progression after radical prostatectomy. Comparison has seldom been made between the outcomes of patients with PSA 20.1–50 ng/ml and those with PSA >50 ng/ml after radical prostatectomy. We retrospectively analyzed the outcomes of these two groups.
Methods: From 1993 to 2002, 60 prostate cancer patients receiving radical prostatectomy were enrolled in this study. Thirty-seven patients with PSA 20.1–50 ng/ml were assigned to Group I. Twenty-three patients with PSA >50 ng/ml were assigned to Group II. Preoperatively, Group II had greater PSA and PSA density than Group I (P < 0.0001). Group II had higher biopsy Gleason score and clinical stage than Group I (P < 0.05). Pathological categories and outcomes of both groups were compared.
Results: Group II had higher Gleason score and tumor volume than Group I (P < 0.05). The incidence of organ-confined diseases was 29.7% in Group I and 0% in Group II (P < 0.05). Group II had higher incidence of extracapsular tumor extension, positive surgical margin and lymph node involvement than Group I (P < 0.05). The incidence of postoperative PSA >0.01 ng/ml and PSA failure were higher in Group II than Group I (P < 0.05). Need for adjuvant treatment and death from prostate cancer was similar in both groups.
Conclusion: Patients with PSA >50 ng/ml had a poorer prognosis than patients with PSA 20.1–50 ng/ml. Those with PSA >50 ng/ml had shorter freedom from PSA failure survivals than those with PSA 20.1–50 ng/ml (P = 0.004). Classification of high-risk prostate patients into two sub-groups with PSA 20.1–50 ng/ml and PSA >50 ng/ml should be considered.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A combination of prostate-specific antigen (PSA), clinical stage and Gleason score to predict pathological staging nomograms (Partin Tables) of localized prostate cancer (PC) has been adopted to identify patients with high risk of progression (1–6). Since the nomograms started to be used for counseling patients prior to radical prostatectomy at the Johns Hopkins Hospital (1993–96), 55% of cases were found to have organ-confined diseases, which represents a 20% improvement over the pre-nomogram era (1). The contemporary version of Partin Tables stratifies PSA into five tiers: 0–2.5, 2.6–4.0, 4.1–6, 6.1–10 and >10 ng/ml (3). The dramatic change may be due to the PSA screening strategies, which caused a major migration of prostate cancer with nearly 75% of newly diagnosed cases presenting with localized or regional PC (7). In one screening study, 78% of PC detected were stage T1c (8). In our previous study, on the other hand, 15% of PC detected were stage T1c because the patients were from a non-screened population and there is low awareness of PC among men in Taiwan (9). Most of the newly diagnosed cases of PC in Taiwan and other developing countries are advanced disease with high PSA. Therefore, PSA levels were classified according to the previous Partin Table as 0–4, 4.1–10, 10.1–20 and >20 ng/ml, which is still valid in Taiwan (1,2). The outcomes of patients with PSA 20.1–50 ng/ml and PSA >50 ng/ml have seldom been reported (1,2,10,11). In this study, a retrospective analysis of PSA more than 20 ng/ml, classified as PSA 20.1–50 ng/ml and PSA >50 ng/ml was performed to compare the outcomes of these two patient groups.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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From January 1993 to December 2002, 280 patients with PC received radical retropubic prostatectomy (RRP) in our hospital. Sixty patients with PSA >20 ng/ml were enrolled in this study. No patients received neoadjuvant hormonal therapy. The 37 patients with PSA 20.1–50 ng/ml were assigned to Group I and the 23 patients with PSA >50 ng/ml were assigned to Group II. The serum total PSA and free PSA concentrations were measured with TPSA-RIACT and FPSA-RIACT kits (Cis Bio International, France). No patients had urinary tract infection or received iatrogenic manipulation before the PSA and free PSA determination. Biopsies of the prostate 6–12 cores were performed using an 18-gauze biopsy gun (Bard, USA) under transrectal urological ultrasound (TRUS) guidance (Bruel and Kjer 3535, Denmark). For each needle biopsy, Gleason score and percentage of cancer were assessed.
Bilateral pelvic lymphadenectomy and RRP without neurovascular bundle preservation were carried out. Prostatectomy specimens were fixed, coated with India ink and sliced from the apex to the base in systematic stepwise sections taken perpendicular to the urethral axis at 3 mm intervals. The tumors were evaluated for Gleason score and tumor location. Tumor volume was calculated by multiplying the resulting tumor area by section thickness (3 mm) and correcting for tissue shrinkage factor (1.5) following fixation (12). Pathological categories were stratified as organ-confined disease (OCD), extracapsular tumor extension (ECE), surgical margin (SM) positive, seminal vesicle (SV) invasion, bladder neck (BN) involvement and lymph node (LN) metastasis. The OCD was defined as tumor limited within the prostate capsule, with no seminal vesicle involvement or lymph node metastasis. The ECE was defined as tumor-involved capsular perforation extending entirely through the prostate capsule. The presence of tumor cells on any inked surgical margin was considered as a positive SM. SV invasion was diagnosed if tumor invaded the SV muscular wall at the junction with the prostate. The base margin positivity was defined as BN involvement. All pathological findings were reviewed by a pathologist (J.T. Chen) to assign Gleason score, percentage of cancer in biopsies, tumor volume and pathological categories.
We defined biochemical or PSA failure as two serial serum PSA >0.2 ng/ml. Patients were observed every month until PSA was undetectable (PSA <0.01 ng/ml), then every 3 months for 3 years, followed by an evaluation every 4 months thereafter. The time of PSA failure was taken to be the time of the first of two detectable PSA measurements postoperatively. Adjuvant treatment was given only when PSA failure was diagnosed. Criteria for adjuvant treatment were as follows: (1) hormonal therapy (HT) was given when PSA failure developed in patients with LN metastasis; (2) radiation therapy (RT) was applied when PSA failure developed in ECE, positive SM, SV invasion and BN involvement with PSA elevation to 0.5–1.0 ng/ml; (3) HT was given in patients with PSA elevation to 0.5 ng/ml after RT.
All data were expressed as mean ± standard deviation and 95% confidence interval (CI) of the mean difference. Statistical analysis was performed using the Mann–Whitney U-test, Fisher’s exact test, Pearson’s chi-squared test and Yates’s correction of contingency as appropriate. To find the most significant variables for preoperative clinical characteristics for PSA failure after RRP we used the Cox proportional hazards model (backward regression method, delete the worst) for multivariate survival analysis. Multivariate survival analyses were carried out with the SPSS–Cox program and P values were assessed by the Wald statistic. Actuarial freedom from PSA failure and cancer-specific survival were calculated using the Kaplan–Meier method and comparisons were made using the log-rank test. A P value <0.05 was considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Clinical characteristics of both groups are shown in Table 1. Group II had a significantly higher PSA level and free PSA level than Group I (P < 0.0001). Group II had a higher prostate volume and PSAD than Group I (P = 0.006 and P < 0.0001). Group II had a significantly higher Gleason score than Group I in needle biopsies (P = 0.013). Group II had a significantly higher clinical stage than Group I (P = 0.037).
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Pathological findings of RRP specimens from patients with PSA >20 ng/ml are shown in Table 2. Group II had higher Gleason scores than Group I (P = 0.026). There were higher specimen volume, tumor volume and percentage of cancer in Group II than Group I (P < 0.005). Group II had a higher incidence of ECE, positive SM and LN metastasis than Group I (P < 0.05). The outcomes for PC patients with PSA >20 ng/ml after RRP are shown in Table 3. The incidence of postoperative PSA >0.01 ng/ml and PSA failure were higher in Group II than in Group I (P < 0.005).
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A postoperative PSA >0.01 ng/ml means that PSA cannot reduce the undetectable level (<0.01 ng/ml) in our laboratory postoperatively. Multivariate survival analysis for the Cox proportional hazards model in preoperative clinical characteristics revealed PSA, prostate volume, PSA density and percentage of cancer of biopsies as the significant parameters (Table 4). The 8-year freedom from PSA failure survival for Group I was 30.5% and for Group II 10.1%, which was a statistically significant difference (Fig. 1). The 8-year cancer-specific survival for Group I was 77.6% and for Group II 79.0%, but this was not statistically significant (Fig. 1).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Pathophysiological factors influence the leakage of PSA into serum, including inflammation, iatrogenic manipulation (e.g. digital rectal examination, prostate biopsy and cystoscopy), and physiological variations (with posture and ejaculation) (5,11). Without confounding factors, preoperative PSA levels in PC patients correlate directly with pathological stage, tumor grade and the probability of organ-confined diseases (1,2,5,13,14). The variable relationship between serum PSA and pathological stage of PC is the result of multiple factors. PSA production varies according to grade and volume of cancer and with co-existing BPH tissue. PSA production per gram of cancer is greater in less differentiated tumors (15). Tumors that arise in the transition zone may acquire a greater volume than their peripheral zone counterparts and may be better differentiated than peripheral zone tumors of equivalent volume (16). The transition zone tumors may be associated with much higher PSA levels than otherwise expected for organ-confined cancer (17). Although preoperative PSA levels correlate positively with the likelihood of ECE, they do not predict capsular penetration and seminal vesicle and lymph node involvement with sufficient reliability for the individual patient (13). There are few published data on the long-term survival for patient cohorts managed by radical prostatectomy and evaluated in the context of serum PSA >20 ng/ml at diagnosis. In this study we analyzed the difference of outcomes between PC patients with PSA 20.1–50 ng/ml and PSA >50 ng/ml in an area with low age-specific prevalence of clinical PC.
The incidence of PSA >20 ng/ml in patients receiving radical prostatectomy was 5.5–20.6% and the incidence of PSA >50 ng/ml was 0.8–1.1% (1,2,5,6,10,11). The incidence of PSA >20 ng/ml was 24% and of PSA >50 ng/ml was 9.2% in this series. The incidence of PSA >20 ng/ml was slightly higher than in Stamey et al.’s report (20.6%) in 1989 and Matsui et al.’s report (16.3%) (11,18). However, the incidence of PSA >50 ng/ml was considerably higher than in other studies (1,2,5,11). This may have been due to the more advanced stage in this series and the loose operative indications. Partin et al. reported in 1993 that the incidence of OCD, ECE, SV positive and LN metastasis was 19.1, 29.8, 21.3 and 29.8%, respectively, in patients with PSA 20.1–50 ng/ml receiving radical prostatectomy (2). Also, the incidence of OCD, ECE, SV positive and LN metastasis was 0, 13, 13 and 74%, respectively, in patients with PSA >50 ng/ml (2). Partin et al. reported for 4133 men from three major academic urological centers in 1997 that the incidence of OCD, ECE, SV positive and LN metastasis was 17, 48, 30.3 and 16% in patients with PSA 20.1–50 ng/ml, respectively (1). The incidence of OCD, ECE, SV positive and LN metastasis was 9, 32, 32 and 27% in patients with PSA >50 ng/ml, respectively (1). In this series, the incidence of OCD, ECE, SV positive and LN metastasis was 29.7, 62.2, 45.9 and 8.1% in patients with PSA 20.1–50 ng/ml and 0, 100, 43.5 and 30.4% in patients with PSA >50 ng/ml, respectively. The high incidence of ECE, especially in patients with PSA >50 ng/ml, may be due to preoperative underestimation of the clinical stage by digital rectal examination, which led to poor selection of surgical indication.
In this series, only 29.7% of patients had OCD and 51.4% experienced freedom from PSA failure in those with PSA 20.1–50 ng/ml, but there were no OCD patients in the PSA >50 ng/ml group with only 13.6% of patients experiencing freedom from PSA failure. The PSA >50 ng/ml group have shorter freedom from PSA failure survivals than the PSA 20.1–50 ng/ml group (P = 0.004). However, the cancer-specific survival was similar in both groups because the case numbers were limited, adjuvant therapy was given and the follow-up period was short. Several models have also been adopted with the use of PSA progression rather than survival as an end point (4,10). Freedom from PSA failure survival may not mean overall survival. Further study is necessary to confirm the cancer-specific and overall survival benefit.
D’Amico et al. reported pathological stage and margin status to be independent predictors of PSA failure but observed that margin status and preoperative PSA were more powerful predictors (P = 0.001) than pathological stage (P < 0.002) or Gleason score (P = 0.034) for T1c or T2 PC patients receiving RRP (19). Blute et al. found the preoperative PSA level to be a significant predictor of biochemical failure with pT2-3N0 treated with RRP (20). However, Roberts et al. did not find the PSA level to add significantly to the model for biochemical failure (21).
The relationship between pathological categories and outcomes has been described previously. Serum PSA >20 ng/ml compared with PSA <20 ng/ml is associated with a four times higher risk of seminal vesicle or lymph node involvement in 20 and 17% of patients, respectively (1). Epstein et al. reported that SV invasion was not associated with a uniformly poor prognosis (22). The relative risk of PSA recurrence of BN involvement/BN negative was only 1.52-fold (23). Our data showed a similar incidence of SV invasion and BN involvement between PSA 20.1–50 ng/ml and PSA >50 ng/ml. LN metastasis developed and radical prostatectomy is still of benefit for cancer-specific survival. Ghavamian et al. demonstrated that RRP and hormone therapy were better than lymph node dissection alone and hormone therapy (5-year cancer specific survival 79 vs 63%) in two cohorts of patients (24). Hence, although nodal involvement and seminal vesicles are much more likely to occur in men with PSA >20 ng/ml, selected patients with PSA >20 ng/ml in surgical cohorts may be effectively treated by RRP.
Univariate and multivariate survival analysis for preoperative clinical characteristics revealed the preoperative PSA level to be the best predictor for PSA failure postoperatively. In conclusion, we compared the outcomes of PC patients receiving RRP with PSA between 20.1 and 50 ng/ml and >50 ng/ml. PSA failure and cancer-specific survival were used as end points. Patients with PSA >50 ng/ml had more poor prognostic factors than patients with PSA 20.1–50 ng/ml. PSA >50 ng/ml patients had shorter freedom from PSA failure survivals than PSA 20.1–50 ng/ml patients (P = 0.004). Selected men with PSA 20.1–50 ng/ml in surgical cohorts may be effectively treated by radical prostatectomy. Classification of PSA into two sub-groups of PSA 20.1–50 ng/ml and PSA >50 ng/ml should be considered for high-risk PC patients.
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FOOTNOTES |
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+ For reprints and all correspondence: Chi-Rei Yang, Division of Urology, Department of Surgery, Taichung Veterans General Hospital, 160, Sec. 3, Taichung-Kang Road, 40705 Taichung, Taiwan. E-mail: ycou{at}vghtc.vghtc.gov.tw
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REFERENCES |
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Received July 20, 2003; accepted October 6, 2003
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