Outcome of Prostate Cancer Patients with Initial PSA I 20 ng/ml Undergoing Radical Prostatectomy

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1 european urology 52 (2007) available at journal homepage: Prostate Cancer Outcome of Prostate Cancer Patients with Initial PSA I 20 ng/ml Undergoing Radical Prostatectomy Ulrike Zwergel *, Henrik Suttmann, Thomas Schroeder, Stefan Siemer, Bernd Wullich, Joern Kamradt, Jan Lehmann, Michael Stoeckle Department of Urology and Pediatric Urology, University of Saarland, D Homburg/Saar, Germany Article info Article history: Accepted March 16, 2007 Published online ahead of print on March 28, 2007 Keywords: Prostate cancer Radical prostatectomy (RP) Survival Initial PSA 20 ng/ml Abstract Objectives: To retrospectively assess the outcome of patients with initial PSA of 20 ng/ml or higher undergoing radical prostatectomy (RP) for prostate cancer (pca). Methods: Between January 1986 and June 2005, 275 patients with preoperative PSA 20 ng/ml underwent RP for pca at our institution. Overall, disease-specific and biochemical progression-free survival rates for the entire cohort and for particular subgroups were determined. Results: Median patient age at time of surgery was 64 yr (range: 44 75). Fifty-seven patients (20.7%) had pt2 stage, 206 (74.9%) pt3, and 10 (3.7%) pt4; 78 (28.4%) presented with local nodal metastases (pn+). To date, 40 patients have died (14.5%), 22 of pca and 18 of other causes. Biochemical progression occurred in 92 patients (33.5%). Overall (and diseasespecific) survivals at 5, 10, and 15 yr were 87% (93%), 70% (83%), and 58% (71%), respectively. These survival rates did not significantly differ between patients receiving immediate versus deferred hormonal therapy (in case of progression). Five-year PSA progression-free survival in patients on surveillance (receiving deferred hormonal treatment at the onset of rising PSA values) was 53%. For patients on immediate hormonal treatment following RP, the 5-yr hormone-refractory PSA progression rate was 76%. Conclusions: According to long-term follow-up results in this high-risk cohort of patients with preoperative PSA 20 ng/ml, RP can be considered a viable therapeutic option. With regard to combining immediate hormonal therapy with surgery, the optimal treatment following RP remains to be defined. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology and Pediatric Urology, Saarland University, Kirrberger Strasse, Homburg/Saar, Germany. Tel ; Fax: address: ulrike.zwergel@uniklinikum-saarland.de (U. Zwergel) /$ see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 european urology 52 (2007) Introduction Prostate-specific antigen (PSA) is established as the most widely used tumor marker in clinical practice for diagnosis, staging, and monitoring of prostate cancer (pca) patients [1,2]. Therefore, initial PSA at the time of pca diagnosis has a great influence on clinical decision making [2,3]. This is of particular concern for patients without evidence of distant metastases presenting with initial PSA 20 ng/ml. Since these patients are estimated to have a poorer prognosis compared with those with lower PSA levels, it is difficult to select the optimal treatment modality and to evaluate the role for radical surgery [4]. Until today, most reports on the follow-up of pca patients undergoing radical prostatectomy (RP) with initial PSA values 20 ng/ml were hampered by small patient numbers and a limited follow-up of 10 yr or less [1,5 8]. We retrospectively analyzed our patients undergoing RP with a preoperative PSA of at least 20 ng/ml and no evidence of distant metastasis at the time of surgery. Our analyses included assessment of patient outcome and postoperative survival at 15 yr. Furthermore, we performed subgroup analyses of patients with immediate versus deferred hormonal treatment. 2. Methods 2.1. Patient population Of 1761 patients who underwent RP for pca between January 1986 and June 2005 at our institution, we identified 275 (15.6%) presenting with an initial preoperative PSA 20 ng/ml. This PSA cut-off was chosen by us and others on the basis of historical considerations [1,7,8]. With regard to patient selection, preoperative imaging included computed tomography (CT) or magnetic resonance imaging only in cases of clinically suspected metastatic disease. Routine bone scans were performed according to existing guidelines in patients with a PSA 10 ng/ml [4]. Surgery was offered to all patients in the absence of metastatic disease in whom RP seemed technically feasible. Before 2000, the treatment policy at our institution included the administration of adjuvant hormonal treatment in patients with pt3, pt4, and/or pn+ disease. Since 2000, adjuvant hormonal treatment was started in case of disease recurrence only. Immediate postoperative radiotherapy was done only exceptionally. The choice of local and/or systemic treatment for recurrent disease was left to the discretion of the referring urologists, who also performed the individual patient follow-up Postoperative evaluation Follow-up examinations after RP included digital rectal examination and serum PSA measurement. Bone scans were performed in case of rising PSA level or clinical symptoms suspicious for bony metastases. Disease progression was defined as a persistent rise of PSA after surgery (with at least two consecutive measurements) and/or diagnosis of local recurrence and distant metastases documented by biopsy or radiographic examination. Life tables were calculated to determine 5-, 10-, and 15-yr survival rates. Events in biochemical progression-free survival analyses were defined with the use of a PSA threshold of >0.2 ng/ml Statistical analyses Overall, disease-specific and biochemical progression/recurrence-free survival from the time of surgery were defined as end points for this retrospective analysis. Similar procedures were applied for all end points. Distributions of event times were calculated separately with the univariate product limit method described by Kaplan-Meier [9]. Case censoring was applied in the analysis of the progression/recurrence-free period if death occurred without progression/recurrence or if, in the analysis of cancer-specific survival, death occurred unrelated to disease. All reported p values are based on twosided tests, and the a-level to accept statistical significance was All analyses were performed with the Statistical Software for the Social Sciences, version 8 (SPSS Inc, Chicago, IL, USA). 3. Results Median age of the 275 patients at the time of surgery was 64 yr (Table 1). None of the patients had initial signs of distant metastases. Table 1 Characteristics of RP patients with initial PSA I 20 ng/ml, n = 275, January 1986 June 2005 Age, median (yr) 64 Range (yr) Tumor stages (n = 275) pt2 57 (20.7%) pt3 206 (74.9%) with pt3b 90/205 (43.9%) pt4 10 (3.7%) ptx 2 (0.7%) pn+ 78 (28.4%) Gleason score of RP (sum) since 1996 (n = 157) 5 and 6 12 (7.6%) 7 68 (43.3%) 8 30 (19.1%) 9 44 (28.1%) 10 3 (1.9%) Androgen-deprivation therapy immediately after RP (n = 129) Before (86.8%) After (13.2%) Surveillance and deferred androgen-deprivation therapy (n = 146) Before (11.6%) After (88.4%) RP = radical prostatectomy; PSA = prostate-specific antigen.

3 Fig. 1 Kaplan-Meier overall and cause-specific survival curves of 275 patients with initial prostate-specific antigen (PSA) I20 ng/ml who were treated with radical prostatectomy. (a) Overall survival. (b) Overall survival survival comparing 129 patients with immediate (1) and 146 with surveillance (i.e. deferred (2) postoperative hormonal treatment (HT) in case of PSA rising). The Kaplan Meier analysis showed no significant difference in overall survival between both subgroups ( p = 0.193). (c) Cancer specific survival. (d) Cancer specific survival comparing 129 patients with immediate (1) and 146 with surveillance (i.e deferred (2) postoperative HT in case of PSA rising). The Kaplan Meier analysis showed no significant difference in cancer specific survival between both subgroups ( p = 0.128) european urology 52 (2007)

4 european urology 52 (2007) An overview of patient demographics at presentation and their pathologic findings are provided in Table 1. Since the Gleason grading system was introduced at our institution in 1996, 157 RP histopathologic examinations have been reported with the respective Gleason scores (Table 1). Preoperative PSA values ranged from 20 ng/ml to 560 ng/ml; 18 patients (6.5%) had an initial PSA of more than 100 ng/ml. Of the 275 patients, 129 patients with locally advanced tumors (in the RP specimen) received immediate hormonal treatment following RP (Table 1). Immediate postoperative hormonal therapy consisted of orchiectomy (121 of 129 patients) or medical treatment (8 of 129). Medical treatment consisted of luteinizing hormone-releasing hormone agonists in most patients and antiandrogens in two cases exclusively. One hundred forty-six patients underwent PSA surveillance following RP irrespective of the pathologic tumor stage (pt) and had deferred hormonal treatment in case of biochemical progression (n = 36). Only two patients in the entire cohort received immediate postoperative radiotherapy. Mortality (within 30 d after RP) was 4 of 275 (1.4%). Two patients died of pulmonary embolism, the other two of unknown causes. To date, 235 patients are still alive, with 92 (33.5%) having experienced biochemical progression (followed by various treatment strategies). Among the 40 patients (14.5%) who died during follow-up, death was related to pca in 22 of 275 (8%) and to other causes in 18 of 275 patients (6.5%). All 22 patients who died of pca had increasing PSA levels at the time of death. Postoperative follow-up ranged from 0.5 to 229 mo with a median of 42 mo for patients remaining free from PSA progression. Median overall survival and median cancer-specific survival were both >229 mo, that is, median overall and cancer-specific survivals were not reached after a maximum follow up of 229 mo. Overall (and cause-specific) survival probabilities at 5, 10 and 15 yr were 87% (93%), 70% (83%), and 58% (71%), respectively (Fig. 1). The two Kaplan-Meier curves with overall and tumor-specific survival rates (Fig. 1b and d) compare the results with immediate therapy versus surveillance and deferred hormonal therapy at the onset of a rise in PSA. Biochemical progression was also evaluated for two subgroups: (1) 129 patients on immediate hormonal treatment showing a median time to hormone-refractory PSA progression of 142 mo and (2) 146 patients with surveillance (deferred hormonal treatment at the onset of rise in PSA) with a median time to biochemical PSA recurrence Table 2 Survival rates of pca patients with initial PSA I 20 ng/ml (n = 275) Years of survival Overall survival (%) Cancer-specific survival (%) Hormone-refractory PSA progression-free survival (%) with hormonal therapy immediately after RP PSA progression-free survival (%) with surveillance (i.e., deferred hormonal therapy at the onset of rise in PSA) pca = prostate cancer; PSA = prostate-specific antigen. of 60 mo. For patients on immediate hormonal treatment following RP, the 5-yr hormone-refractory PSA progression rate was 76%. Biochemical progression-free survival in patients with deferred hormonal therapy (in case of progression) was 53% at 5 yr (Table 2). 4. Discussion In 1986 the Food and Drug Administration (FDA) approved PSA testing to monitor patients with pca. Since then, PSA has been recognized as the most widely used tumor marker available in clinical practice for diagnosis, staging, and treatment of pca patients [1,2,10]. However, the definite impact of PSA on patient outcome remains unclear [1,2,11]. Initial PSA alone does not provide accurate staging information for individual patients [3,12], and it alone is not sufficient to direct management of pca patients [13]. In particular, clinical decision making is most difficult in patients without evidence for distant metastases, but with an elevated PSA over 20 ng/ml. These patients are suspected to harbor locally advanced tumors or occult metastases and, therefore, are considered to have a poor prognosis [1,5,14]. Today, urologists face the dilemma of how to treat these pca patients: whether to initially choose hormonal treatment, radiotherapy, or RP alone, or to use a combined therapeutic approach [2 5,15 18]. These considerations prompted us to analyze the outcome of a large patient cohort who presented initially with preoperative PSA 20 ng/ml and subsequently underwent RP. Until now, most reports on this particular subgroup were hampered by small numbers (<100 patients) [1,5 8]. With 275 patients we not only present the largest study population published so far, but we also demonstrate the highest frequency of patients with initial PSA levels 20 ng/ml in relation to the total number of RPs performed during

5 1062 european urology 52 (2007) Table 3 Study population of pca patients with initial PSA I 20 ng/ml and RP: Comparison of different studies Total no. of pts No. of pts with 20 ng/ml % pts with PSA 20 ng/ml/ total no. of pts Different PSA levels (ng/ml) Pound et al PSA 20 (all) Hull et al PSA (n = 68 [86%]) PSA > 50 (n = 11 [14%]) Brandli et al PSA (all) Freedland et al PSA 20 (all) This series PSA (n = 199 [72%]) PSA (n = 58 [21%]) PSA > 100 (n = 18 [7%]) pca = prostate cancer; PSA = prostate-specific antigen; pts = patients. Table 4 Postoperative pathologic tumor stages of pca patients with initial PSA I 20 ng/ml: Comparison of different studies n Organ confined Seminal vesical involvement Pelvic lymph node metastases Hull et al (20%) 18 (23%) 18 (23%) Brandli et al (74%) 11 (22%) 2 (4%) Freedland et al (25%) 15 (23%) 21 (33%) Tiguert et al (35%) 62 (35%) 56 (32%) This series (21%) 90/205 (44%) 78 (28%) pca = prostate cancer; PSA = prostate-specific antigen. the time period observed (Table 3). However, the data also show that certain limitations of our study have to be kept in mind when comparing the results to previous studies (Tables 3 and 4). Pathologic tumor stages varied considerably among the various reports. In our cohort we had only about 21% patients with pt2 tumors. In contrast, Brandli et al [7] reported that more than 70% of his patients had organ-confined disease, suggesting that their series consisted of a subgroup of highly selected patients. The percentages of patients with seminal vesical invasion or local nodal metastases were also quite different, varying between 22% to 44%, and 4% to 33%, respectively [1,5 8]. Different criteria were applied to define biochemical progression. As opposed to Hull et al [6] and Brandli et al [7] who chose a postoperative PSA cut-off of 0.4 ng/ml to define PSA progression, other studies, including ours, considered PSA levels above 0.2 ng/ml as a threshold for biochemical progression [1,11,13]. Brandli et al argued that lower PSA thresholds could perhaps falsely identify patients without subsequent PSA increases as PSA failures. This argument can certainly be dispelled by repeating PSA measurements, especially around the critical thresholds [1]. In our cohort, a PSA > 0.2 ng/ml was defined as an indicator of biochemical progression only if at least two consecutive measurements confirmed a rising PSA. We had only limited access to further data on other important prognostic parameters (than PSA), most importantly Gleason scores of the resected prostate specimens. The Gleason grading system was introduced at our institution in Therefore, only about two thirds of the histopathologic examinations can be reported with the respective Gleason scores. We requested the staff in our local pathology department to reevaluate those specimens for which Gleason scores were not available; however, because of a restrictive storage policy and inadequate tissue quality of slides older than 10 yr, a retrospective assessment was not possible. When interpreting the different reports in general, we found that the heterogeneity of the data and the retrospective design with an inherent selection bias and lack of control groups made comparison difficult. When clinicians try to counsel patients preoperatively, they are looking for predictive analyses [12]. Because of limited space, we briefly summarize our data of a multivariate Cox regression analysis. We tested the following variables as predictors for tumor-specific survival: age at time of surgery, Gleason sum, pt/pn stage, year of surgery, neoadjuvant hormone therapy, time from RP to orchiectomy, preoperative PSA, and number of buffy coats applied perioperatively. None of the parameters was demonstrated to be of independent prognostic significance.

6 european urology 52 (2007) Until today, most reports on patients with RP and initial PSA values 20 ng/ml were also hampered by a limited follow-up of 10 yr or less [1,5 8]. In this study, we retrospectively assessed the long-term outcome of our patients with particular emphasis on 10- and 15-yr follow-up after surgery (Table 2, Fig. 1). We feel that overall survival rates of about 60% after 15 yr for the cohort reflect a rather favorable outcome following RP in pca patients with preoperative PSA 20 ng/ml. When comparing our results with data published by others, especially on patients with lower initial PSA levels and organconfined tumors, we observed that high preoperative PSA values seemed to be associated with poorer survival rates following RP [1 3,10,11,13]. However, as demonstrated in the recent literature [1,5 8,11,19 24] and in this study, the treatment of high-risk patients with RP results in remarkable long-term survival. Management of patients with advanced cancers by radical surgery might also be considered. Recent data suggest that tumor-reductive surgery of the primary bulk of the prostate allows for a better response to adjuvant hormonal therapy [14,20]. With the growing knowledge that primary tumor control provides a beneficial impact on therapy outcome, it is worthwhile to explore the new role of radical surgery in trying to further improve survival of patients with locally advanced or even metastatic prostate cancer. Furthermore, we know that local complications following surgery have been reduced in the last decade [14,20,21,25,26]. Hu et al [25] performed a retrospective, longitudinal population-based study (12,079 men) to confirm that RP outcomes actually improved with the surgical innovations between 1991 and Not only in-hospital complication rates decreased from 38% to 30%, but 3-yr incontinence rates were reduced from 20% in 1991 to 4% in Although the risks related to radical surgery remain significant, we feel that RP should be considered even in advanced tumor stages. Unfortunately, we cannot yet define the optimal treatment of this high-risk subgroup of patients following RP. Should we administer immediate or deferred hormonal treatment, that is, biochemical and/or clinical progression-triggered hormonal therapy following surgery [19,23]? Until 2000, we usually performed surgery with immediate androgen deprivation in case of locally advanced tumors or limited metastatic disease (pt3 and/or pn+). Since 2000, we have preferred PSA surveillance in our pt3 and/or pn+ patients after RP with deferred hormonal therapy at the onset of a rise in PSA. Our current strategy without immediate hormonal therapy after RP seems worthwhile, since we found that immediate postoperative hormonal treatment does not significantly affect overall and cancer-specific survival compared with deferred hormonal therapy (Fig. 1). With regard to the question of adjuvant treatment after RP, it was interesting to look at the data of the ongoing Early Prostate Cancer (EPC) trial that randomized, among others, pca patients into those receiving immediate androgen deprivation with bicalutamide versus placebo after RP [27,28]. According to recently published results from the EPC trial in advanced tumor stages, immediate bicalutamide significantly improves overall survival in patients receiving radiotherapy as definite therapy, but it does not show a survival benefit in the prostatectomy subgroup [27]. Since only two patients in our patient cohort were treated with immediate postoperative radiotherapy, we cannot comment further on this treatment option. We further studied progression-free survival rates. In Table 5, biochemical progression-free survival rates are compared with different series of RP patients with initial PSA 20 ng/ml [1,5 8]. Yet again, a direct comparison of the results to other studies is hampered by different selection criteria. Brandli et al [7] did not provide any data on hormonal treatment for his study group, probably resulting in a nonhomogeneous group. Freedland et al [1] included only patients who received hormonal therapy in case of biochemical progression after surgery. We distinguished between patients with immediate and those with surveillance following RP and deferred hormonal therapy at the onset of rise in PSA, and analyzed PSA progression-free survival rates separately. After 5 yr, PSA progression-free survival rate was 76% Table 5 Biochemical progression-free survival rates of pca patients after RP with initial PSA I 20 ng/ml: Comparison of different studies n 5 years Pound et al 1997? 50% Hull et al % Brandli et al 2003 * 50 48% Freedland et al % Tiguert et al 2006 y % This series 2006 z % pca = prostate cancer; RP = radical prostatectomy; PSA = prostatespecific antigen. * No data on hormonal therapy. y Of 177 patients, 123 (69.5%) were treated either with adjuvant hormone therapy (59) or with adjuvant and salvage radiation therapy (64). z Only patients with surveillance and deferred hormonal treatment in case of rise in PSA.

7 1064 european urology 52 (2007) in patients with immediate hormonal treatment, and 53% in patients with surveillance and delayed hormonal therapy (Table 2). When we compared these results with the EPC trial data on patients with locally advanced disease, we found similar results: Patients on the EPC trial gained benefit from bicalutamide in terms of objective progression-free survival (according to bone scan, CT, and histologic evidence of metastases), irrespective of the standard therapy [27,28]. Summing up these results concerning progression-free survival, we have two major points of criticism: (1) Different end points of observation were used (e.g., hormone-refractory vs. biochemical or objective progression-free survival), which make a correct comparison impossible. (2) Adjuvant hormonal therapy was started at different time points after surgery [1,8,27,28]. In the EPC trial, patients with advanced tumors received hormonal treatment either immediately after RP or following objective progression after initially receiving placebo [27,28]. Furthermore, in case of pca with extraprostatic extension, there are different therapeutic options following RP; adjuvant radiotherapy is an alternative to postoperative hormonal therapy. From our retrospective cohort, we cannot derive any comments on the value of immediate postoperative radiotherapy (RT). Available data from randomized studies show a decrease in biochemical progression in this clinical situation [29,30]. Further questions still remain: It is unclear whether overall and cancer-specific survival after RT is prolonged in these patients or whether immediate adjuvant RT is superior to RT at the time of PSA increase. On the basis of all these data and since hormonal treatment has considerable side effects such as osteoporosis, hot flushes and/or depression, our current strategy on not starting hormonal therapy immediately after RP seems worthwhile. To date, we favor deferring hormonal treatment after RP until the PSA level begins to rise. 5. Conclusions Our study demonstrates remarkable long-term survival at 15-yr follow-up for patients who had pca with preoperative PSA 20 ng/ml and underwent RP. These patients have a poorer outcome compared with those with lower initial PSA levels [26]. Whether RP alone or in combination with immediate hormonal therapy or irradiation is the optimal choice of treatment in this patient subgroup remains to be defined. To date, we prefer PSA progression-triggered hormonal therapy following RP. References [1] Freedland SJ, Mangold LA, Walsh PC, et al. 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9 1066 european urology 52 (2007) References [1] Dennis LK, Resnick MI. Analysis of recent trends in prostate cancer incidence and mortality. Prostate 2000;42: [2] Gallina A, Jeldres C, Chun FK-H, et al. Prediction of pathological stage is inaccurate in men with PSA values above 20 ng/ml. Eur Urol. In press. doi: /j.eururo [3] Ribeiro FR, Henrique R, Martins AT, Jerónimo C, Teixeira MR. Relative copy number gain of MYC in diagnostic needle biopsies is an independent prognostic factor for prostate cancer patients. Eur Urol 2007;52: [4] Zwergel U, Suttmann H, Schroeder T, et al. Outcome of prostate cancer patients with initial PSA 20 ng/ml undergoing radical prostatectomy. Eur Urol 2007;52: [5] Van Poppel H. Surgery for clinical T3 prostate cancer. Eur Urol Suppl 2005;4(4):12 4. DOI: /j.eururo DOI of original article: /j.eururo