Outcome of Surgery for Clinical Unilateral T3a Prostate Cancer: A Single-Institution Experience

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1 european urology 51 (2007) available at journal homepage: Prostate Cancer Outcome of Surgery for Clinical Unilateral T3a Prostate Cancer: A Single-Institution Experience Chao-Yu Hsu a, Steven Joniau a, Raymond Oyen b, Tania Roskams c, Hein Van Poppel a, * a Department of Urology, University Hospitals KULeuven, Leuven, Belgium b Department of Radiology, University Hospitals KULeuven, Leuven, Belgium c Department of Histopathology, University Hospitals KULeuven, Leuven, Belgium Article info Article history: Accepted May 17, 2006 Published online ahead of print on June 9, 2006 Keywords: Locally advanced Prostate cancer ct3 Outcome Abstract Objectives: The optimal management of locally advanced prostate cancer (ct3) is still a matter of debate. The objective of this study is to present 10-year outcomes of radical prostatectomy (RP) in unilateral ct3a disease. Patients and methods: Between 1987 and 2004, 2273 patients underwent RP at our institution. Two hundred and thirty-five (10.3%) patients were assessed as unilateral ct3a disease by digital rectal examination. Thirtyfive patients who received neoadjuvant treatment before surgery were excluded from further analysis. Mean follow-up was 70.6 months. Kaplan-Meier survival analysis was used to calculate the biochemical progression-free survival (BPFS), clinical progression-free survival (CPFS), cancer-specific survival (CSS), and overall survival (OS) rates. Cox uni- and multivariate regression analyses were used to identify predictive factors in BPFS and CPFS. Results: Clinical overstaging (pt2) occurred in 23.5%. One hundred and twelve (56%) patients received adjuvant or salvage therapy. OS at 5 and 10 years was 95.9% and 77.0%, respectively, and CSS was 98.7% and 91.6%. BPFS at 5 and 10 years was 59.5% and 51.1%, respectively, and CPFS was 95.9% and 85.4%. Margin status was a significant independent predictor in BPFS; cancer volume was a significant independent predictor in CPFS. Conclusions: Clinically advanced prostate cancer is still frequently overstaged. In a well-selected patient group with locally advanced prostate cancer, RP with adjuvant or salvage treatment when needed can yield very high long-term cancer control and survival rates. Margin status and cancer volume are significant predictors of outcome after RP. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. University Hospital Leuven, Herestraat 49, 3000 Leuven, Belgium. Tel ; Fax: address: Hendrik.VanPoppel@uzleuven.be (H. Van Poppel) /$ see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 122 european urology 51 (2007) Introduction Locally advanced prostate cancer is defined as cancer that has extended clinically beyond the prostatic capsule with invasion of the pericapsular tissue, apex, bladder neck, or seminal vesicle, but without lymph node involvement or distant metastases. It is estimated that 12 25% of prostate cancers are stage T3 [1]. Treatment goals of locally advanced prostate cancers are to potentially cure the disease, prolong biochemical progression-free or metastasis-free survival, and improve quality of life. The treatment of T3 prostate cancer can be radical prostatectomy (RP), radiotherapy (RT), androgen deprivation therapy (ADT), or combinations of these treatments. A few years ago, T3 tumors were generally considered to be advanced disease for which RP was not appropriate and either ADT or RT was commonly used. Maeda et al. [2] suggested that patients with clinical T3 and well or moderately differentiated tumors would benefit from RP combined with ADT, while RT would be effective in more-advanced disease. Both the Radiation Therapy Oncology Group (RTOG) trial [3] and the European Organization for the Research and Treatment of Cancer (EORTC) trial [4] showed that the combination of RT and ADT can improve biochemical disease-free survival over RT alone for locally advanced prostate cancer. The optimal treatment of patients with locally advanced prostate cancer remains unknown. According to the guidelines of the European Association of Urology (EAU), RP is an accepted option in selected patients with limited T3a, Gleason score 5 7, low prostate-specific antigen (PSA), and a life expectancy of more than 10 years [5]. Few authors have reported their experience and results with surgery as a primary treatment of locally advanced prostate cancer. The purpose of this study is to present the outcome of clinical unilateral T3a prostate cancer after RP, including biochemical progression-free survival (BPFS), clinical progression-free survival (CPFS), cancer-specific survival (CSS), and overall survival (OS) rates. Furthermore, predictive factors in BPFS and CPFS are analysed. 2. Patients and methods 2.1. Population of patients Between 1987 and 2004, 2273 patients underwent RP at our institution. Two hundred and thirty-five (10.3%) patients were assessed as unilateral ct3 disease by digital rectal examination (DRE). They were selected for operation on the basis of limited unilateral ct3a, any Gleason score, any level of PSA, and Eastern Cooperative Oncology Group (ECOG) performance status 0 1. Thirty-five patients who received neoadjuvant treatment before surgery were excluded. Two hundred (8.8%) patients were included in the final analysis. All included patients underwent RP and bilateral pelvic lymphadenectomy. The mean follow-up was 70.6 months (range, 7 177). The data were retrieved from patient files, and from general practitioners by phone for updated clinical and biochemical information. DRE was performed by one of two senior urologists. One hundred and forty of 200 patients were also assessed as unilateral ct3 by transrectal ultrasound (TRUS). Patients with unilateral T3a assessed by TRUS but not by DRE were excluded from this study. No patient received ADT or RT before RP; no patient had evidence of nodal disease or distant metastasis on both contrast-enhanced computed tomography of the pelvis and bone scan. If necessary, additional imaging of suspect lesions was performed Prostate-specific antigen The last PSA value obtained prior to prostate biopsies was used in the analysis Surgical procedure Patients underwent a bilateral staging pelvic lymphadenectomy without frozen section, followed by a radical retropubic prostatectomy under general or spinal anaesthesia. Surgery was performed by one of two senior surgeons according to the technique previously described [6] Pathologic examination The RP specimens, including prostate, seminal vesicles, and bilateral pelvic lymph nodes, were examined microscopically after routine preparation. The prostate was weighed and cut as whole-mount sections at 4-mm intervals. All specimens were scored according to the Gleason grading system. Microscopic extension of malignant cells to the inked surface of the resected specimen was interpreted as a positive surgical margin. The pathology reports were recorded as pt2a, pt2b, pt2c, pt3a, pt3b, or pt4, and lymph node status was assigned according to the 2002 TNM classification [7]. The cancer volume was also recorded Follow-up Serum PSA and physical examination were performed every 3 months in the first year after surgery, every 4 months in the second and third years, every 6 months in the fourth and fifth years, and annually thereafter Design of criteria Overall survival was defined as the time from RP to death of any cause. Cancer-specific survival was defined as the time from RP to death attributable to prostate cancer or complications of this disease. Biochemical progression was defined as the time from RP to any serum PSA 0.2 ng/ml. Any patient who received adjuvant or salvage treatment, even if PSA at

3 european urology 51 (2007) that time was 0.2 ng/ml, was considered a treatment failure for biochemical recurrence end points from the moment of treatment initiation. Clinical progression is defined as either local recurrence or distant metastasis. Local recurrence is defined as histopathologic recurrence at the resection site. Distant metastasis needed confirmation by imaging. Adjuvant treatment is defined as either radiation or hormonal therapy given within 90 days after radical prostatectomy; salvage treatment is defined as either radiation or hormonal therapy given postoperatively after 90 days (same definitions as used in Ward et al. [8]) Statistical analysis The Kaplan-Meier method was used to calculate the BPFS, CPFS, CSS and OS. The differences were tested with the logrank test. The univariate and multivariate Cox proportional hazard analyses were used to determine prognostic indicators of disease progression. Preoperative PSA, surgical Gleason score, and cancer volume were modeled as continuous variables. MedCalc 1 statistical software, version (MedCalc Software, Belgium) was used for the analysis. 3. Results An overview of patient demographics at presentation and the pathologic findings are provided in Table 1. Five- and 10-year survival rates were as follows: BPFS, 59.5% and 51.1%; CPFS, 95.9% and 85.4%; CSS, 98.7% and 91.6%; and OS, 95.9% and 77.0%, respectively (Fig. 1). Only seven patients died of prostate cancer during the mean follow-up of 70.6 months. Because of this small number of events, we could not Table 1 Patient characteristics Mean patient age (yr) (range) 63.3 (41 79) Mean follow-up (mo) (range) 70.6 (7 177) Mean PSA (ng/ml) (range) ( ) PSA 10 ng/ml (%) 98 (49) PSA > ng/ml (%) 58 (29) PSA > 20 ng/ml (%) 44 (22) Median biopsy Gleason score (range) 7 (2 10) Median surgical Gleason score (range) 7 (4 9) Gleason score 6 (%) 43 (21.5) Gleason score 7 (3+4) (%) 76 (38) Gleason score 7 (4+3) (%) 81 (40.5) Pathology stage (no.) (%) pt2 47 (23.5) pt3a 113 (56.5) pt3b 32 (16) pt4 8 (4) Mean cancer volume (ml) (range) 6.6 ( ) Positive lymph node (no.) (%) 17 (8.5) Positive surgical margin (no.) (%) 67 (33.5) perform uni- and multivariate Cox proportional hazard analyses in CSS and OS. Univariate Cox proportional hazard analysis revealed that, from all the parameters (surgical Gleason score, margin status, nodal status, pathologic stage, preoperative PSA, and cancer volume), only surgical Gleason score was not significantly correlated with BPFS, whereas surgical Gleason score and preoperative PSA were not significantly correlated with CPFS (Table 2). The Kaplan-Meier analysis further confirmed a significant difference between pt3a and pt3b-4 in BPFS and CPFS, whereas there were no differences in BPFS and CPFS between pt2 and pt3a (Fig. 2). Multivariate Cox proportional hazard analysis revealed that status of surgical margin was a significant independent factor in BPFS. Cancer volume was a significant independent factor in CPFS (Table 2). Of the group of 200 patients, 112 (56%) received postoperative treatment, including 44 (22%) with adjuvant and 68 (34%) with salvage treatment. The progression rates (local and distant), and the cause of death in the groups with no postoperative treatment, with adjuvant treatment, and with salvage treatment are detailed in Table 3. We also performed a subanalysis of the data with the log-rank test. There was no significant difference in BPFS ( p = ) and CPFS ( p = ) between the patients who received adjuvant or salvage treatment. 4. Discussion Traditionally, T3 prostate cancers have been treated by either ADT or RT. More recently, after the publication of the landmark trials by RTOG and EORTC, treatment of ct3 prostate cancer has shifted dramatically towards combination of RT and ADT. Nevertheless, according to the guidelines of the EAU, RP is an accepted option in selected patients with limited T3a, Gleason score 5 7, low PSA, and a life expectancy of more than 10 years [5]. Some authors have reported their experience with surgery for locally advanced prostate cancer (Table 4). The CSS at 5 and 10 years was % and %, respectively, and the OS at 5 and 10 years was more than 75% and 60%, respectively. In our study, the CSS at 5 and 10 years was 98.7% and 91.6%, respectively, and the OS at 5 and 10 years was 95.9% and 77%, respectively, corresponding well with the reports in the literature. Bolla et al. [9] reported the 5-year survival rate of radiation alone and the combination of radiation and hormonal therapy in 412 patients with locally

4 124 european urology 51 (2007) Fig. 1 Kaplan-Meier analysis for biochemical progression-free survival (A), clinical progression-free survival (B), cancerspecific survival (C), and overall survival (D) in 200 unilateral ct3a patients. Table 2 Cox univariate and multivariate regression analyses of histopathologic parameters and preoperative PSA * Survival Covariate Univariate analysis Multivariate analysis HR 95% CI p value HR 95% CI p value BPFS Surgical Gleason score Margin < <0.001 Node < Pathologic stage < Preoperatieve PSA < Cancer volume < CPFS Surgical Gleason score Margin Node Pathological stage Preoperatieve PSA Cancer volume < BPFS: biochemical progression-free survival, CI: confidence interval, CPFS: clinical progression-free survival, HR: hazards ratio, PSA: prostatespecific antigen. * A p value of <0.05 is considered significant. PSA, biopsy Gleason score, and cancer volume are coded as continuous variables.

5 european urology 51 (2007) Fig. 2 Kaplan-Meier analysis with log-rank test for biochemical progression-free survival (A), and clinical progression-free survival (B) stratified for pathologic stage. A p value of <0.05 is considered significant. advanced prostate cancer. CSS and OS were 79% and 62% in the radiation-alone group, and 94% and 78% in the combination group. Directly comparing surgical data with the data from Bolla et al. may not be correct, because the selection in favor of surgery may represent a more favorable subset of patients. In our series, patients with a unilateral T3a lesion and a good performance status were selected for operation. Furthermore, most of the study period was within the PSA era, which resulted in a large proportion of patients with PSA 10 (49%). The patients who were included in our series mostly fall within the (rather vague) limits of the EAU guidelines on prostate cancer. This is in contrast with the patient population in the Bolla series, in which some patients were N+, and only 16 19% of patients had PSA 10. Nevertheless, the issue of whether surgical outcomes can be compared with RT outcomes in patients with locally advanced prostate cancer was partially answered by Roach et al. [10]. In their study, 1557 patients from RTOG trials between 1975 and 1992 were analyzed. Different risk groups were defined, with group 2 (Gleason score 2 6, T3Nx or N+; or Gleason score 7, T1 2Nx) and group 3 (Gleason score 7, T3Nx; or Gleason score 7, N+; or Gleason score 8 10, T1 2Nx) corresponding most with our treatment group. For RT only, the 5-year CSS and OS rates were, respectively, 94% and 82% for group 2, and 83% and 68% for group 3. The 10-year CSS and OS rates for RT only were, respectively, 75% and 50% for group 2, and 62% and 32% for group 3. These findings are in contrast with 5-year CSS and OS rates of 98.7% and 95.9%, respectively; and 10-year CSS and OS rates of 91.6% and 77%, respectively, in our series. Even in group 1 (Gleason score 2 6, T1 2Nx), 5-year CSS and OS rates were 96% and 85%, respectively, and 10-year CSS and OS rates were 86% and 59%, respectively, which are again lower than in our patient group. Admittedly, total radiation dose to the prostate in the combined RTOG trials was Gy, which is lower than the doses administered nowadays. In another analysis by Roach et al. [11], the outcomes of combined radiation therapy and long-term ADT were reported for 364 patients from RTOG trials between 1975 and The 5-year CSS and OS rates Table 3 The characterization of patients with adjuvant treatment, salvage treatment, or without postoperative treatment None (n = 88) Adjuvant (n = 44) Salvage (n = 68) Total (n = 200) Local recurrence 0 1 (2.3%) 3 (4.4%) 4 (2%) Distal metastasis 0 4 (9.1%) 9 (13.2%) 13 (6.5%) Died of prostate cancer 0 4 (9.1%) 3 (4.4%) 7 (3.5%) Died of other cause 6 (6.8%) 4 (9.1%) 5 (7.4%) 15 (7.5%)

6 126 european urology 51 (2007) Table 4 Schematic literature review on the outcome of surgery for clinical locally advanced prostate cancer in different studies Survival rate by year of follow-up BPFS CPFS CSS OS (PSA > 0.4) (77.6 at 7.5 yr) Yamada et al. [17] (median FU: 5.4 yr) (n = 57) 72 (meta free) 32 (meta free) Gerber et al. [18] (mean FU: 39 mo; median FU: 26 mo) (n = 242) 29 (PSA > 0.1) Van den Ouden et al. [19] (median FU: 52 mo) (n = 83) 59.8 (PSA > 0.3) Martinez de la Riva et al. [14] (mean FU: 68.7 mo) (ct3a only) (n = 83) 58 (PSA > 0.4) 43 (PSA > 0.4) 38 (PSA > 0.4) Ward et al. [8] (median FU: 10.3 yr) (n = 841) 59.5 (PSA > 0.2) 51.1 (PSA > 0.2) Present series (Mean FU: 70.6 mo) (unilateral ct3a only) (n = 200) BPFS: biochemical progression-free survival, CPFS: clinical progression-free survival, CSS: cancer-specific survival, FU: follow-up, OS: overall survival, PSA: prostate-specific antigen. were, respectively, 93% and 76% for risk group 2, and 93% and 79% for risk group 3. The 8-year CSS and OS rates were, respectively, 89% and 62% for risk group 2, and 88% and 61% for risk group 3. Again, these findings are in contrast with the 5- and 10-year CSS and OS rates in our series. Akakura et al. [12] compared the outcome of RP + ADT with RT + ADT in a randomized trial of patients with locally advanced prostate cancer (stage B2 and stage C). The 5-year CSS and progression-free survival rates were, respectively, 96.6% and 90.5% in the RP + ADT group, and 84.6% and 81.2% in the RT + ADT group. The authors made a case for the combination of radical surgery and ADT, which seemed to provide better outcome results than the combination of RT and ADT. A weakness of their study was the rather low number of patients included. More evidence in favor of multimodality treatment combining surgery with RT was recently provided by the large prospective EORTC trial [13]. In patients with positive margins or extraprostatic extension on final histopathology, this trial showed a significant improvement in progression-free survival in favor of RP with versus without adjuvant RT. In a recent study by Ward et al. [8], 78% of patients treated with RP for locally advanced prostate cancer received adjuvant or salvage treatment, confirming the need of combining treatment modalities in an important number of patients. Nevertheless, this combination achieved very good long-term survival rates. In our study, 56% of patients eventually needed adjuvant or salvage RT or ADT, and very similar outcomes were achieved. The question remains as to how patients should be selected for surgery and which factors are predictive for clinical and biochemical outcome and survival rates. According to our data, the preoperative PSA level was a significant factor for BPFS in univariate analysis only. This was not confirmed in the multivariate analysis. Ward et al. [8] confirmed our finding in their series of patients with ct3 disease, as they could not show a correlation between preoperative PSA and clinical disease progression in multivariate analysis. Martinez de le Riva et al. [14] showed worse BPFS in patients with ct3 prostate cancer with preoperative PSA > 15, compared with those patients with PSA < 15 (logrank test, p = ). From our analysis, the presence of positive surgical margins was a significant independent predictor for BPFS and thus the need for adjuvant or salvage treatment. Neoadjuvant ADT strategies have been

7 european urology 51 (2007) used in ct1 2 disease, but much less information is available on neoadjuvant ADT in ct3 cancers. The SWOG-9109 trial [15] studied the effect of goserelin and flutamide as neoadjuvant ADT in 55 patients with clinical stage T3 (97%) and T4 (3%) prostate cancer before RP. Five-year overall and progressionfree survival rates of 90% and 70%, respectively, were achieved. Histopathology showed organ-confined disease in 62%, and the positive surgical margin rate was 30%. Ward et al. [8] also showed that neoadjuvant ADT is of little help in reducing the positive margin rates in ct3 disease. Both in the neoadjuvant group and the nontreated group, the positive margin rate was 56% ( p = 0.97). In the present series, we excluded all patients who received neoadjuvant ADT. The positive surgical margin rate (33.5%) did not differ from the margin rate in patients who underwent neoadjuvant ADT treatment mentioned in the literature. Pathological T-stage was a significant factor in univariate analysis for BPFS and CPFS in our study, but not in multivariate analysis. Importantly, Kaplan- Meier analysis showed no differences in BPFS and CPFS between pt2 and pt3a disease. Considering the fact that 80% of ct3a cancers in our analysis are in fact either pt2 (23.5%) or pt3a (56.5%), we found that 20% of these ct3a cancers are still understaged and these patients will face poor clinical outcome. Better preoperative staging modalities are urgently needed to provide better patient counseling. The surgical Gleason score was not significantly correlated with BPFS or CPFS on both uni- and multivariate analyses in our analysis. Sciarre et al. [16] studied the impact of the Gleason score in 130 pt3 (66.9% pt3a and 33.1% pt3b) patients. They found a statistically significant difference between Gleason scores of <8 and 8 10 in BPFS and CPFS, but not in CSS. In the study by Ward et al. [8], the pathologic Gleason score 7 was independently associated with clinical disease recurrence. The presence of positive lymph nodes was a significant factor associated with BPFS and CPFS in univariate analysis, but not in multivariate analysis in our series. In T3 disease, the incidence of positive lymph nodes is between 7.9% and 49% [8,14,17 19]. Although there are no prospective randomized trials demonstrating a survival benefit associated with extended pelvic lymphadenectomy (EPLA), there might be an advantage for those with minimal lymph node involvement. Progression-free survival is significantly improved in patients undergoing EPLA with a 35% benefit, compared with standard lymphadenectomy [20]. Cancer volume was a significant predictor for CPFS in both uni- and multivariate analyses, and significantly correlated with BPFS in uni- but not in multivariate analysis in our series. Partin et al. [21] reported that cancer volume and percentage of gland involved with cancer correlated with pathologic stage. Hachiya et al. [22] agreed on this point. They also reported that mean cancer volume and percentage cancer volume to prostate volume were 1.3 ml and 3.23%, respectively, in the surgically cured patients, and 6.2 ml and 18.2%, respectively, in the not surgically cured patients. McNeal [23] found that a cancer volume smaller than 4 ml had favorable morphologic variables, while a volume larger than 12 ml tended to have unfavorable variables. Nevertheless, in a series of 1302 consecutive RP specimens with clinical stage T1 to T3, Kikuchi et al. [24] found that cancer volume did not provide independent prognostic information on BPFS in a multivariate analysis including Gleason score, pathologic stage, and section margin status. Thus, in well-selected patients, RP with adjuvant or salvage treatment when needed may lead to better outcomes than RT alone and may even offer better outcomes than the combination of RT and ADT in the treatment of locally advanced prostate cancer. However, this should ideally be confirmed in well-designed, randomized, prospective trials. 5. Conclusion Clinically advanced prostate cancer is still frequently overstaged. In a well-selected patient group with locally advanced prostate cancer, RP with adjuvant or salvage treatment when needed can yield very high long-term cancer control and survival rates. Margin status and cancer volume are significant predictors of outcome after RP. References [1] Van den Ouden D, Schroder FH. Management of locally advanced prostate cancer. World J Urol 2000;18: [2] Maeda O, Meguro N, Saiki S, et al. Clinical outcome of radical prostatectomy for stage C prostate cancer: comparison with other treatment modalities. Hinyokika Kiyo 1997;43: [3] Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997; 337: [4] Pilepich MV, Caplan R, Byhardt RW, et al. Phase III trial of androgen suppression using Goserelin in unfavorableprognosis carcinoma of the prostate treated with definitive radiotherapy: report of RTOG protocol J Clin Oncol 1997;15:

8 128 european urology 51 (2007) [5] Aus G, Abbou CC, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2005;48: [6] Hsu CY, Joniau S, Van Poppel H. Radical prostatectomy for locally advanced prostate cancer: technical aspects of radical prostatectomy. EAU Update Series 2005;3: [7] Sobin LH, Wittekind C. TNM Classification of prostate cancer. 6th ed. New York, Wiley. Liss; 2002, p [8] Ward JF, Slezak JM, Blute ML, Bergstralh EJ, Zincke H. Radical prostatectomy for clinically advanced (ct3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. BJU Int 2005;95: [9] Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002; 360: [10] Roach M, Lu J, Pilepich MV, et al. Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone on Radiation Therapy Oncology Group clinical trials. Int J Radiat Oncol Biol Phys 2000;47: [11] Roach M, Lu J, Pilepich MV, et al. Predicting long-term survival, and the need for hformonal therapy: a metaanalysis of RTOG prostate cancer trials. Int J Radiation Oncol Biol Phys 2000;47: [12] Akakura k, Isaka S, Akimoto S, et al. Long-term results of a randomized trial for the treatment of stages B2 and C prostate cancer: radical prostatectomy versus external beam radiation therapy with a common endocrine therapy in both modalities. Urology 1999;54: [13] Bolla M, Van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet 2005;366: [14] Martinez de la Riva SI, Lopez-Tomasety JB, Dominguez RM, Cruz EA, Blanco PS. Radical prostatectomy as monotherapy for locally advanced prostate cancer (T3a): 12 years follow-up. Arch Esp Urol 2004;57: [15] Powell IJ, Tangen CM, Miller GJ, et al. Neoadjuvant therapy before radical prostatectomy for clinical T3/T4 carcinoma of the prostate: 5-year followup, Phase II Southwest Oncology Group Study J Urol 2002;168: [16] Sciarre A, Gentile V, Voria G, et al. Role of radical retropubic prostatectomy in patients with locally advanced prostate cancer: the influence of Gleason score Uro Int 2003;70: [17] Yamada AH, Lieskovsky G, Petrovich Z, et al. Results of radical prostatectomy and adjuvant therapy in the management of locally advanced, clinical stage TC, prostate cancer. Am J Clin Oncol 1994;17: [18] Gerber GS, Thisted RA, Chodak GW, et al. Results of radical prostatectomy in men with locally advanced prostate cancer: multi-institution pooled analysis. Eur Urol 1997;32: [19] Van den Ouden D, Hop WCJ, Schroder FH. Progression in and survival of patients with locally advanced prostate cancer (T3) treated with radical prostatectomy as monotherapy. J Urol 1998;160: [20] Heidenreich A, Ohlmann CH. The role of anatomic extented pelvic lymphadenectomy in men undergoing radical prostatectomy for prostate cancer. EAU Update Series 2005;3: [21] Partin AW, Epstein JI, Cho KR, Gittelsohn AM, Walsh PC. Morphometric measurement of tumor volume and percent of gland involvement as predictors of pathological stage in clinical stage B prostate cancer. J Urol 1989;141: [22] Hachiya T, Ichinose T, Kobayashi K, Hirano D, Okada K. Tumor volume and percentage of gland involvement with tumor as predictors of pathological stage in prostate cancer. Nippol Hinyokika Gakkai Zasshi 1998;89: [23] McNeal JE. Cancer volume and site of origin of adenocarcinoma in the prostate: relationship to local and distant spread. Hum Pathol 1992;23: [24] Kikuchi E, Scardino PT, Wheeler TM, Slawin KM, Ohori M. Is tumor volume an independent prognostic factor in clinically localized prostate cancer? J Urol 2004;172: Editorial Comment Stephen Freedland sfreedl1@jhmi.edu Patients with clinical stage T3 disease, though fortunately uncommon today, represent a therapeutic dilemma. They often have high-grade disease, markedly elevated PSA levels, and highvolume disease on needle biopsy. Several facts are known about these patients. First, they are at high risk of treatment failure regardless of the treatment given (i.e. radiation or surgery) [1]. Second, when treated with radiation, overall survival can be increased by the addition of hormonal therapy [2]. Third, though clearly high-risk on the whole, not all men will have pathological T3 disease [3]. Within this conceptual framework, the authors studied the outcome of men with clinical stage T3 disease treated with radical prostatectomy. Overall, the authors found that 10-year outcomes were acceptable: 50% biochemical recurrence rate (defined by either PSA criteria or secondary therapy); 15% progression rate; and 10% prostate cancer mortality. Of note, the risk of prostate cancer death in the current series was similar to men with predominantly clinical stage T2 disease in the radical prostatectomy arm of the randomized study of radical prostatectomy vs. watchful waiting [4], suggesting that men with clinical stage T3 should not be viewed as higher risk than clinical stage T2 patients. This suggestion is supported by the Mayo Clinic data, which found

9 european urology 51 (2007) that men with clinical stage T3 disease had outcomes similar to men with clinical stage T2 disease [3]. The authors of both this series and the Mayo Clinic series credit aggressive early hormonal therapy for their good outcomes. However, given the lack of a control group not treated with early hormonal therapy, it is difficult to assess whether the good outcomes are attributable to early aggressive hormonal therapy or the less indolent nature of the disease than commonly perceived. Either way, studies like this provide some evidence that surgery plus adjuvant therapies may result in long-term cancer-specific survival in men with unilateral ct3 prostate cancer. Prospective randomized trials are clearly needed to further define optimal management for this high risk group. References [1] D Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280: [2] Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997; 337: [3] Ward JF, Slezak JM, Blute ML, Bergstralh EJ, Zincke H. Radical prostatectomy for clinically advanced (ct3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. BJU Int 2005;95: [4] Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005;352: Editorial Comment Shin Egawa, Department of Urology, Jikei University Shool of Medicine, Nishi-Shimbashi, Minato-ku, Tokyo , Japan s-egpro@jikei.ac.jp s-egpro@jcom.home.ne.jp What is the best primary treatment option for locally advanced T3 prostate cancer? The treatment can be radical prostatectomy (RP), radiotherapy (RT), androgen deprivation (ADT) and a combination of these. Patients with node positive or locally advanced prostate cancer who are treated with RP monotherapy are known to be at high risk for early biochemical relapse with rapid progression to clinical disease or even death [1]. Although some high-risk patients may have subclinical distant metastasis at diagnosis, an evaluation of previous Radiation Therapy Oncology Group trials reported improved survival for such patients who received high dose of RT [2]. These findings support an aggressive locoregional approach. Hsu et al. report the long-term outcome of RP series in 200 ct3 disease. 56% (n = 112) received adjuvant or salvage therapy. Overall survival rates at 5 and 10 years were 95.9% and 77.0%, respectively. They believe RP with adjuvant or salvage treatment may lead to better outcomes than RP with or without ADT in the treatment of well-selected, locally advanced prostate cancer. Preoperative selection criteria for those at greatest benefit have not been well defined, however. Though the presented figures are appealing, their statement is based solely on comparison with historical series. They quote contemporary series of small randomized study between RP/ADT versus RT/ADT to make a case for surgery [3]. In this study, at a median followup of 58.5 M, RP/ADT had better 5-year causespecific survival rate than RT/ADT, 96.6% versus 84.6% ( p = 0.024). However, the statistical significance was lost with longer followup at 102 M. The overall survival rates at 10 years were 67.9% versus 60.9% ( p = 0.30), respectively. It is noteworthy that far less than optimal dose of irradiation was applied in that study (60 70 Gy). Thus, their conclusion needs careful reconsideration. Combination of RT and ADT has never been shown to be superior to surgical treatment in combination with other modalities. Well designed, prospective, randomized study with sufficiently long followup can only answer this question. Future adjuvant therapy trials in locally advanced prostate cancer also needs well defined risk group stratification. References [1] Sengupta S, Blute ML, Bagniewski SM, et al. Increasing prostate specific antigen following radical prostatectomy and adjuvant hormonal therapy: doubling time predicts survival. J Urol 2006;175: [2] Valicenti R, Lu J, Pilepich M, et al. Survival advantage from higher-dose radiation therapy for clinically localized prostate cancer treated in the Radiation Therapy Oncology Group trials. J Clin Oncol 2000;18: [3] Akakura K et al. A randomized trial comparing radical prostatectomy plus endocrine therapy versus external beam radiotherapy plus endocrine therapy for locally advanced prostate cancer: results at median followup of 102 months. Personal communication.