Oncologic Outcome and Patterns of Recurrence after Salvage Radical Prostatectomy

european urology 55 (2009) 404 411 available at www.sciencedirect.com journal homepage: www.europeanurology.com Prostate Cancer Oncologic Outcome and Patterns of Recurrence after Salvage Radical Prostatectomy Philippe Paparel, Angel M. Cronin, Caroline Savage, Peter T. Scardino, James A. Eastham * Division of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Article info Article history: Accepted July 3, 2008 Published online ahead of print on July 14, 2008 Keywords: Biochemical recurrence Prostate cancer Salvage prostatectomy Abstract Background: Limited data on patterns of recurrence (local or metastatic) after salvage radical prostatectomy (SP) is available. Objective: To examine biochemical, local and metastatic patterns of recurrence in patients undergoing SP for radiation-recurrent prostate cancer. Design, setting, and participants: 146 patients with biopsy-proven local recurrence of prostate cancer after radiation therapy treated with SP were evaluated in a retrospective study at a single institution. Intervention: All patients underwent SP by mainly two surgeons. Measurements: Biochemical recurrence (BCR) after SP was defined as a serum prostate-specific antigen (PSA) level of 0.2 ng/ml or was defined by the initiation of androgen deprivation therapy. All predictors analyzed were determined after radiotherapy, before SP, and included PSA level, clinical stage, biopsy Gleason score, age at SP, and time interval from radiotherapy to SP. Results and limitations: Of the 146 patients treated with SP, 65 developed BCR. The median follow-up period for recurrence-free patients was 3.8 yr; 43 patients (29%) were followed for >5 yr. Overall, the 5-yr recurrence-free probability was 54% (95% CI, 44 63%). Clinical local recurrence occurred in only one patient who also had bone metastases. Overall, there were 16 prostate cancer specific deaths and 19 deaths from other causes. The 5-yr cumulative incidence of death from prostate cancer was 4% (95% CI, 2 11%). Pre-SP serum PSA level and biopsy Gleason score were significantly associated with death due to prostate cancer ( p < 0.0005 and p = 0.002, respectively). This study is retrospective and included carefully selected patients treated over a long period by, mainly, two experienced surgeons. Conclusions: SP provides excellent local cancer control; only one patient in our series experienced a clinical local recurrence. Earlier identification of patients with persistent, viable local cancer despite radiation therapy will appropriately select patients for SP. # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Division of Urlogy, Memorial Sloan-Kettering Cancer Center, 353 East 68th Street, Suite 527, New York, NY 10021, USA. Tel. +1 646 42 4390; Fax: +1 212 988 0759. E-mail address: easthamj@mskcc.org (J.A. Eastham). 0302-2838/$ see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2008.07.007

european urology 55 (2009) 404 411 405 1. Introduction Despite improved methods of delivery (ultrasoundguided brachytherapy, three-dimensional conformal techniques, and intensity-modulated radiation therapy) that have permitted the administration of higher radiation doses with fewer side effects, up to one-third of patients treated with radiation therapy for clinically localized prostate cancer will have evidence of treatment failure [1,2]. The vast majority of patients with recurrence after radiation therapy are identified by an elevated and rising serum prostate-specific antigen (PSA) level (biochemical rather than clinical failure). The challenge for the clinician is to determine whether the PSA-level elevation originates from local persistence (recurrence) of cancer or from distant metastases or both. If the recurrence is local, there remains an opportunity for cure by additional treatment to the primary site. Treatment options for patients with local recurrence of prostate cancer after radiation therapy include expectant management, immediate continuous or intermittent hormonal therapy, or further attempts at cure with additional local therapy including radio-frequency thermal ablation, high-intensity focused ultrasonography (HIFU), cryoablation, brachytherapy, or salvage radical prostatectomy (SP). While additional local therapies are frequently utilized in patients with locally recurrent prostate cancer after radiation therapy, few studies have documented long-term oncologic outcomes for these procedures. Only SP has been shown to eradicate the cancer for 10 yr; the rate of 10 yr of freedom from biochemical recurrence (BCR) after SP alone was 30% to 43%, and 10-yr cancerspecific survival rates of 70% to 77% have been reported [3 5]. While the likelihood of BCR after SP has been documented, little information is available regarding the clinical patterns of recurrence after SP. The purpose of this study is to examine patterns of biochemical, local, and metastatic progression in patients undergoing SP. 2. Methods 2.1. Study population Between June 1984 and September 2006, 149 consecutive patients with biopsy-confirmed, locally recurrent prostate cancer after radiation therapy underwent SP with curative intent. These patients were treated over a long period of time, and over that period of time, practice patterns have changed. Early in this study period most patients underwent a minimum of six-core, transrectal ultrasound-guided prostate biopsies, whereas more recently, patients had biopsies of at least a 12 cores performed to prove local recurrence. Additionally, since 1998, every patient has had preoperative endorectal magnetic resonance imaging (MRI). This study updates an earlier study published in 2004 [6]. Criteria for SP are strict and include the following: a life expectancy >10 yr, the presence of clinically localized prostate cancer determined by biopsy (at the time of radiotherapy and before SP), the absence of significant voiding symptoms or urinary incontinence, a negative evaluation for systemic disease, no evidence of radiation proctitis, and the absence of lymph node involvement (if a standard pelvic lymph node dissection for staging had been performed at the time of radiation). Clinical information was obtained from a prospectively maintained clinical database. Three patients were not followed after SP, leaving 146 (98%) patients available for analysis. This study received institutional review board approval prior to its initiation. Clinical stage was assigned by the treating physician according to the 1992 TNM system. The technique of SP and preoperative patient preparation has been previously described [3]. The SP specimen was analyzed according to the wholemount, step-section technique. Postoperatively, patients were followed up with serum PSA level determination and digital rectal examination every 3 mo for the first 2 yr and annually thereafter. Disease progression after SP was defined as an increase in serum PSA level 0.2 ng/ml (at least two PSA levels had to be abnormal to meet the criterion for failure) or by the initiation of androgen deprivation therapy (ADT) postoperatively. (The focus of our manuscript is the role of SP as monotherapy to cure radiation-recurrent prostate cancer because the use of any adjuvant treatment [primarily ADT] was considered to be a treatment failure.) Patients with disease progression after SP were evaluated for metastatic disease at the discretion of the treating physician. The decision to initiate ADT was made between the patient and the clinician. 2.2. Statistical methods The probability of freedom from biochemical recurrence following SP was estimated using Kaplan-Meier methods. Multivariable Cox proportional-hazards regression was used to evaluate predictors of BCR following SP. All predictors analyzed were determined postradiotherapy and pre-sp and included the following: PSA, clinical stage, biopsy Gleason score, age at SP, and interval from radiotherapy to SP. As an exploratory analysis, we assessed the association of PSA doubling time (PSA DT) with recurrence using univariate analyses in the subset of 100 patients with a calculable PSA DT. The cumulative incidence of death due to prostate cancer following SP was estimated by adjusting for the competing risk of death due to other causes [7]. A proportional-hazards regression model, adjusting for the competing risk, was used to univariately evaluate predictors of death due to prostate cancer [8]. Multivariable analyses were not conducted because of the limited number of events. Statistical analyses were conducted using Stata 9.0 (Stata Corp, College Station, TX, USA) and R (R Foundation for Statistical Computing, Wien, Austria) with the cmprsk package.

406 european urology 55 (2009) 404 411 3. Results Patient characteristics are summarized in Table 1. Sixty-five patients had a recurrence after SP (60 patients met the definition of BCR, while 5 patients received hormonal therapy prior to BCR following SP). The median follow-up period for patients without BCR was 3.8 yr; 43 patients (29%) were followed-up for >5 yr. The 5-yr recurrence-free probability was 54% (95% CI, 44 63%; Fig. 1). On multivariable analysis, post radiation therapy (RT), pre-sp biopsy Gleason score was significantly associated with recurrence ( p = 0.047; Table 2). In particular, the hazard ratio for recurrence among patients with biopsy Gleason score 8 in relation to biopsy Gleason grade 6 was 2.71 (95% CI, 1.10 6.68). The 5-yr recurrence-free probability was 54% (95% CI, 36 69%) for biopsy Gleason score 6 and 57% (95% CI, 43 70%) for biopsy Gleason score 7 compared to only 35% (95% CI, 11 61%) for biopsy Gleason score 8 (Fig. 2). Pre-SP PSA (hazard ratio [HR]: 1.02; 95% CI, 1.00 1.05; p = 0.10) and age at SP (HR: 1.04; 95% CI, 0.99 1.10; p = 0.15) both showed marginal associations with recurrence. On exploratory univariate analysis, PSA DT between RT and SP Table 1 Summary data on 146 patients undergoing salvage prostatectomy (SP) for radiation therapy (RT) recurrent prostate cancer. Data are given as median (interquartile range) or frequency (percentage) No. of patients 146 Age at SP (yr) 65 (61 69) Pre-SP PSA (ng/ml; n = 130) 5.1 (2.7 8.9) PSA doubling time between RT and SP 9.9 (2.6 20.9) (mo; n = 100) Interval from RT to SP (yr; n = 139) 4.6 (2.7 6.0) Post-RT clinical stage (n = 137) <T2b 58 (42%) T2b 79 (58%) Fig. 1 Kaplan-Meier probability of freedom from recurrence following salvage prostatectomy. was not significantly associated with recurrence (HR: 0.99 per month; 95% CI, 0.98 1.01; p = 0.6). Eighteen (13%) of the 136 patients who underwent a pelvic lymph node dissection at the time of SP were found to have nodal metastases. While the majority of these patients developed BCR, four remained free of disease without hormonal therapy at 1 yr, 2 yr, 7 yr, and 20 yr after SP, respectively. Of the 65 patients who had recurrences, 41 received hormone therapy after SP (5 patients received hormone therapy before the recurrence, and 36 patients received it after the recurrence). Twenty-nine patients progressed to hormonerefractory disease, that is, they developed a documented rise in PSA level despite hormone therapy. Twenty-four of 65 patients who had recurrences subsequently developed radiographic evidence of metastasis. Only one patient developed a clinically detectable local recurrence during the follow-up period. No patient developed upper-tract obstruction. Post-RT biopsy Gleason score 6 49 (34%) 7 61 (42%) 8 16 (11%) Not graded due to treatment effect 8 (5%) Unknown 12 (8%) Post-SP pathology Gleason score 6 15 (10%) 7 83 (57%) 8 29 (20%) Not graded due to treatment effect 2 (1%) Unknown 17 (12%) Extraprostatic extension (n = 143) 80 (56%) Seminal vesical invasion (n = 142) 54 (38%) Lymph node involvement (n = 136) 18 (13%) Positive surgical margins 24 (16%) PSA, prostate-specific antigen. Fig. 2 Kaplan-Meier probability of freedom from recurrence following salvage prostatectomy by biopsy Gleason score.

european urology 55 (2009) 404 411 407 Table 2 Multivariable Cox proportional-hazards regression to evaluate predictors of biochemical recurrence following salvage prostatectomy (SP) for radiation therapy (RT) recurrent prostate cancer (106 patients with complete data for all predictors were included in the analysis). Predictor Hazard ratio 95% CI p value Pre-SP PSA (ng/ml) 1.02 1.00 1.05 0.10 Post-RT clinical stage 0.4 <T2b Reference Reference T2b 0.75 0.38 1.46 Post-RT biopsy Gleason score 0.047 6 Reference Reference 7 0.91 0.46 1.80 8 2.71 1.10 6.68 Age at SP (yr) 1.04 0.99 1.10 0.15 Interval from RT to SP (yr) 0.99 0.89 1.11 0.9 PSA, prostate-specific antigen. Table 3 Univariate proportional-hazards regression to evaluate predictors of death from prostate cancer following salvage prostatectomy (SP), adjusting for the competing risk of death from other causes Predictor Hazard ratio 95% CI p value Pre-SP PSA (ng/ml) 1.04 1.02 1.05 <0.0005 Post-RT clinical stage 0.4 <T2b Reference Reference T2b 1.67 0.50 5.58 Post-RT biopsy Gleason grade 0.002 6 Reference Reference 7 1.14 0.30 4.34 8 5.11 1.53 17.0 Age at SP (yr) 0.98 0.90 1.06 0.6 Interval from RT to SP (yr) 0.93 0.74 1.15 0.5 RT, radiation therapy; PSA, prostate-specific antigen. In total, there were 35 patient deaths: 16 patients died of prostate cancer, and 19 patients died of other causes. The median follow-up period for survivors was 4.6 yr. The 5-yr cumulative incidence of death due to prostate cancer was 4% (95% CI: 2%, 11%; Fig. 3). Predictors of death from prostate cancer were similar to those obtained for the outcome of biochemical recurrence (Table 3): with univariate analysis, PSA and biopsy Gleason score before SP were significantly associated with death due to prostate cancer ( p < 0.0005 and p = 0.002, respectively). Four of 49 patients with biopsy Gleason score 6 died of prostate cancer, 4 of 61 patients with biopsy Gleason score 7 died of prostate cancer, and 5 of 16 patients with biopsy Gleason score 8 died of prostate cancer. Only 1 of 49 patients and 2 of 55 patients with PSA levels measured before SP of <4 and 4 10, respectively, subsequently died of prostate cancer; 6 of 26 patients with PSA 10 died of prostate cancer. In the remaining seven patients who died of prostate cancer, the pre-sp serum PSA level was Fig. 3 Cumulative incidence of death from prostate cancer following salvage prostatectomy.

408 european urology 55 (2009) 404 411 unknown. PSA DT between RT and SP was not significantly associated with disease-specific death (HR: 0.99/mo; 95% CI, 0.97 1.01; p = 0.2). 4. Discussion The primary goal of any salvage local therapy for radiation-recurrent prostate cancer is to provide a durable cure; the prevention of symptomatic local and systemic progression is a secondary objective. As such, the oncologic efficacy of any treatment is judged by the ability of that treatment to accomplish these goals. It is difficult to assess the outcomes of most currently available salvage therapies because of a lack of long-term outcome data and/or the small sample size reported in published series [9 16]. While each of these salvage therapies (HIFU, brachytherapy, cryotherapy, SP) can be safely delivered, information regarding the benefit they provide in terms of cancer control is limited. Gelet et al reported their experience with salvage HIFU [16]. A total of 71 patients were treated with a mean follow-up period of only 14.8 mo. Efficacy was assessed by posttreatment biopsy with 57 (80%) having a negative biopsy. A nadir PSA level of <0.5 ng/ml was achieved in 43 of 71 patients (61%). The nadir level was obtained within 3 mo. At the last follow-up, 44% of the patients had no evidence of any disease progression. Whether or not these results are durable awaits further follow-up, but these short-term oncologic outcomes seem inferior to SP. Experience with salvage brachytherapy is limited, but some successes have been reported in terms of biochemical control [9,12]. Longer-term outcomes with salvage cryotherapy have recently been reported. Ng et al assessed the efficacy of salvage cryotherapy in 187 patients with locally recurrent prostate cancer after radiotherapy [11]. Approximately 70% of these patients also received 3 mo of neoadjuvant ADT. The mean follow-up period was 39 mo. Biochemical recurrence was defined as nadir PSA level plus 2 ng/ml. Patients with precryotherapy PSA levels of <4 ng/ml had 5-yr and 8-yr biochemical recurrence-free survival rates of 56% and 37%, respectively. In contrast, patients with precryotherapy PSA levels of 10 ng/ml had 5-yr and 8-yr biochemically recurrence-free survival rates of only 1% and 7%, respectively. The fourquadrant positive biopsy rate after salvage cryotherapy was 17%. Serum PSA level immediately prior to salvage cryotherapy was a predictive factor for biochemical recurrence according to univariate and multivariate analyses. The investigators recommended that salvage cryotherapy should be performed when serum PSA level is still relatively low because the procedure may potentially be curative in these patients. We have to acknowledge that patient populations may be different among SP and the other miniinvasive salvage therapies (HIFU and cryotherapy) explaining the different oncologic outcomes between these series. The eligibility criteria for SP in our study are very strict and included a lifeexpectancy >10 yr versus 5 yr in the study of Ng et al [11] with salvage cryotherapy. Patients with a life expectancy <10 yr may be less suitable for SP and other minimally invasive procedures such as salvage cryotherapy or HIFU may be more appropriate. Similarly, the median age in the Ng et al study was 70.9 yr (oldest patient, 81 yr) versus 65 yr (range: 61 69) in our current study. The mean PSA level in the largest study of salvage HIFU was 20.4 ng/ml, and the mean PSA level was 5.1 ng/ml in our study [16]. The overall outcomes have favored SP solely based on patient selection; however, as with the cryotherapy study, those with the lowest PSA levels still had an improved oncologic outcome with SP. We have to consider that there are several modalities to treat a local recurrence after radiation failure, but patients with few comorbidities and a life expectancy >10 yr are most appropriate for a SP. Our results demonstrate that SP is an effective oncologic procedure in terms of biochemical and clinical results. Because the presalvage PSA and biopsy Gleason grade markedly affect outcome, methods to better identify patients with radiationrecurrent prostate cancer earlier in the course of their disease are paramount. Although SP has been effective with respect to biochemical results, we cannot be certain that these results would translate into a reduced rate of disease-specific death. For example, those who remained free from recurrence tended have biopsy Gleason 7; from these data we cannot ascertain whether these patients were spared prostate-specific death as a result of SP. An additional benefit of retropubic SP is the staging information and potential therapeutic benefit obtained from the pelvic lymph node dissection. Several studies have assessed the morbidity of local recurrence after radiation failure for prostate cancer [17,18]. Holzman et al examined 121 patients who experienced clinical failure after radiation therapy [17]. With a mean follow-up period of 8.1 yr, 64 patients (53%) developed a symptomatic local recurrence. The most common patterns of recurrence were bladder-outlet obstruction requiring transurethral resection of the prostate (TURP; 44 patients) and hydronephrosis (24 patients) requiring urinary diversion with a ureteral stent or

european urology 55 (2009) 404 411 409 nephrostomy tube. Clearly, failure to control the local cancer resulted in a significant risk for patients with local recurrence after radiation therapy. The reported positive biopsy rates after both HIFU and cryotherapy are thus quite concerning. Whether they will translate into symptomatic local failure requires further follow-up, but the <1% clinical local failure rate after SP is clear evidence as to the oncologic benefit of this procedure. While SP has demonstrated excellent oncologic outcomes, its widespread use has been limited because of the technical demands of the procedure as well as concerns regarding post-sp bladder-neck contracture and urinary incontinence [6]. Fortunately, intraoperative complications have decreased with increasing experience with this procedure. Most SPs are now performed via a standard retropubic approach using techniques similar to those employed for standard radical prostatectomy. Limited data is available on the perineal approach [19]. The risks of rectal injury, ureteral transection, and blood transfusion are similar to standard RP in experienced hands. This is likely related not only to improved surgical techniques but also to better targeted radiation therapy thus reducing the amount of periprostatic fibrosis. Urinary incontinence and bladder neck contracture, however, continue to be problematic. Incontinence after SP occurs in about 40% of patients with up to 25% of patients requiring an artificial urinary sphincter [6]. Concerns regarding urinary incontinence after SP have been one of the primary factors prompting investigation of less invasive salvage therapies. While HIFU, brachytherapy, and cryotherapy are considered less morbid than SP, these therapies are certainly not risk-free. Ng et al report acute urinary retention in 21% of patients, persistent lower urinary tract symptoms in 10% of patients, chronic pelvic pain in 14% of patients, and incontinence in 40% of patients after salvage cryotherapy [11]. One must also remember that, although salvage therapies using HIFU, brachytherapy, or cryotherapy may be associated with fewer postprocedure complications than SP, any salvage technique is first and foremost performed for oncologic reasons. These techniques should be shown to have similar oncologic outcomes for SP before they are considered as standards of care. This study has some limitations. This is a retrospective study over a long period (1984 2006). Irradiation and surgical techniques obviously change over a long period. The last patients of the series have a short follow-up, so it is possible that we have underestimated some BCR. SP in our institution has been performed on a very select population (described in the methods section) by mainly two experienced surgeons. 5. Conclusions Salvage radical prostatectomy is an effective treatment for patients with local failure after radiation therapy. SP provides excellent local cancer control with only one patient in our series experiencing a clinical local recurrence, leading to 5-yr recurrence rates of approximately 45% for patients with biopsy Gleason 7. The effect of SP on prostate-specific mortality remains unclear. Author contributions: James A. Eastham had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Eastham, Paparel. Acquisition of data: Paparel. Analysis and interpretation of data: Cronin, Savage. Drafting of the manuscript: Eastham, Paparel, Scardino. Critical revision of the manuscript for important intellectual content: Eastham, Paparel. Statistical analysis: Cronin, Savage. Obtaining funding: Paparel. Administrative, technical, or material support: Eastham, Scardino, Paparel. Supervision: Eastham, Scardino. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA 2005;294: 1233 9. [2] Zelefsky MJ, Fuks Z, Hunt M, et al. High dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys 2002;53:1111 6. [3] Bianco Jr FJ, Scardino PT, Stephenson AJ, Diblasio CJ, Fearn PA, Easthman JA. Long-term oncologic results of salvage radical prostatectomy for locally recurrent prostate cancer after radiotherapy. Int J Radiat Oncol Biol Phys 2005;62:448 53.

410 european urology 55 (2009) 404 411 [4] Amling CL, Lerner SE, Martin SK, Slezak JM, Blute ML, Zincke H. Deoxyribonucleic acid ploidy and serum prostate-specific antigen predict outcome following salvage prostatectomy for radiation refractory prostate cancer. J Urol 1999;161:857 62. [5] Ward JF, Sebo TJ, Blute ML, Zincke H. Salvage surgery for radiorecurrent prostate cancer: contemporary outcomes. J Urol 2005;173:1156 60. [6] Stephenson AJ, Scardino PT, Bianco Jr FJ, Diblasio CJ, Fearn PA, Eastham JA. Morbidity and functional outcomes of salvage radical prostatectomy for locally recurrent prostate cancer after radiation therapy. J Urol 2004;172: 2239 43. [7] Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Annals of Statistics 1998;16:1141 54. [8] Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. JASA 1999;94:496 509. [9] Beyer DC. Permanent brachytherapy as salvage treatment for recurrent prostate cancer. Urology 1999;54:880 3. [10] Izawa JI, Madsen LT, Scott SM, et al. Salvage cryotherapy for recurrent prostate cancer after radiotherapy: variables affecting patient outcome. J Clin Oncol 2002;20: 2664 71. [11] Ng CK, Moussa M, Downey DB, et al. Salvage cryoablation of the prostate: follow-up and analysis of predictive factors for outcome. J Urol 2007;178:1253 7. [12] Ghafar MA, Johnson CW, De La Taille A, et al. Salvage cryotherapy using an argon based system for locally recurrent prostate cancer after radiation therapy: the Columbia experience. J Urol 2001;166:1333 7. [13] Allen GW, Howard AR, Jarrard DF, et al. Management of prostate cancer recurrences after radiation therapy brachytherapy as a salvage option. Cancer 2007;110:1405 16. [14] Ismail M, Ahmed S, Kastner C, et al. Salvage cryotherapy for recurrent prostate cancer after radiation failure: a prospective case series of the first 100 patients. BJU Int 2007;100:760 4. [15] Ahmed S, Lindsey B, Davies J. Salvage cryosurgery for locally recurrent prostate cancer following radiotherapy. Prostate Cancer Prostatic Dis 2005;8:31 5. [16] Gelet A, Chapelon JY, Poissonnier L, et al. Local recurrence of prostate cancer after external beam radiotherapy: early experience of salvage therapy using high-intensity focused ultrasonography. Urology 2004;63:625 9. [17] Holzman M, Carlton Jr CE, Scardino PT. The frequency and morbidity of local tumor recurrence after definitive radiotherapy for stage C prostate cancer. J Urol 1991;146:1578 82. [18] Stephenson AJ, Eastham JA. Role of salvage radical prostatectomy for recurrent prostate cancer after radiation therapy. J Clin Oncol 2005;23:8198 203. [19] van der Poel HG, Beetsma DB, van Boven H, Horenblas S. Perineal salvage prostatectomy for radiation resistant prostate cancer. Eur Urol 2007;51:1565 72. Editorial Comment on: Oncologic Outcome and Patterns of Recurrence after Salvage Radical Prostatectomy Markus Graefen University Medical Center Eppendorf, Hamburg, Germany graefen@uke.uni-hamburg.de In this noteworthy study written by some of the most recognized experts in the field of radical prostatectomy (RP), two important messages are clear: first, salvage prostatectomy is at the edge of becoming an established therapeutic option for men with recurrent disease after any kind of radiation therapy [1]. Second, however, this procedure definitely belongs in the hands of experienced surgeons, as even with these practitioners the morbidity rate is not comparable to that of primary radical prostatectomy [2,3]. The growing experience with and fine tuning of radical prostatectomy means that today, patients can expect adequate functional results even after salvage RP. Besides continuous improvements of the surgical technique, this is a result of better targeted radiation therapy leading to less periprostatic fibrosis. Nevertheless, even in experienced hands, functional outcomes such as urinary continence are impacted by prior radiation therapy, and patients need to be aware of this. Salvage prostatectomy offers excellent local control, with only one patient with evidence of recurrence in this study; however, despite strict patient and tumour selection criteria (median PSA 5.1 ng/ml), almost half of the patients recurred after 5 yr [1]. Considering the fact that we will not know for some time if salvage RP will lead to an overall survival benefit, we need to find better selection criteria in order to identify patients who will benefit from such a precarious procedure. The current selection criteria, such as presalvage PSA, are controversial and obviously not sufficient. Van der Poel recently showed that PSA doubling time is an important predictor of outcome in this situation, which was not confirmed by the current study. Using the biopsy Gleason sum is suggested by the authors; however, we all know about the potential differences between biopsy Gleason grade and final pathologic Gleason grade [4].

european urology 55 (2009) 404 411 411 Even though it sounds like an editorial comment cliché, better markers and imaging techniques are needed to improve the identification of patients who are ideal candidates for such a procedure those with an adequate life expectancy and nonmetastasized disease. References [1] Paparel P, Cronin AM, Savage C, Scardino PT, Eastham JA. Oncologic outcome and patterns of recurrence after salvage radical prostatectomy. Eur Urol 2009;55: 404 11. [2] Graefen M, Walz J, Huland H. Open retropubic nervesparing radical prostatectomy. Eur Urol 2006;49:38 48. [3] van der Poel HG, Beetsma DB, van Boven H, Horenblas S. Perineal salvage prostatectomy for radiation-resistant prostate cancer. Eur Urol 2007;51:1565 72. [4] Chun FK-H, Steuber T, Erbersdobler A, et al. Development and internal validation of a nomogram predicting the probability of prostate cancer Gleason sum upgrading between biopsy and radical prostatectomy pathology. Eur Urol 2006;49:820 6. DOI: 10.1016/j.eururo.2008.07.008 DOI of original article: 10.1016/j.eururo.2008.07.007