Curr Urol Rep (2012) 13:179186 DOI 10.

1007/s11934-012-0240-6

PROSTATE CANCER (R REITER, SECTION EDITOR)

Radical Prostatectomy as Primary Treatment of High-risk Prostate Cancer

Alexandre Ingels & Alexandre de la Taille & Guillaume Ploussard

Published online: 9 February 2012 # Springer Science+Business Media, LLC 2012

Abstract High-risk prostate cancer (PCa), established according to the dAmico criteria or other prognostic tools, remains very heterogeneous, including a third of patients with excellent prognosis in whom surgical treatment can result in long-term progression-free survival. In contrast, a substantial proportion of high risk will not be cured by local treatment alone and might benefit from a more aggressive multimodal adjuvant treatment strategy. However, to date, except in one adjuvant radiotherapy series, no neoadjuvant or adjuvant therapy has shown a survival improvement after radical prostatectomy for high-risk PCa. Recent observational studies tend to prove that radical prostatectomy may offer benefits over radiotherapy in disease-free and overall survival. However, good Level 1 evidence is lacking and further prospective studies are warranted to directly compare the outcomes of radical prostatectomy to combined radiation and hormonal therapy in high-risk patients. Keywords Prostate cancer . Radical prostatectomy . Highrisk prostate cancer . Outcomes . Adjuvant . Radiotherapy . Adjuvant hormone therapy . Treatment . Combination therapy . Gleason score . Staging . Radical prostatectomy

Introduction Prostate cancer (PCa) is the most common solid malignancy in men in the European Union and the second leading cause of death attributable to cancer. Despite the widespread use of prostate-specific antigen (PSA) screening, some patients are still diagnosed with a locally advanced PCa. Therapeutic strategy remains unclear with no clear consensus for these men. Nomograms also have been established to better characterize high-risk patients and predict the probability of PCa recurrence for each patient [1]. Importantly, after radical prostatectomy (RP), histoprognostic risk factors for disease recurrence and disease-specific survival include extracapsular extension, high Gleason score, positive surgical margins, seminal vesicle invasion, and positive lymph nodes [2]. According to the preoperative dAmico criteria, RP alone in patients with high-risk PCa leads to a cure in about 50% of cases [3]. Relapse is mostly due to distant micrometastasis, and combination therapy should be proposed. The goal of adjuvant therapies would be to control and/or treat distant micrometastases. However, no adjuvant standard treatment after surgery is clearly recommended for high-risk tumors. Adjuvant hormone therapy significantly improves survival in patients with positive lymph nodes, with clear benefit for immediate androgen deprivation therapy (ADT) [4, 5]. In the case of negative lymph nodes, the survival advantage has not been demonstrated [6]. Neoadjuvant hormonotherapy failed to show overall survival (OS) rate increase [7]. This article reviews the state of knowledge for the management of highrisk PCa and describes the evidence comparing the different strategies and the best timing to follow between local and systemic treatments. After describing the various definitions of high-risk PCa, we will describe the different evidencebased strategies from the literature and the place of RP associated or not with combined treatment.

A. Ingels : A. de la Taille : G. Ploussard Department of Urology, APHP, CHU Henri Mondor, 51 Avenue de Lattre de Tassigny, 94010 Crteil, France G. Ploussard (*) INSERM U955, Equipe 7, Universit Paris 12, Crteil, France e-mail: g.ploussard@gmail.com

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Definitions of High-risk Prostate Cancer High-risk disease is defined as a significant likelihood of progressive, symptomatic disease or death from PCa [8]. However, accurate categorization of high-risk PCa cases remains elusive (Table 1). Many studies have been published to assess the best markers to predict the prognosis of PCa. Independent risk factors of recurrence and survival are known to be PSA, clinical tumor stage, Gleason score, and velocity of the PSA. Stratifications of patients according to their prognosis are usually founded on multi-criterial scores based on these independent factors. Many definitions of high-risk PCa are reported in the literature. Some are founded on single-criteria definition, such as a Gleason score higher than 7 on biopsies [9], preoperative PSA of 20 ng/mL or higher [10], or clinical stage T3 on digital rectal examination (DRE) [11]; this last definition considers locally advanced and high-risk PCa as one entity. Locally advanced cancers definitively have a high risk of recurrence after treatment; however, some locally advanced cancers seem to be worse than others, and on the other hand, some small-volume tumors even undetectable on DRE can have a high risk of recurrence. Thus, definitions based on a multi-criterial evaluation combining the clinical stage, biological PSA, and pathological Gleason score seem to be more relevant. The most widely used predictive classification of the risk group is defined by DAmico et al. [12] and is based on the preoperative PSA level, biopsy Gleason score, and American Joint Committee on Cancer tumor stage [12]. High-risk group criteria are T2c PCa or PSA level higher than 20 ng/mL or a Gleason score higher than 7. This predictive prognostic score has been reassessed in a multi-institutional update, and the high-risk group presented an OS rate of 75% at 5 years of the definitive therapy and specific survival of 50% at 10 years [13]. Relative risk for specific mortality of PCa after RP was 14.2 for the patients ranked in the high-risk group (4.9 and 1.0 for the intermediate- and low-risk groups, respectively). Other definitions based on the same criteria with different cut-off limits have been reported by Scardino [14] and Clark et al. [15].

Table 1 Main preoperative definitions of high risk prostate cancer in the literature Biopsy GS 810 Preoperative PSA 20 ng/mL 1992 cTNM cT3 cT2c, biopsy GS 810, PSA 20 ng/mL cT3, biopsy GS 810, PSA 20 ng/mL cT2b, GS 810, PSA 15 ng/mL Preoperative PSA velocity >2 ng/mL per year Kattan nomogram 5-year progression-free probability 50% GS Gleason score, PSA prostate-specific antigen

PSA velocity and PSA doubling time (PSADT) also have been proven as useful predictors of specific survival after definitive therapy. DAmico et al. [13] have evaluated 1095 patients after RP for T1c or T2 tumour stage. Two groups were split according to an annual PSA velocity during the year before the diagnosis over or under (or equal to) 2.0 ng/mL. High-velocity group had a significantly shorter time to recurrence, lower specific survival, and more advanced pathologic stage [13]. PSADT was identified as a good predictor of the time to metastatic disease or death when it was combined with other variables such as Gleason score and time to biochemical progression [16]. The calculation of PSADT is based on the fact that serum PSA levels in patients with newly diagnosed or recurrent PCa follow an exponential growth curve. The formula is as follows: PSADT ln2 t=flnPSAt lnPSAinitialg , where t is the time between the two PSA measurements. In clinical practice, PSADT is quickly accessible with a calculator. These results lead to the idea that PSA kinetics is a useful method to identify high-risk patients for recurrence and death from PCa. Nomograms are integrative tools using clinical, biological, and pathological data to predict the prognostic. Kattan postoperative nomogram has been assessed on patients who underwent RP and is based on preoperative serum PSA, degree of capsular invasion, Gleason score, surgical margin status, seminal vesicle invasion, and lymph node involvement [1]. This nomogram has been first updated to extend the prediction from 7 to 10 years [17] and then externally confirmed by two independent cohorts. Kattan nomogram is a useful tool to determine the risk group and decide on indication of adjuvant therapies, even if it cant suggest the appropriate radical treatment due to the fact that its evaluation is based on RP outcomes. To date, the dAmico criteria are the most used definition of high-risk PCa. However, there is no clear consensus among the urologic community. Yossepowitch et al. [10] have compared eight definitions of high-risk PCa from the literature. From a 4708-patient cohort, and depending on the definition, the cohort comprised 3%38% high-risk PCa patients, suggesting an important heterogeneity among the definitions. Depending on the definition, 22% to 63% of patients had organ-confined cancers, and 41% to 74% remained progression-free 10 years after surgery alone. Nguyen et al. [18] have reported contradictory findings and showed that biochemical recurrence-free survival (RFS) following radiotherapy did not vary significantly based on six different definitions. Thus, various schemes based on clinicopathological criteria have been proposed to stratify cases by presumed recurrence risk. However, when considering high-risk PCa, the relapse-free survival is not the ideal end point. The most relevant parameters would be the PCa-specific mortality and

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the OS. Such outcomes studies of different high-risk definitions are lacking. Despite the diversity of criteria defining high-risk PCa, the dAmico criteria remain largely used and validated in the literature.

What is the Current Place of Radical Prostatectomy for High-risk Disease? The aim of RP in locally advanced PCa is to debulk the tumour and to decrease the risk of metastatic dissemination. Thus, RP might be considered as the best treatment for local control. Another important advantage for RP is that cancer aggressiveness is correctly evaluated on RP specimen. Thus, postoperative nomograms can be used to better characterize high-risk patients and predict the probability of PCa recurrence for each patient. Despite treatment, a significant proportion of these patients will experience PSA-defined failure and cancer-specific death, indicating a need for more aggressive initial therapy and a multimodality treatment approach. However, even if RP and external beam radiotherapy (EBR) are the two recommended treatment options in high-risk PCa [19], only a third of the patients undergo RP as the initial treatment [20]. Urologists traditionally recommended radiotherapy plus ADT over RP, not so much because they felt the oncologic outcomes were better with radiotherapy, but because rates of incontinence and impotence with RP were high and cure rates were discouraging. The effectiveness of RP as single treatment in high-risk PCa has been assessed in large retrospective series. The rate of disease-free survival ranged from 40%50% among studies [2126]. However, it must be stressed that a nonnegligible amount of patients received adjuvant therapy during the follow-up. On a retrospective nationwide study, the PCa committee of the French Association of Urology assessed outcomes of RP for high-risk PCa in 813 patients. Metastasis-free survival, 5-year RFS, and OS were 96.1%, 74.1%, and 98.6%, respectively [27]. In this series, 35% of patients had received adjuvant therapy before diagnosis of PSA relapse. Van Ouden et al. [28] have previously reported 5- and 10-year specific survival rates ranging from 83% 92% and from 72%82%, respectively, in a review of eight RP series. Unfortunately, in most series, the use of adjuvant or salvage therapy after RP was not thoroughly studied. Literature supports evidence that surgical treatment can result in long-term progression-free survival (PFS) in a subset of carefully selected high-risk men. These interesting oncologic outcomes may be explained by an important rate of downstaging. Thus, about a third of patients with a preoperatively suspected high-risk PCa had a pathologically confirmed favorable PCa in RP specimens [25, 26, 27]. Thus, an organ-confined disease, even in preoperatively

high-risk patients, can lead to excellent outcomes after RP. Local therapy, such as RP, has to remain one of the standards of care for these high-risk patients with curative intent. Pathological evaluation on prostatectomy specimens provides better predictive assessment of high risk compared with only preoperative criteria. To date, no large randomized trials have been performed to compare these two local treatments. In 2010, a nationwide retrospective study from the United States compared 404,604 men with clinically localized PCa. In the whole cohort, disease-specific mortality was lowest in the RP group (3.6%) than in the EBR (6.5%) or observational groups (10.8%) [29]. Another study involving the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) in 2010 retrospectively compared 7,538 men treated by RP, EBR, or ADT after risk adjustment. It revealed a significant benefit of RP versus EBR or ADT [30]. Recently, a large multicentric retrospective study involving 1366 patients with high-risk PCa treated with RP and pelvic lymph node dissection at eight European centers between 1987 and 2009 [31]. Roughly 40% of this population presented specimen-confined disease at final pathology with 10 years biochemical RFS and cancer-specific survival of 65.6% and 98.2%, respectively. Authors proposed a nomogram based on routinely available clinical parameters to identify patients who are more likely to have this final pathological feature. This nomogram has to be validated on external cohort. Several other retrospective studies conclude in advantages of RP for high-risk PCa [4, 32, 33]. Large prospective randomized trials are awaited to confirm the place of surgery for local control of high-risk PCa. Further prospective studies are warranted to directly compare the outcomes of RP versus combined radiation and hormonal therapy in highrisk patients.

Association Radical Prostatectomy and Adjuvant Radiotherapy To date, the impact of systematic adjuvant radiotherapy (ART) in high-risk cancers remains controversial. To clarify how far a routinely applied ART in case of pT3 or positive surgical margins of PCa influences outcome, three multiinstitutional randomized trials were opened 20 years ago. The results of these trials were recently updated as mature publications (European Organisation for Research and Treatment of Cancer [EORTC] trial 22911, Southwest Oncology Group [SWOG] trial 8794, and ARO 96-02/AUO AP 09/95) [3436]. The data from these randomized trials concordantly showed that ART improved biochemical-free survival rates and local control in patients with locally advanced PCa after RP. However, to date, ART has not been shown to improve OS compared with active surveillance

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[37]. Only one of them has showed a significant impact on long-term OS [35]. Some biases also could be noticed in the inclusion criteria for all three randomized trials, especially concerning the detectable PSA levels in SWOG and EORTC trials [3840). Also, not all patients of the SWOG trial have a complete registry of PSA levels. Importantly, pT2 cancers with positive margins also were included in these trials, resulting in a limited interpretation of results for the margin status. Thus, adequate selection of patients for ART is still hampered by the lack of strong predictors. Some clinicians tend to favor a wait-and-see policy after RP to avoid possible side effects of ART. Although the prospective trials have not conclusively documented the influence of ART on the development of secondary metastasis, there is still substantial evidence that local failure is associated with a higher risk for metastases whenever the follow-up is long enough. The main disadvantage of adjuvant treatment remains unnecessary radiotherapy in 30% to 40% of men who will never develop biochemical recurrence, and could suffer potential adverse effects of radiotherapy following surgery. Multi-institutional studies have reported that initial observation followed by delayed SRT at the time of PSA recurrence was an effective strategy for selected patients with positive margins or extraprostatic extension [4143]. Thus, to date, wait-and-see management or systematic ART remain acceptable options in high-risk PCa [44].

Association Radical Prostatectomy and Adjuvant Hormonal Therapy Benefits of systematic adjuvant hormonal therapy after RP remain unclear. An advantage of ADT has been proven in a small trial for patients with positive lymph node on surgical specimen [5]. In this small series of 98 patients with pN + cancer, a survival improvement (OR 1.84) was reported in the subgroup of patients receiving adjuvant ADT. In case of negative lymph nodes, this survival advantage has not been demonstrated [6]. Wirth et al. [45] reported the results of a randomized study with flutamide in 309 patients (pT3-4N0). Adjuvant flutamide treatment delayed biochemical progression significantly (HR 0.51). No improvement in OS was verified in this study at a follow-up period of 6.1 years. McLeod at al. [6] reported the results of a randomized, double-blind, placebo-controlled trial study with adjuvant bicalutamide. With a follow up of 6 years, no improvement in OS was reported for the pT3. In the case of pT3bN0 cancers, a retrospective cohort from the Mayo Clinic led to an advantage of adjuvant hormonal therapy versus surgery alone [38]. More recently, intermediate results from the SWOG S9921 study tended to prove that 2 years of ADT significantly reduced the rate of disease recurrence and PCa-specific death after RP [39].

SWOG reports the largest experience of ADT adjuvant to RP for patients with high-risk PCa. The SWOG S9921 study randomly assigned patients after RP to receive ADT for 24 months or ADT in combination with mitoxantrone. Accrual was stopped early after the occurrence of three cases of acute myeloid leukemia in the mitoxantrone arm. The 5-year OS and biochemical RFS rates were 96% and 92.5%, respectively, in the 481-patient control arm. No randomized prospective study has been published with luteinizing hormonereleasing hormone agonists in the PSA era, which is the only reliable tool to clearly separate, after local treatment, adjuvant setting from salvage setting. The SWOG S9921 ADT-only group experienced a very good 5-year OS (96% vs 71% expected), which sheds new light on RP plus ADT for the treatment of high-risk PCa. Definitive results from a large randomized trial are awaited because it seems reasonable to expect the same advantage on the local control of the disease than the standard treatment based on radiotherapy with adjuvant ADT with the advantage of a better analysis of the prognosis due to pathological analysis of the tumor specimen after surgery. Thus, to date, except for patients with positive lymph nodes, the role of the early ADT in association with surgery remains unclear and not recommended. New trials testing ADT are warranted to define the role of ADT after RP in the high-risk PCa. The French Genitourinary Tumor Group (GETUG) is opening a phase 3 trial that will randomly assign 700 high-risk PCa patients with negative surgical margins postoperatively to adjuvant ADT alone for 24 months or salvage treatment.

Association Radical Prostatectomy and Adjuvant Chemotherapy Optimal treatment in men at high risk for disease progression following local therapy is undefined. Neoadjuvant or adjuvant therapies such as radiotherapy, ADT, or chemotherapy have been studied, combined or isolated, but no standard of care is clearly recommended. Thus, the role of neoadjuvant or adjuvant cytotoxics remains unclear for high-risk PCa. Accumulating clinical and preclinical data suggest that the use of early adjuvant therapy will improve the outcome in patients with high-risk localized PCa. Recently, Thompson et al. [46] demonstrated that adjuvant radiotherapy after RP significantly reduced the risk of metastasis and increased survival in pT3N0 disease [46]. However, ART is not sufficient to control and/or treat distant micrometastases. In comparison with the previous situation, the role of chemotherapy after surgery in PCa has been poorly investigated in the literature. It is clearly accepted that taxane-based chemotherapy prolongs OS in patients with hormone-refractory PCa [40, 47]. Chemotherapy represents an interesting treatment option

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as adjuvant therapy [48]. The hypothesis is that androgenindependent tumor cells are responsible for disease progression and patient mortality. Adjuvant weekly taxanebased chemotherapy after RP for patients with high-risk PCa was recently demonstrated feasible with acceptable toxicity [7, 49]. Kibel et al. [7] reported a median PFS that appeared better than the Kattan nomogrampredicted PFS. Cetnar et al. [49] demonstrated, in a nonrandomized trial, feasibility of paclitaxel associated with estramustine but with no ADT. Randomized pilot trials are warranted. In this sense, the Veterans Affairs Cooperative Study 553 has been designed to prospectively evaluate the efficacy of early adjuvant chemotherapy using docetaxel and prednisone added to the standard of care [50]. A small prospective trial, comparing ADT alone versus combination of ADT and weekly paclitaxel for eight cycles for patients presenting high-risk PCa and who underwent RP, has been opened in France. Interim analysis revealed no difference in the quality of life and continence recovery between the two arms [51]. Long-term oncologic outcomes are awaited. Actually, longer follow-ups and larger cohorts are needed to assess oncologic results of these randomized trials in terms of PFS and OS to determine whether adjuvant chemotherapy adds any survival advantages in high-risk PCa.

Hormonal Therapy and Radiotherapy: The Standard Treatment? This multimodal strategy is founded on the two therapeutic challenges of high-risk nonmetastatic PCa: local control of the disease and treatment of the very likely existing micrometastases that are undetectable with the routine imaging techniques. In 2002, Bolla et al. [34] published a phase 3 trial for the European Organisation for Research and Treatment of Cancer (EORTC), EORTC 22863, in which 415 patients were enrolled to compare in two arms (radiotherapy and adjuvant ADT vs radiotherapy alone [use of ADT was allowed in case of relapse]) for high-risk PCa. With a median follow-up of 66 months, combination therapy yielded significantly better survival (78% vs 62%) [34]. Various combinations have been assessed in numerous randomized trials [34, 5964] and resulted in recommendations of long-term administration of ADT combined with radiotherapy. Recently, an update of this trial confirmed the benefit of associated ADT with a significantly improved 10-year disease-free and OS in high-risk PCa patients [65]. However, the exact duration of adjuvant ADT is still controversial (trials: EORTC 22863; RTOG [Radiation Therapy Oncology Group] 8531; RTOG 9202; EORTC 22961) [66, 67]. Radiotherapy plus ADT have also demonstrated superiority as compared to ADT alone in locally advanced PCa [68], emphasizing the impact of a multimodal approach combining local and systemic treatments. To date, no large randomized trials have been performed to compare RP and radiotherapy in high-risk PCa. However, although radiotherapy plus ADT clearly benefits a higher level of evidence in the literature, we can emphasize at this point natural advantages of RP plus ADT that should motivate initiation of large prospective protocol. Indeed, prostate removal allows a pathological staging that can be compared to the pretreatment clinical staging. Patients with cT3 stages are overstaged 9% to 44% of the time [11, 22, 23, 69, 70]. When these patients were ranked in high-risk PCa just because of the clinically advanced disease (with a Gleason score <7 and pretreatment PSA level <10 ng/mL), they seem to be cured with RP alone without a higher rate of complications and enjoy the benefits of a less aggressive treatment. It has to be clear that this advantage is more applicable for locally advanced cancer than for the whole high-risk group. Other advantages of RP versus radiotherapy before ADT are the accurate detection of recurrence with routine monitoring of PSA levels and assessment of lymph node invasion after surgical removal. Indeed, accurate pathological staging aids in more effective therapy after initial treatment [11, 69, 70].

Radical Prostatectomy after Neoadjuvant Therapy Two meta-analyses have shown that neoadjuvant hormonal therapy reduced the rate of positive surgical margins after RP and other adverse pathologic findings, and improved the rate of downstaging [52, 53]. However, any long-term benefit on OS has been demonstrated concerning the use of neoadjuvant ADT [54]. In a prospective randomized open trial, after 6 years of follow-up, there was no overall benefit with 3 months of neoadjuvant hormonal therapy. However, a biochemical RFS benefit favoring neoadjuvant hormonal therapy was seen in men with a baseline PSA greater than 20. Authors concluded the possibility that high-risk patients may benefit from neoadjuvant hormonal therapy, which warrants further investigation. Recently, neoadjuvant ketoconazole combined with docetaxel has been assessed in high-risk PCa. Authors found an appreciable but acceptable toxicity with interesting short-term oncologic outcomes at a median follow-up of 18 months [55]. Similar toxicity profiles have been reported with paclitaxel [56]. Combinations of docetaxel and gefitinib or hormonal therapy also have been assessed [57, 58]. Pathologic complete responses were rare. Neoadjuvant therapy appeared well tolerated and did not result in increased surgical morbidity. In all these studies, a small cohort of patients was included and long-term results remain lacking. To date, no neoadjuvant therapy before RP can be recommended because survival advantage has never been conclusively demonstrated.

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Curr Urol Rep (2012) 13:179186 retropubic prostatectomy in 3,478 consecutive patients: long-term results. J Urol. 2004;172(3):9104. 3. DAmico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280(11):969 74. 4. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999;341 (24):17818. 5. Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol. 2006;7 (6):4729. 6. McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP. Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int. 2006;97(2):24754. 7. Kibel AS, Rosenbaum E, Kattan MW, Picus J, Dreicer R, Klein EA, et al. Adjuvant weekly docetaxel for patients with high risk prostate cancer after radical prostatectomy: a multi-institutional pilot study. J Urol. 2007;177(5):177781. 8. Thompson IM, Carroll PR, Carducci MA. Recommendations for defining and treating high risk localized prostate cancer. J Urol. 2006;176(6 Pt 2):S610. quiz S35. 9. Donohue JF, Bianco Jr FJ, Kuroiwa K, Vickers AJ, Wheeler TM, Scardino PT, et al. Poorly differentiated prostate cancer treated with radical prostatectomy: long-term outcome and incidence of pathological downgrading. J Urol. 2006;176(3):9915. 10. Yossepowitch O, Eggener SE, Bianco Jr FJ, Carver BS, Serio A, Scardino PT, et al. Radical prostatectomy for clinically localized, high risk prostate cancer: critical analysis of risk assessment methods. J Urol. 2007;178(2):4939. discussion 499. 11. 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(6):7516. 12. DAmico AV, Moul J, Carroll PR, Sun L, Lubeck D, Chen M-H. Cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. J Clin Oncol. 2003;21(11):2163 72. 13. DAmico AV, Chen M-H, Roehl KA, Catalona WJ. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med. 2004;351(2):12535. 14. Scardino P. Update: NCCN prostate cancer Clinical Practice Guidelines. J Natl Compr Canc Netw. 2005;3 Suppl 1:S2933. 15. Clark PE, Peereboom DM, Dreicer R, Levin HS, Clark SB, Klein EA. Phase II trial of neoadjuvant estramustine and etoposide plus radical prostatectomy for locally advanced prostate cancer. Urology. 2001;57(2):2815. 16. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281(17):15917. 17. Stephenson AJ, Scardino PT, Eastham JA, Bianco FJ, Dotan ZA, DiBlasio CJ, et al. Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Clin Oncol. 2005;23(28):700512. 18. Nguyen CT, Reuther AM, Stephenson AJ, Klein EA, Jones JS. The specific definition of high risk prostate cancer has minimal impact on biochemical relapse-free survival. J Urol. 2009;181 (1):7580. This study showed that biochemical recurrence-free survival following radiotherapy did not vary significantly based on six different definitions.

Hormonal Therapy Alone The only relevant indication for this strategy in the case of high-risk nonmetastatic PCa is for the patients with contraindications for definitive local treatment (surgery or radiotherapy). The EORTC trial 30891 led by Studer et al. [71] in 2006 emphasized that hormonal castration had a limited OS not related to cancer-specific survival. Therefore, immediate ADT alone is not suitable for local treatment of PCa with curative intents in nonsymptomatic patients.

Conclusions Surgical treatment can result in long-term PFS in a subset of carefully selected high-risk men. To be clinical useful, criteria defining high-risk cancer should reliably distinguish patients whose cancer is amenable to cure with local therapy alone from those who may require multimodal therapy. Despite high accuracy and mandatory use for selecting men for clinical trials, high-risk group established according to the dAmico criteria or other prognostic tools remains very heterogeneous, including a third of patients with excellent prognosis and organ-confined disease. In contrast, a substantial proportion of high-risk patients will not be cured by local treatment alone and might benefit from a more aggressive adjuvant treatment strategy. However, to date, except in one ART series, no neoadjuvant or adjuvant therapy has shown a survival improvement after RP for high-risk PCa. Recent observational studies tend to prove that RP may offer benefits over radiotherapy in disease-free survival and OS. However, good Level 1 evidence is lacking. Thus, concerning the choice of local treatment, further prospective studies are warranted to directly compare the outcomes of RP versus combined radiation and hormonal therapy in high-risk patients.

Disclosures No potential conflicts of interest relevant to this article were reported.

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