PROSTATE CANCER (R REITER, SECTION EDITOR)

Radical Prostatectomy as Primary Treatment of High-riskProstate 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), establishedaccording to the d’Amico criteria or other prognostic tools,remains very heterogeneous, including a third of patientswith excellent prognosis in whom surgical treatment canresult in long-term progression-free survival. In contrast, asubstantial proportion of high risk will not be cured by localtreatment alone and might benefit from a more aggressivemultimodal adjuvant treatment strategy. However, to date,except in one adjuvant radiotherapy series, no neoadjuvantor adjuvant therapy has shown a survival improvement afterradical prostatectomy for high-risk PCa. Recent observa-tional studies tend to prove that radical prostatectomy mayoffer benefits over radiotherapy in disease-free and overallsurvival. However, good Level 1 evidence is lacking andfurther prospective studies are warranted to directly com-pare the outcomes of radical prostatectomy to combinedradiation and hormonal therapy in high-risk patients.

Keywords Prostate cancer . Radical prostatectomy . High-risk prostate cancer . Outcomes . Adjuvant . Radiotherapy .

Adjuvant hormone therapy . Treatment . Combinationtherapy . Gleason score . Staging . Radical prostatectomy

Introduction

Prostate cancer (PCa) is the most common solid malignancyin men in the European Union and the second leading causeof death attributable to cancer. Despite the widespread useof prostate-specific antigen (PSA) screening, some patientsare still diagnosed with a locally advanced PCa. Therapeuticstrategy remains unclear with no clear consensus for thesemen. Nomograms also have been established to better char-acterize high-risk patients and predict the probability of PCarecurrence for each patient [1]. Importantly, after radicalprostatectomy (RP), histoprognostic risk factors for diseaserecurrence and disease-specific survival include extracapsularextension, high Gleason score, positive surgical margins,seminal vesicle invasion, and positive lymph nodes [2].

According to the preoperative d’Amico criteria, RP alonein patients with high-risk PCa leads to a cure in about 50% ofcases [3]. Relapse is mostly due to distant micrometastasis,and combination therapy should be proposed. The goal ofadjuvant therapies would be to control and/or treat distantmicrometastases. However, no adjuvant standard treatmentafter surgery is clearly recommended for high-risk tumors.Adjuvant hormone therapy significantly improves survivalin patients with positive lymph nodes, with clear benefit forimmediate androgen deprivation therapy (ADT) [4, 5]. In thecase of negative lymph nodes, the survival advantage has notbeen demonstrated [6]. Neoadjuvant hormonotherapy failedto show overall survival (OS) rate increase [7]. This articlereviews the state of knowledge for the management of high-risk PCa and describes the evidence comparing the differentstrategies and the best timing to follow between local andsystemic treatments. After describing the various definitionsof high-risk PCa, we will describe the different evidence-based strategies from the literature and the place of RP asso-ciated or not with combined treatment.

A. Ingels :A. de la Taille :G. PloussardDepartment of Urology, APHP, CHU Henri Mondor,51 Avenue de Lattre de Tassigny,94010 Créteil, France

G. Ploussard (*)INSERM U955,Equipe 7, Université Paris 12,Créteil, Francee-mail: g.ploussard@gmail.com

Curr Urol Rep (2012) 13:179–186DOI 10.1007/s11934-012-0240-6

Definitions of High-risk Prostate Cancer

High-risk disease is defined as a significant likelihood ofprogressive, symptomatic disease or death from PCa [8].However, accurate categorization of high-risk PCa casesremains elusive (Table 1). Many studies have been publishedto assess the best markers to predict the prognosis of PCa.Independent risk factors of recurrence and survival are knownto be PSA, clinical tumor stage, Gleason score, and velocity ofthe PSA. Stratifications of patients according to their progno-sis are usually founded onmulti-criterial scores based on theseindependent factors. Many definitions of high-risk PCa arereported in the literature. Some are founded on single-criteriadefinition, such as a Gleason score higher than 7 on biopsies[9], preoperative PSA of 20 ng/mL or higher [10], or clinicalstage T3 on digital rectal examination (DRE) [11]; this lastdefinition considers locally advanced and high-risk PCa asone entity. Locally advanced cancers definitively have a highrisk of recurrence after treatment; however, some locallyadvanced cancers seem to be worse than others, and on theother hand, some small-volume tumors even undetectable onDRE can have a high risk of recurrence. Thus, definitionsbased on a multi-criterial evaluation combining the clinicalstage, biological PSA, and pathological Gleason score seem tobe more relevant. The most widely used predictive classifica-tion of the risk group is defined by D’Amico et al. [12] and isbased 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 than20 ng/mL or a Gleason score higher than 7. This predictiveprognostic score has been reassessed in a multi-institutionalupdate, and the high-risk group presented anOS rate of 75% at5 years of the definitive therapy and specific survival of 50%at 10 years [13]. Relative risk for specific mortality of PCaafter RP was 14.2 for the patients ranked in the high-riskgroup (4.9 and 1.0 for the intermediate- and low-risk groups,respectively). Other definitions based on the same criteria withdifferent cut-off limits have been reported by Scardino [14]and Clark et al. [15].

PSA velocity and PSA doubling time (PSADT) also havebeen proven as useful predictors of specific survival afterdefinitive therapy. D’Amico et al. [13] have evaluated 1095patients after RP for T1c or T2 tumour stage. Two groupswere split according to an annual PSAvelocity during the yearbefore the diagnosis over or under (or equal to) 2.0 ng/mL.High-velocity group had a significantly shorter time torecurrence, lower specific survival, and more advancedpathologic stage [13].

PSADT was identified as a good predictor of the time tometastatic disease or death when it was combined with othervariables such as Gleason score and time to biochemicalprogression [16]. The calculation of PSADT is based on thefact that serum PSA levels in patients with newly diagnosedor recurrent PCa follow an exponential growth curve. Theformula is as follows: PSADT ¼ ln2� tð Þ= ln PSAt½ ��fln PSAinitial½ �g , where t is the time between the two PSAmeasurements. In clinical practice, PSADT is quickly ac-cessible with a calculator. These results lead to the idea thatPSA kinetics is a useful method to identify high-risk patientsfor recurrence and death from PCa.

Nomograms are integrative tools using clinical, biologi-cal, and pathological data to predict the prognostic. Kattanpostoperative nomogram has been assessed on patients whounderwent RP and is based on preoperative serum PSA,degree of capsular invasion, Gleason score, surgical marginstatus, seminal vesicle invasion, and lymph node involve-ment [1]. This nomogram has been first updated to extendthe prediction from 7 to 10 years [17] and then externallyconfirmed by two independent cohorts. Kattan nomogram isa useful tool to determine the risk group and decide onindication of adjuvant therapies, even if it can’t suggestthe appropriate radical treatment due to the fact that itsevaluation is based on RP outcomes.

To date, the d’Amico criteria are the most used definitionof high-risk PCa. However, there is no clear consensusamong the urologic community. Yossepowitch et al. [10]have compared eight definitions of high-risk PCa from theliterature. From a 4708-patient cohort, and depending on thedefinition, the cohort comprised 3%–38% high-risk PCapatients, suggesting an important heterogeneity among thedefinitions. Depending on the definition, 22% to 63% ofpatients had organ-confined cancers, and 41% to 74%remained progression-free 10 years after surgery alone.Nguyen et al. [18•] have reported contradictory findingsand showed that biochemical recurrence-free survival(RFS) following radiotherapy did not vary significantlybased on six different definitions.

Thus, various schemes based on clinicopathological cri-teria have been proposed to stratify cases by presumedrecurrence risk. However, when considering high-risk PCa,the relapse-free survival is not the ideal end point. The mostrelevant parameters would be the PCa-specific mortality and

Table 1 Main preoperative definitions of high risk prostate cancer inthe literature

Biopsy GS 8–10

Preoperative PSA ≥20 ng/mL

1992 cTNM cT3

≥cT2c, biopsy GS 8–10, PSA ≥20 ng/mL

≥cT3, biopsy GS 8–10, PSA ≥20 ng/mL

≥cT2b, GS 8–10, 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

180 Curr Urol Rep (2012) 13:179–186

the OS. Such outcomes studies of different high-risk defi-nitions are lacking. Despite the diversity of criteria defininghigh-risk PCa, the d’Amico criteria remain largely used andvalidated in the literature.

What is the Current Place of Radical Prostatectomyfor High-risk Disease?

The aim of RP in locally advanced PCa is to debulk thetumour and to decrease the risk of metastatic dissemina-tion. Thus, RP might be considered as the best treatmentfor local control. Another important advantage for RP isthat cancer aggressiveness is correctly evaluated on RPspecimen. Thus, postoperative nomograms can be used tobetter characterize high-risk patients and predict theprobability of PCa recurrence for each patient. Despitetreatment, a significant proportion of these patients willexperience PSA-defined failure and cancer-specific death,indicating a need for more aggressive initial therapy anda multimodality treatment approach.

However, even if RP and external beam radiotherapy(EBR) are the two recommended treatment options inhigh-risk PCa [19], only a third of the patients undergo RPas the initial treatment [20]. Urologists traditionally recom-mended radiotherapy plus ADT over RP, not so much be-cause they felt the oncologic outcomes were better withradiotherapy, but because rates of incontinence and impo-tence with RP were high and cure rates were discouraging.

The effectiveness of RP as single treatment in high-riskPCa has been assessed in large retrospective series. The rateof disease-free survival ranged from 40%–50% among stud-ies [21–26]. However, it must be stressed that a non-negligible amount of patients received adjuvant therapyduring the follow-up. On a retrospective nationwide study,the PCa committee of the French Association of Urologyassessed 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% ofpatients had received adjuvant therapy before diagnosis ofPSA relapse. Van Ouden et al. [28] have previously reported5- and 10-year specific survival rates ranging from 83%–92% and from 72%–82%, respectively, in a review of eightRP series. Unfortunately, in most series, the use of adjuvantor salvage therapy after RP was not thoroughly studied.

Literature supports evidence that surgical treatment canresult in long-term progression-free survival (PFS) in asubset of carefully selected high-risk men. These interestingoncologic outcomes may be explained by an important rateof downstaging. Thus, about a third of patients with apreoperatively suspected high-risk PCa had a pathologicallyconfirmed 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 stand-ards of care for these high-risk patients with curative intent.Pathological evaluation on prostatectomy specimens pro-vides better predictive assessment of high risk comparedwith only preoperative criteria. To date, no large randomizedtrials have been performed to compare these two local treat-ments. In 2010, a nationwide retrospective study from theUnited States compared 404,604 men with clinically local-ized PCa. In the whole cohort, disease-specific mortalitywas lowest in the RP group (3.6%) than in the EBR(6.5%) or observational groups (10.8%) [29••]. Anotherstudy involving the Cancer of the Prostate Strategic Urolog-ic Research Endeavor (CaPSURE) in 2010 retrospectivelycompared 7,538 men treated by RP, EBR, or ADT after riskadjustment. It revealed a significant benefit of RP versusEBR or ADT [30••]. Recently, a large multicentric retro-spective study involving 1366 patients with high-risk PCatreated with RP and pelvic lymph node dissection at eightEuropean centers between 1987 and 2009 [31]. Roughly40% of this population presented specimen-confined diseaseat final pathology with 10 years biochemical RFS andcancer-specific survival of 65.6% and 98.2%, respectively.Authors proposed a nomogram based on routinely availableclinical parameters to identify patients who are more likelyto have this final pathological feature. This nomogram hasto be validated on external cohort.

Several other retrospective studies conclude in advan-tages of RP for high-risk PCa [4, 32, 33]. Large prospectiverandomized trials are awaited to confirm the place of surgeryfor local control of high-risk PCa. Further prospective stud-ies are warranted to directly compare the outcomes of RPversus combined radiation and hormonal therapy in high-risk patients.

Association Radical Prostatectomy and AdjuvantRadiotherapy

To date, the impact of systematic adjuvant radiotherapy(ART) in high-risk cancers remains controversial. To clarifyhow far a routinely applied ART in case of pT3 or positivesurgical margins of PCa influences outcome, three multi-institutional randomized trials were opened 20 years ago.The results of these trials were recently updated as maturepublications (European Organisation for Research andTreatment of Cancer [EORTC] trial 22911, Southwest On-cology Group [SWOG] trial 8794, and ARO 96-02/AUOAP 09/95) [34–36]. The data from these randomized trialsconcordantly showed that ART improved biochemical-freesurvival rates and local control in patients with locallyadvanced PCa after RP. However, to date, ART has not beenshown to improve OS compared with active surveillance

Curr Urol Rep (2012) 13:179–186 181

[37]. Only one of them has showed a significant impact onlong-term OS [35]. Some biases also could be noticed in theinclusion criteria for all three randomized trials, especiallyconcerning the detectable PSA levels in SWOG and EORTCtrials [38–40). Also, not all patients of the SWOG trial havea complete registry of PSA levels. Importantly, pT2 cancerswith positive margins also were included in these trials,resulting in a limited interpretation of results for the marginstatus. Thus, adequate selection of patients for ART is stillhampered by the lack of strong predictors. Some clinicianstend to favor a “wait-and-see” policy after RP to avoidpossible side effects of ART. Although the prospective trialshave not conclusively documented the influence of ART onthe development of secondary metastasis, there is still sub-stantial evidence that local failure is associated with a higherrisk for metastases whenever the follow-up is long enough.The main disadvantage of adjuvant treatment remains un-necessary radiotherapy in 30% to 40% of men who willnever develop biochemical recurrence, and could sufferpotential adverse effects of radiotherapy following surgery.Multi-institutional studies have reported that initial observa-tion followed by delayed SRT at the time of PSA recurrencewas an effective strategy for selected patients with positivemargins or extraprostatic extension [41–43]. Thus, to date,wait-and-see management or systematic ART remain ac-ceptable options in high-risk PCa [44].

Association Radical Prostatectomy and AdjuvantHormonal Therapy

Benefits of systematic adjuvant hormonal therapy after RPremain unclear. An advantage of ADT has been proven in asmall trial for patients with positive lymph node on surgicalspecimen [5]. In this small series of 98 patients with pN +cancer, a survival improvement (OR 1.84) was reported inthe subgroup of patients receiving adjuvant ADT.

In case of negative lymph nodes, this survival advantagehas not been demonstrated [6]. Wirth et al. [45] reported theresults of a randomized study with flutamide in 309 patients(pT3-4N0). Adjuvant flutamide treatment delayed biochem-ical progression significantly (HR 0.51). No improvement inOS was verified in this study at a follow-up period of6.1 years. McLeod at al. [6] reported the results of a ran-domized, double-blind, placebo-controlled trial study withadjuvant bicalutamide. With a follow up of 6 years, noimprovement in OS was reported for the pT3.

In the case of pT3bN0 cancers, a retrospective cohortfrom the Mayo Clinic led to an advantage of adjuvanthormonal therapy versus surgery alone [38]. More recently,intermediate results from the SWOG S9921 study tended toprove that 2 years of ADT significantly reduced the rate ofdisease recurrence and PCa-specific death after RP [39].

SWOG reports the largest experience of ADT adjuvant toRP for patients with high-risk PCa. The SWOG S9921 studyrandomly assigned patients after RP to receive ADT for24 months or ADT in combination with mitoxantrone. Ac-crual was stopped early after the occurrence of three cases ofacute myeloid leukemia in the mitoxantrone arm. The 5-yearOS and biochemical RFS rates were 96% and 92.5%, re-spectively, in the 481-patient control arm. No randomizedprospective study has been published with luteinizinghormone–releasing hormone agonists in the PSA era, whichis the only reliable tool to clearly separate, after local treat-ment, adjuvant setting from salvage setting. The SWOGS9921 ADT-only group experienced a very good 5-yearOS (96% vs 71% expected), which sheds new light on RPplus ADT for the treatment of high-risk PCa. Definitiveresults from a large randomized trial are awaited because itseems reasonable to expect the same advantage on the localcontrol of the disease than the standard treatment based onradiotherapy with adjuvant ADT with the advantage of abetter analysis of the prognosis due to pathological analysisof the tumor specimen after surgery.

Thus, to date, except for patients with positive lymphnodes, the role of the early ADT in association with surgeryremains unclear and not recommended. New trials testingADT are warranted to define the role of ADT after RP in thehigh-risk PCa. The French Genitourinary Tumor Group(GETUG) is opening a phase 3 trial that will randomlyassign 700 high-risk PCa patients with negative surgicalmargins postoperatively to adjuvant ADT alone for24 months or salvage treatment.

Association Radical Prostatectomy and AdjuvantChemotherapy

Optimal treatment in men at high risk for disease progressionfollowing local therapy is undefined. Neoadjuvant or adjuvanttherapies such as radiotherapy, ADT, or chemotherapy havebeen studied, combined or isolated, but no standard of care isclearly recommended. Thus, the role of neoadjuvant or adju-vant cytotoxics remains unclear for high-risk PCa.

Accumulating clinical and preclinical data suggest thatthe use of early adjuvant therapy will improve the outcomein patients with high-risk localized PCa. Recently, Thompsonet al. [46] demonstrated that adjuvant radiotherapy after RPsignificantly reduced the risk of metastasis and increasedsurvival in pT3N0 disease [46]. However, ART is not suffi-cient to control and/or treat distant micrometastases. In com-parison with the previous situation, the role of chemotherapyafter surgery in PCa has been poorly investigated in theliterature. It is clearly accepted that taxane-based chemother-apy prolongs OS in patients with hormone-refractory PCa [40,47]. Chemotherapy represents an interesting treatment option

182 Curr Urol Rep (2012) 13:179–186

as adjuvant therapy [48]. The hypothesis is that androgen-independent tumor cells are responsible for disease pro-gression and patient mortality. Adjuvant weekly taxane-based chemotherapy after RP for patients with high-riskPCa was recently demonstrated feasible with acceptabletoxicity [7, 49]. Kibel et al. [7] reported a median PFS thatappeared better than the Kattan nomogram–predicted PFS.Cetnar et al. [49] demonstrated, in a nonrandomized trial,feasibility of paclitaxel associated with estramustine butwith no ADT. Randomized pilot trials are warranted. In thissense, the Veterans Affairs Cooperative Study 553 has beendesigned to prospectively evaluate the efficacy of earlyadjuvant chemotherapy using docetaxel and prednisoneadded to the standard of care [50]. A small prospective trial,comparing ADT alone versus combination of ADT andweekly paclitaxel for eight cycles for patients presentinghigh-risk PCa and who underwent RP, has been opened inFrance. Interim analysis revealed no difference in the qual-ity 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 assessoncologic results of these randomized trials in terms of PFSand OS to determine whether adjuvant chemotherapy addsany survival advantages in high-risk PCa.

Radical Prostatectomy after Neoadjuvant Therapy

Two meta-analyses have shown that neoadjuvant hormonaltherapy reduced the rate of positive surgical margins after RPand other adverse pathologic findings, and improved the rate ofdownstaging [52, 53]. However, any long-term benefit on OShas been demonstrated concerning the use of neoadjuvant ADT[54]. In a prospective randomized open trial, after 6 years offollow-up, there was no overall benefit with 3 months of neo-adjuvant hormonal therapy. However, a biochemical RFS ben-efit favoring neoadjuvant hormonal therapy was seen in menwith a baseline PSA greater than 20. Authors concluded thepossibility that high-risk patients may benefit from neoadjuvanthormonal therapy, which warrants further investigation.

Recently, neoadjuvant ketoconazole combined with doce-taxel has been assessed in high-risk PCa. Authors found anappreciable but acceptable toxicity with interesting short-termoncologic 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 hormonaltherapy also have been assessed [57, 58]. Pathologic completeresponses were rare. Neoadjuvant therapy appeared well tol-erated and did not result in increased surgical morbidity. In allthese studies, a small cohort of patients was included andlong-term results remain lacking. To date, no neoadjuvanttherapy before RP can be recommended because survivaladvantage has never been conclusively demonstrated.

Hormonal Therapy and Radiotherapy: The StandardTreatment?

This multimodal strategy is founded on the two thera-peutic challenges of high-risk nonmetastatic PCa: localcontrol of the disease and treatment of the very likelyexisting micrometastases that are undetectable with theroutine imaging techniques. In 2002, Bolla et al. [34]published a phase 3 trial for the European Organisationfor Research and Treatment of Cancer (EORTC), EORTC22863, in which 415 patients were enrolled to comparein two arms (radiotherapy and adjuvant ADT vs radio-therapy alone [use of ADT was allowed in case ofrelapse]) for high-risk PCa. With a median follow-up of66 months, combination therapy yielded significantlybetter survival (78% vs 62%) [34]. Various combinationshave been assessed in numerous randomized trials [34,59–64] and resulted in recommendations of long-termadministration of ADT combined with radiotherapy. Re-cently, an update of this trial confirmed the benefit ofassociated ADT with a significantly improved 10-yeardisease-free and OS in high-risk PCa patients [65]. How-ever, the exact duration of adjuvant ADT is still contro-versial (trials: EORTC 22863; RTOG [Radiation TherapyOncology Group] 8531; RTOG 9202; EORTC 22961)[66, 67].

Radiotherapy plus ADT have also demonstrated superi-ority as compared to ADT alone in locally advanced PCa[68], emphasizing the impact of a multimodal approachcombining local and systemic treatments.

To date, no large randomized trials have been performedto compare RP and radiotherapy in high-risk PCa. However,although radiotherapy plus ADT clearly benefits a higherlevel of evidence in the literature, we can emphasize atthis point natural advantages of RP plus ADT that shouldmotivate initiation of large prospective protocol. Indeed,prostate removal allows a pathological staging that canbe compared to the pretreatment clinical staging. Patientswith cT3 stages are overstaged 9% to 44% of the time[11, 22, 23, 69, 70]. When these patients were ranked inhigh-risk PCa just because of the clinically advanceddisease (with a Gleason score <7 and pretreatment PSAlevel <10 ng/mL), they seem to be cured with RP alonewithout a higher rate of complications and enjoy thebenefits of a less aggressive treatment. It has to be clearthat this advantage is more applicable for locally ad-vanced cancer than for the whole high-risk group.

Other advantages of RP versus radiotherapy beforeADT are the accurate detection of recurrence with rou-tine monitoring of PSA levels and assessment of lymphnode invasion after surgical removal. Indeed, accuratepathological staging aids in more effective therapy afterinitial treatment [11, 69, 70].

Curr Urol Rep (2012) 13:179–186 183

Hormonal Therapy Alone

The only relevant indication for this strategy in the case ofhigh-risk nonmetastatic PCa is for the patients with contra-indications for definitive local treatment (surgery or radio-therapy). The EORTC trial 30891 led by Studer et al. [71] in2006 emphasized that hormonal castration had a limited OSnot related to cancer-specific survival. Therefore, immediateADT alone is not suitable for local treatment of PCa withcurative intents in nonsymptomatic patients.

Conclusions

Surgical treatment can result in long-term PFS in a subset ofcarefully selected high-risk men. To be clinical useful, criteriadefining high-risk cancer should reliably distinguish patientswhose cancer is amenable to cure with local therapy alonefrom those who may require multimodal therapy. Despite highaccuracy and mandatory use for selecting men for clinicaltrials, high-risk group established according to the d’Amicocriteria or other prognostic tools remains very heterogeneous,including a third of patients with excellent prognosis andorgan-confined disease. In contrast, a substantial proportionof high-risk patients will not be cured by local treatment aloneand might benefit from a more aggressive adjuvant treatmentstrategy. However, to date, except in one ART series, no neo-adjuvant or adjuvant therapy has shown a survival improve-ment after RP for high-risk PCa. Recent observational studiestend to prove that RP may offer benefits over radiotherapy indisease-free survival and OS. However, good Level 1 evi-dence is lacking. Thus, concerning the choice of local treat-ment, further prospective studies are warranted to directlycompare the outcomes of RP versus combined radiation andhormonal therapy in high-risk patients.

Disclosures No potential conflicts of interest relevant to this articlewere reported.

References

Papers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. Kattan MW, Wheeler TM, Scardino PT. Postoperative nomogramfor disease recurrence after radical prostatectomy for prostatecancer. J Clin Oncol. 1999;17(5):1499–507.

2. Roehl KA, Han M, Ramos CG, Antenor JAV, Catalona WJ. Cancerprogression and survival rates following anatomical radical

retropubic prostatectomy in 3,478 consecutive patients: long-termresults. J Urol. 2004;172(3):910–4.

3. D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K,Broderick GA, et al. Biochemical outcome after radical prostatecto-my, external beam radiation therapy, or interstitial radiation therapyfor 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 observationafter radical prostatectomy and pelvic lymphadenectomy in menwith node-positive prostate cancer. N Engl J Med. 1999;341(24):1781–8.

5. Messing EM, Manola J, Yao J, Kiernan M, Crawford D, WildingG, et al. Immediate versus deferred androgen deprivation treatmentin patients with node-positive prostate cancer after radical prosta-tectomy and pelvic lymphadenectomy. Lancet Oncol. 2006;7(6):472–9.

6. McLeod DG, Iversen P, See WA, Morris T, Armstrong J, WirthMP. Bicalutamide 150 mg plus standard care vs standard carealone for early prostate cancer. BJU Int. 2006;97(2):247–54.

7. Kibel AS, Rosenbaum E, Kattan MW, Picus J, Dreicer R, KleinEA, et al. Adjuvant weekly docetaxel for patients with high riskprostate cancer after radical prostatectomy: a multi-institutionalpilot study. J Urol. 2007;177(5):1777–81.

8. Thompson IM, Carroll PR, Carducci MA. Recommendations fordefining and treating high risk localized prostate cancer. J Urol.2006;176(6 Pt 2):S6–10. quiz S3–5.

9. Donohue JF, Bianco Jr FJ, Kuroiwa K, Vickers AJ, Wheeler TM,Scardino PT, et al. Poorly differentiated prostate cancer treatedwith radical prostatectomy: long-term outcome and incidence ofpathological downgrading. J Urol. 2006;176(3):991–5.

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 meth-ods. J Urol. 2007;178(2):493–9. discussion 499.

11. Ward JF, Slezak JM, Blute ML, Bergstralh EJ, Zincke H. Radicalprostatectomy for clinically advanced (cT3) prostate cancer sincethe advent of prostate-specific antigen testing: 15-year outcome.BJU Int. 2005;95(6):751–6.

12. D’Amico AV, Moul J, Carroll PR, Sun L, Lubeck D, Chen M-H.Cancer-specific mortality after surgery or radiation for patientswith clinically localized prostate cancer managed during theprostate-specific antigen era. J Clin Oncol. 2003;21(11):2163–72.

13. D’Amico AV, Chen M-H, Roehl KA, Catalona WJ. PreoperativePSA velocity and the risk of death from prostate cancer afterradical prostatectomy. N Engl J Med. 2004;351(2):125–35.

14. Scardino P. Update: NCCN prostate cancer Clinical PracticeGuidelines. J Natl Compr Canc Netw. 2005;3 Suppl 1:S29–33.

15. Clark PE, Peereboom DM, Dreicer R, Levin HS, Clark SB, KleinEA. Phase II trial of neoadjuvant estramustine and etoposide plusradical prostatectomy for locally advanced prostate cancer. Urolo-gy. 2001;57(2):281–5.

16. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD,Walsh PC. Natural history of progression after PSA elevationfollowing radical prostatectomy. JAMA. 1999;281(17):1591–7.

17. Stephenson AJ, Scardino PT, Eastham JA, Bianco FJ, Dotan ZA,DiBlasio CJ, et al. Postoperative nomogram predicting the 10-yearprobability of prostate cancer recurrence after radical prostatecto-my. J Clin Oncol. 2005;23(28):7005–12.

18.• Nguyen CT, Reuther AM, Stephenson AJ, Klein EA, Jones JS.The specific definition of high risk prostate cancer has minimalimpact on biochemical relapse-free survival. J Urol. 2009;181(1):75–80. This study showed that biochemical recurrence-freesurvival following radiotherapy did not vary significantly basedon six different definitions.

184 Curr Urol Rep (2012) 13:179–186

19. Heidenreich A, Aus G, Bolla M, Joniau S, Matveev VB, SchmidHP, et al. EAU guidelines on prostate cancer. Eur Urol. 2008;53(1):68–80.

20. Meng MV, Elkin EP, Latini DM, Duchane J, Carroll PR. Treatmentof patients with high risk localized prostate cancer: results fromcancer of the prostate strategic urological research endeavor (CaP-SURE). J Urol. 2005;173(5):1557–61.

21. Bastian PJ, Gonzalgo ML, Aronson WJ, Terris MK, Kane CJ,Amling CL, et al. Clinical and pathologic outcome after radicalprostatectomy for prostate cancer patients with a preoperativeGleason sum of 8 to 10. Cancer. 2006;107(6):1265–72.

22. Carver BS, Bianco Jr FJ, Scardino PT, Eastham JA. Long-termoutcome following radical prostatectomy in men with clinicalstage T3 prostate cancer. J Urol. 2006;176(2):564–8.

23. Freedland SJ, Partin AW, Humphreys EB, Mangold LA, WalshPC. Radical prostatectomy for clinical stage T3a disease. Cancer.2007;109(7):1273–8.

24. Spahn M, Joniau S, Gontero P, Fieuws S, Marchioro G, Tombal B,et al. Outcome predictors of radical prostatectomy in patients withprostate-specific antigen greater than 20 ng/ml: a European multi-institutional study of 712 patients. Eur Urol. 2010;58(1):1–7. dis-cussion 10–1.

25. Loeb S, Schaeffer EM, Trock BJ, Epstein JI, Humphreys EB,Walsh PC. What are the outcomes of radical prostatectomy forhigh-risk prostate cancer? Urology. 2010;76(3):710–4.

26. Ploussard G, Salomon L, Allory Y, Terry S, Vordos D, Hoznek A,et al. Pathological findings and prostate-specific antigen outcomesafter laparoscopic radical prostatectomy for high-risk prostate can-cer. BJU Int. 2010;106(1):86–90.

27. • Ploussard G, Masson-Lecomte A, Beauval J-B, Ouzzane A,Bonniol R, Buge F, et al. Radical prostatectomy for high-riskprostate cancer defined by preoperative criteria: oncologicfollow-up in national multicenter study in 813 patients andassessment of easy-to-use prognostic substratification. Urolo-gy. 2011;78(3):607–13. This is one of the largest retrospec-tive studies of outcomes for high-risk prostate cancer afterRP.

28. van den Ouden D, Hop WC, Schröder FH. Progression in andsurvival of patients with locally advanced prostate cancer (T3)treated with radical prostatectomy as monotherapy. J Urol.1998;160(4):1392–7.

29. •• Abdollah F, Sun M, Thuret R, Jeldres C, Tian Z, BrigantiA, et al. A competing-risks analysis of survival after alterna-tive treatment modalities for prostate cancer patients: 1988–2006. Eur Urol. 2011;59(1):88–95. This nationwide retrospec-tive study from the United Stated emphasized that disease-specific mortality was lowest in the RP group than in the EBRor observational groups.

30. •• Cooperberg MR, Vickers AJ, Broering JM, Carroll PR. Com-parative risk-adjusted mortality outcomes after primary surgery,radiotherapy, or androgen-deprivation therapy for localized pros-tate cancer. Cancer. 2010;116(22):5226–34. This is a second studyrevealing a significant benefit of RP versus EBR or ADT in high-risk prostate cancer patients.

31. Briganti A, Joniau S, Gontero P, Abdollah F, Passoni NM, TombalB, et al. Identifying the best candidate for radical prostatectomyamong patients with high-risk prostate cancer. European Urology[Internet]. 2011 Dec 2 [cited 2012 Jan 6];Available from: http://www.ncbi.nlm.nih.gov/pubmed/22153925.

32. Zelefsky MJ, Eastham JA, Cronin AM, Fuks Z, Zhang Z, YamadaY, et al. Metastasis after radical prostatectomy or external beamradiotherapy for patients with clinically localized prostate cancer: acomparison of clinical cohorts adjusted for case mix. J Clin Oncol.2010;28(9):1508–13.

33. Boorjian SA, Karnes RJ, Viterbo R, Rangel LJ, Bergstralh EJ,Horwitz EM, et al. Long-term survival after radical prostatectomy

versus external-beam radiotherapy for patients with high-risk pros-tate cancer. Cancer. 2011;117(13):2883–91.

34. Bolla M, van Poppel H, Collette L, van Cangh P, Vekemans K, DaPozzo L, et al. Postoperative radiotherapy after radical prostatectomy:a randomised controlled trial (EORTC trial 22911). Lancet. 2005;366(9485):572–8.

35. Thompson IM, Tangen CM, Paradelo J, Lucia MS, Miller G,Troyer D, et al. Adjuvant radiotherapy for pathologically advancedprostate cancer: a randomized clinical trial. JAMA. 2006;296(19):2329–35.

36. Wiegel T, Bottke D, Steiner U, Siegmann A, Golz R, Störkel S, etal. Phase III postoperative adjuvant radiotherapy after radical pros-tatectomy compared with radical prostatectomy alone in pT3 pros-tate cancer with postoperative undetectable prostate-specificantigen: ARO 96-02/AUO AP 09/95. J Clin Oncol. 2009;27(18):2924–30.

37. Morgan SC, Waldron TS, Eapen L, Mayhew LA, Winquist E,Lukka H. Adjuvant radiotherapy following radical prostatectomyfor pathologic T3 or margin-positive prostate cancer: a systematicreview and meta-analysis. Radiother Oncol. 2008;88(1):1–9.

38. Zincke H, Lau W, Bergstralh E, Blute ML. Role of early adjuvanthormonal therapy after radical prostatectomy for prostate cancer. JUrol. 2001;166(6):2208–15.

39. Dorff TB, Flaig TW, Tangen CM, Hussain MHA, Swanson GP,Wood DP, et al. Adjuvant androgen deprivation for high-riskprostate cancer after radical prostatectomy: SWOG S9921 study.J Clin Oncol. 2011;29(15):2040–5.

40. Petrylak DP, Tangen CM, Hussain MHA, Lara PN, Jones JA,Taplin ME, et al. Docetaxel and estramustine compared withmitoxantrone and prednisone for advanced refractory prostate can-cer. N Engl J Med. 2004;351(15):1513–20.

41. Loeb S, Roehl KA, Viprakasit DP, Catalona WJ. Long-term ratesof undetectable PSA with initial observation and delayed salvageradiotherapy after radical prostatectomy. Eur Urol. 2008;54(1):88–94.

42. Trock BJ, Han M, Freedland SJ, Humphreys EB, DeWeese TL,Partin AW, et al. Prostate cancer-specific survival following sal-vage radiotherapy vs observation in men with biochemical recur-rence after radical prostatectomy. JAMA. 2008;299(23):2760–9.

43. Song DY, Thompson TL, Ramakrishnan V, Harrison R, BhavsarN, Onaodowan O, et al. Salvage radiotherapy for rising or persis-tent PSA after radical prostatectomy. Urology. 2002;60(2):281–7.

44. Ploussard G, Agamy MA, Alenda O, Allory Y, Mouracade P,Vordos D, et al. Impact of positive surgical margins on prostate-specific antigen failure after radical prostatectomy in adjuvanttreatment-naïve patients. BJU Int. 2011;107(11):1748–54.

45. Wirth MP, Weissbach L, Marx F-J, Heckl W, Jellinghaus W,Riedmiller H, et al. Prospective randomized trial comparing fluta-mide as adjuvant treatment versus observation after radical pros-tatectomy for locally advanced, lymph node-negative prostatecancer. Eur Urol. 2004;45(3):267–70. discussion 270.

46. Thompson IM, Tangen CM, Paradelo J, Lucia MS, Miller G,Troyer D, et al. Adjuvant radiotherapy for pathological T3N0M0prostate cancer significantly reduces risk of metastases andimproves survival: long-term followup of a randomized clinicaltrial. J Urol. 2009;181(3):956–62.

47. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, etal. Docetaxel plus prednisone or mitoxantrone plus prednisone foradvanced prostate cancer. N Engl J Med. 2004;351(15):1502–12.

48. Sokoloff MH, Rinker-Schaeffer CW, Chung LWK, Brendler CB.Adjunctive therapy for men with high risk localized and locallyadvanced prostate cancer: targeting disseminated tumor cells. JUrol. 2004;172(6 Pt 2):2539–44.

49. Cetnar JP, Malkowicz SB, Palmer SC, Wein AJ, Vaughn DJ. Pilottrial of adjuvant paclitaxel plus estramustine in resected high-riskprostate cancer. Urology. 2008;71(5):942–6.

Curr Urol Rep (2012) 13:179–186 185

50. Montgomery B, Lavori P, Garzotto M, Lee K, Brophy M,Thaneemit-Chen S, et al. Veterans Affairs Cooperative StudiesProgram study 553: Chemotherapy after prostatectomy, a phaseIII randomized study of prostatectomy versus prostatectomy withadjuvant docetaxel for patients with high-risk, localized prostatecancer. Urology. 2008;72(3):474–80.

51. Ploussard G, Paule B, Salomon L, Allory Y, Terry S, Vordos D, etal. Pilot trial of adjuvant paclitaxel plus androgen deprivation forpatients with high-risk prostate cancer after radical prostatectomy:results on toxicity, side effects and quality-of-life. Prostate CancerProstatic Dis. 2010;13(1):97–101.

52. Kumar S, Shelley M, Harrison C, Coles B, Wilt TJ, Mason MD.Neo-adjuvant and adjuvant hormone therapy for localised andlocally advanced prostate cancer. Cochrane Database Syst Rev.2006;4:CD006019.

53. Shelley MD, Kumar S, Wilt T, Staffurth J, Coles B, Mason MD. Asystematic review and meta-analysis of randomised trials of neo-adjuvant hormone therapy for localised and locally advanced pros-tate carcinoma. Cancer Treat Rev. 2009;35(1):9–17.

54. Klotz LH, Goldenberg SL, Jewett MA, Fradet Y, Nam R, Barkin J,et al. Long-term followup of a randomized trial of 0 versus3 months of neoadjuvant androgen ablation before radical prosta-tectomy. J Urol. 2003;170(3):791–4.

55. Womble PR, VanVeldhuizen PJ, Nisbet AA, Reed GA, ThrasherJB, Holzbeierlein JM. A phase II clinical trial of neoadjuvantketoconazole and docetaxel chemotherapy before radical prosta-tectomy in high risk patients. J Urol. 2011;186(3):882–7.

56. Shepard DR, Dreicer R, Garcia J, Elson P, Magi-Galluzzi C,Raghavan D, et al. Phase II trial of neoadjuvant nab-paclitaxel inhigh risk patients with prostate cancer undergoing radical prosta-tectomy. J Urol. 2009;181(4):1672–7. discussion 1677.

57. Vuky J, Porter C, Isacson C, Vaughan M, Kozlowski P, Picozzi V,et al. Phase II trial of neoadjuvant docetaxel and gefitinib followedby radical prostatectomy in patients with high-risk, locally ad-vanced prostate cancer. Cancer. 2009;115(4):784–91.

58. Chi KN, Chin JL, Winquist E, Klotz L, Saad F, Gleave ME.Multicenter phase II study of combined neoadjuvant docetaxeland hormone therapy before radical prostatectomy for patientswith high risk localized prostate cancer. J Urol. 2008;180(2):565–70. discussion 570.

59. Pilepich MV, Winter K, Lawton CA, Krisch RE, Wolkov HB,Movsas B, et al. Androgen suppression adjuvant to definitiveradiotherapy in prostate carcinoma–long-term results of phase IIIRTOG 85–31. Int J Radiat Oncol Biol Phys. 2005;61(5):1285–90.

60. Mason M, Warde P, Sydes M, Cowan R, James N, Kirkbride P, etal. Defining the need for local therapy in locally advanced prostatecancer: an appraisal of the MRC PR07 study. Clin Oncol (R CollRadiol). 2005;17(4):217–8.

61. Widmark A,KleppO, Solberg A, Damber J-E, Angelsen A, FranssonP, et al. Endocrine treatment, with or without radiotherapy, in locallyadvanced prostate cancer (SPCG-7/SFUO-3): an open randomisedphase III trial. Lancet. 2009;373(9660):301–8.

62. Horwitz EM, Bae K, Hanks GE, Porter A, Grignon DJ, BreretonHD, et al. Ten-year follow-up of radiation therapy oncology groupprotocol 92-02: a phase III trial of the duration of elective andro-gen deprivation in locally advanced prostate cancer. J Clin Oncol.2008;26(15):2497–504.

63. Bolla M, de Reijke TM, Van Tienhoven G, Van den Bergh ACM,Oddens J, Poortmans PMP, et al. Duration of androgen suppressionin the treatment of prostate cancer. N Engl J Med. 2009;360(24):2516–27.

64. Zelefsky MJ, Yamada Y, Kollmeier MA, Shippy AM, NedelkaMA. Long-term outcome following three-dimensional conformal/intensity-modulated external-beam radiotherapy for clinical stageT3 prostate cancer. Eur Urol. 2008;53(6):1172–9.

65. Bolla M, Van Tienhoven G, Warde P, Dubois JB, Mirimanoff R-O,Storme G, et al. External irradiation with or without long-termandrogen suppression for prostate cancer with high metastatic risk:10-year results of an EORTC randomised study. Lancet Oncol.2010;11(11):1066–73.

66. Zurlo A, Collette L, van Tienhoven G, Blank L,Warde P, Dubois J, etal. Acute toxicity of conventional radiation therapy for high-riskprostate cancer in EORTC trial 22863. Eur Urol. 2002;42(2):125–32.

67. Hamstra DA, Bae K, Pilepich MV, Hanks GE, Grignon DJ,McGowan DG, et al. Older age predicts decreased metastasis andprostate cancer-specific death for men treated with radiation ther-apy: meta-analysis of radiation therapy oncology group trials. Int JRadiat Oncol Biol Phys [Internet]. 2011 Mar 31;Available from:http://www.ncbi.nlm.nih.gov/pubmed/21458924.

68. Widmark A, Klepp O, Solberg A, Damber J-E, Angelsen A,Fransson P, et al. Endocrine treatment, with or without radiother-apy, in locally advanced prostate cancer (SPCG-7/SFUO-3): anopen randomised phase III trial. Lancet. 2009;373(9660):301–8.

69. Van Poppel H, Vekemans K, Da Pozzo L, Bono A, Kliment J,Montironi R, et al. Radical prostatectomy for locally advancedprostate cancer: results of a feasibility study (EORTC 30001).Eur J Cancer. 2006;42(8):1062–7.

70. Loeb S, Smith ND, Roehl KA, Catalona WJ. Intermediate-termpotency, continence, and survival outcomes of radical prostatecto-my for clinically high-risk or locally advanced prostate cancer.Urology. 2007;69(6):1170–5.

71. Studer UE, Whelan P, Albrecht W, Casselman J, de Reijke T, HauriD, et al. Immediate or deferred androgen deprivation for patientswith prostate cancer not suitable for local treatment with curativeintent: European Organisation for Research and Treatment of Can-cer (EORTC) Trial 30891. J Clin Oncol. 2006;24(12):1868–76.

186 Curr Urol Rep (2012) 13:179–186

Copyright of Current Urology Reports is the property of Springer Science & Business Media B.V. and its

content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's

express written permission. However, users may print, download, or email articles for individual use.