Radical prostatectomy in high-risk and locally advanced prostate cancer: Mayo Clinic perspective

Urologic Oncology: Seminars and Original Investigations ] (2014) ∎∎∎–∎∎∎

Seminar article

Radical prostatectomy in high-risk and locally advanced prostate cancer: Mayo Clinic perspective Suzanne B. Stewart, M.D., Stephen A. Boorjian, M.D.* Department of Urology, Mayo Clinic, Roschester, MN Received 24 July 2014; received in revised form 30 September 2014; accepted 5 October 2014

Abstract Purpose: Men diagnosed with high-risk prostate cancer represent the cohort of prostate cancer patients at greatest risk for subsequent disease-specific mortality. Unfortunately, however, the classification of high-risk tumors remains imprecise and heterogeneous. There has been a historical reluctance to offer such patients aggressive local treatment, and considerable debate exists regarding the optimal management in this setting. Methods: We present here our institutional experience, as well as data from several other centers, with radical prostatectomy for high-risk tumors. Results: We discuss that surgery affords accurate pathological staging, thereby improving the identification of patients for secondary therapies. Moreover, prostatectomy not only provides durable local disease control but in addition numerous contemporary surgical series in high-risk patients have shown radical prostatectomy to be associated with excellent long-term cancer-specific survival. Further, although studies comparing surgical and radiotherapy modalities in high-risk prostate patients have been wrought with methodological challenges, consistently these observational studies have found equivalent to improved oncologic outcomes when surgery is utilized as the primary treatment. Conclusions: Herein, we review the advantages, long-term outcomes, and technique of surgery for high-risk prostate cancer. r 2014 Elsevier Inc. All rights reserved.

Keywords: Prostate cancer; Prostatectomy; High risk; Treatment

Introduction Despite the stage migration in prostate cancer (PC), which has been noted over the course of the prostatespecific antigen (PSA) era, between 14% and 24% of men with newly diagnosed disease continue to be classified as high risk based on clinicopathological tumor features [1]. Notably, the designation of high risk represents a term that has been applied to heterogeneous cohorts of patients, including the classifications proposed by D'Amico et al. [2], now used as the definition by the American Urological Association [3], the National Comprehensive Cancer Center (NCCN) [4], and the University of California San Francisco [5]. Nevertheless, regardless of classification system, highrisk patients harbor the greatest risk of death owing to PC. Corresponding author. Tel.: þ1-507-2-844-015; fax: þ1-507-2-844-951. E-mail address: [email protected] (S.A. Boorjian).

*

http://dx.doi.org/10.1016/j.urolonc.2014.10.003 1078-1439/r 2014 Elsevier Inc. All rights reserved.

Unfortunately, however, the optimal management of these men continues to be debated, as no accepted standardized treatment paradigm currently exists for such patients. Historically, men with high-risk PC have been managed most often with external beam radiation therapy (RT) or androgen-deprivation therapy (ADT) or both [1,6]. In fact, the practice of combining these modalities for high-risk patients has become recommended following randomized clinical trials, which demonstrated a survival benefit to long-term ADT with RT for men with locally advanced PC [7,8]. By contrast, surgical therapy (i.e., radical prostatectomy [RP]) has previously been discouraged in the setting of high-risk tumors, secondary to concerns regarding increased side effects, positive surgical margins, and inadequate disease control [9]. The lack of a standardized method of incorporation of surgery into the multimodal approach for patients with high-risk PC represents a stark contrast to the typical

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S.B. Stewart, S.A. Boorjian / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–10

management algorithms used, for example, in breast [10,11] and colorectal cancers [12]. That is, for these malignancies, multimodal treatment for advanced tumors has shown superior efficacy compared with a single-treatment approach [13–15]. Importantly, however, a role for RP in high-risk PC has not been rigorously tested in randomized clinical trials, and thus the quality of evidence to support its use is limited. Nevertheless, increasing data suggest a variety of benefits afforded by the inclusion of surgery as part of the treatment paradigm for men with high-risk tumors, and in fact, surgery has been considered the treatment of choice for these patients at our institution. Herein, we review our experience and data from other centers regarding surgery for men with high-risk PC. Particular focus is given to presenting long-term outcomes and comparative results vs. RT as well as to providing technical aspects of the procedure to facilitate the integration of surgery into a multimodal treatment approach.

Advantages of surgery in high-risk PC Accurate pathological staging A continued challenge to establishing an optimal management paradigm for patients with high-risk PC has been the lack of a consensus definition for high-risk disease, that is, patients who have met any of a variety of criteria involving pretreatment PSA or PSA kinetics or both, clinical stage, and biopsy Gleason score have historically been classified as high risk [16]. This heterogeneity in high-risk PC classifications in turn creates difficulties for individualized patient counseling, for defining clinical trial enrollment criteria, and for interpreting comparative outcome assessments between treatment modalities and even between surgical series. Indeed, widely disparate clinicopathological outcomes have been noted when various high-risk definitions were applied among men undergoing RP [16]. Importantly, moreover, not only is PC risk classification heterogeneous, it is often imprecise as well. That is, the various criteria that are used to assign pretreatment disease risk have not infrequently been noted to inaccurately represent tumor pathology. For example, clinical staging, which relies on digital rectal examination, has been reported to be incorrectly assigned in 35.4% of men, with downstaging occurring more commonly than upstaging [17]. Indeed, 22% to 63% of men initially defined as high risk have been found to have pathologically organ-confined disease at RP [16]. Similarly, the designation of clinical T3–4 stage has been found to be inaccurate in up to 33% of cases [18]. Within our institution, downstaging to pathological T2 occurred in 26% of patients initially designated with clinical T3 PC [19,20]. Meanwhile, discrepancies in Gleason score have likewise been noted frequently between biopsy and RP, such that up to 51.3% of Gleason 8 tumors at biopsy have been found to have a lower score at RP, with

31.1% of Gleason 9 to 10 biopsies demonstrating an RP grade of 7 or less [21]. At the Mayo Clinic, discordance between biopsy and pathological Gleason scores, even in more contemporary years (1999–2003), occurred in 26.9% of patients [22]. Interestingly, we learned that these patients were more likely to harbor adverse pathological features at time of surgery, such as advanced tumor stage, lymph node metastasis, and positive surgical margins. Furthermore, increasing biopsy Gleason score was an independent predictor of biochemical recurrence and systemic progression and death due to PC in patients with pathological Gleason 3 þ 4 [22]. Although the use of more sophisticated strategies such as diffusion-weighted magnetic resonance imaging (MRI) and magnetic resonance spectroscopy may improve our accuracy with clinical staging, currently their application is limited by their lack of widespread availability, standardization of technique, and cost [23–25]. An unfortunate potential consequence of the inaccuracies in risk assignment in PC is the implication for subsequent risk-based treatment. For example, patients assigned as high risk may be subjected to “therapeutic nihilism,” that is, a clinicians' assessment of high-risk tumors as not surgically curable may lead to historical practice patterns of preferentially offering radiation or hormones or both rather than surgery [6]. As high-risk patients are recommended by guidelines to receive 24 to 36 months of ADT [4], some may be subject, unnecessarily, to the attendant side effects of ADT [26,27], if they actually harbor lower risk disease. In fact, an assessment of practice patterns within the Cancer of the Prostate Strategic Research Endeavor database illustrates that patients classified as having high-risk disease who undergo radiation are significantly more likely to receive ADT than those treated with surgery [6]. As such, one of the critical benefits of surgery for patients considered to harbor high-risk PC is the ability to obtain accurate pathological staging. Indeed, as noted previously, clinical stage or Gleason score or both may change in 30% to 50% of men undergoing RP, leading to a potential change in risk classification. Specifically, in our experience, the 57% of patients initially classified as D'Amico high risk were found to have organ-confined disease following RP [28]. Pathological staging through surgery thereby affords clinicians the ability to guide secondary therapy utilization based on more precise and individualized data than would be available from PSA, clinical stage, and biopsy parameters alone. Indeed, 3 randomized trials have demonstrated a benefit to adjuvant RT for men found to have locally advanced tumors at RP [7,29,30], whereas a separate randomized trial noted significantly increased survival with adjuvant ADT after surgery for men with lymph node–positive disease [31]. In a retrospective matched analysis of Mayo Clinic patients with pathological lymph node–positive disease, use of adjuvant ADT was found to improve cancer-specific survival (CSS) and systemic progression–free survival following prostatectomy. However, this benefit was lost when ADT was administered at time of PSA recurrence or systemic progression [32].

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Mayo Clinic data also suggest that adjuvant ADT may be beneficial among patients with pathological seminal vesicle invasion (pT3b). Using a similar retrospective matched cohort design, patients with pT3b who received adjuvant ADT were found to have improved local and systemic control as well as CSS following prostatectomy [33]. Nevertheless, as these treatments are not without cost and potential morbidity, obtaining as accurate information as possible to assess a patient's risk for disease progression/ mortality facilitates maximizing oncologic outcomes while minimizing the burden of treatment. In particular, ADT has been associated with a 44% increased risk of incident diabetes, 16% increased risk of coronary heart disease, 11% increased risk of myocardial infarction (MI), and a 16% increased risk of sudden cardiac death [27]. The linkage between ADT and cardiac disease has been further solidified by D'Amico et al. [26] through evaluating the differences in time to fatal MI among men enrolled in randomized trials receiving RT with/without ADT. Specifically, the group found that among men aged 65 years and older who were at risk of having a fatal MI, half of them were observed to have a MI sooner if they had received a 6-month course of ADT [26]. Furthermore, receipt of adjuvant ADT has been associated with poor outcomes across multiple quality-of-life domains and ultimately exacerbates the adverse effects of RT [34]. Thus, utilizing surgery as an initial treatment modality for patients with high-risk PC may help to identify patients who are unlikely to benefit from adjuvant therapy, allowing them to avoid or at least delay RT and ADT along with their adverse side effects. Durable local control Surgical removal of the prostate in the setting of highrisk disease affords patients the opportunity to decrease, if not completely avoid, the often debilitating complications of locally advanced tumor growth, including persistent gross hematuria, bladder outlet obstruction, pelvic pain, and ureteral obstruction. Such sequelae, as noted of local tumor extension, may significantly affect patients' quality of life and prevent the need for secondary procedures to manage these complications. For example, the rates of urethral stricture formation and hematuria requiring intervention have been noted to be higher among lymph node– positive patients treated with ADT only (24.6%) vs. those who had undergone RP (9.5%) [35]. More recently, Nam et al. [36], in a Canadian cohort of 15,870 men who underwent RP and 16,595 men treated with RT, demonstrated that treatment with RT was associated with a significantly higher incidence of subsequent non–diseasespecific complications. In particular, men who underwent RT had a higher incidence of rectal or anal procedures (hazard ratio [HR] ¼ 2.72; 95% CI: 2.40–3.08; P o 0.0001), hospital admissions (HR ¼ 10.8, 95% CI: 9.04–12.9; P o 0.0001), and open surgical procedures

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(HR ¼ 3.68, 95% CI: 2.16–6.26; P o 0.0001) at 5 years compared with patients treated with RP [36]. Another potential benefit to achieving local control is that primary PC tumor removal may also be associated with a survival benefit for patients with regionally metastatic disease. Specifically, it has been postulated that eliminating the primary tumor may eradicate a source of cancer cells that can continue to “seed” or perpetuate metastatic disease [37]. For example, in a secondary analysis of a randomized trial from the Southwest Oncology Group Study trial comparing orchiectomy and placebo vs. orchiectomy and flutamide among men with metastatic PC, Thompson et al. [37] noted that men who had undergone RP earlier in their disease course had a significantly decreased risk of mortality (HR ¼ 0.77; 95% CI: 0.53–0.89) compared with men who did not undergo prior RP. A survival benefit to local tumor control in the setting of advanced PC has also been supported, albeit indirectly, by several studies that have matched patients with lymph node– positive disease who underwent RP vs. those who did not. Consistently, these (admittedly retrospective analyses) have demonstrated improved survival in the RP cohorts [38–41]. In a study performed at the Mayo Clinic, Ghavamian et al. [41] found that patients with pathological lymph node– positive disease treated with RP, pelvic lymph node dissection, and early adjuvant orchiectomy had a significantly improved 10-year overall (66% vs. 28%; P o 0.001) and CSS (79% vs. 39%; P o 0.001) compared with matched controls who underwent only pelvic lymph node dissection and orchiectomy. Similarly, Steuber et al. [39] reported a 10-year CSS of 76% among patients treated with RP plus adjuvant ADT, compared with the 46% among patients in whom RP was aborted and ADT was the sole therapy. Likewise, Engel et al. [38] more recently found a 10-year overall survival of 64% among lymph node–positive patients who underwent RP vs. 28% among men in whom RP was aborted. Moreover, after controlling for clinicopathological factors including the number of positive lymph nodes, these authors found a 2-fold greater risk of overall mortality among patients in whom RP was aborted (HR ¼ 2.042, 95% CI: 1.59–2.63; P o 0.0001) [38]. Long-term CSS following surgery for high-risk tumors Although patients with high-risk PC have been subjected to therapeutic nihilism, leading clinicians to avoid surgery, numerous series have reported favorable long-term survival after RP in this setting. Table 1 summarizes a compilation of studies, specifically from the Mayo Clinic, that have reported on cancer-specific outcomes following RP in highrisk PC. As can be seen, 10-year CSS rates approach/exceed 90% after surgery. Importantly, as discussed previously, the heterogeneity in the definitions used to classify patients as high risk has resulted in a diverse range of reported outcomes. In 2008, using data from Memorial SloanKettering Cancer Center, Yossepowitch et al. [42]

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Table 1 Selected references summarizing Mayo Clinic experience with radical prostatectomy in high-risk prostate cancer References

High-risk definition

Mitchell et al. [19]

cT3

Boorjian et al. [44]

No. of patients

Median follow-up, mo

Receipt of adjuvant treatment, %

10-year CCS, %

843

172

90a

Gleason 8–10

584

100

Inman et al. [46]

PSA Z 50 ng/ml

234

151

Boorjian et al. [28]

D'Amico high-risk criteriac

1,513

92

Boorjian et al. [48]

pNþ

507

124

ADT: 344 (40.8) RT: 109 (12.9) ADT: 224 (38.4) RT: 70 (12) ADT: 138 (58.9) RT: 39 (16.6) ADT: 872 (57.6) RT: 324 (21.4) ADT: 455 (89.7) RT: 44 (8.7)

89b 87 95 86

20-Year cancer-specific survival estimate ¼ 81%. 7-Year event rates. c Z Clinical stage T2c, biopsy Gleason score 8–10, or PSA 4 20 ng/ml. a

b

specifically explored this outcome variability among 8 different preclinical high-risk PC definitions. The authors found that the 10-year cumulative incidence of PC-specific mortality following RP ranged from 3% to 11%, depending on the preclinical high-risk definition used. In addition to this heterogeneity, the authors importantly noted that the observed risk of PC-specific mortality remains strikingly low for high-risk patients treated with RP [42]. We have likewise evaluated outcomes following RP in our institutional data set using various definitions for high-risk disease, and as such, a review of these data may help facilitate patient counseling and an individualized approach to management (Table 1). For example, regarding the high-risk criterion of clinical stage, Ward et al. [20] evaluated 841 men with cT3 tumors who underwent RP at Mayo Clinic and noted a 10-year CSS in this cohort of 90%. More recently, Mitchell et al. [19] updated this experience with extended follow-up and reported an 81% CSS at 20 years after surgery in these patients. Importantly, 40.8% of these patients received adjuvant ADT and 12.9% received adjuvant RT [19]. By comparison, Hsu et al. similarly found the 10-year CSS to be 91.6% when RP was used as the primary treatment among 235 men with cT3a tumors. Notably, 56% of these patients received adjuvant or salvage therapy [43]. Thus, such studies illustrate that surgery within a multimodal treatment platform may lead to durable survival for patients with high-risk tumors. Meanwhile, when patients with Gleason 8–10 tumors were evaluated separately among our entire Mayo Clinic cohort, we found that the 10-year CSS following RP was 89% [44]. Again, 38.4% of patients received adjuvant ADT and 12% received adjuvant RT, illustrating the frequency and importance of using a multimodal treatment approach in these patients to achieve a durable control [44]. We have also used our institutional data set to validate the D'Amico risk classification, a commonly used set of criteria based on clinical stage, biopsy Gleason score, and PSA at diagnosis [2]. Using the D'Amico classification, we found the 10-year CSS for high-risk patients was 95% [28]. Likewise, in a single-surgeon series from Johns

Hopkins University, Loeb et al. [45] reported that the 10-year CSS following RP was 92% in 175 men defined as high-risk by D'Amico classification. When evaluating PSA as the criteria of high-risk disease, Inman et al. [46] found, using Mayo Clinic data, a 10-year CSS following RP of 87% among 236 men with a pretreatment PSA Z 50 ng/ml. Moreover, among 712 men with a pretreatment PSA 4 20 ng/ml from 6 different European centers, Spahn et al. [47] found the 10-year CSS following RP to be 84.5%. Again, such studies exemplify the ability of surgery to achieve oncologic control irrespective of the high-risk definition used for PC. Furthermore, the durable survival following surgery may be experienced as well in the setting of lymph node– positive disease. That is, in the PSA era, Boorjian et al. [48] reported from the Mayo Clinic a 10-year CSS of 85.8% after RP among patients with lymph node–positive disease, with 56% of men free of biochemical recurrence, at a median follow-up of 10.3 years. Additionally, using combined data from the Mayo Clinic and San Raffaele Hospital in Milan, Italy, Abdollah et al. [49] showed that patients with lymph node–positive disease were afforded a 10-year cancer-specific mortality–free rate of 87% when RP was combined with both adjuvant ADT and RT and an 82% cancer-specific mortality–free rate with adjuvant ADT alone. Likewise, separate institutional series have demonstrated favorable outcomes following RP for lymph node– positive disease as outlined in the aforementioned section on “Advantages of surgery in high-risk prostate cancer: durable local control” [38,39,41].

Surgery vs. radiation for high-risk PC In addition to outlining the results when using surgery for high-risk PC, it remains important to contextualize these data with what has been reported following RT as a primary treatment modality. An awareness of comparative outcomes

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is particularly critical given the noted historic practice patterns of using RT in high-risk patients [6]. Unfortunately, randomized clinical trial evidence of RP vs. RT is lacking. While we await the results of the ProtecT (Prostate Testing for Cancer and Treatment) study [50], a prospective randomized trial comparing RP, RT, and watchful waiting in PC, a number of retrospective analyses reporting on the comparative survival following surgery vs. RT are important to highlight. Although interpretation of the findings are limited by selection bias of patients undergoing RT vs. RP, as well as differences in the classification of high-risk disease, treatment eras, and definitions of outcome, the majority of such studies have found improved outcomes with RP, particularly for high-risk patients [51–58], with a few demonstrating a benefit to radiation [59,60], and others noting no difference in efficacy [2,61,62]. Table 2 outlines the findings from some of these comparative series. In 1 such investigation, we compared the outcomes between 1,238 men with NCCN-defined high-risk prostate tumors who underwent RP at Mayo Clinic to 609 men with NCCN high-risk disease treated with RT ⫾ ADT at Fox Chase Cancer Center [51]. Of note, 41% of men who underwent RP received adjuvant ADT [51]. Median followup was 10.2 years after RP and 6 years following RT ⫾ ADT [51]. We found a significantly higher 10-year overall survival among patients treated with RP (77%) vs. those who received RT þ ADT (67%) or RT alone (52%) (P o 0.001) [51]. Moreover, on multivariable analysis controlling for tumor features as well as patient parameters, men treated with RT þ ADT remained at significantly increased risk of all-cause mortality compared with men

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treated with surgery (HR ¼ 1.60; 95% CI: 1.25–2.05; P ¼ 0.0002) [51]. Similarly, Zelefsky et al. [52] compared 1,318 men who underwent RP and 1,062 men treated with RT for cT1c– T3b PC and found that RP was associated with both reduced risk of metastasis (HR ¼ 0.35; 95% CI: 0.19–0.65; P o 0.001) and cancer-specific mortality (HR ¼ 0.32; 95% CI: 0.13–0.80; P ¼ 0.015) compared with RT. Importantly, after risk stratifying patients according to the NCCN classification, the difference in 8-year metastasis-free survival between RP and RT was more substantial in high-risk patients (7.8%) than among intermediate- (3.3%) or low-risk (1.9%) patients [52]. Likewise, Cooperberg et al. [56] reported among patients in the Cancer of the Prostate Strategic Urologic Research Endeavor registry a greater benefit among high-risk patients treated with RP as compared with RT. Specifically, after adjusting for disease risk using Cancer of the Prostate Risk Assessment score [5], these investigators determined that the absolute difference in cancer-specific mortality after treatment with RP vs. RT became more substantial with higher Cancer of the Prostate Risk Assessment scores [56], indicating that men with higher-risk PC derive a greater relative benefit from RP vs. RT than men with lower risk tumors. This separation in treatment outcome by risk classification has been further explored in the Surveillance, Epidemiology, and End Results registry [57]. Indeed, Abdollah et al. [57] noted that, for patients with high-risk disease who were r69 years old, the lowest cancer-specific mortality rates occurred among those who had been treated with RP.

Table 2 Selected references summarizing comparative outcomes following radical prostatectomy vs. radiation therapy for high-risk prostate cancer References

High-risk definition

No. of patients

Median follow-up, mo

Receipt of adjuvant treatment, %

10-Year CSM, %

Boorjian et al. [51]

NCCNa

RP: 1,238

122.4

8

RT: 609 RP: 1,318b

RT alone: 87.6 RT þ ADT: 72 61.2

RT: 1,062b RP: 328 RT: 279 53,177 48,279

60 46.8 54 61 52

ADT: 367 (29.6) RT: 85 (6.9) ADT þ RT 51 (4.1) – ADT: 344 (56.5) ADT: 17 (1) RT: 79 (6) ADT: 597 (56) 63 (19.3)e ADT: 189 (67.6) NR NR

Zelefsky et al. [52]

NCCNa

Cooperberg et al. [56]

CAPRA score 6–10d

Abdollah et al. [57]

cT2c or Gleason 8–10 or both

12 8 3.8c 9.5c 11.1–36.2f 15.2–46.6f 5.8 9.9

CAPRA ¼ Cancer of the Prostate Risk Assessment; NR ¼ not reported. NCCN high-risk definition: PSA Z 20 ng/ml, or clinical stage Z T3N0M0, or biopsy Gleason score 8–10. b Total of 409 patients were considered NCCN high risk (allocation by treatment type not provided) and were used in the aforementioned reported CSS analysis. c 8-Year cancer-specific survival probabilities. d CAPRA score ranges from 0 to 10 and is calculated from PSA level, biopsy Gleason grade, clinical T stage, age at diagnosis, and percentage of positive biopsy cores. e RP patients who received neoadjuvant treatment; 136 men from entire RP cohort (n ¼ 5,066) received adjuvant RT; information not provided by CAPRA score. f Range for CAPRA scores of 6 to 10. a

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Notably, these reported survival differences may reflect selection bias inherent to retrospective study design, differences in the efficacy between primary treatment modalities, as well as the potential effect of increased ADT use among RT patients. Nevertheless, it should be noted that the reported data have consistently demonstrated a survival advantage to RP (vs. RT) in the high-risk setting, challenging the aforementioned therapeutic nihilism of seeing these patients as unlikely to benefit from surgery. It remains important as well to note that surgery has not been associated with adverse disease-specific functional outcomes and has in fact been noted to have lower non– disease-related compilations than RT. That is, using the Prostate Cancer Outcomes Study cohort of 1,164 men treated with RP and 491 treated with RT, Resnick et al. [63] reported no significant differences in patient-reported urinary incontinence, erectile dysfunction, or bowel urgency between treatment modalities after 15 years of follow-up. Further, as outlined previously, Nam et al. [36] found a higher incidence of non–disease-specific complications among patients treated with RT vs. RP. In addition, patients in that series who were treated with RT had a greater than 2-fold increased risk of secondary malignancy compared with patients treated with RP (HR ¼ 2.08, 95% CI: 1.48– 2.91; P o 0.0001) [36]. Moreover, when considering complications arising from a multimodal approach to PC, Tefilli et al. [64] found that quality-of-life parameters were higher among men treated with surgery first followed by salvage RT vs. RT first followed by salvage RP. Indeed, complications with salvage RP have been reported to range as high as 30% to 66% for urinary incontinence, 0% to 35% for rectal injuries, and 0% to 28% for bladder neck contractures [65].

Safety and approach to surgery for high-risk PC Despite the reported advantages of surgery for men with high-risk PC, concerns exist regarding the potential for increased perioperative morbidity in these cases [66]. Importantly, however, numerous series have now demonstrated similar morbidity rates following RP across disease risk stratifications. For example, Berglund et al. [67] found that among 281 patients with ZcT2b, PSA 4 15 ng/ml, and Gleason score Z8 who underwent RP, the overall postoperative complication rate was 9.7% vs. 6.9% for patients with lower risk tumors. In addition, the group reported similar rates of urinary continence among high- vs. low-risk men [67]. Our experience at the Mayo Clinic has been similar, such that Ward et al. [20] reported that both perioperative complication and continence rates of 843 patients with cT3 disease following RP paralleled the outcomes of patients with cT2 disease. Additionally, Novara et al. [68], in an analysis of 308 men, noted that D'Amico risk classification was not significantly associated with 12-month continence rates following RP.

Meanwhile, the increased adoption of robotic-assisted RP (RARP) [69] has led as well to an interest in applying RARP in the treatment of men with high-risk disease. To date, however, there have only been a few small series, with short follow-up, reporting the outcomes of RARP in this setting. For example, Punnen et al. [70] reported in a single institution retrospective analysis that oncologic outcomes were similar between 233 robotic and 177 open RP cases among men with high-risk disease defined by NCCN criteria [4]. No difference was found between the cohorts regarding pathological grade, stage, or positive surgical margin rates (open 23% vs. robotic 29%) [70]. Recurrence-free survival estimates were also similar between open and robotic RP at both 2 years (84% vs. 79%) and 4 years (68% vs. 66%) (P ¼ 0.52) [70]. In a matched cohort analysis using Mayo Clinic data, Krambeck et al. [71] showed no significant differences in perioperative, functional, or early oncologic outcomes between robotic and open RP techniques. Specifically, in this cohort, of which 7.4% of patients were designated as high risk, similarities were seen in overall perioperative complication rates between RARP and RP (8% vs. 4.8%; P ¼ 0.064), 1-year continence (91.8% vs. 93.7%; P ¼ 0.344), and potency rates (70% vs. 62.8%; P ¼ 0.081). Furthermore, 3-year biochemical progression–free survival was similar between techniques (RARP 92.4% vs. RP 92.2%; P ¼ 0.69) [71]. Among patients with PC classified as intermediate and high risk according to D'Amico, Ritch et al. [72] showed surgical approach (robotic vs. open RP) was not an independent predictor of biochemical recurrence after controlling for surgeon, PSA, stage, and Gleason score (HR ¼ 1.01, 95% CI: 0.76–1.36; P ¼ 0.927). Additionally, there was no significant difference in 5-year biochemical recurrence–free survival between surgical approaches after categorizing patients according to pathological stage. The authors concluded that such evidence supports the use of the RARP in patients with D'Amico intermediateand high-risk PC from an oncologic perspective [72]. Moreover, a recent systematic review by Yuh et al. [73], inclusive of 12 series, the majority of which used the D'Amico classification for high-risk disease [2], concluded that robotic RP in high-risk PC appears safe and effective for select patients. Specifically, mean blood loss was 189 ml, whereas the mean length of hospital stay and catheterization time was 3.2 and 7.8 days, respectively [73]. The mean rate of pathologically organ-confined disease was 35% (7%–48%), and the positive surgical margin rate was 35% (12%–53%) [73]. Biochemical recurrence occurred in 14% to 55% of patients, with 3-year recurrence-free survival ranging from 45% to 86% [73]. Moreover, 12-month potency rates ranged from 52% to 60%, with continence rates (defined as utilizing 0 pads) at 1 year between 51% and 95% [73]. The authors stated that these oncologic outcomes appeared comparable to what has been reported with open RP and that the perioperative and functional outcomes were likewise similar to robotic RPs performed in non–high-risk patients [73]. Ultimately, the determination of the surgical approach should be based on the surgeon's experience. We believe

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that the ability to achieve negative surgical margins, to perform an extended pelvic lymph node dissection, to complete the procedure safely, and to maximize preservation of quality-of-life outcomes is much more likely to depend on the expertise of the surgeon than the technique employed. Indeed, current population-based data support the similarity in outcomes between approaches for patients overall [74]. As such, at our institution, high-risk cancers are routinely treated with both RARP and open RP, depending on individual surgeon preference. Surgical technique in high-risk PC Our preoperative evaluation for patients with high-risk PC at Mayo Clinic includes bone scan as well as cross-sectional imaging, most frequently with prostate MRI. MRI may be used not only to assess for pelvic lymphadenopathy but also to evaluate local tumor extension, for example, into the neurovascular bundle, seminal vesicle, urethral sphincter, and bladder neck. Such information may then assist with operative planning, for example, as a component of the decision regarding the extent of nerve sparing. As well, if there is a suspicion for bladder neck invasion with cancer based on this evaluation, we perform preoperative cystoscopy. Although significant attention has been given over the past several years regarding the optimal surgical approach to PC, including high-risk disease, as open vs. robotic, our institutional practice for these patients includes both approaches and is based on surgeon experience. During open retropubic prostatectomy, consideration may be given to performing an antegrade dissection of the gland during neurovascular bundle resection, particularly if retrograde tissue dissection proves difficult. That is, for patients with high-risk features, but without clear evidence for non– organ-confined disease, we will consider nerve-sparing procedure. In fact, we have found that for such cases, nerve sparing (vs. wide local excision) does not comprise biochemical progression rates [75]. Nevertheless, if there is a concern intraoperatively regarding tumor extension, we obtain a frozen section analysis of the periprostatic tissue in the region of interest, and additional resection may be considered. As well, it has been our practice to consider the lymphadenectomy as a critical component of the surgery for high-risk PC. Reproducibly, it has been demonstrated that an extended pelvic lymph node dissection retrieves more nodes and identifies more positive nodes than standard lymph node dissection. Indeed, lymphadenectomy may have both a diagnostic and therapeutic role here, that is, identification of the presence and extent of lymph node involvement may help guide the application of secondary therapies. Moreover, eradication of disease in this setting as outlined previously may be of oncologic benefit as well. As such, in these cases, we perform an extended dissection, with the boundaries typically extending cephalad to where the ureter crosses over the common iliac artery, caudad to Cooper

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ligament, including removal of the node of Cloquet, laterally to the genitofemoral nerve, and posteriorally to below the obturator nerve and along the internal iliac artery. Care is taken to dissect the lymphatic tissue within the fossa of Marcille. Interestingly, a recent study by Abdollah et al. [76] investigated whether the number of nodes removed in patients with PC with lymph node invasion was associated with outcome. In fact, these investigators found that the 10year CSS ranged from 74.7% for patients with 8 nodes removed to 97.9% for patients with 45 nodes removed. Moreover, the number of lymph nodes removed remained independently associated with CSS for patients with lymph node invasion [76]. Importantly, extended lymph node dissection is performed in high-risk cases regardless of whether the surgical approach is open or robotic. Conclusions Surgery for high-risk PC offers patients accurate pathological staging to assist with an individualized approach to secondary therapies, durable local control, and excellent long-term cancer-specific control. Although comparisons between surgery and radiation in the setting of high-risk disease are comprised of retrospective analysis subject to the potential for significant bias, nevertheless these observational studies consistently have reported favorable oncologic outcomes with surgery as the primary treatment modality. Overall, the accumulating evidence in support of surgery appears to be transforming historical practice patterns, as current trends reflect an increase in these patients being treated with RP [77,78]. Furthermore, guidelines from the European Association of Urology [79], NCCN [4], and American Urological Association [3] now support the discussion of surgery among men with high-risk disease. As the treatment paradigm for high-risk PC shifts, it will be crucial to standardize the definition for high-risk disease and focus our attention on individualizing multimodal approaches for specific subsets of high-risk PC to facilitate continued improvement in survival. References [1] Cooperberg MR, Cowan J, Broering JM, Carroll PR. High-risk prostate cancer in the United States, 1990-2007. World J Urol 2008; 26:211–8. [2] D'Amico 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. J Am Med Assoc 1998;280: 969–74. [3] Thompson I, Thrasher JB, Aus G, Burnett AL, Canby-Hagino ED, Cookson MS, et al. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol 2007;177:2106–31. [4] Mohler JL KP, Armstrong AJ, Bahnson RR, Cohen M, D'Amico AV, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guideline): Prostate Cancer. 2.2014 ed: NCCN.org; 2014. [5] Cooperberg MR, Freedland SJ, Pasta DJ, Elkin EP, Presti JC Jr., Amling CL, et al. Multiinstitutional validation of the UCSF cancer of

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