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Special Article Arch. Esp. Urol. 2013; 66 (3): 259-273 CURRENT ROLE OF SURGERY FOR HIGH RISK PROSTATE CANCER Steven Joniau1*, Kathy Van der Eeckt1*, Alberto Briganti2, Paolo Gontero3, Siska Van Bruwaene1, R Jeffrey Karnes4, Martin Spahn5 and Hein Van Poppel1. For the European Multicenter Prostate Cancer Clinical and Translational research Group (EMPaCT). Urology, Department of Development and Regeneration. University Hospitals of Leuven. Leuven. Belgium. Department of Urology. Vita-Salute San Raffaele Hospital. Milan. Italy. 3 Department of Urology. University of Turin. Turin. Italy. 4 Department of Urology. Mayo Clinic. Rochester. United States. 5 Department of Urology. Inselspital. Bern. Switzerland. *Both authors contributed equally to the manuscript. 1 2 Summary.- In this review, the role of surgery in patients with adverse tumor characteristics and a high risk of tumor progression are discussed. In the current PSA era the proportion of patients presenting with high risk prostate cancer (PCa) is estimated to be between 15% and 25% with a 10-year cancer specific survival in the range of 80-90% for those receiving active local treatment. The treatment of high risk prostate cancer is a contemporary challenge. Surgery in this group is gaining popularity since 10-year cancer specific survival data of over 90% has been described. Radical prostatectomy should be combined with extended lymphadenectomy. Adjuvant or salvage therapies may be needed in more than half of patients, guided by pathologic findings and @ CORRESPONDENCE Steven Joniau, MD, PhD Urology, Department of Development and Regeneration University Hospitals Leuven Herestraat 49, 3000 Leuven (Belgium) Accepted for publication: January 22nd, 2013 postoperative PSA. Unfortunately there are no randomized controlled trials comparing radical prostatectomy to radiotherapy and no single treatment can be universally recommended. This group of high risk prostate cancer patients should be considered a multi-disciplinary challenge; however, for the properly selected patient, radical prostatectomy either as initial or as the only therapy can be considered an excellent treatment. Keywords: High-risk prostate cancer. Multimodality approach. Radical prostatectomy. Extended lymphadenectomy. Adjuvant treatment. Salvage treatment. Resumen.- En esta revisión se discute el papel de la cirugía en los pacientes con tumor de características adversas y alto riesgo de progresión tumoral. En la actual era del PSA, la proporción de pacientes que presentan cáncer de próstata (CaP) de alto riesgo se estima que es entre el 15% y 25%, con una supervivencia de 10 años cáncer-específica en el rango de 80-90% de los que recibieron tratamiento local activo. El tratamiento del cáncer de próstata de alto riesgo es un reto contemporáneo. La cirugía en este grupo está ganando popularidad, dado que se han publicado datos de 10 años de supervivencia cáncer-específica del 90%. La prostatectomía radical se debe combinar con linfadenectomía extendida. Los tratamientos adyuvantes o de rescate pueden ser necesarios en más de la mitad de los pacientes, basándose en los hallazgos anatomopatológicos y el PSA postoperatorio. Lamentablemente no hay ensayos aleatorios controlados que comparen la 260 S. Joniau, K. Van der Eeckt, A. Briganti, et al. prostatectomía radical y la radioterapia y no hay ningún tratamiento que pueda ser recomendado universalmente. Este grupo de pacientes de cáncer de próstata de alto riesgo debería ser considerado como un desafío multidisciplinario; sin embargo, la prostatectomía radical, para el paciente adecuadamente seleccionado, ya sea como primer o como único tratamiento puede ser considerada un tratamiento excelente. Palabras clave: Cáncer de próstata de alto riesgo. Estrategia multimodal. Prostatectomía radical. Linfadenectomía extendida. Tratamiento adyuvante. Tratamiento de rescate. INTRODUCTION AND BACKGROUND Epidemiology and definition of high-risk prostate cancer Prostate cancer (PCa) constitutes a major health problem and poses specific challenges in the male population. World wide, PCa is the second most frequent cancer with an estimated 903,500 new cases in 2008. It was the sixth most frequent cause of cancer death in the same year, resulting in 258,400 estimated deaths. In developed countries, PCa is the most prevalent cancer with 648,400 new cases, taking third place in cancer mortality with an estimated 136,500 deaths in 2008 (1). In the US, approximately 241,740 men will be diagnosed with PCa and 28,170 will die of their disease this year. PCa is second only to lung cancer as a cause of cancer mortality among men in the US (2). In the EU, the number of newly diagnosed cases increased from 145,000 in 1996 to 345,000 in 2006 (3). PCa represents the third cause of cancerrelated death in men in Europe; in 2006, 171,900 (26.3%), 74,500 (11.4%) and 67,800 (10.4%) cancer deaths were attributable to lung, colorectal and PCa, respectively (3). Despite the dramatic increase in diagnosis, the number of deaths attributed to the disease over the same time period remained almost unchanged (75,000 in 1996 vs. 67,800 in 2006) (3,4). Thus, advances in screening and diagnostic techniques have resulted in detection of PCa at progressively earlier stages and lower levels of prognostic risk. In many men, PCa will have a prolonged natural history, while some will rapidly progress to metastatic stage and die of their disease. The challenge faced daily by the physician is to identify men with clinically localized PCa who are at risk of suffering or dying from their disease, without over-treating men who are likely to die of another cause. The current inability to accurately distinguish risk of life-threatening, aggressive PCa from indolent cases contributes to the dilemma. The outcome of PCa is strongly related to its TNM (Tumor Node Metastasis) clinical stage, biopsy Gleason score (GS) -which determines cancer aggressiveness- and pretreatment serum prostatespecific antigen (PSA) levels. The TNM classification recognizes four stages of local tumor growth, from T1 (incidental) to T4 (invasion ofadjacent organs), with each stage describing the state of pathological development of the tumor (5). The nodal stage (NX, N0, N1) and the metastatic stage (MX, M0, M1AC) reflect the clinical spread of the disease to lymph nodes (LN) and distant sites. It is widely accepted that patients with localized PCa who are at elevated risk of dying from the disease are those with clinical stage T3 or T4 disease (cT3 or cT4; i.e. patients whose tumor extends through the capsule or invades the seminal vesicles (T3) or invades adjacent structures other than the seminal vesicles (T4)). However, some patients with cT2c disease (i.e. palpable disease that has spread to both lobes) also fall within this high-risk group. Indeed, once the pathological assessment has shown that the tumor has grown through the capsule (pathological T3a; pT3a) or into the seminal vesicles (pT3b) or has invaded organs nearby (pT4), outcome and progression-free survival are dramatically decreased indicating that pathological stage of the tumor is an important predictor of PCa progression. This is supported by the findings of Epstein and coworkers who investigated the percentage of patients with PCa who remained progression-free (defined as postoperative PSA ≤0.2 ng/mL, no evidence of local recurrence and no radiological evidence of distant metastases) after radical prostatectomy (RP) (6). After 10 years, the proportion of patients who were progression-free was significantly different between men with localized disease (pT2) and focal capsular penetration (pT3a) (84.7 vs. 67.7, respectively; p≤0.0001), and between men with focal and established capsular penetration (67.7 vs. 58.4%, respectively; p=0.001). Of the men with seminal vesicle invasion (pT3b), 27% were progression-free, and all men with LN metastases or adjacent organ invasion progressed (pT4 / N+). The Gleason grading system, which is based on the degree of loss of normal glandular tissue architecture of the prostate, assigns a grade to each of the two largest areas of the tumor biopsy sample. CURRENT ROLE OF SURGERY FOR HIGH RISK PROSTATE CANCER A GS of 2 to 4 is considered to be low grade; 5 to 7, intermediate grade; and 8 to 10, high grade (7). Patients with a GS of 8, 9 or 10 typically have a markedly higher PCa death rate compared with those patients with a lower score (8,9). In a retrospective analysis of 751 men with non-metastatic PCa treated with RP, the cumulative incidence of PCa death within 20 years was 36-43% for men with GS of 8 to 10 compared with 10-13%, 15-19% and 29-35%, for men with scores of 5, 6 and 7, respectively (9). PSA alone is not a good predictor of highrisk PCa patients. However, a study conducted by D’Amico and co-workers suggested that the rate of increase in PSA levels in the year before diagnosis may be an important predictor of outcome. In this study in 1,095 men with localized PCa, patients with a PSA velocity >2 ng/mL/year had a significantly shorter time to death from PCa (p<0.001) and death from any cause (p=0.01) despite RP compared with those patients who had a PSA velocity of ≤2 ng/mL/ year (10). Although TNM stage, biopsy GS and pretreatment PSA relate directly to outcome, no single criterion is able to adequately identify all patients with localized PCa who have a high likelihood of progression after therapy. In an attempt to address this, nomograms such as the Partin tables and the Kattan nomogram have been developed which use a combination of these three tumor parameters (11,12). Furthermore, in 1998, D’Amico et al. proposed a risk group stratification based on the known prognostic factors: PSA level, biopsy GS, and T-stage. These risk groups were derived to predict a patient’s risk to biochemical recurrence (BCR) after RP, radiation therapy (RT) or brachytherapy for clinically localized disease. The proposed classification defines three risk groups: “low-risk” with <25% probability of PSA failure at 5 years (≤T2a and GS ≤6 and PSA <10 ng/mL), “intermediate-risk”with 25-50% probability of PSA failure at 5 years (T2b or GS 7 or PSA 10-20 ng/mL) and“high-risk” with >50% probability of PSA failure at 5 years (T2c or GS 8-10 orPSA >20 ng/mL) (13). By using these pretreatment risk groups, D’Amico and coworker shave also shown that it is possible to predict the probability of PCa-specific mortality after RP or RT. In a study of 7,316 patients with localized PCa, the relative risk of PCa-related mortality following RP for high- and intermediate-risk (vs. low-risk) PCa was 14.2 (95% CI: 5.0-23.4; p<0.0001) and 4.9 (95% CI: 1.7-8.1; p=0.0037), respectively. For RT the relative risk was 14.3 (95% CI: 5.2-24.0; p<0.0001) for high-risk and 5.6 (95% CI: 2.0-9.3; p=0.0012) for intermediate-risk patients (14). Together these findings confirm that a considerable number of RT- or RP-managed patients in the high-risk group will die 261 from PCa despite having clinically localized disease. Interestingly, there is no definitive consensus on the definition of high-risk PCa. For example, D’Amico et al. define high-risk localized PCa as stage cT2c, or PSA>20 ng/mL, or GS 8-10, while the European Association of Urology (EAU) guidelines and the National Comprehensive Cancer Network (NCCN) guidelines define high-risk PCa asstage ≥cT3a or PSA >20 ng/mL or GS 8-10 (15,16). Trials exploring the feasibility of (neo)adjuvant chemotherapy have also each used different criteria to enroll patients with high-risk PCa (17). Furthermore, not all patients diagnosed with high-risk PCa have an invariably poor prognosis. Several reports indicate heterogeneous outcomes for the group of high-risk PCa patients. For example, Yossepowitch et al. have compared eight different definitions of high-risk PCa to classify 4,708 men treated with RP (18). Depending on the definition of high-risk PCa used, the 5-year biochemical progression-free survival (BPFS) after RP ranged from 49% to 80%. Of the tumors classified as high-risk, 22% to 63% were actually confined to the prostate. In a similar study using the same criteria it was shown that the risk of secondary therapy, metastatic progression and PCa-specific mortality were also depending on the definition of high-risk PCa used (19). This means that there is a substantial proportion of high-risk patients that remains free from additional therapy or metastatic disease after surgery. Considering these results, patients with currently classified high-risk PCa should not be categorically disqualified from having surgical therapy with curative intent despite their increased risk of treatment failure. Interestingly, both Yossepowitch et al. (18) and Stephenson et al. (20), have shown that patients with either PSA ≥20 ng/mL or biopsy GS of 8-10 or cT3 PCa had the highest PCa-specific mortality. These high-risk PCa factors are now widely accepted and recommended by the NCCN and EAU guidelines (15,16). Both guidelines also define very high-risk PCa as cT3b-T4 N0 or any T with N1. Despite an extensive awareness on PSA screening and early detection of PCa, a fair proportion of patients still present at diagnosis with high-risk PCa. Indeed, Cooperberg et al. evaluated the trend in high-risk PCa in the US between 1990-2007. They revealed an evolution in the number of patients with high-risk PCa, defined by the NCCN definition, from 27.4% in 1990-1994 to 21.7% in 1995-1999, to 26.3% in 2000-2003 and to 13.7% between 20042007 (21). Furthermore, in the recently published European Randomized Study of Screening for PCa (ERSPC), 9.8% of the patients had T3/T4 tumors and 8.8% had GS >7 in the screening arm, while in the control arm, these figures were 15.8% and 19.5%, respectively (22). 262 S. Joniau, K. Van der Eeckt, A. Briganti, et al. The natural evolution of high-risk PCa RP for high-risk PCa Albertsen et al. reported in 2005 the 20-year outcome of patients with localized PCa managed by observation or androgen deprivation therapy (ADT) alone (8). They concluded that patients with highgrade PCa have a high probability of dying from PCa within 10 years of diagnosis (GS 8-10, 121 deaths per 1,000 person-years, 95% CI: 90-156). At 20 years, the estimated risk of dying from PCa was 60-90% (depending on the age of the patient) when managed expectantly or hormonal therapy alone. A Swedish study by Akre et al. evaluated the mortality in a large cohort of men (12,184 patients) with locally advanced PCa (cT3 or cT4 or cT2 with PSA between 50 and 99 ng/mL) managed with non-curative intent. They described a PCa-specific mortality at 8 years of follow-up of 52% in patients with biopsy GS 8 and 64% in those with biopsy GS 9-10 PCa (23). • RP for GS 8-10 PCa RP for locally advanced, high-risk PCa The management of locally advanced and high-risk PCa is one of the most compelling contemporary challenges. In the absence of a randomized trial comparing the true benefit of currently available treatment modalities (i.e., surgery, RT, ADT or a combination of these), it is very difficult to properly counsel patients on the optimal treatment. Cooperberg et al. recently published the local variation and time trends in primary treatment of localized PCa (24). Data were analyzed from 36 clinical sites that contributed data to the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry. PCa risk was assessed using the D’Amico risk groups. Of the11,892 patients, 1,790 patients (15.1%) had high-risk PCa. Of those, 3.2% opted for active surveillance, 7.5% for brachytherapy, 18.1% for external RT, 32.8% for hormonaltherapy, 6.1% underwent cryotherapy and 32.2% underwent RP. RP combined with an extended pelvic lymph node dissection (PLND) is a valid strategy accepted by international guidelines (15,16). The putative benefits of RP as first-line treatment are to achieve tumor volume reduction and optimal local control. Furthermore, pathologic examination of the resection specimen and postoperative PSA allow for better treatment individualization by carefully selecting patients that require adjuvant treatment. Indeed, in high-risk PCa, RP must often be combined with adjuvant RT or ADT. Prospective randomized controled trials have been conducted in that setting to provide clues on the indication of each of these strategies, yet definitive cure is far from being achieved in each of the patients (25-29). The biopsy GS is a significant predictor of pathologic outcomes, as well as one of the key predictors of clinical outcomes after RP (30,31). Furthermore, GS on needle biopsy may be used to determine therapeutic choices, the extent of neurovascular bundle resection, or performing a PLND (15). As GS has been successfully incorporated into predictive tools that have been designed for PCa, the accurate and reproducible application of this system is clinically meaningful (11, 12, 20). One of the reasons to opt for surgery is the high rate of downgrading between the biopsy GS and the GS of the resected specimen. Indeed, Donohue et al.(32) reported a 45% downgrading to GS ≤7 in the RP specimen in men with biopsy GS8-10. Downgraded patients had an improved BPFS probability (56% vs. 27%). Moreover, patients with a biopsy GS 8 and a cT1c were more likely to be downgraded and thus had a better BPFS probability (33). Of these patients, 64% were free of biochemical or clinical recurrence during further follow-up. Several other studies corroborated these observations and concluded that one third of patients with a biopsy GS 8 are downgraded (3436). These men in particular may benefit most from potentially curative resection. Indeed, several studies have demonstrated good outcomes after RP in the context of a multimodal approach for patients with a biopsy GS of ≥8. BPFS at 5- and 10-year follow-up ranged from 35-51% and 24-39%, respectively, while cancer-specific survival (CSS) at 5-, 10- and 15-year follow-up was 96%, 8488% and 66%, respectively (Table I). • RP for PCa with a PSA >20 ng/mL Initial PSA has long been recognized as an important risk indicator (38). Several articles report that men considered to have high-risk PCa based upon preoperative PSA >20 ng/mL have good outcomes after surgery. Even in more extreme PSA ranges (PSA above 50 ng/mL), Inman et al. (39) presented the outcomes of RP with adjuvant therapy when needed. BPFS at 10-year follow-up in the groups with a PSA level 50-99 ng/mL and >100 ng/mL were 43% and 36%, respectively. Estimated CSS of the whole group was 87% at 10 years. Even though patients with a PSA ≥50 ng/mL may be considered as having very high-risk PCa, 10-year survival outcomes remained excellent. These observations provide support for an aggressive local management of these cases. Recent reports in patients with a PSA >20 ng/mL who underwent surgery as initial therapy CURRENT ROLE OF SURGERY FOR HIGH RISK PROSTATE CANCER within a multimodal approach, demonstrated a BPFS at 5-, 10- and 15-year follow-up ranging between 4063%, 25-48% and 25% respectively. CSS at 5, 10 and 15 year ranges between 93-97%, 83-91% and 71-78% respectively (Table I). 263 • RP for patients with cT3b-T4 PCa organs (bladder, rectum, pelvic floor, sphincter). When seminal vesicle involvement is suspected, most urologists will consider the patient inoperable and opt for a combination of RT and ADT (15,16). Nevertheless, according to international guidelines, RP is considered optional in highly selected very high-risk PCa patients strictly in the context of a multimodality treatment approach (15,16). Very high-risk PCa patients present two specific challenges. There is a need for local control as well as a need to treat any microscopic metastases, likely to be present but undetectable until disease progression. The optimal treatment approach will therefore often necessitate multiple modalities. The exact combinations, timing and intensity of treatment continues to be strongly debated (15). A recent population-based study used data from the Surveillance, Epidemiology and End Results (SEER) database to determine the likelihood of having pathologically non-organ-confined disease in patients who were staged clinically as having T3T4 disease (48). A total of 235 cT3b and 57 cT4 patients were included in the analysis. Of patients staged cT3b, 4.7% had organ-confined disease, 12.4% had extracapsular extension, 66.8% were pathologically confirmed to have pT3b disease, while 2.6% had pT4 disease and 13.6% had positive LN. Of those presenting with cT4 disease, 15.8% had organ-confined disease, 7.1% had extracapsular extension, 7% had seminal vesicle invasion, 50.9% were pT4 and 19.3% had positive LN. These data show that in very high-risk disease, clinical staging is highly accurate in predicting extraprostatic disease. Gontero et al. compared the results of RP in very highrisk PCa with those having localized PCa. There were no significant differences in surgical morbidity except for blood transfusion, operative time and lymphoceles. The OS and CSS at 7 years were 76.7% and 90.2% in the advanced disease group and 88.4% and 99.3% in the organ confined disease group, respectively (49). Another study by Johnstone et al., also using the SEER database, showed that patients who underwent RP for cT4 PCa had a better survival than those who received ADT alone or RT alone and had a survival comparable with that of patients who received RTplus ADT (50). Joniau et al. described single-center results of RP in 51 patients presenting with cT3b or cT4 PCa. Intriguingly, over-staging in this group was still substantial, with roughly one third of patients having organ-confined disease (7.8%) or capsular perforation only (29.4%). Over-staged patients were often cured by surgery alone, as 35.3% of the whole group did not receive any form of (neo)adjuvant treatment and 21.6% remained free of additional therapies at a median follow-up of 108 months. T3b PCa invades the seminal vesicles. T4 PCa is defined as cancer extending into neighboring In the 2 latter studies, describing oncological outcomes of RP in cT3b-T4 PCa, 5- and 10-year CSS • RP for cT3a PCa Stage T3a PCa is defined as a tumor that has perforated the prostatic capsule. Extraprostatic extension (pT3a) represents an adverse disease characteristic (6). Despite the lack of randomized prospective trials and large observational series comparing alternative treatment methods for highrisk PCa patients, about two thirds of the patients will receive non-surgical management when they show unfavorable clinical characteristics (24). Nevertheless, RP can provide an acceptable treatment option for well-selected patients with stage T3a PCa (43,44). In a recent study of 200 patients with clinically locally advanced PCa (cT3a) who underwent RP, the 10year BPFS for patients with pT3a disease was not significantly different from that for patients with pT2 disease; however, patients with pT3b or pT4 PCa fared significantly worse in terms of BPFS (44). It should be noted, however, that more than half of the patients included in this study also received adjuvant or salvage treatment when necessary. Recent studies demonstrate 5-, 10- and 15year BPFS to range between 45-62%,43-51% and 38-49%, respectively. RP may provide excellent tumor control in selected patients with cT3 disease, with 5-, 10- and 15-year CSS ranging between 90-99%, 8592% and 62-84%, respectively. Even though more than half of the patients received adjuvant hormonal therapy and/or RT in most of the presented studies, the high CSS suggests that local cancer control remains especially important in men with locally advanced disease. Five- and 10-year overall survival (OS) ranged from 90-96% and 76-77%, respectively (Table I). It appears that in well-selected patients, RP combined with adjuvant or salvage treatment when needed may result in better outcomes than RT alone, while published outcomes are similar to the combination of RT plus adjuvant ADT. However, these findings should ideally be confirmed in randomized, prospective studies (33). RP for very high-risk PCa 220 246 pts No of BJU Int 201 Gontero et al. (42) BJU Int 2010 Walz et al. (37) J Clin Oncol 2009 Stephenson et al.(20) (19)Eur Urol 2008 Yossepowitch et al. J Urol 2007 Magheli et al.(41) Eur Urol 2007 Zwergel et al.(40) BJU Int 2010 Walz et al. (37) J Clin Oncol 2009 Stephenson et al.(20) Eur Urol 2008 712 370 726 441 265 275 269 702 Yossepowitch et al. (19) 401 Cancer 2006 Bastian et al. (35) J Urol 2006 Donohue et al. (32) Author 1987-2005 1987-2005 1987-2005 1985-2005 1984-2005 1986-2005 1987-2005 1987-2005 1985-2005 1982-2004 1983-2004 Time span 90 - - - - 87 - - - - - 5 73 - - - - 70 - - - - - 10 OS 5 10 - - - - - - - 96 - - 84 88 - 95 - - 97 - 93 89 - 90 91 - 83 PSA >20 ng/mL 58 - - - - GS 8-10 at biopsy - 15 CSS - - 78 - - 71 - 66 - - - 15 63 40 - - 47 53 35 - - 40 51 5 48 26 - - 33 25 24 - - 27 39 10 BPFS - - - - - 25 - - - - - 15 82 - - 89 - - - - 85 - - 5 71 - - 82 - - - - 76 - - 10 CPFS - - - - - - - - - - 15 Table I. Recent reports of overall (OS), cancer-specific survival (CSS), biochemical progression-free survival (BPFS) and clinical progression-free survival (CPFS) for high-risk PCa. 264 S. Joniau, K. Van der Eeckt, A. Briganti, et al. 44 52 - - BJU Int 2010 Walz et al. (37) J Clin Oncol 2009 293 1987-2005 - - 1987-2005 254 Stephenson et al.(20) BJU Int 2009 Although the incidence of LN metastasis has dramatically decreased in the PSA era, LN invasion is still diagnosed in up to 40% of patients submitted to extended PLND (52). Historically, patients with LN invasion were considered to be affected by systemic and non-curable disease. - 85 90 Xylinas et al. (47) Eur Urol 2008 100 1995-2005 - - 96 Yossepowitch et al. (19) 243 Cancer 2007 Freedland et al. (46) Eur Urol 2007 62 1985-2005 - - - - 89 - 49 91 98 1987-2003 - - 62 45 - 72 85 - 73 80 49 90 62 84 85 51 92 77 Hsu et al. (44) J Urol 2006 200 1987-2004 96 - 94 Carver et al.(45) BJU Int 2005 176 1983-2003 76 Ward et al. (43) pts 841 1987-1997 90 - 53 99 85 44 - 96 60 - 76 86 48 76 67 73 38 43 90 cT3a 95 15 10 10 5 10 5 15 85 58 79 15 10 • RP for patients with any T, N1 PCa 5 5 was 88-92% and 92%, respectively. Five- and 10-year OS was 73-88% and 71%, respectively (Table II). 15 CPFS BPFS CSS OS 265 These results suggests that RP may be a reasonable step in the context of a multimodality treatment approach in selected patients with cT3b-T4 PCa, provided that the tumor is not fixed to the pelvic wall or invaded in the urethral sphincter. Nevertheless, data describing outcomes after surgery in very high-risk PCa are extremely scarce and further studies are urgently needed in this domain. Time span No of Author Table I. Recent reports of overall (OS), cancer-specific survival (CSS), biochemical progression-free survival (BPFS) and clinical progression-free survival (CPFS) for high-risk PCa. CURRENT ROLE OF SURGERY FOR HIGH RISK PROSTATE CANCER They were traditionally not considered suitable for a surgical approach. However, recent studies described excellent survival outcomes after surgery, with 5-, 10- and 15-year CSS ranging from 84-95%, 51-86% and 45%, respectively. OS at 5, 10 and 15 years ranged from 7985%, 36-69% and 42%, respectively (Table II). Two studies (56,57) compared lymphadenectomy with completed vs. aborted 36 55* 71 - 10 Eur Urol 2011 Briganti et al. (51) BJU Int 2011 Steuber et al. (57) Eur Urol 2010 Engel et al. (56) Eur Urol 2009 Da pozzo et al. (55) Eur Urol 2008 364 108 688 250 1988-2003 1992-2004 1988-2007 1988-2002 85 79 84 - 60 69 64 - 52 83 88 73 5 OS Schumacher et al. (54) 1989-2007 1988-1993 1989-2004 1995-2001 Time span (11.5 yr) 122 98 51 72 pts No of (*with vs without ADT) Lancet Oncol 2006 Messing et al. (53) 2012 Scand J Urol Nephrol Joniau et al. (51) Cancer 2006 Johnstone et al. (50) Author - - - - 42 - - 15 90 84 95 89 85 92 - 10 75 81 86 80 60 (11.5 yr) 51 85* Any T and N1 92 88 cT3b-T4 5 CSS - - - - 45 - - 15 - - - 72 14 53 - 5 - - - 53 3 (11.5 yr) 14 53* 46 - 10 BPFS - - - - - - - 15 - 71 - - - 78 - 5 - 61 - - - (11.5 yr) 25 60* 73 - 10 CPFS - - - - - - - 15 Table II.Recent reports of overall (OS), cancer-specific survival (CSS), biochemical progression-free survival (BPFS) and clinical progression-free survival (CPFS) veryhigh-risk PCa following RP. 266 S. Joniau, K. Van der Eeckt, A. Briganti, et al. CURRENT ROLE OF SURGERY FOR HIGH RISK PROSTATE CANCER RP for patients with positive LN. Both showed very significant survival differences in favor of completed prostatectomy. This obvious advantage should encourage urologists to complete RP, regardless of pelvic LN status. Briganti et al. (58) demonstrated that patients with up to 2 positive nodes experienced excellent CSS, which was significantly higher compared with patients with >2 positive nodes, regardless of adjuvant treatment administration. CSS at 15-year follow-up was 84% vs. 62%, respectively (p<0.001). These results on the one hand suggest that some patients with limited LN invasion may benefit from extended PLND, while on the other hand the primary tumor needs to be optimally controlled. Surgery may provide a first and important step to achieve both these goals. Admittedly, surgery as sole therapy is not likely to achieve cure in such patients, and adjuvant treatment strategies will be necessary in most of them. Multimodality treatment for localized PCa at high risk of relapse It is clear that although some patients with high-risk PCa can benefit from RP alone, this approach will result in biochemical relapse in a high proportion of patients, necessitating multimodality therapy. For instance, in a large retrospective analysis conducted by the Mayo Clinic, 78% of 842 patients with T3 PCa were not controlled by surgery alone and required either adjuvant or salvage RT or hormonal therapy or a combination of both (43). The above mentioned available data suggest that multimodality treatment starting with RP in patients with high-risk disease is associated with convincing CSS rates. Prospective, randomized trials have been conducted in this area. Below, the most important findings from those studies are listed. • Adjuvant or salvage RT The eradication of microscopic residual disease within the prostate bed after RP can potentially be achieved with the use of RT by two distinct strategies: in the adjuvant setting shortly after surgery, but in the absence of any measurable disease, or in the salvage setting at the time of BCR or later at clinical recurrence. The lack of randomized trials comparing adjuvant vs. salvage RT has created a long standing dilemma: which one is best? RP followed by immediate RT was compared with RP alone in patients with positive surgical margin or pT3 PCa in three randomized trials, EORTC 22911 (25), ARO 96-02 (27), and SWOG-S8794 (26). All three trials showed a benefit in BPFS for the adjuvant RT group of at least 267 15% at 5 years. Whereas the largest (EORTC 22911, n=1,005) and the smallest (ARO 96-02, n=307) trials were powered to detect a benefit in BPFS, the SWOG-S8794 with 431 randomized patients had as primary end point metastasis-free survival. The inclusion criteria were similar with the exception that in the EORTC trial also pT2 with positive resection margins patients could be included and in the other two trials only pT3 cancers with or without a positive resection margin. pN1 patients were excluded in all three trials. The presence of patients with a positive surgical margin was relatively high in all three trials ranging from 63% to 68%. Of note is the fact that the randomized population differed with respect to the postoperative PSA level prior to randomization for adjuvant RT between the three trials. In the German ARO 96-02 trial only men with a PSA <0.1 ng/ mL were eligible for randomization whereas in the EORTC trial 11% had a PSA level >0.2 ng/mL prior to randomization. In the SWOG trial this percentage was even higher (34%). This indicates that in the EORTC and SWOG trial a substantial number of patients received “salvage” RT for a non-normalized PSA rather than adjuvant RT. In a subanalysis of the SWOG trial, Swanson et al. (59) showed that men in all categories of post-RP PSA level (<0.2,0.2-1.0, >1.0 ng/mL) showed improvement of metastasis-free survival suggesting that although less effective, also salvage RT may be beneficial to improve metastasisfree survival. The relatively high number of men with a non-normalized PSA after surgery (PSA >0.2 ng/mL) may however result in an under estimation of the true value of adjuvant RT. More recently, the SWOG trial data have been updated. With a median follow-up of 152 months this is the trial with the longest follow-up. Although in the initial publication at a median followup of 130 months no significant OS advantage was observed (26), in the most recent update a significant hazard ratio (HR) of 0.72 for adjuvant RT was found (60). This translates into an estimated 10-year OS of 74% for adjuvant RT vs. 66% for the non-adjuvant arm. A recent Cochrane analysis reviewed the three afore mentioned trials (61). From this meta-analysis, it was concluded that there was no OS benefit at 5 years for men treated with adjuvant RT (p=0.95). At 10 years however, adjuvant RT significantly improved survival (p=0.02). PCa-specific mortality at 5 years was not improved by adjuvant RT. Five-year metastasisfree survival was not improved by adjuvant RT, but10year CSS was significantly improved. Adjuvant RT decreased local recurrence at 5 years (p<0.00001) and at 10 years (p=0.00001). BPFS was decreased by adjuvant RT at 5 years and 10 years. Although the results seem to show superiority of BPFS in favor of adjuvant RT compared with the wait and see arm, the definition of what constituted biochemical relapse differed in the included studies. Two recent studies have 268 S. Joniau, K. Van der Eeckt, A. Briganti, et al. attempted to compare adjuvant vs. salvage RT using a matched-control study design. Ost et al. matched 178 patients (62). In the whole group comparisons, the 5-year BPFS survival of 84% favored the adjuvant treatment group vs. 68% for salvage treatment group (p= 0.04). Nevertheless, no difference was seen between adjuvant and early salvage RT. Briganti et al. studied 390 (43.8%) and 500 (56.2%) patients who were treated with adjuvant RT and initial observation, respectively. Within the latter group, 225 (45.0%) patients experienced BCR and underwent early salvage RT. In the post-propensity-matched cohort, the 2- and 5-yr BPFS survival rates were 91.4% and 78.4% in the adjuvant RT versus 92.8% and 81.8% in the initial observation and early salvage RT groups, respectively (p=0.9). No differences BPFS was found, even when patients were stratified according to pT3 substage and surgical margin status (all p ≥ 0.4). These findings were also confirmed in multivariable analyses (p=0.6).(63). These two studies concluded that early salvage RT at PSA relapse (with PSA ≤0.5 ng/ml) equals the results of adjuvant RT, while avoiding unnecessary treatment in roughly half of the patients. Three ongoing clinical trials which compare adjuvant RT with observation and early salvage RT (NCT00667069; RADICALS (ISRCTN40814031); RAVES (NCT00860652)) will hopefully provide us with an answer to the lingering dilemma whether observation and early salvage RT is equally as good as adjuvant RT. Furthermore, these trials may clarify uncertainties related to differences in early and late toxicity between adjuvant vs. early salvage RT. • Adjuvant ADT RT alone for locally advanced PCa is associated with a 5-year OS rate of 62%; however, this can be improved by the addition of longterm (3 years) adjuvant ADT (64). Immediate ADT (goserelin 3.6 mg subcutaneously every 4 weeks plus cyproterone150 mg/day) plus RT was associated with a significant improvement in 5-year OS (79%, 95% CI: 72-86 vs. 62%, 95% CI: 52-72, p=0.001) and a significant increase in the proportion of patients who were disease-free at 5 years (85%, 95% CI: 78-92 vs. 48%, 95% CI: 38-58, p<0.001) compared with RT alone. There are currently no data available to suggest that the use of adjuvant ADT after surgery for locally advanced PCa is associated with a significant survival benefit. In the Early PCa (EPC) trial program, the administration of oral bicalutamide 150 mg/day to surgically-treated patients with locally advanced disease (T3-T4) was not associated with an improvement in OS (65). However, early ADT has been reported to provide asurvival benefit in patients with nodal metastases. In an assessment of 98 patients with nodal metastases who had undergone prostatectomy and lymphadenectomy, immediate ADT was associated with a significant improvement in OS (HR 1.84, 95%CI: 1.01-3.35, p=0.04), CSS (HR 4.09, 95% CI: 1.76-9.49, p=0.0004) and CPFS (HR 3.42,95% CI: 1.96-5.98, p<0.0001) compared with deferred ADT (53). Nevertheless, this was a small study including patients before the PSA era with large cancer volumes, a high proportion of seminal vesicle invasion, positive margins and bulky nodal disease.Patients were either given immediate adjuvant ADT or late ADT at the appearance of symptoms. Nowadays, patients usually present with lower stage/lower volume disease and mostly present with low-burden nodal disease. Furthermore, PSA is an extremely useful parameter during followup, allowing early salvage ADT. Thus, it is unclear whether the conclusions drawn from this study are still valid at present. Recently, Dorff et al. described the results of the SWOG-S9921 study (29). This study was designed to investigate the effectiveness of 2 years of adjuvant ADT alone or in combination with mitoxantrone chemotherapy after RP for high-risk PCa (GS≥8; preoperative PSA ≥15 ng/mL; pT3b, pT4, or pN1 or N1 disease; or GS of 7 with either preoperative PSA >10 ng/mL or a positive margin). The authors reported on the results in the ADT-alone control arm with a median follow-up of 4.4 years. Of the 481 men, 61% presented with stage ≥T3 disease, 53% had high-grade tumors (GS8-10) and 16% node-positive disease. BPFS at 5 years was 92.5%. Only 27 deaths occurred (13 were disease-specific), which translated to 96% OS at 5 years and 88% at 8 years. These numbers hold across risk groups that were defined. Although the data on adjuvant RT in this study are limited, the BPFS and OS results are not changed when those receiving RT were excluded from the analysis, with a 5-year freedom from biochemical failure estimated at 92.7% compared with 92.5% for the whole group. The authors concluded that 2 years of ADT after RP resulted in an extremely low rate of disease recurrence and PCa-related death for high-risk PCa patients in SWOG-S9921. These data support the consideration of adjuvant ADT in patients with high-risk PCa after RP. • Chemotherapy It is likely that some patients with highrisk localized PCa have occult micrometastases at diagnosis, which would explain that they are unlikely to be cured by local therapy alone. In analogy with other types of carcinoma (e.g. breast, colon, lung), neoadjuvant or adjuvant chemotherapy are being explored in phase 2 and 3 trials with the hope to help improve the curative rate of definitive CURRENT ROLE OF SURGERY FOR HIGH RISK PROSTATE CANCER therapies. Two prospective phase 3 trials for men with metastatic castration-resistant PCa(CRPC) helped to establish docetaxel and prednisone as the preferred chemotherapy regimen. SWOG 9916, a prospective trial randomizing 674 men with CRPC, compared survival outcomes and toxicity profiles in a head-tohead comparison of docetaxel plus estramustine vs. mitoxantrone. The docetaxel-containing regimens demonstrated a significant increase in OS of nearly 2 months; however, there was also an increase in side effects, including neutropenic fever and cardiovascular events (66). The second pivotal study was the TAX 327 trial which compared docetaxel and mitoxantrone; prednisone was also administered in both regimens. Docetaxel was given in a weekly or in a 3-weekly schedule. Patients in the 3-weekly docetaxel arm demonstrated an improved median survival of 2.5 months with a 24% reduction in risk of death (67). These studies in metastatic castrationrefractory patients helped lay the groundwork for phase 2 and 3 trials of docetaxel and other agents as part of the primary treatment for high-risk and locally advanced PCa patients. The rationale of using chemotherapy and other systemic agents in the adjuvant setting is that micrometastatic disease as well as androgen-resistant clones will encounter cytotoxic treatment earlier. Recently, the role of chemotherapy in conjunction with RP has been examined. In this randomized phase 3 trial (SWOG 9921), 983 patients with high-risk features were randomized to receive adjuvant ADT with or without mitoxantrone in the post-RPsetting. Unfortunately, the study prematurely closed the chemotherapy plus ADT arm due to the development of acute myelogenous leukemias. This study underlined the importance of prospective trials to assess potential safety issues for patients. In this particular case, the risk of secondary malignancies associated with a mitoxantrone containing adjuvant chemotherapy regimen was an unexpected problem (68). Importantly, in 2011 Dorff et al. reported preliminary data from the SWOG-S9921 study because of the potential implications for future prospective trial design. As mentioned in the former paragraph, 5-year OS was as high as 95.9%. In light of the favorable outcomes achieved with adjuvant ADT post-RP, this study highlights the difficulty in demonstrating that the addition of chemotherapy can improve upon currently available therapies (29). Of note, the cancer and leukemia group B has initiated an ongoing phase 3 trial (CALGB 90203) in highrisk patients randomizing them to be treated with neoadjuvant estramustine and docetaxel followed by surgery or surgery alone (69). Recently, interesting progress has been made in the treatment of CRPC following docetaxelfailure. Better understanding of the biology of CRPC 269 has demonstrated two important mechanisms: (1) the androgen receptor is over expressed in many of the CRPC tumor cells and (2) PCa cells are capable of producing steroids, activating the androgen receptor (70,71). These observations clearly demonstrate that the androgen receptor is still the key therapeutic target. Two molecules have been developed and tested in phase 3 clinical trials in the CRPC post-docetaxel setting: abiraterone acetate (AA) and MDV3100. Briefly, AA is a potent and selective irreversible androgen biosynthesis inhibitor of the cytochrome P450 c17 (CYP17) enzyme blocking 17alphahydroxylation and C17,20-lyase activity. This results in blocking the androgen synthesis by the adrenal glands and testes and within the prostate tumor. A recently published phase 3 study (COU-AA-301) randomized 1,195 docetaxel-treated CRPC patients to receive 1,000 mg AA along with 5 mg prednisone twice daily (797 patients) vs. placebo and the same dose of prednisone (398 patients). The study met its primary endpoint, demonstrating an improved OS with AA and prednisone compared with placebo and prednisone (14.8 vs. 10.9 months, HR 0.646, p<0.001) (72). MDV3100 is an androgen receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumor cell apoptosis, and has no agonist activity. Encouraging antitumor activity had been shown in a phase 1-2 clinical trial with MDV3100 in patients with CRPC (73). Recently, the results of a phase 3 trial (AFFIRM) were published, demonstrating a 4.8-month OS benefit for MDV3100 compared with placebo in post-docetaxel CRPC patients (74). It is at the moment unclear whether these new molecules could play a role in a multimodality treatment approach of high-risk PCa. Such role will have to be defined in future clinical trials. CONCLUSIONS In the high-risk PCa group, patient outcome will be largely dependent on cancer characteristics and the intensity of treatment, and less on age and co-morbidities. Thus, these patients need a proactive, multimodality treatment approach, consisting of the combination of external beam RT and hormonal deprivation, or initial radical surgery with adjuvant RT or ADT when appropriate. The current role of RP in patients with high-risk disease remains controversial. Recent studies in patients with high-risk disease show convincing CSS and OS. However, in order to achieve complete eradication of local disease and to improve outcomes, multimodality treatment is often recommended. 270 S. Joniau, K. Van der Eeckt, A. Briganti, et al. High-risk PCa is still ill defined and constitutes an extremely heterogeneous patient group. Pathological stage varies from localized disease (pT2) to cancers that have grown into neighboring organs (pT4) or have affected nearby LN (N1). Therefore, cancer-related outcomes which may be achieved with surgery may vary from cure in patients with organconfined disease or with limited extracapsular extension and negative section margins, to rapid progression and death from the disease in patients with pT4 PCa, massive nodal invasion and micrometastatic disease, even when applying adjuvant RT and ADT. Patients with favorable pathologic characteristics at RP will obtain the greatest benefit from surgery alone (54). Indeed, the EMPaCT group has recently published a nomogram predicting specimen confined PCa (pT23a N0, margin negative). Of all 1366 high-risk PCa patients who underwent RP, 505 (37%) had specimen confined disease at histopathology. The latter patients had excellent 10-yr CSS of 98.2%, vs. 87.6% for those with non-specimen confined PCa (p<0.001). Moreover, only 16.8% of patients with specimenconfined PCa received any form of adjuvant treatment (any form), versus 66.4% in those with non-specimen confined disease (p<0.001) (75). Furthermore, because of the lack of a uniform definition of high-risk PCa and the lack of specificity of the definitions used, studies evaluating high-risk PCa include heterogeneous populations and report a large variance in outcomes after initial therapy. Therefore, there is an urgent need to produce a subclassification of patients into different prognosis categories. Improved ability to stratify patients from the heterogeneous high-risk group into demarcated subgroups would enable better patient counseling before treatment and would allow better comparison between different treatment strategies. Finally, such substratification may prove to be extremely useful in future trial development. 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