High-risk prostate cancer: the role of surgical management

G Model

ARTICLE IN PRESS

ONCH-2181; No. of Pages 9

Critical Reviews in Oncology/Hematology xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

Critical Reviews in Oncology/Hematology journal homepage: www.elsevier.com/locate/critrevonc

High-risk prostate cancer: the role of surgical management Alessandro Morlacco a,b , R. Jeffrey Karnes a,∗ a b

Urology Department, Mayo Clinic, Rochester, MN, USA Department of Surgical, Oncological and Gastroenterological Sciences, Urology Clinic, University of Padova, Padova, Italy

Contents 1. 2. 3. 4.

Introduction and epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Disease sub-stratifications: nomograms and biomarkers in HR PCa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Local treatment: why you should consider it. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00 Which therapy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1. Surgery as a primary treatment: clinical and biological rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2. RT vs RP: comparative studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5. Outcomes of surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.1. Neoadjuvant therapy and lymph node dissection: what’s new? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Source of funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

a r t i c l e

i n f o

Article history: Received 5 January 2016 Received in revised form 8 March 2016 Accepted 26 April 2016 Keywords: High risk Prostate cancer Prostate surgery Radical prostatectomy Radiation therapy

a b s t r a c t High-risk prostate cancer (HR Pca) is a highly heterogeneous disease from a biological and clinical standpoint, and it carries a significant chance of morbidity and mortality. Despite the impact of PSA screening, a significant number of men continue to present with high risk disease and need adequate management: clinical evidence shows that a considerable fraction on men with HR PCa can be actually cured with either uni- or multi-modality approaches. Surgical treatment, once considered unfeasible in this setting, is acquiring more and more diffusion in modern clinical practice. Herein we discuss the main treatment strategies for high-risk prostate cancer, providing an expert opinion on the role of surgical management and its outcomes in the most recent literature. © 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction and epidemiology In 2015, over 220,000 men in the U.S.A. were diagnosed with prostate cancer (PCa), and over 24,000 died of their disease. Prostate cancer accounts for approximately a quarter of all invasive cancers diagnosed in men and for 10% of all cancer deaths in men, second to lung cancer (Siegel et al., 2015). In the European Union, the estimated number of deaths attributable to PCa in 2015 is 72,600, an increase when compared to 69,733 deaths in 2009 (Malvezzi et al., 2015).

∗ Corresponding author at: Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA. E-mail address: [email protected] (R.J. Karnes).

Under the diagnosis of PCa, there are neoplasms with very different biological and clinical behaviors; many PCa patients will experience a prolonged natural history, while some patients will rapidly progress to or with metastasis and die of disease. In their practice, clinicians are faced with the challenge of identifying and properly treating men with clinically localized PCa who are at risk of cancer morbidity and/or mortality, without over-treating men with potentially biologically indolent tumors, who are likely to die of another cause even if left untreated. Most PCa encountered today are lower-grade, and organconfined tumors. Part of this shift towards lower risk at presentation can be attributed to the prostate-specific antigen (PSA) screening. On the other hand, as shown by the Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE) database, a considerable number of men continue to present with

http://dx.doi.org/10.1016/j.critrevonc.2016.04.011 1040-8428/© 2016 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Morlacco, A., Karnes, R.J., High-risk prostate cancer: the role of surgical management. Crit Rev Oncol/Hematol (2016), http://dx.doi.org/10.1016/j.critrevonc.2016.04.011

G Model

ARTICLE IN PRESS

ONCH-2181; No. of Pages 9

A. Morlacco, R.J. Karnes / Critical Reviews in Oncology/Hematology xxx (2016) xxx–xxx

2 Table 1 Summary of high-risk PCa definitions. Definition

D’Amico (D’Amico, 1998) NCCN “high risk” (NCCN, 2015) NCCN “very high risk” (NCCN, 2015) EAU (EAU, 2015) American College Radiol (Eberhardt et al., 2013) CAPRA (Cooperberg et al., 2005)

Criteria PSA

cT

bGS

≥20 ng/ml ≥20 ng/ml Any ≥20 ng/ml ≥20 ng/ml CAPRA score 6–10

≥cT2c ≥cT3a cT3b-T4 ≥cT3a ≥cT2c

≥8 ≥8 Grade 5 or <4 cores with GS 8–10 ≥8 ≥8

NB: a single criterion is necessary and sufficient for all definitions.

a high-risk prostate cancer (Cooperberg et al., 2003) (HR PCa) and the impact of PSA on their outcomes has been less clear. More recently on this topic, a study by Cooperberg et al. (2008) analyzed the incidence of HR PCa in the U.S, revealing a range spanning from 27.4% in 1990–1994 to 21.7% in 1995–1999, to 13.2% in 2000–2003 and to 13.7% between 2004 and 2007. These data show a substantial reduction of men presenting with HR disease between the early PSA era (1990–1994) and the 2000s, but an overall stability of HR PCa at diagnosis thereafter, thus not supporting the concept of risk migration within this group in the last decades. It’s unclear how the US Preventive Services Task Force (USPSTF) recommendation against PSA screening in average-risk men, announced in 2011 and published in 2012 (Moyer, 2012) will impact the epidemiology of HR PCa. A recent study, (Jemal et al., 2015) on this topic, found overall PCa incidence declining, yet it’s too early to draw any conclusion on possible stage migration and oncological outcomes. Men with HR PCa have a more substantial likelihood of tumor progression, and a lethal phenotype. These cancers harbor biological elements and a different landscape of genetic mutations, which ultimately translate into higher chance of adverse events. However, ‘high-risk prostate cancer’ is far from being a uniform definition or a ‘one-size-fits-all.’ In 1998, D’Amico (1998) first stratified men on the basis of the pretreatment PSA level, biopsy Gleason score, (GS), and clinical T stage in order to predict a patient’s risk of biochemical recurrence (BCR) after radical prostatectomy (RP), external radiotherapy (EBRT), or brachytherapy for clinically localized disease. Since then, many others definitions have been proposed. A subsequent study conducted on 7591 patients confirmed the validity of this risk-group stratification to predict not only BCR but also disease progression and survival after RP in the PSA era (Boorjian et al., 2008). Additionally, one of the most widely used definitions of ‘HR PCa’ is the National Comprehensive Cancer Network (NCCN) definition (NCCN, 2016), which includes patients with stage T3a or higher or GS ≥ 8 or PSA ≥ 20 ng/ml. This definition differs from the original D’Amico definition, whereas T2c patients were classified as high risk. Some, such as the European Association of Urology (EAU) guidelines, share the NCCN definition, while others, such as AUA 2007 (Thompson et al., 2007) and American College of Radiology (Eberhardt et al., 2013), still consider cT2c as high risk, as it was in the original D’Amico classification. More recently, other authors (Sundi et al., 2014) have proposed a further sub-classification of HR PCa, which has been implemented in the newest versions of NCCN, giving birth to a “very high-risk” PCa definition, which includes patients with cT3b-T4, or primary Gleason pattern 5 or >4 cores with GS 8–10, based on treatment outcomes which are worse than others with “regular” HR PCa. Another way to address the definition is the use of a scoring system. The most important clinical variables (PSA, age, cT, primary and secondary Gleason grade, % of positive cores/total biopsy cores) can be summarized in clinical scores. Among the most common such systems is the Cancer of the Prostate Risk Assessment (CAPRA)

score (Cooperberg et al., 2005). According to this model, a CAPRA score from 6 to 10 defines a HR PCa. Table 1 compares the most common definitions of HR PCa.

2. Disease sub-stratifications: nomograms and biomarkers in HR PCa The heterogeneity of HR PCa clinical behavior has fostered efforts to improve on patient prognosis and perhaps treatment selection. New tools might allow for better selection and counseling of patients potentially curable with a single-modality primary treatment, but also be useful to counsel those more likely to benefit from multimodal treatment. A multicenter study by Joniau et al. (2014) has further taken into consideration the NCCN high risk definition and used a cohort to stratify RP outcomes in three clusters: a good prognosis subgroup (one single high-risk defining factor), an intermediate prognosis subgroup (PSA > 20 and ≥cT3) and a poor prognosis subgroup (GS 8–10 in combination with at least one other high-risk factors). Of interest, the 10-year cancer specific survival worsens in a stepwise fashion between good-intermediate prognosis subgroups to poorprognosis subgroup, from 88.3% in the good prognosis and 88.8% in the intermediate prognosis to 79.7% in the poor prognosis group. Briganti et al. (2012) analyzed a large, multi-institutional highrisk cohort and developed a nomogram based on age, PSA, GS and cT, which demonstrated a 0.72 accuracy (AUC) in preoperative prediction of specimen-confined PCa, defined as pT2–pT3a with negative surgical margins and no lymph node invasion. In this group, 37% of patients had specimen-confined disease, an important finding if we take into consideration that in the same study these men had a 10-years cancer-specific survival of 98.2%, versus an 87.6% for men with non-specimen confined disease. This model has subsequently received external validations; in particular, Roumiguié et al. (2014), demonstrated an AUC of 0.64, only slightly inferior of what is reported in the original study. Plus, also in this cohort study, the proportion of specimen-confined disease was relatively high, at 44.4%, and highlights the importance of this finding that not all HR PCa is destined to require multimodal therapy. Since the population of HR PCa patients undergoing roboticassisted radical prostatectomy (RARP) is increasing, a similar tool has been developed and tested on such a population (Abdollah et al., 2014). In this study, 55.2% of patients had specimen-confined disease on histology and the nomogram, based on PSA, clinical stage, primary/secondary Gleason scores, and maximum percentage tumor biopsy quartiles, showed 0.76 accuracy. Notwithstanding these important advancements, new genomic markers can provide some clarity in understanding the vast heterogeneity of the disease and to better risk-stratify HR PCa patients, since some men will have a prolonged disease-free survival and others will not. As an example of potential biomarker application in this setting, Den et al. (2015) recently tested the accuracy of a genomic classifier to predict the development of clinical metastasis

Please cite this article in press as: Morlacco, A., Karnes, R.J., High-risk prostate cancer: the role of surgical management. Crit Rev Oncol/Hematol (2016), http://dx.doi.org/10.1016/j.critrevonc.2016.04.011

G Model ONCH-2181; No. of Pages 9

ARTICLE IN PRESS

RP: 1% RT: 56%

Two referral center + 20 US community based centers, USAd Two referral centers, USA Westover et al. (2012)

Zelefsky et al. (2010)

1993–2002

1980–1997 Single institution, USA c Tewari et al. (2007)

1991–2005

1999–2010 Single institution, Chile Merino et al. (2013)

CSM: PCa cancer-specific mortality—y: years—RP: radical prostatectomy—RT: external-beam radiation therapy BT: brachitherapy—ADT: androgen deprivation therapy. Note: when the study encompasses different risk groups, data refers to HR group only. b Data not stratified per risk class (all risk classes). a Range for CAPRA score 6–10. c Gleason score 8–10 or grade 3, any T, any PSA, cM0. d Gleason score 8–10, any T, any PSA.

≥ 81 Gy RP 8y CSM 3.8% RT 8y CSM RP 5.1 y RT 5.0 y

RP: 7.6 y; RT: 6.3 y RP 5.7 y; RT 4.5 y 4.6 y

5.6 y 1995–2005 Two referral centers, USA Kibel et al. (2012)

RP + RT: 409

RT: 76% RP: no ADT RT: 19% NO RP: 18.5% 45 Gy RT + 90–108 Gy BT RT + BT: 100% RP: 6% 76 Gy

RP: unknown RT: 37% RP: unknown 74–78 Gy

RT: 56% 72 Gy

RP 10y CSM 8% RT + ADT 10y CSM 8% RT alone 10y CSM 12% RP CSM HR: 1 RT CSM HR: 1.3 (0.8–2.1) p = 0.2 BT CSM HR 1.6 (0.4–6.6) p = 0.5 RP 7y CSM 7.0% RT 7y CSM 14.6% (p = 0.07) RP 10y CSM 25% RT 10y CSM 43% RP 5y CSM 0% RT + BT 5y CSM 1.5% Two tertiary referral centers, USA

10.2 y 1988–2004

PcBaSe, Sweden

Sooriakumaran et al. (2014) Boorjian et al. (2011)

5.37 y 1996–2010

SEER database, USA Abdollah et al. (2011)

5y

SEER database, USA

1992–2005

3

RT 609 RP 525 RT 676 BT 33 RP 216 RT 78 RP 119 RT 137 RP 285 RT 372

NO NO

NO

NO

RT 49% pts RP: unknown NO

RT dose details outcome

RP 10y CSM 11.1–36%a RT 10y CSM 15.2–46.6%a RP 10y CSM 5.8% RT 10y CSM 9.9% CSM HR 1.5 for RT vs RP

Median F-U

4.2 y

N of HR PTS

RP 328; RT 279 RP 53,177; RT 48,279 RP 2609 RT 5040 RP 1238

year

1987–2007

Population

Cooperberg et al. (2010)

Historically, men with HR PC, especially if clinically advanced, were often managed with androgen-deprivation therapy (ADT) alone or external beam radiation therapy (EBRT) or both, while surgery was discouraged secondary to concerns regarding morbidity, risks of positive surgical margins, and inadequate disease control. In a 2005 study using the CaPSURE database, Meng et al. (2005) found that patients with HR PCa were significantly less likely to be treated with RP and more likely to receive EBRT or even primary treatment with ADT. On the other hand, Widmark et al. (2009) has demonstrated the importance of treating the primary with definitive therapy rather

Study

3. Local treatment: why you should consider it

Table 2 Selection of recent studies comparing RT and RP in HR Pca.

in a cohort of men with pT3 disease or positive margins after RP. The results, with some limitations linked to the retrospective nature, demonstrate the ability of GC to reclassify CAPRA-S score based predictions, potentially guiding the choice of adjuvant radiation therapy versus initial observation-salvage radiation therapy. A gene panel model, developed in a research study by Cheville et al. (2008), showed a role as a prognostic outcome tool in men with high risk features at RP. As a follow-up, Karnes et al. (2010a) utilized a similar case-control study in high-risk men after RP and investigated tumor protein levels of MIB-1 (Ki-67; proliferation index), TOP2a (DNA topoisomerase 2) and the ERG or fusion status (transcription factor of TMPRSS2-ETS fusion), finding associations between these markers and cancer-specific outcomes. Matrix metalloproteinase polymorphisms have been evaluated in this context (prognostication of clinical recurrence or metastasis), and a single polymorphism (rs10895304) has been found predictive of decreased recurrence-free survival in patients with clinically localized prostate cancer treated with RP. Findings like this suggest that for some genetically identifiable subsets of patients, RP alone may not be adequate for local control, potentially leading to the early administration of adjuvant therapies (Jaboin et al., 2011). A 2013 study by Schubert et al. (2013) has taken into consideration the role of distinct micro-RNA expression profiles in HR PCa progression, finding that let-7b, a tumor suppressor miRNA, has an impact as an independent prognostic marker for biochemical relapse and clinical failure, with a potential role in improving individual therapy for HR PCa patients. A 22-marker genomic classifier now known as Decipher® has been tested on a cohort of 1010 post-RP HR PCa patients, and it showed its efficacy in predicting 5-year metastasis (AUC 0.79), and the net benefit exceeded that of clinical variable-only models, as the strongest predictor of metastasis on multivariable analysis (Karnes et al., 2013). Similarly, the Prolaris assay, a test which produces a score from 33 genes RNA expression levels, has been shown to better predict biochemical recurrence over clinicopathologic variables in a postRP cohort either on the biopsy or RP specimen (Cuzick et al., 2011; Bishoff et al., 2014) and PCa death in a TURP cohort (Cuzick et al., 2011). Furthermore, Klein et al. (2014) developed and validated a 17-gene Genomic Prostate Score known as Oncotype, which was able to predict adverse pathology (primary grade 4 and/or extraprostatic extension) and clinical recurrence after being applied to biopsy samples. These findings underscore the potential role of biomarkers in improving HR PCa decision-making. To be useful in clinical practice, however, a biomarker study should address a population with precise clinical needs: in the post-surgical setting, in particular, the aim is to improve our ability to identify prognostic and predictive factors in order to provide tailored treatment to our patients.

ADT details

A. Morlacco, R.J. Karnes / Critical Reviews in Oncology/Hematology xxx (2016) xxx–xxx

Please cite this article in press as: Morlacco, A., Karnes, R.J., High-risk prostate cancer: the role of surgical management. Crit Rev Oncol/Hematol (2016), http://dx.doi.org/10.1016/j.critrevonc.2016.04.011

G Model ONCH-2181; No. of Pages 9

ARTICLE IN PRESS NaHT 11.8% aADT 21.6%d – 15.7% 92% 46%

NaHT 24% aHT 40.8% sHT 37.8% 20.2% 81% 20y 41% 20y

12.9%

excl 85.2%c 55.2% 5y

–

29% – 39.7% 1.1% HT 37% sHT + sRT aHT excl 7.4% – – – 1.7% – 20.2% 4.8% 92% – 69.5% 87% CRFS 68% 35% 49.6% 50%

−: not specified/not available. OC: organ-confined disease (
9 RRP 2012 Joniau et al. (2012)

very high: cT3b/T4 N0

51

all

14.3 – RRP 843 2012 Mitchell et al. (2012)

cT3

– – 2065 2015 Briganti et al. (2015a)

D’Amico

2010 2010 2012 2015 Loeb et al. (2010) Walz et al. (2011) Lughezzani et al. (2012) Abdollah et al. (2015c)

D’Amico D’Amico GS ≥ 8 D’Amico

5.8

OC 36% FP 21%b SCD 25.1% PSM 35% N+ 12% PSM 54.7% ≥pT3b 22.7% N+ 10.0% PSM 56% pT2 26% ≥pT3b 24% N+ 27% PSM 62.7% pN+ 21.6% 8 2.4 4.4 4 all – all 93.6% RRP – – RARP 175 887 580 1100

sRT aRT 10y CSS 10 y bPFS HPF mFU(y) PLND Technique pts

a

HR def year

External beam RT, alone or combined with brachytherapy, plus long term (2–3 years) ADT and RP plus pelvic lymph node dissection (PLND) are currently the two main modalities for primary treatment of HR PCa (NCCN, 2015; EAU, 2015). A direct comparison between these modalities is challenging because of the intrinsic limitations of the involved studies: most of them are based on retrospective series, and no high-quality RCTs have been conducted to address this problem neither in terms of survival nor quality of life. Nevertheless, results from a recent web-based survey among European urologists indicated that over 60% would choose RP as first-step treatment in HR PCa (Surcel et al., 2015).

Study

4. Which therapy?

Table 3 Selection of recent studies reporting outcomes of RP for HR PCa.

than hormones alone: they reported on an improved CSS, with a relative risk of 0.44, with the addition of EBRT to androgen deprivation compared to androgen deprivation alone for locally advanced prostate cancer (over 75% had clinical T3 disease) in the appropriate men without significant differences in comorbidity. Two large, randomized trials have studied the long-term benefit of RP versus expectant management (watchful waiting) in all the PCa risk classes. Results from the PIVOT trial (Wilt et al., 2012) suggest that RP might reduce mortality among men with higher PSA values and possibly among men with other higher-risk features: RP vs expectant management (5.6% vs. 12.8%, p = 0.02) and among men with a definition of HR PCa (9.1% vs. 17.5%, p = 0.04). Additionally, the Scandinavian (SPCG-4) (Bill-Axelson et al., 2014) trial showed only a modest, non-significant reduction in the absolute mortality risk within the high-risk group. However, a substantial proportion of men in this high-risk group had micrometastases at diagnosis and many did not undergo surgery. Both these studies have important drawbacks as not designed to address high-risk PCa specifically; thus, the number of HR patients is small. This limits the generalizability of the findings of these randomized studies to the whole HR PCa population. Notwithstanding these limitations, HR PCa patients, once considered not amenable to radical curative intent treatment, are increasingly receiving such treatment, with surgery on the highest upswing. A recent study by Cooperberg and Carroll (2015) shows dramatic changes in treatment of men with CAPRA score 6–10 from 1990 to 2013 in the U.S. CaPSURE registry. In particular, in the last 5–8 years the fraction of patients treated with RP has increased sharply, while ADT alone declined and RT has also seen a decrease. Trends in HR PCa treatments are changing, this change being sparked by more research and data using RP and our understanding that untreated or undertreated patients have a high disease-specific mortality and morbidity, even among older men once thought to have an overriding competing risk of not only age but also non-PCa comorbidities. A 2011 study by a Akre et al. (2011) has shown that men with locally advanced PCa (clinical stage T3 or T4 or with T2 with PSA levels between 50 and 99 ng/ml) managed with non-curative intent, the PCa-specific mortality at 8 yrs. of follow-up was 52% for GS 8 and 64% for GS 9–10. Furthermore, given the substantial mortality and morbidity risk of HR PCa, age shouldn’t be seen as an absolute contraindication. Most guidelines have shifted the attention from an “absolute” concept of age to a concept of life expectancy, which is more relevant to today’s elderly men. A recent work addressing the role of age in men with HR PCa (Bratt et al., 2015) raised a significant concern for undertreatment in otherwise healthy >70 year old men.

HT (any)

A. Morlacco, R.J. Karnes / Critical Reviews in Oncology/Hematology xxx (2016) xxx–xxx

4

Please cite this article in press as: Morlacco, A., Karnes, R.J., High-risk prostate cancer: the role of surgical management. Crit Rev Oncol/Hematol (2016), http://dx.doi.org/10.1016/j.critrevonc.2016.04.011

G Model ONCH-2181; No. of Pages 9

ARTICLE IN PRESS A. Morlacco, R.J. Karnes / Critical Reviews in Oncology/Hematology xxx (2016) xxx–xxx

4.1. Surgery as a primary treatment: clinical and biological rationale RP is a viable choice for treatment of high-risk prostate cancer in the properly selected men. The assignment of a high-risk classification should not preclude surgical treatment since singularly it can often be curative. Excellent long-term (≥10 years) survival outcomes can be found with RP either as a single or as part of a multi-modal regimen. There are several arguments in favor of upfront operative management of HR PCa. First of all, surgical staging allows identification of the strongest predictors of CSS: the presence of positive lymph nodes, accurate Gleason score, and pathologic tumor stage. It has been demonstrated that primary treatment of high-risk cancers with RP allows to obtain accurate pathologic information, assisting in the selection of patients who might benefit the most from adjuvant therapies versus those that benefit from routine surveillance (Messing et al., 2006). Another interesting element supporting the use of RP as a primary therapy in the HR PCa setting is the following: in a population of selected patients, who did not receive androgen deprivation after RP, CSS rate was 85% at 10 years and 76% at 15 years (Carver et al., 2006); the same study also revealed an approximately 25% downstaging rate, i.e. cT3 to pT2. This percentage can be as high as 35–45% in more recent series (Briganti et al., 2012; Abdollah et al., 2014). Downgrading is also a possibility after surgery for HR PCa: 31% of patients with a biopsy GS of 8 or more have been found to have a pathologic Gleason score of 7 or less at RP (Manoharan et al., 2003; Boorjian et al., 2009). Thus, not only does the RP provide an accurate assessment of the pathology and prognosis, but it can also spare morbidity associated with ADT since RT essentially requires it in all the cases. The opportunity to avoid ADT in a substantial proportion of patients is noteworthy: long-term ADT is not without adverse effects. Some of the most well-known events associated with ADT include depression, loss of libido, debilitating hot flashes, diabetes, metabolic syndrome (Braga-Basaria et al., 2006), cardiovascular disease with increased risk of morbidity and mortality (Kohutek et al., 2015; Tsai et al., 2007), osteoporosis and bone fracture (Alibhai et al., 2006), all consequences particularly worrisome in the context of non-metastatic HR PCa. One of the main concerns brought by opponents of RP in HR PCa is the purported lack of benefit if the prostate cancer is not completely excised, i.e. due to a high risk of micrometastases. This argument does not consider the importance of local pelvic control even in presence of micrometastatic disease; RP for HR PCa can provide excellent local control, as shown by a 2008 work by Inman et al. (2008), where the local recurrence rate is around 10%. Additionally, the debulking effect is an argument potentially supporting the use of RP, since primary prostate cancers can contain up to 108 malignant cells per cc (Bruchovsky et al., 1987). A RP for large tumor volumes dramatically debulks the quantity of cancer cells, setting the stage for possibly improved efficacy of EBRT, ADT, or other therapies against residual locoregional or micrometastatic disease (Karnes et al., 2010b). A comprehensive pelvic lymph node dissection done at RP could accomplish something similar for lowvolume nodal metastasis. Coen et al. (2002) found an independent association between delayed metastatic disease and the local persistence of cancer on biopsy, with an increased risk in RT-treated men. These findings suggest that a biologically altered prostate cancer after RT could cause a late wave of metastatic seeding. In fact, some historical biopsy studies after EBRT have shown persistent prostate cancer in fractions from 14% to 91% of patients, although the clinical significance of this element is less clear (Crook et al., 1995).

5

Some other aspects need to be considered when dealing with local control. RP, in fact, can allow avoidance of the debilitating complications of locally advanced tumor growth, including gross hematuria, voiding symptoms related to bladder outlet obstruction, pelvic pain, and ureteral obstruction, all complications that, if they occur, often require additional surgical or interventional measures.

4.2. RT vs RP: comparative studies There are no expectations that randomized controlled trials will produce a clear winner as to the best survival and/or quality of life in the next years. The dilemma of which treatment to choose will not be resolved shortly. For instance, a recently published multicenter RCT designed to address this topic (Lennernäs et al., 2015), comparing RP vs. RT (a combination of external beam RT and brachytherapy) has enrolled only 89 patients over 5 years, with an insufficient statistical power to make any conclusions on survival outcomes. Several retrospective studies have compared RT and RP in HR PCa. A 2014 systematic review and metaanalysis (Petrelli et al., 2014) included a total of 17 eligible papers (1990–2013, 16 retrospective studies and 1 small RCT), all using the HR PCa D’Amico classification. The final analysis showed an increased benefit of RP over RT in all the oncological outcomes (Odds Ratio: 0.51 for all mortality, 0.56 for PCa specific mortality) but also in non-PCa mortality (OR for RP: 0.53). Not unexpectedly, selection biases were inherent in most studies; RT patients were older, with more comorbidities and harbored more adverse clinical PC features (e.g., higher rate of Gleason score ≥8 and higher median PSA values) than RP treated patients. Similar results have been reported in other recent studies, depicted in Table 2. All of them share the main limitations: population-based (with several key variables missing), unbalanced RT and RP patient populations, different statistical approaches used to overcome differences, and other latent confounders. Moreover, the definition of HR PCa used often varies among the studies; for example, some (Boorjian et al., 2011; Zelefsky et al., 2010) used the NCCN definition, others the CAPRA score definition (Cooperberg et al., 2010), most older studies accepted the D’Amico classification (Kibel et al., 2012; Merino et al., 2013) Abdollah et al. (2011) used a definition of HR PCa as cT2c or Gleason 8–10 or both, Sooriakumaran et al. (2014) used a NCCN definition but limited the PSA to a maximum of 50, Tewari et al. (2007) included patients with GS 8–10 and any T/any PSA. Of note for one of the aforementioned studies, Boorjian et al. (2011) depicted a very similar cancer survival for RP and RT, but a significantly increased risk of all-cause mortality in RT patients, potentially confirming the concerns expressed above such as use of ADT and/or unbalanced population, despite controlling for comorbidity indices. Furthermore, the authors provided more detail about the RT dose (median: 72 Gy) and the use adjuvant ADT in EBRT (median duration: 22.8 months). We have to acknowledge, however, that most of these studies refer to RT techniques that now would be considered less than adequate in terms of dosage and field optimization. In a study not specifically aimed at the HR PCa population, but with a considerable number of HR patients, Zelefsky et al. (2010), used high dose (≥81 Gy) RT and analyzed the risk of metastatic progression compared to RP. This work, despite obvious limitations linked to the retrospective nature and possible imbalance between the two comparison groups in terms of use of adjuvant and salvage treatments, showed a reduced cancer-specific mortality and metastatic progression for the RP cohort. Interestingly, the highrisk group experienced the highest difference in metastasis-free survival in favor of RP (7.8% difference).

Please cite this article in press as: Morlacco, A., Karnes, R.J., High-risk prostate cancer: the role of surgical management. Crit Rev Oncol/Hematol (2016), http://dx.doi.org/10.1016/j.critrevonc.2016.04.011

G Model ONCH-2181; No. of Pages 9

ARTICLE IN PRESS A. Morlacco, R.J. Karnes / Critical Reviews in Oncology/Hematology xxx (2016) xxx–xxx

6

Of note, a recent systematic review and metaanalysis (Wallis et al., 2015a) summarized the available studies on RT vs RP in treatment of PCa (all-risk classes), including 19 comparative studies. The author concluded showing increased overall (HR 1.63, 95% IC 1.54–1.73) and prostate cancer (HR 2.08, 95% IC 1.76–2.47) mortality risk in the radiation group after adjustment for patient and tumor prognostic factors. In spite of that, we believe that comparison between RT and RP is still affected by huge selection biases and uncertainties regarding adjuvant and salvage therapies. As far as complications are concerned, specific and even general side effects of RP vs RT+ ADT are different, making direct comparisons very difficult. For example, a recent population-based Canadian study on a very large number of patients (Wallis et al., 2015b) analyzed the difference in complications between (open) RP, followed or not by RT, and RT-only for PCa (all risk groups). The endpoints taken into consideration were: complications requiring a hospital admission, a minimally invasive urologic procedure, a rectal or anal procedure, or an open surgical procedure related to the urinary tract, rectum, or anus for management; or the development of a secondary malignancy at any site. The authors found that RT-only treated patients are at the highest risk of all complications, excluding those requiring open management (which had a similar risk in all the three groups), while RP + RT-treated patients are at intermediate risk and RP-only patients are at the lowest risk. One obvious limitation to this is that it does not give us any information in terms of functional and patient perceived outcomes (potency, continence, quality of life), which could be significantly affected by the different treatments, too.

5. Outcomes of surgery Most would not argue that RP is a viable option for HR PCa. Several well designed retrospective studies have reported on the outcomes of RP for this PCa risk group. A 2008 Memorial Sloan Kettering Cancer Center (MSKCC) study (Yossepowitch et al., 2008) demonstrated satisfactory cancerspecific survival (CSS), albeit survival outcomes varied depending on which definition of “high-risk” was utilized, highlighting the heterogeneity of this patient population. Stephenson et al. (2009) reported data on a cohort of over 12,000 men treated with RP at 4 academic centers (Baylor, Cleveland Clinic, MSKCC, U. of Michigan) between 1987 and 2005: more than 1900 men in this study were high risk (D’Amico), with a 10-year cancer specific mortality of 8% (95% C.I. 7–10) and 15 year of 19% (95% C.I. 14–24). A 2008 study by Boorjian et al. (2008) on 584 patients treated with RP during the PSA era analyzed the impact of a GS of 8–10 on systemic progression (metastasis) and CSS during a median followup of 8.3 years. Rate of organ-confined disease was increasing over the years (35% of patients treated after 1993, compared with 23% between 1988 and 1993). In multivariate analysis, seminal vesicle invasion (pT3b) and lymph node metastases (pN1) impacted the CSS the most. Associated pathologic features of these GS 8–10 tumors were noted to have improved (less pT3 and pN1) from the early (1988–1993) to late (1998–2001) PSA era, but the CSS outcome for patients did not significantly change over time although a slight trend toward an improved rate of BCR was evident (37% vs. 45%, p = 0.09). As far as higher PSA values are concerned, in a study by Inman et al. (2008) on PSAs ≥ 50 ng/ml, patients with values between 50 and 99 ng/ml had a CSS rate of 90% and a 10-year metastasis-free survival rate of 83% after RP. Patients with a PSA level higher than 100 ng/ml showed a 10-year metastasis-free survival rate of 74% and a CSS rate of 79%. Early ADT was used in approximately 60% of patients (meant to be lifelong only in pN1 disease) and late or salvage ADT in 34%; men could have received both therapies if the

ADT was discontinued and then reinstituted later. Adjuvant RT was provided to 17% and late or salvage RT to 21% (little over a third postop RP patients with PSA > 50 received RT). In another study by Ward et al. (2005), 842 RP for patients with stage cT3 disease (median follow-up 10.3 years) had a CSS rate of 90% at 10 years and 79% at 15 years. Overall, 78% of patients received adjuvant ADT or salvage RT. One of the most important findings, as already mentioned above, is that 27% of patients had clinical overstaging of their disease as T3, with a histopathological examination showing organ-confined disease (pT2N0M0) instead. The morbidity of RP for cT3 cases does not appear different than that of cT1c/T2 cases, confirming the feasibility of the approach. In a more recent study on same topic, the follow-up reached 20 years (Mitchell et al., 2012). Again, among the postoperative results, 42% did not undergo any neoadjuvant or adjuvant therapy, for an overall 20 year CSS of 81%. Outcomes of RP have been considered for the whole ‘high risk’ population instead of concentrating on single high-risk parameters. Briganti et al. (2015a) provide interesting details on the natural history of HR PCa after surgical treatment only. They retrospectively analyzed 2065 men who underwent RP, excluding all patients treated by adjuvant RT or ADT, and found a 55.2% BCR-free survival at 5 years. Overall, the longer the time from surgery, the smaller the risk of BCR for GS 8–10, while for men with stage ≥ pT3a the risk of BCR remained stable over time. After stratifying these patients according to the time-to-BCR, the data suggested a significant difference in cancer specific mortality for men with early (<36 months from surgery) BCR compared to late BCR (>36 months). Table 3 lists studies reporting surgical outcome either for exclusive HR PCa or substantial proportion of cases. As one can see, there is heterogeneity in outcome reporting. Some studies use the ‘specimen-confined” definition, while many others only provide the rate of positive surgical margins and the TNM stage. Since minimally invasive approaches have become much more popular and now widely accepted in treatment of HR PCa, outcome comparisons between these techniques have been performed. A 2013 systematic review (Yuh et al., 2014) examined 12 studies on robotic-assisted radical prostatectomy (RARP) in HR PCa and found short-term oncological outcomes similar to the reported literature from open RP data. A large variability between studies was found regarding nodal status, with a range of node positivity between 1 and 33%, which likely reflects many differences among surgeon commitment and institutional variables along with the HR PCa population. Two recent studies analyzed the short term outcomes of RARP versus open RP in HR PCa, a single-academic institution study (Pierorazio et al., 2013) and a SEER-Medicare linked database study (Gandaglia et al., 2014). Both studies failed to demonstrate a difference in terms of positive surgical margins: the first study, by Pierorazio et al. (2013), show an equivalent 3-year biochemical recurrence while the second one, by Gandaglia et al. (2014), focused on short-term surgical outcomes and found a shorter hospital stay and blood transfusion rate for RARP. Overall, the literature does not seem to favor one approach over the other, each approach can achieve excellent outcomes. The choice of RP should be driven by an informed decision-making process and reflect patient and clinician preferences. 5.1. Neoadjuvant therapy and lymph node dissection: what’s new? Neoadjuvant therapy could be a promising tool in order to improve cancer control rates and long-term outcomes, as seen in several other solid tumors. Antiandrogens, LHRH agonists and antagonists, newer agents (abiraterone, enzalutamide, ipilimumab), and classic cytotoxic agents may be all suitable candidates

Please cite this article in press as: Morlacco, A., Karnes, R.J., High-risk prostate cancer: the role of surgical management. Crit Rev Oncol/Hematol (2016), http://dx.doi.org/10.1016/j.critrevonc.2016.04.011

G Model ONCH-2181; No. of Pages 9

ARTICLE IN PRESS A. Morlacco, R.J. Karnes / Critical Reviews in Oncology/Hematology xxx (2016) xxx–xxx

for preoperative administration. Unfortunately, various investigations carried out so far, using different regimens, have produced discordant results, as described in a 2013 review by McKay et al. (2013). To date, there is no convincing evidence that neoadjuvant therapy can influence long-term survival outcomes, despite improvement of surgical outcome in terms of organ-confined rate, positive surgical margin rate, and number of pathologic N1 cases (Shelley et al., 2009). Reasons for these results are severalfold: some of these older studies were underpowered, included patients with heterogeneous disease features and used different therapy schedules. Some phase III and several phase II trials addressing this issue are ongoing: the CALGB 90203/NCT00430183 (Anon., 2016), also known as “PUNCH” (Preoperative Use of Neoadjuvant Chemohormonal Therapy) trial is testing neo-adjuvant docetaxel and androgen deprivation therapy +RP versus immediate RP in patients with HR localized PCa, the final data collection for primary outcome measure is scheduled for June 2018. The senior author of the present paper has been an investigator on this trial and other various neoadjuvant studies. Another highly debated subject is the role of pelvic lymph node (PLND) dissection. There’s wide consensus that RP for HRPCa should include an extended PLND. ePLND remains the gold standard for N staging, and cannot be replaced by imaging techniques (EAU, 2015; NCCN, 2016). Anatomic boundaries and oncological benefit of ePLND are topics much less agreed upon (Briganti et al., 2015b), and would warrant a separate review. Conventional ePLND comprehends the removal of node-bearing tissue overlying the external iliac artery and vein, the nodes within the obturator fossa located cranially and caudally to the obturator nerve, and the nodes medial and lateral to the internal iliac artery. Such a template has been explored in mapping studies (Joniau et al., 2013), confirming its ability to correctly stage 94% of patients, which increased to 97% with a template including the common iliac and presacral regions. Nevertheless, in pN+ patients, the ePLND template would have a 24% risk of incomplete positive nodes clearance. Sentinel lymph nodes techniques have been proposed, but the complexity of prostate lymphatic drainage, as confirmed by mapping studies (Nguyen et al., 2016), seems to prevent a real clinical application. The idea of complete removal of positive nodes is critical for the other debated issue: the direct oncological benefit of ePLND. Some studies, indeed, have shown a survival advantage in N+ patients receiving more extended PLND (Joslyn and Konety, 2006; Bader et al., 2003; Daneshmand et al., 2004). A recent paper by Abdollah et al. (2015a), in particular, has found that the number of harvested lymph nodes independently predicted lower CSM rates. This idea has raised a sharp debate (Bogdanovic´ et al., 2015; Abdollah et al., 2015b). However, an ongoing multicenter RCT analyzing the extent of PLND in HR PCa (SEAL, AUO AP 55/09) should provide an adequate and evidence-based answer to this question.

6. Conclusion RP for HR PCa provides accurate pathologic staging, with the advantage of downstaging towards organ-confined disease in a quarter of patients with cT3 tumors and possible downgrading. All these findings can reduce the need for adjunctive therapies, in turn reducing the attendant risks of secondary therapies. On the other hand, the presence of pathologically advanced disease (pT3a/b or pTxN1) at RP allows better risk stratification and perhaps a more tailored approach to the HR PCa patient in the delivery of secondary therapy. In the absence of randomized trials comparing RT +ADT to upfront RP with selected postoperative intervention, there is not a clear winner as to the most effica-

7

cious and tolerable treatment. Nonetheless, RP, either as a single approach or as part of a multimodal regimen, is a viable option for the management of HR PCa, affording excellent and durable local control as well as survival for the appropriately selected surgical patient. Conflict of interest None. Source of funding None. References Abdollah, F., et al., 2011. A competing-risks analysis of survival after alternative treatment modalities for prostate cancer patients: 1988–2006. Eur. Urol. 59, 88–95. Abdollah, F., et al., 2014. Predicting pathologic outcomes in patients undergoing robot-assisted radical prostatectomy for high risk prostate cancer: a preoperative nomogram. BJU Int., http://dx.doi.org/10.1111/bju.12998. Abdollah, F., et al., 2015a. More extensive pelvic lymph node dissection improves survival in patients with node-positive prostate cancer. Eur. Urol. 67, 212–219. Abdollah, F., Montorsi, F., Briganti, A., 2015b. Reply to Jovo Bogdanovic´ and Vuk ´ letter to the editor re: Firas Abdollah, Giorgio Gandaglia, Nazareno Sekulic’s Suardi, et al. More extensive pelvic lymph node dissection improves survival in patients with node-positive Prostate Cancer. Eur Urol 2015 67: 212–219. Eur. Urol. 68, e37–e38. Abdollah, F., et al., 2015c. Long-term cancer control outcomes in patients with clinically high-risk prostate cancer treated with robot-assisted radical prostatectomy: results from a multi-institutional study of 1100 patients. Eur. Urol. 68, 497–505. Akre, O., et al., 2011. Mortality among men with locally advanced prostate cancer managed with noncurative intent: a nationwide study in PCBaSe Sweden. Eur. Urol. 60, 554–563. Alibhai, S.M.H., Gogov, S., Allibhai, Z., 2006. Long-term side effects of androgen deprivation therapy in men with non-metastatic prostate cancer: a systematic literature review. Crit. Rev. Oncol. Hematol. 60, 201–215. Anon, 2016. Surgery With or Without Docetaxel and Leuprolide or Goserelin in Treating Patients With High-Risk Localized Prostate Cancer—ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00430183. Bader, P., Burkhard, F.C., Markwalder, R., Studer, U.E., 2003. Disease progression and survival of patients with positive lymph nodes after radical prostatectomy. Is there a chance of cure? J. Urol. 169, 849–854. Bill-Axelson, A., et al., 2014. Radical prostatectomy or watchful waiting in early prostate cancer. New. Engl. J. Med. 370, 932–942. Bishoff, J.T., et al., 2014. Prognostic utility of the cell cycle progression score generated from biopsy in men treated with prostatectomy. J. Urol. 192, 409–414. ´ J., Sekulic, ´ V. Re, Abdollah, Firas, Gandaglia, Giorgio, Suardi, Nazareno, Bogdanovic, et al., 2015. More extensive pelvic lymph node dissection improves survival in patients with node-positive prostate cancer. Eur. Urol. 67, 212–219, Eur. Urol. 68 e35-6 (2015). Boorjian, S.A., et al., 2008. Impact of prostate-specific antigen testing on the clinical and pathological outcomes after radical prostatectomy for Gleason 8–10 cancers. BJU Int. 101, 299–304. Boorjian, S.A., et al., 2009. The impact of discordance between biopsy and pathological Gleason scores on survival after radical prostatectomy. J. Urol. 181, 95–104 (discussion 104). Boorjian, S.A., et al., 2011. Long-term survival after radical prostatectomy versus external-beam radiotherapy for patients with high-risk prostate cancer. Cancer 117, 2883–2891. Braga-Basaria, M., et al., 2006. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J. Clin. Oncol. 24, 3979–3983. Bratt, O., et al., 2015. Undertreatment of men in their seventies with high-risk nonmetastatic prostate cancer. Eur. Urol. 68, 53–58. Briganti, A., et al., 2012. Identifying the best candidate for radical prostatectomy among patients with high-risk prostate cancer. Eur. Urol. 61, 584–592. Briganti, A., et al., 2015a. Natural history of surgically treated high-risk prostate cancer. Urol. Oncol. 33, 163.e7–163.e13. Briganti, A., et al., 2015b. What evidence do we need to support the use of extended pelvic lymph node dissection in prostate cancer? Eur. Urol. 67, 597–598. Bruchovsky, N., et al., 1987. The endocrinology and treatment of prostate tumor progression. Prog. Clin. Biol. Res. 239, 347–387. Carver, B.S., Bianco, F.J., Scardino, P.T., Eastham, J.A., 2006. Long-term outcome following radical prostatectomy in men with clinical stage T3 prostate cancer. J. Urol. 176, 564–568. Cheville, J.C., et al., 2008. Gene panel model predictive of outcome in men at high-risk of systemic progression and death from prostate cancer after radical retropubic prostatectomy. J. Clin. Oncol. 26, 3930–3936.

Please cite this article in press as: Morlacco, A., Karnes, R.J., High-risk prostate cancer: the role of surgical management. Crit Rev Oncol/Hematol (2016), http://dx.doi.org/10.1016/j.critrevonc.2016.04.011

G Model ONCH-2181; No. of Pages 9 8

ARTICLE IN PRESS A. Morlacco, R.J. Karnes / Critical Reviews in Oncology/Hematology xxx (2016) xxx–xxx

Coen, J.J., Zietman, A.L., Thakral, H., Shipley, W.U., 2002. Radical radiation for localized prostate cancer: local persistence of disease results in a late wave of metastases. J. Clin. Oncol. 20, 3199–3205. Cooperberg, M.R., Carroll, P.R., 2015. Trends in management for patients with localized prostate cancer, 1990–2013. JAMA 314, 80–82. Cooperberg, M.R., Lubeck, D.P., Mehta, S.S., Carroll, P.R., 2003. Time trends in clinical risk stratification for prostate cancer: implications for outcomes (data from CaPSURE). J. Urol. 170, S21–S25 (discussion S26–S27). Cooperberg, M.R., et al., 2005. The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable preoperative predictor of disease recurrence after radical prostatectomy. J. Urol. 173, 1938–1942. Cooperberg, M.R., Cowan, J., Broering, J.M., Carroll, P.R., 2008. High-risk prostate cancer in the United States, 1990–2007. World J. Urol. 26, 211–218. Cooperberg, M.R., Vickers, A.J., Broering, J.M., Carroll, P.R., 2010. Comparative risk-adjusted mortality outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for localized prostate cancer. Cancer 116, 5226–5234. Crook, J.M., Perry, G.A., Robertson, S., Esche, B.A., 1995. Routine prostate biopsies following radiotherapy for prostate cancer: results for 226 patients. Urology 45, 624–631 (discussion 631–632). Cuzick, J., et al., 2011. Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. Lancet Oncol. 12, 245–255. D’Amico, A.V., 1998. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 280, 969–974. Daneshmand, S., et al., 2004. Prognosis of patients with lymph node positive prostate cancer following radical prostatectomy: long-term results. J. Urol. 172, 2252–2255. Den, R.B., et al., 2015. Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy. J. Clin. Oncol. 33, 944–951. EAU, 2015. Guidelines on Prostate Cancer. https://uroweb.org/guideline/prostatecancer/. Eberhardt, S.C., et al., 2013. ACR Appropriateness Criteria prostate cancer–pretreatment detection, staging, and surveillance. J. Am. Coll. Radiol. 10, 83–92. Gandaglia, G., et al., 2014. Is robot-assisted radical prostatectomy safe in men with high-risk prostate cancer? Assessment of perioperative outcomes, positive surgical margins, and use of additional cancer treatments. J. Endourol. 28, 784–791. Inman, B.A., et al., 2008. Long-term outcomes of radical prostatectomy with multimodal adjuvant therapy in men with a preoperative serum prostate-specific antigen level> or =50 ng/mL. Cancer 113, 1544–1551. Jaboin, J.J., et al., 2011. The matrix metalloproteinase-7 polymorphism rs10895304 is associated with increased recurrence risk in patients with clinically localized prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 79, 1330–1335. Jemal, A., et al., 2015. Prostate cancer incidence and PSA testing patterns in relation to USPSTF screening recommendations. JAMA 314, 2054–2061. Joniau, S., Hsu, C.-Y., Gontero, P., Spahn, M., Van Poppel, H., 2012. Radical prostatectomy in very high-risk localized prostate cancer: long-term outcomes and outcome predictors. Scand. J. Urol. Nephrol. 46, 164–171. Joniau, S., et al., 2013. Mapping of pelvic lymph node metastases in prostate cancer. Eur. Urol. 63, 450–458. Joniau, S., et al., 2014. Stratification of high-risk prostate cancer into prognostic categories: a European Multi-institutional Study. Eur. Urol. 67, 157–164. Joslyn, S.A., Konety, B.R., 2006. Impact of extent of lymphadenectomy on survival after radical prostatectomy for prostate cancer. Urology 68, 121–125. Karnes, R.J., et al., 2010a. The ability of biomarkers to predict systemic progression in men with high-risk prostate cancer treated surgically is dependent on ERG status. Cancer Res. 70, 8994–9002. Karnes, R.J., Hatano, T., Blute, M.L., Myers, R.P., 2010b. Radical prostatectomy for high-risk prostate cancer. Jpn. J. Clin. Oncol. 40, 3–9. Karnes, R.J., et al., 2013. Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. J. Urol. 190, 2047–2053. Kibel, A.S., et al., 2012. Survival among men with clinically localized prostate cancer treated with radical prostatectomy or radiation therapy in the prostate specific antigen era. J. Urol. 187, 1259–1265. Klein, E.A., et al., 2014. A 17-gene assay to predict prostate cancer aggressiveness in the context of gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur. Urol. 66, 550–560. Kohutek, Z.A., et al., 2015. Long-term impact of androgen-deprivation therapy on cardiovascular morbidity after radiotherapy for clinically localized prostate cancer. Urology, http://dx.doi.org/10.1016/j.urology.2015.08.029. Lennernäs, B., et al., 2015. Radical prostatectomy versus high-dose irradiation in localized/locally advanced prostate cancer: a Swedish multicenter randomized trial with patient-reported outcomes. Acta Oncol. 54, 875–881. Loeb, S., et al., 2010. Prostate Cancer What Are the Outcomes of Radical Prostatectomy for High-risk Prostate Cancer? Urology 76 (3), 710–714. Lughezzani, G., et al., 2012. Radical prostatectomy represents an effective treatment in patients with specimen-confined high pathological Gleason score prostate cancer. BJU Int. 111, 723–730.

Malvezzi, M., et al., 2015. European cancer mortality predictions for the year 2015: does lung cancer have the highest death rate in EU women? Ann. Oncol. 26, 779–786. Manoharan, M., Bird, V.G., Kim, S.S., Civantos, F., Soloway, M.S., 2003. Outcome after radical prostatectomy with a pretreatment prostate biopsy Gleason score of ≥8. BJU Int. 92, 539–544. McKay, R.R., Choueiri, T.K., Taplin, M.-E., 2013. Rationale for and review of neoadjuvant therapy prior to radical prostatectomy for patients with high-risk prostate cancer. Drugs 73, 1417–1430. Meng, M.V., Elkin, E.P., Latini, D.M., Duchane, J., Carroll, P.R., 2005. Treatment of patients with high risk localized prostate cancer: results from cancer of the prostate strategic urological research endeavor (CaPSURE). J. Urol. 173, 1557–1561. Merino, T., et al., 2013. Intensity-modulated radiotherapy versus radical prostatectomy in patients with localized prostate cancer: long-term follow-up. BMC Cancer 13, 530. Messing, E.M., et al., 2006. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet. Oncol. 7, 472–479. Mitchell, C.R., et al., 2012. 20-year survival after radical prostatectomy as initial treatment for cT3 prostate cancer. BJU Int. 110, 1709–1713. Moyer, V.A., 2012. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 157, 120–134. NCCN, 2015. Prostate Cancer Guidelines. https://www.nccn.org/store/login/login. aspx?ReturnURL=http://www.nccn.org/professionals/physician gls/pdf/ prostate.pdf. NCCN, 2016. NCCN Guidelines on Prostate Cancer. https://www.nccn.org/store/ login/login.aspx?ReturnURL=http://www.nccn.org/professionals/physician gls/pdf/prostate.pdf. Nguyen, D.P., et al., 2016. A specific mapping study using fluorescence sentinel lymph node detection in patients with intermediate- and high-risk prostate cancer undergoing extended pelvic lymph node dissection. Eur. Urol., http:// dx.doi.org/10.1016/j.eururo.2016.01.034. Petrelli, F., et al., 2014. Radical prostatectomy or radiotherapy in high-risk prostate cancer: a systematic review and metaanalysis. Clin. Genitourin. Cancer 12, 215–224. Pierorazio, P.M., et al., 2013. Contemporaneous comparison of open vs minimally-invasive radical prostatectomy for high-risk prostate cancer. BJU Int. 125, 751–757. Roumiguié, M., et al., 2014. External validation of the Briganti nomogram to estimate the probability of specimen confined disease in patients with high-risk prostate cancer. BJU Int. 113–119, http://dx.doi.org/10.1111/bju. 12763. Schubert, M., et al., 2013. Distinct microRNA expression profile in prostate cancer patients with early clinical failure and the impact of let-7 as prognostic marker in high-risk prostate cancer. PLoS One 8, e65064. Shelley, M.D., et al., 2009. A systematic review and meta-analysis of randomised trials of neo-adjuvant hormone therapy for localised and locally advanced prostate carcinoma. Cancer Treat. Rev. 35, 9–17. Siegel, R.L., Miller, K.D., Jemal, A., 2015. Cancer statistics, 2015. CA Cancer J. Clin. 65, 5–29. Sooriakumaran, P., et al., 2014. Comparative effectiveness of radical prostatectomy and radiotherapy in prostate cancer: observational study of mortality outcomes. BMJ 348, g1502. Stephenson, A.J., et al., 2009. Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J. Clin. Oncol. 27, 4300–4305. Sundi, D., et al., 2014. Very-high-risk localized prostate cancer: definition and outcomes. Prostate Cancer Prostatic Dis. 17, 57–63. Surcel, C.I., et al., 2015. Preferences in the management of high-risk prostate cancer among urologists in Europe: results of a web-based survey. BJU Int. 115, 571–579. Tewari, A., et al., 2007. Long-term survival in men with high grade prostate cancer: a comparison between conservative treatment, radiation therapy and radical prostatectomy—a propensity scoring approach. J. Urol. 177, 911–915. Thompson, I., et al., 2007. Guideline for the management of clinically localized prostate cancer: 2007 update. J. Urol. 177, 2106–2131. Tsai, H.K., D’Amico, A.V., Sadetsky, N., Chen, M.-H., Carroll, P.R., 2007. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J. Natl. Cancer Inst. 99, 1516–1524. Wallis, C.J.D., et al., 2015a. Surgery versus radiotherapy for clinically-localized prostate cancer: a systematic review and meta-analysis. Eur. Urol., http://dx. doi.org/10.1016/j.eururo.2015.11.010. Wallis, C.J.D., et al., 2015b. Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer. Br. J. Cancer 112, 977–982. Ward, J.F., Slezak, J.M., Blute, M.L., Bergstralh, E.J., Zincke, H., 2005. Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. BJU Int. 95, 751–756. Walz, J., et al., 2011. Pathological results and rates of treatment failure in high-risk prostate cancer patients after radical prostatectomy. BJU Int. 107, 765–770. Westover, K., et al., 2012. Radical prostatectomy vs radiation therapy and androgen-suppression therapy in high-risk prostate cancer. BJU Int. 110, 1116–1121.

Please cite this article in press as: Morlacco, A., Karnes, R.J., High-risk prostate cancer: the role of surgical management. Crit Rev Oncol/Hematol (2016), http://dx.doi.org/10.1016/j.critrevonc.2016.04.011

G Model ONCH-2181; No. of Pages 9

ARTICLE IN PRESS A. Morlacco, R.J. Karnes / Critical Reviews in Oncology/Hematology xxx (2016) xxx–xxx

Widmark, A., et al., 2009. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet 373, 301–308. Wilt, T.J., et al., 2012. Radical prostatectomy versus observation for localized prostate cancer. New. Engl. J. Med. 367, 203–213. Yossepowitch, O., et al., 2008. Secondary therapy, metastatic progression, and cancer-specific mortality in men with clinically high-risk prostate cancer treated with radical prostatectomy. Eur. Urol. 53, 950–959. Yuh, B., et al., 2014. The role of robot-assisted radical prostatectomy and pelvic lymph node dissection in the management of high-risk prostate cancer: a systematic review. Eur. Urol. 65, 918–927. Zelefsky, M.J., et al., 2010. Metastasis after radical prostatectomy or external beam radiotherapy for patients with clinically localized prostate cancer: a comparison of clinical cohorts adjusted for case mix. J. Clin. Oncol. 28, 1508–1513.

9

Biographies Alessandro Morlacco, MD Currently completing a Urologic Oncology Research Fellowship at Mayo Clinic (Rochester MN, USA), Dr. Morlacco is an in-training Urology resident at the Padua University Hospital (Padua, Italy). Surgical management of urological malignances, especially prostate and bladder cancers and urological imaging, are his main research interests. R. Jeffrey Karnes, MD, FACS Consultant of Urology at Mayo Clinic (Rochester MN, USA), Prof. Karnes is also Regional Chair of Urology in the Mayo Clinic Health Care System, Director of Department of Urology Radical Prostatectomy Registry and member of several international and national research committees and groups. His main research interests include high-risk prostate cancer, radical prostatectomy outcomes and prostate cancer biomarker discovery and implementation. He has published over 185 papers in various journals.

Please cite this article in press as: Morlacco, A., Karnes, R.J., High-risk prostate cancer: the role of surgical management. Crit Rev Oncol/Hematol (2016), http://dx.doi.org/10.1016/j.critrevonc.2016.04.011