Guillaume Ploussard

Contemporary Role of Systematic Prostate Biopsies: Indications, Techniques, and Implications for Patient Care

CONTEXT Prostate cancer (PCa) screening to detect early stage PCa has resulted in increased identification of small-volume, low-grade PCa, many of which meet criteria for clinically indolent disease. Nevertheless, there remains some degree of underdetection of high-risk PCa in substantial numbers of men despite current diagnostic strategies. OBJECTIVE To discuss the contemporary role of prostate biopsy (PB), focusing on the indications, techniques, and limitations of current PB techniques and evolving techniques affecting patient care. EVIDENCE ACQUISITION A comprehensive Medline search was performed using the medical subject heading search terms prostate cancer, detection, prostate biopsy, significant cancer, and diagnosis, with restriction to the English language. Emphasis was given to publications within the past 5 yr. EVIDENCE SYNTHESIS Because abnormal digital rectal examination (DRE) and prostate-specific antigen (PSA) tests alone lack specificity for cancer, there is no universal indication for PB. This lack has inspired exploration for a cancer-specific biomarker and prediction tools such as risk calculators. Indication for biopsy should involve a balance between the underdiagnosis of high-risk cancers and the potential risks for the overdetection of clinically insignificant cancers as well as biopsy-related morbidity. Evidence supports the inclusion of laterally directed cores during transrectal ultrasound (TRUS) PB in addition to the traditional sextant pattern, which significantly improves cancer detection without a demonstrable increase in morbidity. These data indicate that such PB templates, typically 12 cores, represent the optimal template in initial PB. Optimised techniques and templates for repeat PB remain controversial. However, debate continues regarding indications, sampling number, and location as well as on the potential of modern image-guided approaches or three-dimensional (3D) mapping biopsy in this unique setting. Additional limitations of repeat PB techniques include associated procedural risks if general anaesthesia is required and inherent sampling errors of template-based techniques that are not targeted to the specific tumour site. CONCLUSIONS Current data support the utility of extended PB templates for initial TRUS PB intended to detect clinically significant PCa. Repeat PB in the setting of prior negative PB on the grounds of clinical suspicion or for risk-stratified approaches to management of low risk PCa requires balancing overdetection of low-risk cancer with the potential to miss significant cancer. Several options, including modern image-guided targeting, biomarker development, transrectal saturation PB, and 3D template mapping PB, are changing the clinical paradigms for evaluation and management. Evidence to support adopting approaches other than the current established standards should be tested through appropriately designed prospective studies.

Prostate Cancer Antigen 3 Score Accurately Predicts Tumour Volume and Might Help in Selecting Prostate Cancer Patients for Active Surveillance

BACKGROUND The optimal selection of prostate cancer (PCa) patients for active surveillance (AS) is currently being debated. OBJECTIVE To assess the impact of urinary prostate cancer antigen 3 (PCA3) score as an AS criterion instead of and in addition to the current criteria. DESIGN, SETTING, AND PARTICIPANTS We prospectively studied 106 consecutive low-risk PCa patients (prostate-specific antigen [PSA] ≤10 ng/ml, clinical stage T1c-T2a, and biopsy Gleason score 6) who underwent a PCA3 urine test before radical prostatectomy (RP). MEASUREMENTS Performance of AS criteria (biopsy criteria, PCA3 score, PSA density, and magnetic resonance imaging [MRI] findings) was tested in predicting four prognostic pathologic findings in RP specimens: (1) pT3-4 disease; (2) overall unfavourable disease (OUD) defined by pT3-4 disease and/or pathologic primary Gleason pattern 4; (3) tumour volume <0.5 cm(3); and (4) insignificant PCa. RESULTS AND LIMITATIONS The PCA3 score was strongly correlated with the tumour volume in a linear regression analysis (p<0.001, r=0.409). The risk of having a cancer ≥0.5 cm(3) and a significant PCa was increased three-fold in men with a PCA3 score of ≥25 compared with men with a PCA3 score of <25 with most AS biopsy criteria used. There was a trend towards higher PCA3 scores in patients with unfavourable and non-organ-confined disease and Gleason >6 cancers. In a multivariate analysis taking into account each AS criterion, a high PCA3 score (≥25) was an important predictive factor for tumour volume ≥0.5 cm(3) (odds ratio [OR]: 5.4; p=0.010) and significant PCa (OR: 12.7; p=0.003). Biopsy criteria and MRI findings were significantly associated with OUD (OR: 3.9 and 5.0, respectively; p=0.030 and p=0.025, respectively). CONCLUSIONS PCA3 score may be a useful marker to improve the selection for AS in addition to the current AS criteria. With a predictive cut-off of 25, PCA3 score is strongly indicative for tumour volume and insignificant PCa.

Class III beta-tubulin expression predicts prostate tumor aggressiveness and patient response to docetaxel-based chemotherapy.

Expression of class III β-tubulin (βIII-tubulin) correlates with tumor progression and resistance to taxane-based therapies for several human malignancies, but its use as a biomarker of tumor behavior in prostate cancer (PCa) remains largely unexplored. Here, we describe βIII-tubulin immunohistochemical staining patterns of prostate tumors obtained from a broad spectrum of PCa patients, some of whom subsequently received docetaxel therapy for castration-resistant PCa (CRPC). Elevated βIII-tubulin expression was significantly associated with tumor aggressiveness in PCa patients with presumed localized disease, as it was found to be an independent marker of biochemical recurrence after treatment. Additionally, βIII-tubulin expression in tumor cells was an independent predictor of lower overall survival for patients receiving docetaxel-based chemotherapy for CRPC. Manipulation of βIII-tubulin expression in human PCa cell lines using a human βIII-tubulin expression vector or βIII-tubulin small interfering RNA altered cell survival in response to docetaxel treatment in a manner that supports a role for βIII-tubulin expression as a mediator of PCa cell resistance to docetaxel therapy. Our findings suggest a role for βIII-tubulin as candidate theranostic biomarker to predict the response to docetaxel-based chemotherapy as well as to target for treatment of docetaxel-resistant CRPC.

A Systematic Review of Immunotherapy in Urologic Cancer: Evolving Roles for Targeting of CTLA-4, PD-1/PD-L1, and HLA-G

CONTEXT Overexpression of immune checkpoint molecules affects tumor-specific T-cell immunity in the cancer microenvironment, and can reshape tumor progression and metastasis. Antibodies targeting checkpoints could restore antitumor immunity by blocking the inhibitory receptor-ligand interaction. OBJECTIVE To analyze data and current trends in immune checkpoint targeting therapy for urologic cancers. EVIDENCE ACQUISITION Systematic literature search for clinical trials in the PubMed and Cochrane databases up to August 2014 according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Endpoints included oncologic results, tumor response rates, safety, and tolerability. EVIDENCE SYNTHESIS Anti-CTLA-4 monotherapy has demonstrated biochemical responses in prostate cancer. One phase 3 trial assessing ipilimumab efficacy in castration-resistant disease was negative overall. Nevertheless, ipilimumab may significantly improve overall survival compared with placebo in subgroups of patients with favorable prognostic features. In renal cancer, phase 1 trials showed interesting stabilization or long-lasting objective response rates approaching 50% using anti-PD-1/PD-L1 drugs in heavily pretreated metastatic patients. In bladder cancer, one phase 2 trial indicated a good safety profile for ipilimumab as a neoadjuvant drug before radical cystectomy. Overall, immune-related effects such as colitis and dermatitis were common and well tolerated. CONCLUSIONS Our systematic review shows that antibodies blocking immune checkpoints offer interesting and long-lasting response rates in heavily pretreated patients with advanced urologic cancers. More promising results are currently provided by anti-CTLA-4 antibodies in prostate cancer and by PD-1/PD-L1 inhibitors in renal cancer. These should encourage new clinical trials of immune therapy combinations and immunotherapy monotherapy combined with conventional anticancer drugs. In bladder cancer, the use of targeted immunotherapy still remains underevaluated; however, preliminary results reported at recent conferences seem encouraging. PATIENT SUMMARY Data from studies support the activity and safety of immune checkpoint inhibitors in urologic cancers, alone or in combination with conventional cancer therapies. Encouraging data in other oncologic fields could translate into interesting responses in urological cancers.

Pathological findings and prostate specific antigen outcomes after radical prostatectomy in men eligible for active surveillance--does the risk of misclassification vary according to biopsy criteria?

PURPOSE We compared the pathological findings and prostate specific antigen outcome after radical prostatectomy in men eligible for active surveillance according to 3 biopsy inclusion criteria. MATERIALS AND METHODS The study population included 177 men eligible for active surveillance who fulfilled clinicobiological criteria and biopsy criteria as group 1-less than 3 positive cores and less than 3 mm total tumor length, group 2-less than 3 positive cores with cancer involvement of less than 50% in any core and group 3-less than 33% of positive cores. Prostate specific antigen density cutoffs were also studied in these groups. Pathological findings on radical prostatectomy specimens and biochemical recurrence-free survival were studied. Median followup after radical prostatectomy was 34 months. RESULTS A majority of Gleason score 6 disease was observed in group 1 (51.7%) whereas a majority of Gleason score 7 or greater disease was reported in groups 2 (53.6%) and 3 (55.4%). Extracapsular extension was noted in 17.5% of radical prostatectomy specimens in group 3 vs 11.2% in group 1 (p = 0.175). The risk of overall unfavorable disease (defined as pT3-4 stage and/or Gleason score 8 or greater) was significantly higher in men with cancer involvement of 3 mm or greater on initial biopsy (27.3% vs 13.5%, respectively, p = 0.023). The 3-year biochemical recurrence-free survival rate was 94.0% and was not affected by the 3 active surveillance definitions. CONCLUSIONS Even with the use of a 21-core biopsy protocol the rate of unfavorable disease in radical prostatectomy specimens remains increased in men eligible for active surveillance. Patients must be informed of this risk of misclassification which ranges from 20% to 28% in men who fulfill the less stringent biopsy criteria.

Can we expand active surveillance criteria to include biopsy Gleason 3+4 prostate cancer? A multi-institutional study of 2,323 patients.

OBJECTIVE To test the expandability of active surveillance (AS) to Gleason score 3+4 cancers by assessing the unfavorable disease risk in a large multi-institutional cohort. MATERIALS AND METHODS We performed a retrospective analysis including 2,323 patients with localized Gleason score 3+4 prostate cancer who underwent a radical prostatectomy between 2005 and 2013 from 6 academic centers. We analyzed the rates of biopsy downgrading/upgrading and advanced stage in the overall cohort by employing standardized AS criteria (using biopsy Gleason score 3+4). RESULTS The final pathologic Gleason score was 3+3 = 6 in 8%, 3+4 = 7 in 67%, 4+3 = 7 in 20%, and 8 to 10 in 5% cases. The overall rate of unfavorable disease (upgrading or advanced stage or both) was 46%. In multivariable analysis, prostate-specific antigen (PSA) level>10 ng/ml, PSA density (PSAD) >0.15 ng/ml/g, clinical stage >T1, and>2 positive cores were predictors of unfavorable disease. According to the AS criteria used, the risk of unfavorable disease ranged from 30% to 42%. In patients without any risk factor (PSA level≤ 10 ng/ml, PSAD ≤ 0.15 ng/ml/g, T1c, and ≤ 2 positive cores), the unfavorable disease rate was 19%. The main limitations of this study are the retrospective design and nonstandardization of pathologic assessment between centers. CONCLUSIONS Approximately half of patients with biopsy Gleason score 3+4 cancer have unfavorable disease at final pathology. Nevertheless, expanding AS eligibility to these patients may be acceptable provided adherence to strict selection criteria leading to a<20% risk of unfavorable disease. Future tools for selection such as magnetic resonance imaging, early rebiopsy, and serum markers may be especially beneficial in this group of patients.

Impact of positive surgical margins on prostate-specific antigen failure after radical prostatectomy in adjuvant treatment-naïve patients

Study Type – Therapy (case series)
Level of Evidence 4

The prostate cancer gene 3 (PCA3) urine test in men with previous negative biopsies: does free-to-total prostate-specific antigen ratio influence the performance of the PCA3 score in predicting positive biopsies?

Study Type – Diagnosis (exploratory cohort)
Level of Evidence 2b

Analysis of outcomes after radical prostatectomy in patients eligible for active surveillance (PRIAS)

Several criteria have been described to select patients with prostate cancer in active surveillance (AS) protocols; however, the risk of missing unfavourable disease remains. We report the risk of misclassification using the Prostate Cancer Research International: Active Surveillance (PRIAS) study in an analysis of pathological results after radical prostatectomy. We also define predictors of favourable disease that can be used to better select patients eligible for AS, as well as risk factors associated with disease progression.

Comparisons of the Perioperative, Functional, and Oncologic Outcomes After Robot-Assisted Versus Pure Extraperitoneal Laparoscopic Radical Prostatectomy

BACKGROUND In spite of the increasing use of robot-assisted radical prostatectomy (RALP) worldwide, no level 1 evidence-based benefit favouring RALP versus pure laparoscopic approaches has been demonstrated in extraperitoneal laparoscopic procedures. OBJECTIVE To compare the operative, functional, and oncologic outcomes between pure laparoscopic radical prostatectomy (LRP) and RALP. DESIGN, SETTING, AND PARTICIPANTS From 2001 to 2011, 2386 extraperitoneal LRPs were performed consecutively in cases of localised prostate cancers. INTERVENTION A total of 1377 LRPs and 1009 RALPs were performed using an extraperitoneal approach. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Patient demographics, surgical parameters, pathologic features, and functional outcomes were collected into a prospective database and compared between LRP and RALP. Biochemical recurrence-free survival was tested using the Kaplan-Meier method. Mean follow-up was 39 and 15.4 mo in the LRP and RALP groups, respectively. RESULTS AND LIMITATIONS Shorter durations of operative time and of hospital stay were reported in the RALP group compared with the LRP group (p<0.001) even beyond the 100 first cases. Mean blood loss was significantly lower in the RALP group (p<0.001). The overall rate and the severity of the complications did not differ between the two groups. In pT2 disease, lower rates of positive margins were reported in the RALP group (p=0.030; odds ratio [OR]: 0.396) in multivariable analyses. The surgical approach did not affect the continence recovery. Robot assistance was independently predictive for potency recovery (p=0.045; OR: 5.9). Survival analyses showed an equal oncologic control between the two groups. Limitations were the lack of randomisation and the short-term follow-up. CONCLUSIONS Robotic assistance using an extraperitoneal approach offers better results than pure laparoscopy in terms of operative time, blood loss, and hospital stay. The robotic approach independently improves the potency recovery but not the continence recovery. When strict indications of nerve-sparing techniques are respected, RALP gives better results than LRP in terms of surgical margins in pathologically organ-confined disease. Longer follow-up is justified to reach conclusions on oncologic outcomes.