James A. Eastham

Integrative Genomic Profiling of Human Prostate Cancer

Annotation of prostate cancer genomes provides a foundation for discoveries that can impact disease understanding and treatment. Concordant assessment of DNA copy number, mRNA expression, and focused exon resequencing in 218 prostate cancer tumors identified the nuclear receptor coactivator NCOA2 as an oncogene in approximately 11% of tumors. Additionally, the androgen-driven TMPRSS2-ERG fusion was associated with a previously unrecognized, prostate-specific deletion at chromosome 3p14 that implicates FOXP1, RYBP, and SHQ1 as potential cooperative tumor suppressors. DNA copy-number data from primary tumors revealed that copy-number alterations robustly define clusters of low- and high-risk disease beyond that achieved by Gleason score. The genomic and clinical outcome data from these patients are now made available as a public resource.

Risk Factors for Urinary Incontinence after Radical Prostatectomy

PURPOSE We identified risk factors associated with urinary incontinence after radical retropubic prostatectomy. MATERIALS AND METHODS The time from operation until urinary continence was achieved was determined by chart review and questionnaire in 581 patients who were continent before undergoing radical retropubic prostatectomy between 1983 and 1994. Using univariate and multivariate analyses of data gathered prospectively, we examined risk factors associated with incontinence in these patients. RESULTS The actuarial rate of urinary continence at 24 months was 91% for the entire patient population and 95% for those treated after 1990. Many factors were associated with the risk of incontinence in univariate Cox proportional hazards regression analysis (patient age and weight, degree of obstructive voiding symptoms, prior transurethral resection of the prostate, clinical stage, intraoperative blood loss, resection of neurovascular bundles, postoperative anastomotic stricture and technique of vesicourethral anastomosis). However, in a multivariate analysis the factors that were independently associated with increased chance of regaining continence were decreasing age, a modification in the technique of anastomosis (introduced in 1990), preservation of both neurovascular bundles and absence of an anastomotic stricture. With introduction of the new surgical technique in 1990 the median time to continence decreased from 5.6 to 1.5 months and the rate of continence at 24 months increased from 82 to 95%. CONCLUSIONS While the risk of urinary incontinence after radical prostatectomy is related to the uncontrollable factor of patient age, it is also sensitive to the surgical technique used.

Do margins matter? The prognostic significance of positive surgical margins in radical prostatectomy specimens.

PURPOSE The prognostic significance of positive surgical margins (PSM) in radical prostatectomy (RP) specimens remains unclear. While most studies have concluded that a PSM is an independent adverse prognostic factor, others report that surgical margin status has no effect on prognosis. One reason for these discordant conclusions is the variable number of patients with a PSM who receive adjuvant therapy and the differing statistical methods used to account for the effects of the time course of adjuvant treatment on recurrence. We evaluated the prognostic significance of PSMs using multiple methods of analysis accounting for patients who received adjuvant therapy. MATERIALS AND METHODS We analyzed 1,389 consecutive patients with clinical stage T1-3 prostate cancer treated with RP by 2 surgeons from 1983 to 2000. Of 179 patients with a PSM, 37 received adjuvant therapy (AT), 29 radiation therapy and 8 received hormonal therapy. Because the method used to account for men receiving AT can affect the outcome of the analysis, data were analyzed by the Cox proportional hazards technique accounting for patients receiving AT using 5 methods: 1) exclusion, 2) inclusion (AT ignored), 3) censoring at time of AT, 4) failing at time of AT and 5) considering AT as a time dependent covariate. RESULTS Overall 179 patients (12.9%) had a PSM, including 6.8% of 847 patients with pT2 and 23% of 522 patients with pT3 disease. A PSM was a significant predictor of cancer recurrence when analyzed using methods 1, 3, 4 and 5 (p=0.005, p=0.014, p=0.0005, p=0.002, respectively). However, it was not a predictor of recurrence using method 2 in which AT was ignored (p=0.283). Using method 5 multivariate analysis demonstrated that a PSM (p=0.002) was an independent predictor of 10-year progression-free probability (PFP) along with Gleason score (p=0.0005), extracapsular extension (p=0.0005), seminal vesicle invasion (p <0.0005), positive lymph nodes (p <0.0005) and preoperative serum prostate specific antigen (p <0.0001). Using method 5 the 10-year PFP was 58% +/- 12% and 81% +/- 3% for patients with and without a PSM, respectively (p <0.00005). The relative risk of recurrence in men with a PSM using method 5 was 1.52 (95% confidence interval 1.06-2.16). CONCLUSIONS We confirm that a PSM has a significant adverse impact on PFP after RP in multivariate analysis using multiple statistical methods to account for patients who received AT. While prostate cancer screening strategies have resulted in a majority of men having organ confined disease at RP, surgeons should continue to strive to reduce the rate of positive surgical margins to improve cancer control outcomes.

Predicting 15-Year Prostate Cancer Specific Mortality After Radical Prostatectomy

PURPOSE Long-term prostate cancer specific mortality after radical prostatectomy is poorly defined in the era of widespread screening. An understanding of the treated natural history of screen detected cancers and the pathological risk factors for prostate cancer specific mortality are needed for treatment decision making. MATERIALS AND METHODS Using Fine and Gray competing risk regression analysis we modeled clinical and pathological data, and followup information on 11,521 patients treated with radical prostatectomy at a total of 4 academic centers from 1987 to 2005 to predict prostate cancer specific mortality. The model was validated on 12,389 patients treated at a separate institution during the same period. Median followup in the modeling and validation cohorts was 56 and 96 months, respectively. RESULTS The overall 15-year prostate cancer specific mortality rate was 7%. Primary and secondary Gleason grade 4-5 (each p<0.001), seminal vesicle invasion (p<0.001) and surgery year (p=0.002) were significant predictors of prostate cancer specific mortality. A nomogram predicting 15-year prostate cancer specific mortality based on standard pathological parameters was accurate and discriminating with an externally validated concordance index of 0.92. When stratified by patient age at diagnosis, the 15-year prostate cancer specific mortality rate for pathological Gleason score 6 or less, 3+4, 4+3 and 8-10 was 0.2% to 1.2%, 4.2% to 6.5%, 6.6% to 11% and 26% to 37%, respectively. The 15-year prostate cancer specific mortality risk was 0.8% to 1.5%, 2.9% to 10%, 15% to 27% and 22% to 30% for organ confined cancer, extraprostatic extension, seminal vesicle invasion and lymph node metastasis, respectively. Only 3 of 9,557 patients with organ confined, pathological Gleason score 6 or less cancer died of prostate cancer. CONCLUSIONS Poorly differentiated cancer and seminal vesicle invasion are the prime determinants of prostate cancer specific mortality after radical prostatectomy. The prostate cancer specific mortality risk can be predicted with remarkable accuracy after the pathological features of prostate cancer are known.

Systematic Review and Meta-analysis of Studies Reporting Potency Rates After Robot-assisted Radical Prostatectomy

BACKGROUND Although the initial robot-assisted radical prostatectomy (RARP) series showed 12-mo potency rates ranging from 70% to 80%, the few available comparative studies did not permit any definitive conclusion about the superiority of this technique when compared with retropubic radical prostatectomy (RRP) and laparoscopic radical prostatectomy (LRP). OBJECTIVES The aims of this systematic review were (1) to evaluate the current prevalence and the potential risk factors of erectile dysfunction after RARP, (2) to identify surgical techniques able to improve the rate of potency recovery after RARP, and (3) to perform a cumulative analysis of all available studies comparing RARP versus RRP or LRP. EVIDENCE ACQUISITION A literature search was performed in August 2011 using the Medline, Embase, and Web of Science databases. Only comparative studies or clinical series including >100 cases reporting potency recovery outcomes were included in this review. Cumulative analysis was conducted using Review Manager v.4.2 software designed for composing Cochrane Reviews (Cochrane Collaboration, Oxford, UK). EVIDENCE SYNTHESIS We analyzed 15 case series, 6 studies comparing different techniques in the context of RARP, 6 studies comparing RARP with RRP, and 4 studies comparing RARP with LRP. The 12- and 24-mo potency rates ranged from 54% to 90% and from 63% to 94%, respectively. Age, baseline potency status, comorbidities index, and extension of the nerve-sparing procedure represent the most relevant preoperative and intraoperative predictors of potency recovery after RARP. Available data seem to support the use of cautery-free dissection or the use of pinpointed low-energy cauterization. Cumulative analyses showed better 12-mo potency rates after RARP in comparison with RRP (odds ratio [OR]: 2.84; 95% confidence interval [CI]: 1.46-5.43; p=0.002). Only a nonstatistically significant trend in favor of RARP was reported after comparison with LRP (OR: 1.89; p=0.21). CONCLUSIONS The incidence of potency recovery after RARP is influenced by numerous factors. Data coming from the present systematic review support the use of a cautery-free technique. This update of previous systematic reviews of the literature showed, for the first time, a significant advantage in favor of RARP in comparison with RRP in terms of 12-mo potency rates.

Prostate Cancer–Specific Mortality After Radical Prostatectomy for Patients Treated in the Prostate-Specific Antigen Era

PURPOSE The long-term risk of prostate cancer-specific mortality (PCSM) after radical prostatectomy is poorly defined for patients treated in the era of widespread prostate-specific antigen (PSA) screening. Models that predict the risk of PCSM are needed for patient counseling and clinical trial design. METHODS A multi-institutional cohort of 12,677 patients treated with radical prostatectomy between 1987 and 2005 was analyzed for the risk of PCSM. Patient clinical information and treatment outcome was modeled using Fine and Gray competing risk regression analysis to predict PCSM. RESULTS Fifteen-year PCSM and all-cause mortality were 12% and 38%, respectively. The estimated PCSM ranged from 5% to 38% for patients in the lowest and highest quartiles of predicted risk of PSA-defined recurrence, based on a popular nomogram. Biopsy Gleason grade, PSA, and year of surgery were associated with PCSM. A nomogram predicting the 15-year risk of PCSM was developed, and the externally validated concordance index was 0.82. Neither preoperative PSA velocity nor body mass index improved the models accuracy. Only 4% of contemporary patients had a predicted 15-year PCSM of greater than 5%. CONCLUSION Few patients will die from prostate cancer within 15 years of radical prostatectomy, despite the presence of adverse clinical features. This favorable prognosis may be related to the effectiveness of radical prostatectomy (with or without secondary therapy) or the low lethality of screen-detected cancers. Given the limited ability to identify contemporary patients at substantially elevated risk of PCSM on the basis of clinical features alone, the need for novel markers specifically associated with the biology of lethal prostate cancer is evident.

A Contemporary Prostate Cancer Grading System: A Validated Alternative to the Gleason Score.

BACKGROUND Despite revisions in 2005 and 2014, the Gleason prostate cancer (PCa) grading system still has major deficiencies. Combining of Gleason scores into a three-tiered grouping (6, 7, 8-10) is used most frequently for prognostic and therapeutic purposes. The lowest score, assigned 6, may be misunderstood as a cancer in the middle of the grading scale, and 3+4=7 and 4+3=7 are often considered the same prognostic group. OBJECTIVE To verify that a new grading system accurately produces a smaller number of grades with the most significant prognostic differences, using multi-institutional and multimodal therapy data. DESIGN, SETTING, AND PARTICIPANTS Between 2005 and 2014, 20,845 consecutive men were treated by radical prostatectomy at five academic institutions; 5501 men were treated with radiotherapy at two academic institutions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Outcome was based on biochemical recurrence (BCR). The log-rank test assessed univariable differences in BCR by Gleason score. Separate univariable and multivariable Cox proportional hazards used four possible categorizations of Gleason scores. RESULTS AND LIMITATIONS In the surgery cohort, we found large differences in recurrence rates between both Gleason 3+4 versus 4+3 and Gleason 8 versus 9. The hazard ratios relative to Gleason score 6 were 1.9, 5.1, 8.0, and 11.7 for Gleason scores 3+4, 4+3, 8, and 9-10, respectively. These differences were attenuated in the radiotherapy cohort as a whole due to increased adjuvant or neoadjuvant hormones for patients with high-grade disease but were clearly seen in patients undergoing radiotherapy only. A five-grade group system had the highest prognostic discrimination for all cohorts on both univariable and multivariable analysis. The major limitation was the unavoidable use of prostate-specific antigen BCR as an end point as opposed to cancer-related death. CONCLUSIONS The new PCa grading system has these benefits: more accurate grade stratification than current systems, simplified grading system of five grades, and lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa. PATIENT SUMMARY We looked at outcomes for prostate cancer (PCa) treated with radical prostatectomy or radiation therapy and validated a new grading system with more accurate grade stratification than current systems, including a simplified grading system of five grades and a lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa.

Adult UrologyOncology: Prostate/Testis/Penis/UrethraPredicting 15-Year Prostate Cancer Specific Mortality After Radical Prostatectomy

PURPOSE Long-term prostate cancer specific mortality after radical prostatectomy is poorly defined in the era of widespread screening. An understanding of the treated natural history of screen detected cancers and the pathological risk factors for prostate cancer specific mortality are needed for treatment decision making. MATERIALS AND METHODS Using Fine and Gray competing risk regression analysis we modeled clinical and pathological data, and followup information on 11,521 patients treated with radical prostatectomy at a total of 4 academic centers from 1987 to 2005 to predict prostate cancer specific mortality. The model was validated on 12,389 patients treated at a separate institution during the same period. Median followup in the modeling and validation cohorts was 56 and 96 months, respectively. RESULTS The overall 15-year prostate cancer specific mortality rate was 7%. Primary and secondary Gleason grade 4-5 (each p<0.001), seminal vesicle invasion (p<0.001) and surgery year (p=0.002) were significant predictors of prostate cancer specific mortality. A nomogram predicting 15-year prostate cancer specific mortality based on standard pathological parameters was accurate and discriminating with an externally validated concordance index of 0.92. When stratified by patient age at diagnosis, the 15-year prostate cancer specific mortality rate for pathological Gleason score 6 or less, 3+4, 4+3 and 8-10 was 0.2% to 1.2%, 4.2% to 6.5%, 6.6% to 11% and 26% to 37%, respectively. The 15-year prostate cancer specific mortality risk was 0.8% to 1.5%, 2.9% to 10%, 15% to 27% and 22% to 30% for organ confined cancer, extraprostatic extension, seminal vesicle invasion and lymph node metastasis, respectively. Only 3 of 9,557 patients with organ confined, pathological Gleason score 6 or less cancer died of prostate cancer. CONCLUSIONS Poorly differentiated cancer and seminal vesicle invasion are the prime determinants of prostate cancer specific mortality after radical prostatectomy. The prostate cancer specific mortality risk can be predicted with remarkable accuracy after the pathological features of prostate cancer are known.

Diffusion-weighted Endorectal MR Imaging at 3 T for Prostate Cancer: Tumor Detection and Assessment of Aggressiveness

PURPOSE To assess the incremental value of diffusion-weighted (DW) magnetic resonance (MR) imaging over T2-weighted MR imaging at 3 T for prostate cancer detection and to investigate the use of the apparent diffusion coefficient (ADC) to characterize tumor aggressiveness, with whole-mount step-section pathologic analysis as the reference standard. MATERIALS AND METHODS The Internal Review Board approved this HIPAA-compliant retrospective study and waived informed consent. Fifty-one patients with prostate cancer (median age, 58 years; range, 46-74 years) underwent T2-weighted MR imaging and DW MR imaging (b values: 0 and 700 sec/mm(2) [n = 20] or 0 and 1000 sec/mm(2) [n = 31]) followed by prostatectomy. The prostate was divided into 12 regions; two readers provided a score for each region according to their level of suspicion for the presence of cancer on a five-point scale, first using T2-weighted MR imaging alone and then using T2-weighted MR imaging and the ADC map in conjunction. Areas under the receiver operating characteristic curve (AUCs) were estimated to evaluate performance. Generalized estimating equations were used to test the ADC difference between benign and malignant prostate regions and the association between ADCs and tumor Gleason scores. RESULTS For tumor detection, the AUCs for readers 1 and 2 were 0.79 and 0.76, respectively, for T2-weighted MR imaging and 0.79 and 0.78, respectively, for T2-weighted MR imaging plus the ADC map. Mean ADCs for both cancerous and healthy prostatic regions were lower when DW MR imaging was performed with a b value of 1000 sec/mm(2) rather than 700 sec/mm(2). Regardless of the b value used, there was a significant difference in the mean ADC between malignant and benign prostate regions. A lower mean ADC was significantly associated with a higher tumor Gleason score (mean ADCs of [1.21, 1.10, 0.87, and 0.69] × 10(-3) mm(2)/sec were associated with Gleason score of 3 + 3, 3 + 4, 4 + 3, and 8 or higher, respectively; P = .017). CONCLUSION Combined DW and T2-weighted MR imaging had similar performance to T2-weighted MR imaging alone for tumor detection; however, DW MR imaging provided additional quantitative information that significantly correlated with prostate cancer aggressiveness.

A Critical Analysis of the Current Knowledge of Surgical Anatomy Related to Optimization of Cancer Control and Preservation of Continence and Erection in Candidates for Radical Prostatectomy

CONTEXT Detailed knowledge of the anatomy of the prostate and adjacent tissues is mandatory during radical prostatectomy to ensure reliable oncologic and functional outcomes. OBJECTIVE To review critically and to summarize the available literature on surgical anatomy of the prostate and adjacent structures involved in cancer control, erectile function, and urinary continence. EVIDENCE ACQUISITION A search of the PubMed database was performed using the keywords radical prostatectomy, anatomy, neurovascular bundle, fascia, pelvis, and sphincter. Relevant articles and textbook chapters were reviewed, analyzed, and summarized. EVIDENCE SYNTHESIS Anatomy of the prostate and the adjacent tissues varies substantially. The fascia surrounding the prostate is multilayered, sometimes either fused with the prostate capsule or clearly separated from the capsule as a reflection of interindividual variations. The neurovascular bundle (NVB) is situated between the fascial layers covering the prostate. The NVB is composed of numerous nerve fibers superimposed on a scaffold of veins, arteries, and variable amounts of adipose tissue surrounding almost the entire lateral and posterior surfaces of the prostate. The NVB is also in close, cage-like contact to the seminal vesicles. The external urethral sphincter is a complex structure in close anatomic and functional relationship to the pelvic floor, and its fragile innervation is in close association to the prostate apex. Finally, the shape and size of the prostate can significantly modify the anatomy of the NVB, the urethral sphincter, the dorsal vascular complex, and the pubovesical/puboprostatic ligaments. CONCLUSIONS The surgical anatomy of the prostate and adjacent tissues involved in radical prostatectomy is complex. Precise knowledge of all relevant anatomic structures facilitates surgical orientation and dissection during radical prostatectomy and ideally translates into both superior rates of cancer control and improved functional outcomes postoperatively.