Burkhard Beyer

Clinical Utility of Quantitative Gleason Grading in Prostate Biopsies and Prostatectomy Specimens

BACKGROUND Gleason grading is the strongest prognostic parameter in prostate cancer. Gleason grading is categorized as Gleason ≤ 6, 3 + 4, 4 + 3, 8, and 9-10, but there is variability within these subgroups. For example, Gleason 4 components may range from 5-45% in a Gleason 3 + 4 = 7 cancer. OBJECTIVE To assess the clinical relevance of the fractions of Gleason patterns. DESIGN, SETTING, AND PARTICIPANTS Prostatectomy specimens from 12823 consecutive patients and of 2971 matched preoperative biopsies for which clinical data with an annual follow-up between 2005 and 2014 were available from the Martini-Klinik database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS To evaluate the utility of quantitative grading, the fraction of Gleason 3, 4, and 5 patterns seen in biopsies and prostatectomies were recorded. Gleason grade fractions were compared with prostatectomy findings and prostate-specific antigen recurrence. RESULTS AND LIMITATIONS Our data suggest a striking utility of quantitative Gleason grading. In prostatectomy specimens, there was a continuous increase of the risk of prostate-specific antigen recurrence with increasing percentage of Gleason 4 fractions with remarkably small differences in outcome at clinically important thresholds (0% vs 5%; 40% vs 60% Gleason 4), distinguishing traditionally established prognostic groups. Also, in biopsies, the quantitative Gleason scoring identified various intermediate risk groups with respect to Gleason findings in corresponding prostatectomies. Quantitative grading may also reduce the clinical impact of interobserver variability because borderline findings such as tumors with 5%, 40%, or 60% Gleason 4 fractions and very small Gleason 5 fractions (with pivotal impact on the Gleason score) are disclaimed. CONCLUSIONS Quantitative Gleason pattern data should routinely be provided in addition to Gleason score categories, both in biopsies and in prostatectomy specimens. PATIENT SUMMARY Gleason score is the most important prognostic parameter in prostate cancer, but prone to interobserver variation. The results of our study show that morphological aspects that define the Gleason grade in prostate cancer represent a continuum. Quantitation of Gleason patterns provides clinically relevant information beyond the traditional Gleason grading categories ≤ 3 + 3, 3 + 4, 4 + 3, 8, 9 -1 0. Quantitative Gleason scoring can help to minimize variations between different pathologists and substantially aid in optimized therapy decision-making.

A Multi-institutional Analysis of Perioperative Outcomes in 106 Men Who Underwent Radical Prostatectomy for Distant Metastatic Prostate Cancer at Presentation

BACKGROUND Current trials are investigating radical intervention in men with metastatic prostate cancer. However, there is a lack of safety data for radical prostatectomy as therapy in this setting. OBJECTIVE To examine perioperative outcomes and short-term complications after radical prostatectomy for locally resectable, distant metastatic prostate cancer. DESIGN, SETTING, AND PARTICIPANTS A retrospective case series from 2007 to 2014 comprising 106 patients with newly diagnosed metastatic (M1) prostate cancer from the USA, Germany, Italy, and Sweden. INTERVENTION Radical prostatectomy and extended pelvic lymphadenectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Descriptive statistics were used to present margin status, continence, and readmission, reoperation, and overall complication rates at 90 d, as well as for 21 specific complications. Kaplan-Meier plots were used to estimate survival function. Intercenter variability and M1a/ M1b subgroups were examined. RESULTS AND LIMITATIONS Some 79.2% of patients did not suffer any complications; positive-margin (53.8%), lymphocele (8.5%), and wound infection (4.7%) rates were higher in our cohort than in a meta-analysis of open radical prostatectomy performed for standard indications. At a median follow-up of 22.8 mo, 94/106 (88.7%) men were still alive. The study is limited by its retrospective design, differing selection criteria, and short follow-up. CONCLUSIONS Radical prostatectomy for men with locally resectable, distant metastatic prostate cancer appears safe in expert hands for meticulously selected patients. Overall and specific complication rates related to the surgical extirpation are not more frequent than when radical prostatectomy is performed for standard indications, and the use of extended pelvic lymphadenectomy in all of this cohort compared to its selective use in localized/locally advanced prostate cancer accounts for any extra morbidity. PATIENT SUMMARY Men presenting with advanced prostate cancer that has spread beyond the prostate are increasingly being considered for treatments directed at the prostate itself. On the basis of results for our international series of 106 men, surgery appears reasonably safe in this setting for certain patients.

Shear Wave Elastography for Localization of Prostate Cancer Lesions and Assessment of Elasticity Thresholds: Implications for Targeted Biopsies and Active Surveillance Protocols

PURPOSE Shear wave elastography allows the detection of cancer by using focused ultrasound pulses for locally deforming tissue. The differences in tissue elasticity and stiffness have been used increasingly in breast cancer imaging and help detect potential tumor lesions in the prostate. In this study we localized prostate cancer lesions using shear wave elastography before radical prostatectomy and assessed the examiner independent elasticity threshold for cancer foci detection. MATERIALS AND METHODS Shear wave elastography scanning of the whole prostate was performed before radical prostatectomy in 60 consecutive patients with high, intermediate and low risk disease. Localization of suspected lesions and density threshold (kPa) were recorded in up to 12 areas and resulted in 703 different fields. Shear wave elastography findings were correlated with final pathology. Initially 381 areas were used to establish shear wave elastography cutoffs (development cohort 32 patients). Subsequently these cutoffs were validated in 322 areas (validation cohort 28 patients). RESULTS Using shear wave elastography significant differences were recorded for the elasticity of benign tissue vs prostate cancer nodules at 42 kPa (range 29 to 71.3) vs 88 kPa (range 54 to 132) (all p <0.001). Median cancer lesion diameter was 26 mm (range 18 to 41). Applying the most informative cutoff of 50 kPa to the validation cohort resulted in 80.9% and 69.1% sensitivity and specificity, respectively, and 74.2% accuracy for detecting cancer nodules based on final pathological finding. The corresponding positive and negative predictive values were 67.1% and 82.2%, respectively. CONCLUSIONS Shear wave elastography allows the identification of cancer foci based on shear wave elastography differences. Moreover, reliable cutoffs for this approach can be established, allowing examiner independent localization of prostate cancer foci.

A Feasible and Time-efficient Adaptation of NeuroSAFE for da Vinci Robot-assisted Radical Prostatectomy

BACKGROUND The benefit of intraoperative neurovascular structure-adjacent frozen section examination (NeuroSAFE) of the prostate was demonstrated in open radical prostatectomy. In da Vinci robot-assisted prostatectomy (DVP), this approach is often avoided due to suspected difficulties in harvesting the prostate, loss in pneumoperitoneum, increased blood loss, and prolonged operating room (OR) time. OBJECTIVE To provide a detailed description of the technique, feasibility, and impact of the NeuroSAFE technique on OR time, blood loss, frequency of nerve sparing (NS), and positive surgical margins (PSMs) in DVP. DESIGN, SETTING, AND PARTICIPANTS We analyzed 1570 consecutive patients undergoing DVP from 2004 to 2012. NeuroSAFE was performed in 1178 patients. SURGICAL PROCEDURE The prostate was intraoperatively harvested via an extension of the camera trocar incision without undocking the robotic arms. Blood spillage from the dorsal vein complex due to the loss of pneumoperitoneum was avoided by upward traction on the transurethral catheter. After prostate removal, pneumoperitoneum was reestablished by closing the extended incision with running sutures and repositioning the optical trocar. The NeuroSAFE procedure consisted of intraoperative bilateral frozen sections covering the entire neurovascular bundles adjacent prostate surface. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We compared OR time, blood loss, NS frequency, and PSMs in non-NeuroSAFE versus NeuroSAFE DVP. RESULTS AND LIMITATIONS There was no significant difference in blood loss (253.5 ± 204.4 ml vs 265.8 ± 246.7 ml; p=0.49) and OR time (220 min ± 51 vs 224 min ± 64; p=0.22). No complications associated with specimen harvesting occurred. NS rate increased significantly with versus without NeuroSAFE (overall 97% vs 81%; pT2 99% vs 90%, pT3a 94% vs 74%, pT3b 91% vs 30). PSM rate dropped significantly with NeuroSAFE (overall 16% vs 24%; pT2 8% vs 15%, pT3a 22% vs 39%, pT3b 49% vs 67%; all p<0.05). CONCLUSIONS We demonstrate a time-efficient and safe adaption of the NeuroSAFE technique to DVP. PATIENT SUMMARY We describe a feasible and secure adaption of the neurovascular structure-adjacent frozen section examination (NeuroSAFE) procedure for da Vinci robot-assisted prostatectomy. We showed that there was no increased blood loss and operating room time. We maximized the nerve-sparing frequency and could reduce positive surgical margins even in non-organ-confined tumors.

Use of Phosphodiesterase Type 5 Inhibitors May Adversely Impact Biochemical Recurrence after Radical Prostatectomy

PURPOSE Experimental evidence suggests that phosphodiesterase type 5 inhibitors may suppress tumor growth, postpone metastasis and prolong survival, but clinical data are lacking. We studied the effect of phosphodiesterase type 5 inhibitors on biochemical recurrence after radical prostatectomy for prostate cancer. MATERIALS AND METHODS The study was comprised of 4,752 consecutive patients with localized prostate cancer treated with bilateral nerve sparing radical prostatectomy between January 2000 and December 2010. Of these patients 1,110 (23.4%) received phosphodiesterase type 5 inhibitors postoperatively while 3,642 (76.6%) did not. The risk of biochemical recurrence was compared between the phosphodiesterase type 5 inhibitor group and the nonphosphodiesterase type 5 inhibitor group. Cox multivariate proportional hazard models and confidence intervals were used to estimate the hazard ratio of biochemical recurrence associated with phosphodiesterase type 5 inhibitor use. Propensity score matched analysis was performed. RESULTS Median followup was 60.3 months (IQR 36.7-84.5). Five-year biochemical recurrence-free survival estimates in the phosphodiesterase type 5 inhibitor vs nonphosphodiesterase type 5 inhibitor groups were 84.7% (95% CI 82.1-87.0) and 89.2% (95% CI 88.1-90.3), respectively (p=0.0006). Multivariate regression analysis showed that phosphodiesterase type 5 inhibitor use was an independent risk factor for biochemical recurrence (HR 1.38, 95% CI 1.11-1.70, p=0.0035) and this was also true after propensity score matching. CONCLUSIONS Contrary to experimental data, the use of phosphodiesterase type 5 inhibitors after radical prostatectomy may adversely impact biochemical recurrence. Further studies are needed to validate our results.

Functional Outcomes and Quality of Life After Radical Prostatectomy Only Versus a Combination of Prostatectomy with Radiation and Hormonal Therapy

BACKGROUND While the optimal use and timing of secondary therapy after radical prostatectomy (RP) remain controversial, there are limited data on patient-reported outcomes following multimodal therapy. OBJECTIVE To assess the impact of additional radiation therapy (RT) and/or androgen deprivation therapy (ADT) on urinary continence, potency, and quality of life (QoL) after RP. DESIGN, SETTING, AND PARTICIPANTS Among 13150 men who underwent RP from 1992 to 2013, 905 received RP + RT, 407 RP + ADT and 688 RP + RT + ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES Urinary function, sexual function, and overall QoL were evaluated annually using self-administered validated questionnaires. Propensity score-matched and bootstrap analyses were performed, and the distributions for all functional outcomes were analyzed as a function of time after RP. RESULTS AND LIMITATIONS Patients who received RP + RT had a 4% higher overall incontinence rate 3 yr after surgery, and 1% higher rate for severe incontinence (>3 pads/24h) compared to matched RP-only patients. ADT further increased the overall and severe incontinence rates by 4% and 3%, respectively, compared to matched RP + RT patients. RP + RT was associated with an 18% lower rate of potency compared to RP alone, while RP + RT + ADT was associated with a further 17% reduction compared to RP + RT. Additional RT reduced QoL by 10% and additional ADT by a further 12% compared to RP only and RP + RT, respectively. The timing of RT after RP had no influence on continence, but adjuvant compared to salvage RT was associated with significantly lower potency (37% vs 45%), but higher QoL (60% vs 56%). Limitations of our study include the observational study design and potential for selection bias in the treatments received. CONCLUSIONS Secondary RT and ADT after RP have an additive negative influence on urinary function, potency, and QoL. Patients with high-risk disease should be counseled before RP on the potential net impairment of functional outcomes due to multimodal treatment. PATIENT SUMMARY Men with high-risk disease choosing surgery upfront should be counseled on the potential need for additional radiation and or androgen deprivation, and the potential net impairment of functional outcomes arising from multimodal treatment.

Improved detection of circulating tumor cells in non-metastatic high-risk prostate cancer patients

The relevance of blood-based assays to monitor minimal residual disease (MRD) in non-metastatic prostate cancer (PCa) remains unclear. Proving that clinically relevant circulating tumor cells (CTCs) can be detected with available technologies could address this. This study aimed to improve CTC detection in non-metastatic PCa patients by combining three independent CTC assays: the CellSearch system, an in vivo CellCollector and the EPISPOT. Peripheral blood samples from high-risk PCa patients were screened for CTCs before and three months after radical prostatectomy (RP). Combining the results of both time points, CTCs were detected in 37%, 54.9% and 58.7% of patients using CellSearch, CellCollector and EPISPOT, respectively. The cumulative positivity rate of the three CTC assays was 81.3% (87/107) with 21.5% (23/107) of patients harboring ≥5 CTCs/7.5 ml blood. Matched pair analysis of 30 blood samples taken before and after surgery indicated a significant decrease in CTCs captured by the CellCollector from 66% before RP to 34% after therapy (p = 0.031). CTC detection by EPISPOT before RP significantly correlated with PSA serum values (p < 0.0001) and clinical tumor stage (p = 0.04), while the other assays showed no significant correlations. In conclusion, CTC-based liquid biopsies have the potential to monitor MRD in patients with non-metastatic prostate cancer.

Tumor volume in insignificant prostate cancer: increasing threshold gains increasing risk.

An increased tumor volume threshold (<2.5 ml) is suggested to define insignificant prostate cancer (iPCa). We hypothesize that an increasing tumor volume within iPCa patients increases the risk of biochemical recurrence (BCR) after radical prostatectomy (RP).

Integrating Tertiary Gleason 5 Patterns into Quantitative Gleason Grading in Prostate Biopsies and Prostatectomy Specimens

BACKGROUND Presence of small (tertiary) Gleason 5 pattern is linked to a higher risk of biochemical recurrence in prostate cancer. It is unclear, however, how to integrate small Gleason 5 elements into clinically relevant Gleason grade groups. OBJECTIVE To analyze the prognostic impact of Gleason 5 patterns in prostate cancer and to develop a method for integrating tertiary Gleason 5 patterns into a quantitative Gleason grading system. DESIGN, SETTING, AND PARTICIPANTS Prostatectomy specimens from 13 261 consecutive patients and of 3295 matched preoperative biopsies were available. Percentages of Gleason 3, 4, and 5 had been recorded for each cancer. Outcome measurements and statistical analysis: RESULTS AND LIMITATIONS: Our data demonstrate that minimal Gleason 5 areas have strong prognostic impact in Gleason 7 carcinomas, while further expansion of the Gleason 5 pattern population has less impact. We thus defined an integrated quantitative Gleason score (IQ-Gleason) by adding a lump score of 10 to the percentage of unfavorable Gleason pattern (Gleason 4/5) if any Gleason 5 was present and by adding another 7.5 points in case of a Gleason 5 fraction >20%. There was a continuous increase of the risk of prostate-specific antigen recurrence with increasing IQ-Gleason. This was also true for subgroups with identical Cancer of the Prostate Risk Assessment Postsurgical scores (p<0.0001) or Gleason grade groups (p<0.0001). CONCLUSIONS The IQ-Gleason represents a simple and efficient approach for combining both quantitative Gleason grading and tertiary Gleason grades in one highly prognostic numerical variable. PATIENT SUMMARY Prostatectomy specimens (13 261) were analyzed to estimate the relevance of small Gleason 5 elements in prostate cancers. Even the smallest Gleason 5 areas markedly increased the risk of prostate-specific antigen recurrence after surgery. Larger fractions of Gleason 5 patterns had less further impact on prognosis. Based on this, a numerical Gleason score (integrated quantitative Gleason score) was defined by the percentages of Gleason 4 and 5 patterns, enabling a refined estimate of patient prognosis.

Prediction of Significant Prostate Cancer at Prostate Biopsy and Per Core Detection Rate of Targeted and Systematic Biopsies Using Real-Time Shear Wave Elastography

Introduction: Prostate cancer (PCa) detection is accompanied by overdiagnosis and mischaracterization of PCa. Therefore, new imaging modalities like shear wave elastography (SWE) are required. Aim: The aim of this study was to evaluate per-core detection rates (DRs) of targeted biopsies and systematic biopsies and to test if SWE findings can predict presence of clinically significant PCa (csPCa) at biopsy. Patients and Methods: Overall, 95 patients scheduled for prostate biopsy in our center underwent SWE. SWE findings were classified into suspicious or normal. Targeted biopsies were taken in up to 3 SWE-suspicious areas. csPCa was defined as the presence of Gleason pattern ≥4, level of prostate-specific antigen ≥10 ng/ml or >2 positive cores. Results: Overall DR for csPCa in our study cohort was 40%. Per-core DR for exclusively SWE-targeted cores versus systematic samples cores was 10.5 vs. 8.6% (p = 0.3). In the logistic regression models, individuals with suspicious SWE findings are at 6.4-fold higher risk of harboring csPCa (p = 0.03). Gain in predictive accuracy was 2.3% (0.82 vs. 0.84, p = 0.01). Conclusions: Presence of suspicious SWE findings is an independent predictor of csPCa. Therefore, SWE may be helpful in selecting patients for biopsy. Nonetheless, per-core DR for SWE-targeted cores was not statistically significant higher than DR of systematic sampled cores. Therefore, additional systematic biopsy is mandatory.