Effect of Extended Pelvic Lymph Node Dissection on Oncologic Outcomes in Patients with D'Amico Intermediate and High Risk Prostate Cancer Treated with Radical Prostatectomy: A Multi-Institutional Study.

PURPOSE: Pelvic lymph node dissection represents the gold standard of lymph node staging in patients with prostate cancer. We sought to assess the effect of extended pelvic lymph node dissection on oncologic outcomes in patients with characteristics of D'Amico intermediate or high risk prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS: In a multi-institutional database of 4 centers we identified 9,742 patients who underwent radical prostatectomy from 2000 to 2017 with or without pelvic lymph node dissection. Only patients with a greater than 5% probability of lymph node invasion according to the Briganti nomogram were included in study. We performed 2:1 propensity score matching to account for potential differences between the 2 cohorts. Cox regression models were used to test the effect of pelvic lymph node dissection on biochemical recurrence, metastasis and cancer specific mortality. RESULTS: Overall 707 patients (7.3%) did not undergo pelvic lymph node dissection, of whom 520 and 187 harbored D'Amico intermediate and high risk characteristics, respectively. A median of 14 lymph nodes (IQR 8-21) were removed in the pelvic lymph node dissection cohort and 1,714 of these cases (19.0%) harbored lymph node metastasis. After propensity score matching the biochemical recurrence-free, metastasis-free and cancer specific mortality-free survival rates were 60.4% vs 65.6% (p=0.07), 87.0% vs 90.0% (p=0.06) and 95.2% vs 96.4% (p=0.2) for pelvic lymph node dissection vs no pelvic lymph node dissection 120 months after radical prostatectomy. Multivariable Cox regression models adjusted for postoperative and preoperative tumor characteristics revealed that pelvic lymph node dissection performed at radical prostatectomy was no independent predictor of biochemical recurrence, metastasis or cancer specific mortality (all p ≥0.1). CONCLUSIONS: There was no significant difference in oncologic outcomes in patients with D'Amico high or intermediate risk prostate cancer in whom pelvic lymph node dissection was or was not performed at radical prostatectomy. The therapeutic value of pelvic lymph node dissection remains unclear.

Focal therapy in localised prostate cancer: Real-world urological perspective explored in a cross-sectional European survey.

INTRODUCTION: The urological community's opinion over focal therapy (FT) for prostate cancer (PCa) has never been assessed. Our aim was to investigate the current opinion on FT in the European urological community. METHODS: A 25-item questionnaire was devised according to the Cherries checklist and distributed through SurveyMonkey using a web link from November 2016 to October 2017. After a pilot validation (n = 40 urologists), the survey was sent through EAU and 9 other national European urological societies mailing list. Twitter was also used. RESULTS: We received 484 replies from 51 countries. Almost half (44.8%, n = 217) stated FT would represent a step forward, and 52.0% (n = 252) would suggest FT to a patient. Almost three-quarters (70.8%, n = 343) agreed FT will become a standard option after improvements in patient selection (n = 66) or when its effectiveness will be proven (n = 78), or both (n = 199). Most frequently used definition of FT was treatment of all significant (life-threatening) cancer foci whilst leaving untreated the rest of the gland (39.3%, n = 190). FT use was considered as an alternative to whole-gland treatments by 29.7% (n = 144), and to AS by 25.0% (n = 121). On multivariate analysis, FT availability and publications were associated with a positive opinion on FT. Conversely, attending International congresses, treating high PCa volumes and high percentages of high-risk PCa was associated with a negative opinion. CONCLUSIONS: FT is considered as an attractive option for PCa treatment by the European urological community sampled by our survey. FT availability positively influences these thoughts. The present survey suggests whilst some early adopters already embraced FT, the relative majority of the urological community is prone to embrace FT in the near future, once current areas of debate are solved.

How can we expand active surveillance criteria in patients with low- and intermediate-risk prostate cancer without increasing the risk of misclassification? Development of a novel risk calculator.

OBJECTIVE: To develop a novel tool to increase the number of patients with prostate cancer eligible for active surveillance (AS) without increasing the risk of unfavourable pathological features (i.e., misclassification) at radical prostatectomy (RP). PATIENTS AND METHODS: Overall, 16 049 patients with low- or intermediate-risk prostate cancer treated with RP were identified. Misclassification was defined as non-organ confined or grade group ≥3 disease at RP. The coefficients of a logistic regression model predicting misclassification were used to develop a risk score. We then performed a systematic analysis of different thresholds to discriminate between patients with or without unfavourable disease and we compared it to available AS criteria. RESULTS: Overall, 5289 (33.0%) patients had unfavourable disease. At multivariable analyses, PSA level, clinical stage, biopsy grade group, the number of positive cores, and PSA density were associated with the risk of unfavourable disease (all P < 0.001). The Prostate Cancer Research International: Active Surveillance (PRIAS) criteria were associated with a lower risk of misclassification (13%) compared to other criteria. Overall, 3303 (20.6%) patients were eligible according to the PRIAS protocol. The adoption of an 18% threshold according to the risk score increased the proportion of eligible patients from 20.6% to 29.4% without increasing the risk of misclassification as compared to the PRIAS criteria. CONCLUSIONS: The use of a novel risk score for AS selection would result in an absolute increase of 10% in the number of patients eligible for this approach without increasing the risk of misclassification.

Systematic ultrasound-guided saturation and template biopsy of the prostate: indications and advantages of extended sampling.

OBJECTIVES: Prostate biopsy (PB) is the gold standard for the diagnosis of prostate cancer (PCa). However, the optimal number of biopsy cores remains debatable. We sought to compare contemporary standard (10-12 cores) vs. saturation (=18 cores) schemes on initial as well as repeat PB. METHODS: A non-systematic review of the literature was performed from 2000 through 2013. Studies of highest evidence (randomized controlled trials, prospective non-randomized studies, and retrospective reports of high quality) comparing standard vs saturation schemes on initial and repeat PB were evaluated. Outcome measures were overall PCa detection rate, detection rate of insignificant PCa, and procedure-associated morbidity. RESULTS: On initial PB, there is growing evidence that a saturation scheme is associated with a higher PCa detection rate compared to a standard one in men with lower PSA levels (<10 ng/ml), larger prostates (>40 cc), or lower PSA density values (<0.25 ng/ml/cc). However, these cut-offs are not uniform and differ among studies. Detection rates of insignificant PCa do not differ in a significant fashion between standard and saturation biopsies. On repeat PB, PCa detection rate is likewise higher with saturation protocols. Estimates of insignificant PCa vary widely due to differing definitions of insignificant disease. However, the rates of insignificant PCa appear to be comparable for the schemes in patients with only one prior negative biopsy, while saturation biopsy seems to detect more cases of insignificant PCa compared to standard biopsy in men with two or more prior negative biopsies. Very extensive sampling is associated with a high rate of acute urinary retention, whereas other severe adverse events, such as sepsis, appear not to occur more frequently with saturation schemes. DISCUSSION: Current evidence suggests that saturation schemes are associated with a higher PCa detection rate compared to standard ones on initial PB in men with lower PSA levels or larger prostates, and on repeat PB. Since most data are derived from retrospective studies, other endpoints such as detection rate of insignificant disease - especially on repeat PB - show broad variations throughout the literature and must, thus, be interpreted with caution. Future prospective controlled trials should be conducted to compare extended templates with newer techniques, such as image-guided sampling, in order to optimize PCa diagnostic strategy.

Systematic ultrasound-guided saturation and template biopsy of the prostate: indications and advantages of extended sampling / Biopsia de próstata sistemática guiada por ecografía por saturación y utilizando plantilla: indicaciones y ventajas de la ampliación del número de muestras

OBJECTIVES: Prostate biopsy (PB) is the gold standard for the diagnosis of prostate cancer (PCa). However, the optimal number of biopsy cores remains debatable. We sought to compare contemporary standard (10-12 cores) vs. saturation (≥18 cores) schemes on initial as well as repeat PB. METHODS: A non-systematic review of the literature was performed from 2000 through 2013. Studies of highest evidence (randomized controlled trials, prospective non-randomized studies, and retrospective reports of high quality) comparing standard vs saturation schemes on initial and repeat PB were evaluated. Outcome measures were overall PCa detection rate, detection rate of insignificant PCa, and procedure-associated morbidity. RESULTS: On initial PB, there is growing evidence that a saturation scheme is associated with a higher PCa detection rate compared to a standard one in men with lower PSA levels (40 cc), or lower PSA density values lower PSA density values (<0.25 ng/ml/cc). However, these cutaffs are not uniform and differ among studies. Detection rates of insignificant PCa do not differ in a significant fashion between standard and saturation biopsies. On repeat PB, PCa detection rate is likewise higher with saturation protocols. Estimates of insignificant PCa vary widely due to differing definitions of insignificant disease. However, the rates of insignificant PCa appear to be comparable for the chemes in patients with only one prior negative biopsy, while saturation biopsy seems to detect more cases of insignificant PCa compared to standard biopsy in men with two or more prior negative biopsies. Very extensive sampling is associated with a high rate of acute urinary retention, whereas other severe adverse events, such as sepsis, appear not to occur more frequently with saturation schemes. DISCUSSION: Current evidence suggests that saturation schemes are associated with a higher PCas detection rate compared to standard ones oninitial PB inmen with lower PSA levels or larger prostates, and on repeat PB. Since most data are derived from retrospective studies, other endpoints such as detection rate of insignificant disease - especially on repeat PB - show broad variations throughout the literature and must, thus, be interpreted with caution. Future prospective controlled trials should be conducted to compare extended templates with newer techniques, such as image-guided sampling, in order to optimize PCa diagnostic strategy

OBJECTIVE: La biopsia de próstata (BP) es el patrón oro para el diagnóstico de cáncer de próstata (CaP). Sin embargo, el número óptimo de muestras de la biopsia continua en debate. Comparamos los esquemas de biopsia estándar contemporánea (10-12 muestras) y de saturación (≥18 muestras) tanto en biopsia inicial como en biopsias repetidas. MÉTODOS: Realizamos una revisión no sistemática de la literatura desde el año 2000 al 2013. Evaluamos los estudios comparativos entre el esquemas estándar y la saturación, tanto en BP iniciales como repetidas, con mayor evidencia (Ensayos clínicos aleatorizados, estudios prospectivos no aleatorizados y comunicaciones retrospectivas de alta calidad). Las medidas de resultados fueron tasa de detección global de CaP, detección de CaP insignificante y morbilidad asociada con el procedimiento. RESULTADOS: En biopsia inicial, hay un aumento de la evidencia de que el esquema de saturación se asocia con una tasa de detección de CaP mayor en comparación con el estándar en varones con valores de PSA menores(40 cc), o valores de densidad del PSA menores (<0.25 ng/ml/cc). Sin embargo, estos valores de corte no son uniformes y difieren entre los estudios. Las tasas de detección de CaP insignificante no difieren de manera significativa entre las biopsias estándar y de saturación. En BP repetidas, la tasa de detección de CaP es igualmente más alta con los protocolos de saturación. Las estimaciones de CaP insignificante varían ampliamente debido a diferentes definiciones de la enfermedad insignificante. Sin embargo, las tasas de CaP insignificante parecen ser comparables entre ambos esquemas en pacientes con sólo una biopsia previa negativa, mientras que la biopsia por saturación parece detectar más casos de CaP insignificante en comparación con la estándar en varones con dos o más biopsias previas negativas. Un número de muestras muy amplio se asocia con una tasa alta de retención urinaria aguda, mientras que otros eventos adversos graves, como sepsis, no parece que aparezcan más frecuentemente con los esquemas de saturación. DISCUSSION: La evidencia actual sugiere que los esquemas de saturación se asocian con mayores tasas de detección de CaP en comparación con los estándar en BP inicial en varones con niveles de PSA menores o próstatas más grandes, y en biopsias repetidas. Puesto que la mayorías de los datos provienen de estudios retrospectivos, otras variables de resultados como la tasa de detección de enfermedad insignificante- especialmente en BP repetidas- muestran amplias variaciones en la literatura y , por lo tanto deben ser interpretadas con precaución. Deberían llevarse a cabo futuros ensayos prospectivos controlados para comparar plantillas extendidas con nuevas técnicas, tales cómo toma de muestras guiada por la imagen, para optimizar la estrategia de diagnóstico del CaP

What is the optimal definition of misclassification in patients with very low-risk prostate cancer eligible for active surveillance? Results from a multi-institutional series.

BACKGROUND: The risk of unfavorable prostate cancer in active surveillance (AS) candidates is nonnegligible. However, what represents an adverse pathologic outcome in this setting is unknown. We aimed at assessing the optimal definition of misclassification and its effect on recurrence in AS candidates treated with radical prostatectomy (RP). MATERIALS AND METHODS: Overall, 1,710 patients eligible for AS according to Prostate Cancer Research International: Active Surveillance criteria treated with RP between 2000 and 2013 at 3 centers were evaluated. Patients were stratified according to pathology results at RP: organ-confined disease and pathologic Gleason score ≤ 6 (group 1); organ-confined disease and Gleason score 3+4 (group 2); and non-organ-confined disease, Gleason score ≥ 4+3, and nodal invasion (group 3). Biochemical recurrence (BCR) was defined as 2 consecutive prostate-specific antigen (PSA) ≥ 0.2 ng/ml. Kaplan-Meier curves assessed time to BCR. Multivariable Cox regression analyses tested the association between pathologic features and BCR. Multivariable logistic regression analyses identified the predictors of adverse pathologic characteristics. RESULTS: Overall, 926 (54.2%), 653 (33.0%), and 220 (12.9%) patients were categorized in groups 1, 2, and 3, respectively. Median follow-up was 32.2 months. The 5-year BCR-free survival rate was 94.2%. Patients in group 3 had lower BCR-free survival rates compared with those in group 1 (79.1% vs. 97.0%, P<0.001). No differences were observed between patients included in group 1 vs. group 2 (97.0% vs. 94.7%, P = 0.1). These results were confirmed at multivariable analyses and after stratification according to margin status. Older age and PSA density ≥ 10 ng/ml/ml were associated with higher risk of unfavorable pathologic characteristics (i.e., inclusion in group 3; all P<0.001). CONCLUSIONS: Among patients eligible for AS treated with RP, only men with Gleason score ≥ 4+3 or non-organ-confined disease at final pathology were at increased risk of BCR. These individuals represent the real misclassified AS patients, who can be predicted based on older age and higher PSA density.

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.

The oncologic role of local treatment in primary metastatic prostate cancer.

PURPOSE: To determine the oncologic benefit or otherwise of local treatment of the prostate in patients with primary metastatic prostate cancer. METHODS: A review of the literature was performed in April 2014 using the Medline/PubMed database. Studies were identified using the search terms "prostate cancer," "metastatic," "metastasis," "high risk," "radiation therapy," "radiotherapy" and "prostatectomy" from 1990 until April, 2014. Articles were also identified through searches of references of these articles. RESULTS: Retrospective series and population-based data suggest that the use of local treatment of the prostate in patients with primary metastatic prostate cancer may improve cancer-specific survival and overall survival compared with treating these patients with androgen deprivation therapy alone. The clinical outcome in metastatic prostate cancer is largely determined by the extent of lymph node involvement and overall metastatic burden. Contemporary data are lacking to recommend one alternative of local therapy (radiotherapy or radical prostatectomy) over the other. The primary limitation of this literature review is the lack of published randomized trial assessing the role of local treatment in addition to systemic therapy. CONCLUSIONS: Local treatment appears to improve oncologic outcomes in metastatic prostate cancer patients. Nevertheless, due to the lack of high-quality evidence, its role needs to be confirmed in future prospective trials. The selection of ideal candidates and optimal treatment alternative (radiotherapy, radical prostatectomy or other) warrants further investigation.