Improving the prediction of biochemical recurrence after radical prostatectomy with the addition of detailed pathology of the positive surgical margin and cribriform growth.

The risk on biochemical recurrence (BCR) after radical prostatectomy (RP) is usually estimated using PSA and pathological stage and grading including the presence of positive surgical margins (PSM). Objective was to investigate whether the presence of cribriform growth in the primary tumor, Grade Group (GG) at the PSM, and length of the PSM have added value in the prognostication. We analyzed data of 835 patients initially treated with RP between 2000 and 2017. Cox regression models were developed to compare the baseline model (PSA, pT-stage, pN-stage, GG at RP, and presence of PSM) with an extended model (adding the presence of cribriform growth, length and GG at the PSM) using the likelihood ratio test. Discrimination was assessed at internal validation by the time-dependent area under the receiver operating characteristic curve (AUC) at 3- and 5-year. A total of 224 men experienced BCR. Median follow-up for men without BCR was 50.4 months (interquartile range, IQR 11.9-95.5). The extended model had a significant better fit, χ2(4) = 31.0, p < 0.001 than the baseline model. The AUC of the 3- and 5-year extended model was 0.85 (95% CI 0.81-0.88) compared to 0.83 (95% CI 0.79-0.87) for the baseline model. Importantly, the presence of cribriform growth in the primary tumor, and GG ≥ 2 at PSM were associated with a higher risk on BCR. In conclusion, the addition of pathological variables improved the prediction of the risk on BCR after RP slightly. However, the clinical implications of this model are important.

Prostate Specific Membrane Antigen Positron Emission Tomography/Computerized Tomography in the Evaluation of Initial Response in Candidates Who Underwent Salvage Radiation Therapy after Radical Prostatectomy for Prostate Cancer.

PURPOSE: We assessed predictors of short-term oncologic outcomes of patients who underwent salvage radiation therapy for biochemical recurrence after robot-assisted laparoscopic radical prostatectomy without evidence of metastases on prostate specific membrane antigen positron emission tomography/computerized tomography. MATERIALS AND METHODS: We retrospectively analyzed 194 patients with biochemical recurrence after robot-assisted laparoscopic radical prostatectomy who underwent prostate specific membrane antigen positron emission tomography/computerized tomography prior to salvage radiation therapy. Patients with lymph node or distant metastases on restaging imaging or at the time of extended pelvic lymph node dissection during robot-assisted laparoscopic radical prostatectomy were excluded, as were patients who received androgen deprivation therapy during or prior to salvage radiation therapy. A multivariable logistic regression analysis was performed to assess predictors of treatment response, defined as prostate specific antigen value ≤0.1 ng/ml after salvage radiation therapy. RESULTS: Overall treatment response after salvage radiation therapy was 75% (146/194 patients). On multivariable analysis, prostate specific antigen value at initiation of salvage radiation therapy (OR 0.42, 95% CI 0.27-0.62, p <0.001), pathological T stage (pT3a vs pT2 OR 0.28, 95% CI 0.11-0.69, p=0.006; pT3b vs pT2 OR 0.26, 95% CI 0.09-0.71, p=0.009) and local recurrent disease on imaging (OR 5.53, 95% CI 1.96-18.52, p=0.003) were predictors of treatment response. CONCLUSIONS: Salvage radiation therapy in patients without evidence of metastases on prostate specific membrane antigen positron emission tomography/computerized tomography showed a good overall treatment response of 75%. Higher treatment response rates were observed in patients with lower prostate specific antigen values at initiation of salvage radiation therapy, those with local recurrent disease on imaging and those with lower pathological T stage (pT2 vs pT3a/b).

Optimal Timing of Prostate Specific Membrane Antigen Positron Emission Tomography/Computerized Tomography for Biochemical Recurrence after Radical Prostatectomy.

PURPOSE: We developed a model predicting the probability of detecting prostate cancer recurrence outside the prostatic fossa on prostate specific membrane antigen positron emission tomography/computerized tomography in patients with biochemical recurrence after radical prostatectomy. MATERIALS AND METHODS: We retrospectively included 419 consecutive patients with biochemical recurrence (prostate specific antigen less than 2.0 ng/ml) after radical prostatectomy who underwent 68Ga-prostate specific membrane antigen-11 positron emission tomography/computerized tomography to guide salvage therapy. Patients receiving androgen deprivation therapy between radical prostatectomy and prostate specific membrane antigen positron emission tomography/computerized tomography were excluded from the study. We used multivariable logistic regression to assess predictors for the detection of prostate cancer recurrence outside the prostatic fossa on prostate specific membrane antigen positron emission tomography/computerized tomography. We minimized overfitting of the model and used decision curve analysis to determine clinical utility. RESULTS: Median prostate specific antigen at scanning was 0.40 ng/ml (IQR 0.30-0.70). Overall 174 (42%) patients had prostate cancer recurrence outside the prostatic fossa. Prostate specific antigen at time of scanning, and grade group, N stage and surgical margin status at radical prostatectomy specimen were significant predictors for detecting prostate cancer recurrence outside the prostatic fossa. The bootstrapped AUC of this model was 0.75 (IQR 0.73-0.77). The decision curve analysis showed a net benefit by a model based probability from 16%. Limitations include the retrospective design and the missing histological correlation of positive lesions. CONCLUSIONS: Next to the prostate specific antigen at time of scanning, grade group, N stage and surgical margin status at radical prostatectomy specimen are significant predictors for detecting prostate cancer recurrence outside the prostatic fossa on prostate specific membrane antigen positron emission tomography/computerized tomography. The presented model is implemented in a dashboard to assist clinicians in determining the optimal time to perform 68Ga-prostate specific membrane antigen-11 positron emission tomography/computerized tomography in patients with biochemical recurrence after radical prostatectomy.

Use of gallium-68 prostate-specific membrane antigen positron-emission tomography for detecting lymph node metastases in primary and recurrent prostate cancer and location of recurrence after radical prostatectomy: an overview of the current literature.

OBJECTIVES: To review the literature to determine the sensitivity and specificity of gallium-68 prostate-specific membrane antigen (68 Ga-PSMA) positron-emission tomography (PET) for detecting pelvic lymph node metastases in patients with primary prostate cancer (PCa), and the positive predictive value in patients with biochemical recurrence (BCR) after initial curative treatment, and, in addition, to determine the detection rate and management impact of 68 Ga-PSMA PET in patients with BCR after radical prostatectomy (RP). MATERIALS AND METHODS: We performed a comprehensive literature search. Search terms used in MEDLINE, EMBASE and Science Direct were '(PSMA, 68 Ga-PSMA, 68 Gallium-PSMA, Ga-68-PSMA or prostate-specific membrane antigen)' and '(histology, lymph node, staging, sensitivity, specificity, positive predictive value, recurrence, recurrent or detection)'. Relevant abstracts were reviewed and full-text articles obtained where possible. References to and from obtained articles were searched to identify further relevant articles. RESULTS: Nine retrospective and two prospective studies described the sensitivity and specificity of 68 Ga-PSMA PET for detecting pelvic lymph node metastases before initial treatment, which ranged from 33.3% to 100% and 80% to 100%, respectively. In eight retrospective studies, the positive predictive value of 68 Ga-PSMA PET in patients with BCR before salvage lymph node dissection ranged from 70% to 100%. The detection rate of 68 Ga-PSMA PET in patients with BCR after RP in the PSA subgroups <0.2 ng/mL, 0.2-0.49 ng/mL and 0.5 to <1.0 ng/mL ranged from 11.3% to 50.0%, 20.0% to 72.7% and 25.0% to 87.5%, respectively. CONCLUSION: The review results showed that 68 Ga-PSMA PET had a high specificity for the detection of pelvic lymph node metastases in primary PCa. Furthermore, 68 Ga-PSMA PET had a very high positive predictive value in detecting lymph node metastases in patients with BCR. By contrast, sensitivity was only moderate; therefore, based on the currently available literature, 68 Ga-PSMA PET cannot yet replace pelvic lymph node dissection to exclude lymph node metastases. In the salvage phase, 68 Ga-PSMA PET had both a high detection rate and impact on radiotherapy planning in early BCR after RP.

Distribution of prostate cancer recurrences on gallium-68 prostate-specific membrane antigen (68 Ga-PSMA) positron-emission/computed tomography after radical prostatectomy with pathological node-positive extended lymph node dissection.

OBJECTIVES: To examine the anatomical distribution of prostate cancer (PCa) recurrence on gallium-68 prostate-specific membrane antigen (68 Ga-PSMA) positron-emission tomography (PET)/computed tomography (CT) in patients with biochemical recurrence (BCR) after undergoing radical prostatectomy (RP) with pathological lymph node metastasis (pN1) in their extended pelvic lymph node dissection (ePLND), and to compare the location of PCa recurrence with the location of the initial lymph node metastasis at ePLND. MATERIALS AND METHODS: We retrospectively reviewed 100 patients with BCR (PSA 0.05-5.00 ng/mL) after RP with pN1 ePLND who underwent 68 Ga-PSMA PET/CT to guide salvage therapy. Clinical and pathological features and anatomical locations of PCa recurrence on 68 Ga-PSMA PET/CT were obtained, and management impact was recorded. RESULTS: In all, 68 patients (68%) had a positive and 32 patients (32%) had a negative 68 Ga-PSMA PET/CT result. Of the 68 patients with a positive 68 Ga-PSMA PET/CT, 44 (65%) showed abnormal uptake only in the pelvic area, seven (10%) only outside the pelvic area, and 17 (25%) both within and outside the pelvic area. 68 Ga-PSMA PET/CT-positive pelvic lymph nodes were often (84%) detected on the same side as the lymph node metastasis diagnosed at ePLND. Based on the outcomes of the 68 Ga-PSMA PET/CT, change of management was noted in 68% of the patients. CONCLUSION: Recurrence of PCa on 68 Ga-PSMA PET/CT was limited to the pelvis in the majority of patients with BCR after RP with pN1 ePLND. Moreover, recurrence was often detected on the same side as the lymph node metastasis at ePLND. The results confirm the diagnostic value of 68 Ga-PSMA PET/CT in patients with BCR after RP with pN1 ePLND. Prospective studies are needed to support the long-term benefit of 68 Ga-PSMA PET/CT-dictated management changes.

Prostate cancer upgrading with serial prostate magnetic resonance imaging and repeat biopsy in men on active surveillance: are confirmatory biopsies still necessary?

OBJECTIVES: To investigate whether serial prostate magnetic resonance imaging (MRI) may guide the utility of repeat targeted (TBx) and systematic biopsy (SBx) when monitoring men with low-risk prostate cancer (PCa) at 1-year of active surveillance (AS). PATIENTS AND METHODS: We retrospectively included 111 consecutive men with low-risk (International Society of Urological Pathology [ISUP] Grade 1) PCa, who received protocolled repeat MRI with or without TBx and repeat SBx at 1-year of AS. TBx was performed in Prostate Imaging-Reporting and Data System (PI-RADS) score ≥3 lesions (MRI-positive men). Upgrading defined as ISUP Grade ≥2 PCa (I), Grade ≥2 with cribriform growth/intraductal carcinoma PCa (II), and Grade ≥3 PCa (III) was investigated. Upgrading detected by TBx only (not by SBx) and SBx only (not by TBx) was investigated in MRI-positive and -negative men, and related to radiological progression on MRI (Prostate Cancer Radiological Estimation of Change in Sequential Evaluation [PRECISE] score). RESULTS: Overall upgrading (I) was 32% (35/111). Upgrading in MRI-positive and -negative men was 48% (30/63) and 10% (5/48) (P < 0.001), respectively. In MRI-positive men, there was upgrading in 23% (seven of 30) by TBx only and in 33% (10/30) by SBx only. Radiological progression (PRECISE score 4-5) in MRI-positive men was seen in 27% (17/63). Upgrading (I) occurred in 41% (seven of 17) of these MRI-positive men, while this was 50% (23/46) in MRI-positive men without radiological progression (PRECISE score 1-3) (P = 0.534). Overall upgrading (II) was 15% (17/111). Upgrading in MRI-positive and -negative men was 22% (14/63) and 6% (three of 48) (P = 0.021), respectively. In MRI-positive men, there was upgrading in three of 14 by TBx only and in seven of 14 by SBx only. Overall upgrading (III) occurred in 5% (five of 111). Upgrading in MRI-positive and -negative men was 6% (four of 63) and 2% (one of 48) (P = 0.283), respectively. In MRI-positive men, there was upgrading in one of four by TBx only and in two of four by SBx only. CONCLUSION: Upgrading is significantly lower in MRI-negative compared to MRI-positive men with low-risk PCa at 1-year of AS. In serial MRI-negative men, the added value of repeat SBx at 1-year surveillance is limited and should be balanced individually against the harms. In serial MRI-positive men, the added value of repeat SBx is substantial. Based on this cohort, SBx is recommended to be performed in combination with TBx in all MRI-positive men at 1-year of AS, also when there is no radiological progression.

Three novel methods to measure the postoperative displacement of lower urinary tract structures following radical prostatectomy in a sample of Korean patients.

BACKGROUND: There is a change in the position of the remaining anatomical structures of the lower urinary tract system following radical prostatectomy. The aims of this investigation were to describe three novel methods used to measure the displacement of i) the vesico-urethral junction (VUJ), proximal membranous urethra (PMU) and anorectal junction (ARJ) and ii) the VUJ angle of displacement in men following radical prostatectomy and determine their intra- and interrater reliability. METHODS: Retrospective comparative measurement of twenty pre- and postoperative MRI scans was undertaken by one observer on two separate occasions and on one occasion by another observer. Three standardized midsagittal pelvimetry reference lines were used to describe three X, Y axis measurement systems. The displacement (mm) of the VUJ, PMU and ARJ, and the angle of displacement (degrees) of the VUJ was measured for each of the three methods. Interrater reliability of VUJ, PMU and ARJ displacement and the VUJ angle of displacement measurements was assessed using a two-way mixed-effects agreement intra-class correlation coefficient (ICC) with 95% confidence intervals (CI). Test-retest (intrarater) reliability was calculated using a two-way random effects consistency ICC with 95% CI for all displacement measures of the VUJ, PMU and ARJ for one observer between two days. RESULTS: The pubococcygeal line (PCL) axis measurement system demonstrated good to excellent intrarater and interrater reliability (ICC 95% interval lower bound > 0.75) for the VUJ and PMU displacement and the VUJ angle of displacement measurements. Other measurement systems were less reliable and more variable. CONCLUSIONS: In this sample of 20 Korean patients with median prostate volume 27.5 mL and maximum volume 70 mL, the measurement methodology using the PCL consistently demonstrated good to excellent reliability and the lowest variability for the measurement of the displacement of the VUJ and PMU and the VUJ angle of displacement. The PCL methodology is recommended as the method of choice. Further studies should validate these results in patients with large prostate volumes.

Active Surveillance for Prostate Cancer: Past, Current, and Future Trends.

In response to the rising incidence of indolent, low-risk prostate cancer (PCa) due to increased prostate-specific antigen (PSA) screening in the 1990s, active surveillance (AS) emerged as a treatment modality to combat overtreatment by delaying or avoiding unnecessary definitive treatment and its associated morbidity. AS consists of regular monitoring of PSA levels, digital rectal exams, medical imaging, and prostate biopsies, so that definitive treatment is only offered when deemed necessary. This paper provides a narrative review of the evolution of AS since its inception and an overview of its current landscape and challenges. Although AS was initially only performed in a study setting, numerous studies have provided evidence for the safety and efficacy of AS which has led guidelines to recommend it as a treatment option for patients with low-risk PCa. For intermediate-risk disease, AS appears to be a viable option for those with favourable clinical characteristics. Over the years, the inclusion criteria, follow-up schedule and triggers for definitive treatment have evolved based on the results of various large AS cohorts. Given the burdensome nature of repeat biopsies, risk-based dynamic monitoring may further reduce overtreatment by avoiding repeat biopsies in selected patients.

Predictive Value of Cribriform and Intraductal Carcinoma for the Nomogram-based Selection of Prostate Cancer Patients for Pelvic Lymph Node Dissection.

OBJECTIVE: To assess the predictive value of biopsy-identified cribriform carcinoma and/or intraductal carcinoma (CR/IDC) within the Briganti and MSKCC nomograms predicting lymph node metastasis (LNM) in patients with primary prostate cancer (PCa). METHODS: We retrospectively included 393 PCa patients who underwent radical prostatectomy with extended pelvic lymph node dissection at 3 tertiary referral centers. We externally validated 2 prediction tools: the Briganti 2012 nomogram and the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram. Both nomograms were augmented with CR/IDC. The original model was compared with the CR/IDC-updated model using the likelihood ratio test. The performance of the prediction tools was assessed using calibration, discrimination, and clinical utility. RESULTS: Overall, 109 (28%) men were diagnosed with LNM. Calibration plots of the Briganti and MSKCC nomograms demonstrated an underestimation of the LNM risk across clinically relevant thresholds (≤15%). The addition of CR/IDC to the Briganti nomogram increased the fit of the data (χ2(1) = 4.30, P = .04), but did not improve the area under the curve (AUC) (0.69, 95% CI 0.63-0.75 vs 0.69, 95% CI 0.64-0.75). Incorporation of CR/IDC in the MSKCC nomogram resulted in an increased fit on the data (χ2(1) = 10.04, P <.01), but did not increase the AUC (0.66, 95% CI 0.60-0.72 vs 0.68, 95% CI 0.62-0.74). The addition of CR/IDC to the Briganti and MSKCC nomograms did not improve the clinical risk prediction. CONCLUSION: Incorporation of CR/IDC into the 2 clinically most used pre-radical prostatectomy nomograms does not improve LNM prediction in a multinational, contemporary PCa cohort.

External Validation of Two Nomograms Developed for 68Ga-PSMA-11 Applied to the Prostate-specific Membrane Antigen Tracer 18F-DCFPyl: Is Prediction of the Optimal Timing of Salvage Therapy Feasible?

Two nomograms have been developed to predict the outcome of positron emission tomography (PET)/computed tomography (CT) imaging with68Ga-labeled ligands for prostate-specific membrane antigen (68Ga-PSMA) for patients with rising prostate-specific antigen after radical prostatectomy (RP). These nomograms quantify the ability of PSMA PET/CT to detect prostate cancer recurrences, and therefore provide critical information in determining the optimal timing for PSMA PET/CT in guiding salvage therapies. We validated the ability of these nomograms to accurately predict PET/CT outcome using another ligand tracer, 18F-DCFPyL. The external validation cohort consisted of 157 men from the Prostate Cancer Network Netherlands who underwent 18F-DCFPyL PET/CT to guide salvage therapies after RP. The nomogram of Rauscher et al (predicting a positive scan) showed accurate prediction of 50-80% (discrimination 0.68, 95% confidence interval [CI] 0.59-0.76). The nomogram of Luiting et al (predicting recurrence outside the prostatic fossa) showed accurate prediction for predicted probability values between 15% and 65%, with a small degree of overestimation for predicted probability values between 30% and 50% (discrimination 0.74, 95% CI 0.28-1.24). According to calibration curves, discrimination results, and decision curve analysis, we conclude that clinicians can use these 68Ga-PSMA-based nomograms to predict 18F-DCFPyL PET/CT outcome. These nomograms improve shared decision-making in determining the optimal time to initiate PSMA PET/CT-guided salvage therapies. PATIENT SUMMARY: Prediction tools developed for prostate scans (positron emission tomography, PET) using one type of radioactive tracer (chemicals labeled with gallium-68) are also accurate in predicting scan findings with another tracer (a chemical labeled with fluorine-18). Our study confirms that these tools can be used to guide decisions on the timing of treatments for prostate cancer recurrence.

False positives in PIRADS (V2) 3, 4, and 5 lesions: relationship with reader experience and zonal location.

PURPOSE: To investigate the effect of reader experience and zonal location on the occurrence of false positives (FPs) in PIRADS (V2) 3, 4, and 5 lesions on multiparametric (MP)-MRI of the prostate. MATERIALS AND METHODS: This retrospective study included 139 patients who had consecutively undergone an MP-MRI of the prostate in combination with a transrectal ultrasound MRI fusion-guided biopsy between 2014 and 2017. MRI exams were prospectively read by a group of inexperienced radiologists (cohort 1; 54 patients) and an experienced radiologist (cohort 2; 85 patients). Multivariable logistic regression analysis was performed to determine the association of experience of the radiologist and zonal location with a FP reading. FP rates were compared between readings by inexperienced and experienced radiologists according to zonal location, using Chi-square (χ2) tests. RESULTS: A total of 168 lesions in 139 patients were detected. Median patient age was 68 years (Interquartile range (IQR) 62.5-73), and median PSA was 10.9 ng/mL (IQR 7.6-15.9) for the entire patient cohort. According to multivariable logistic regression, inexperience of the radiologist was significantly (P = 0.044, odds ratio 1.927, 95% confidence interval [CI] 1.017-3.651) and independently associated with a FP reading, while zonal location was not (P = 0.202, odds ratio 1.444, 95% CI 0.820-2.539). In the transition zone (TZ), the FP rate of the inexperienced radiologists 59% (17/29) was significantly higher (χ2P = 0.033) than that of the experienced radiologist 33% (13/40). CONCLUSION: Inexperience of the radiologist is significantly and independently associated with a FP reading, while zonal location is not. Inexperienced radiologists have a significantly higher FP rate in the TZ.

The measurement of membranous urethral length using transperineal ultrasound prior to radical prostatectomy.

OBJECTIVE: To compare preoperative membranous urethral length (MUL) measurements using magnetic resonance imaging (MRI) with two-dimensional transperineal ultrasound imaging (TPUS) in two supine positions on two separate days in men prior to radical prostatectomy. MATERIALS AND METHODS: MUL was prospectively measured in 18 male volunteers using MRI and on two separate occasions in two different patient positions using TPUS; the patient supine with the knees extended (Supine) and supine with the knees flexed to 70 degrees (Supine KF). Agreement between TPUS and MRI measurements of MUL was assessed using Bland-Altman method comparison techniques and a two-way mixed-effects single measures intraclass correlation (ICC). Test-retest reliability was assessed using a two-way random effects single measures ICC. RESULTS: The mean difference in MUL measurements between MRI and i) TPUS Supine was -0.8 mm (95% limits of agreement (LOA): -3.2, 1.7) and ii) TPUS Supine KF was -0.8mm (95% LOA: -3.5, 1.9). ICC indicated a point estimate of excellent agreement between MRI and TPUS Supine ICC 0.93 (95% CI: 0.76, 0.98) and TPUS Supine KF ICC 0.91 (95%CI 0.79, 0.97). There was excellent agreement between TPUS Supine and TPUS Supine KF (ICC 0.98, 95% CI: 0.96, 0.99) with a mean difference of 0.3mm (95% LOA: -1.2 to 1.3mm). CONCLUSIONS: Preoperative MUL can be reliably measured using TPUS and demonstrates excellent agreement with MRI measurements of MUL. TPUS provides clinicians with an accessible non-invasive alternative to MRI for the measurement of MUL that can be used in outpatient urological settings and for patients where MRI is contraindicated.