Centralized prostatectomy with intraoperative NeuroSAFE margin assessment improves surgical margin control.

AIMS: To investigate the surgical margin status in patients with prostate cancer who underwent robot-assisted radical prostatectomy (RARP) with intraoperative neurovascular structure-adjacent frozen-section analysis (NeuroSAFE) and evaluate differences compared to patients who underwent radical prostatectomy without NeuroSAFE. PATIENTS AND METHODS: Between September 2018 and January 2021, 962 patients underwent centralized RARP with NeuroSAFE. A secondary resection was performed in case of a positive surgical margin (PSM) on intraoperative frozen section (IFS) analysis to convert a PSM into a negative surgical margin (NSM). A retrospective cohort consisted of 835 patients who had undergone radical prostatectomy in a tertiary centre without NeuroSAFE between January 2000 and December 2017. We performed multivariable logistic regression to evaluate differences in risk of PSM between cohorts after controlling for clinicopathological variables. RESULTS: Patients operated with NeuroSAFE in the centralized clinic had 29% PSM at a definitive pathological RP examination. The median cumulative length of definitive PSM was 1.1 mm (interquartile range: 0.4-3.8). Among 275 men with PSM, 136 (49%) had a cumulative length ≤1 mm and 198 (72%) ≤3 mm. After controlling for PSA, Grade group, cribriform pattern, pT-stage, and pN-stage, patients treated in the centralized clinic with NeuroSAFE had significantly lower odds on PSM (odds ratio [OR]: 0.70, 95% confidence interval [CI]: 0.56-0.88; P = 0.002), PSM length >1 mm (OR: 0.14, 95% CI: 0.09-0.22; P < 0.001), and >3 mm (OR: 0.21, 95% CI: 0.14-0.30; P < 0.001). CONCLUSION: This study provides a detailed overview of surgical margin status in a centralized RP NeuroSAFE cohort. Centralization with NeuroSAFE was associated with lower PSM rates and significantly shorter PSM cumulative lengths, indicating improved control of surgical margin status.

Biopsy prostate cancer perineural invasion and tumour load are associated with positive posterolateral margins at radical prostatectomy: implications for planning of nerve-sparing surgery.

AIMS: Radical prostatectomy (RP) for prostate cancer is frequently complicated by erectile dysfunction and urinary incontinence. However, sparing of the nerve bundles adjacent to the posterolateral sides of the prostate reduces the number of complications at the risk of positive surgical margins. Preoperative selection of men eligible for safe, nerve-sparing surgery is therefore needed. Our aim was to identify pathological factors associated with positive posterolateral surgical margins in men undergoing bilateral nerve-sparing RP. METHODS AND RESULTS: Prostate cancer patients undergoing RP with standardised intra-operative surgical margin assessment according to the NeuroSAFE technique were included. Preoperative biopsies were reviewed for grade group (GG), cribriform and/or intraductal carcinoma (CR/IDC), perineural invasion (PNI), cumulative tumour length and extraprostatic extension (EPE). Of 624 included patients, 573 (91.8%) received NeuroSAFE bilaterally and 51 (8.2%) unilaterally, resulting in a total of 1197 intraoperative posterolateral surgical margin assessments. Side-specific biopsy findings were correlated to ipsilateral NeuroSAFE outcome. Higher biopsy GG, CR/IDC, PNI, EPE, number of positive biopsies and cumulative tumour length were all associated with positive posterolateral margins. In multivariable bivariate logistic regression, ipsilateral PNI [odds ratio (OR) = 2.98, 95% confidence interval (CI) = 1.62-5.48; P < 0.001] and percentage of positive cores (OR = 1.18, 95% CI = 1.08-1.29; P < 0.001) were significant predictors for a positive posterolateral margin, while GG and CR/IDC were not. CONCLUSIONS: Ipsilateral PNI and percentage of positive cores were significant predictors for a positive posterolateral surgical margin at RP. Biopsy PNI and tumour volume can therefore support clinical decision-making on the level of nerve-sparing surgery in prostate cancer patients.

NeuroSAFE in radical prostatectomy increases the rate of nerve-sparing surgery without affecting oncological outcome.

OBJECTIVES: To investigate the impact of intra-operative neurovascular structure-adjacent frozen-section examination (NeuroSAFE) on the rate of nerve-sparing surgery (NSS) and oncological outcome in a large radical prostatectomy (RP) cohort. PATIENTS AND METHODS: Between January 2016 and December 2020, 1756 prostate cancer patients underwent robot-assisted RP, of whom 959 (55%) underwent this with NeuroSAFE and 797 (45%) without (control cohort). In cases where NeuroSAFE showed tumour in the margin, a secondary resection was performed. The effect of NeuroSAFE on NSS and positive surgical margin (PSM) status was analysed using logistic regression. Cox regression was used to identify predictors of biochemical recurrence-free survival (BCRFS). RESULTS AND LIMITATIONS: Patients in the NeuroSAFE cohort had a higher tumour grade (P < 0.001) and clinical stage (P < 0.001) than those in the control cohort. NeuroSAFE enabled more frequent NSS for both pT2 (93% vs 76%; P < 0.001) and pT3 disease (83% vs 55%; P < 0.001). In adjusted analysis, NeuroSAFE resulted in more frequent unilateral (odds ratio [OR] 3.90, 95% confidence interval (CI) 2.90-5.30; P < 0.001) and bilateral (OR 5.22, 95% CI 3.90-6.98; P < 0.001) NSS. While the PSM rate decreased from 51% to 42% in patients with pT3 stage disease (P = 0.031), NeuroSAFE was not an independent predictor of PSM status (OR 0.85, 95% CI 0.68-1.06; P = 0.2) in the entire cohort. Patients who underwent NeuroSAFE had better BCRFS compared to the control cohort (hazard ratio 0.62, 95% CI 0.45-0.84; P = 0.002). This study is limited by its comparison with a historical cohort and lack of functional outcomes. CONCLUSIONS: NeuroSAFE enables more unilateral and bilateral NSS without negatively affecting surgical margin status and biochemical recurrence. This validation study provides a comprehensive overview of the implementation, evaluation and intra-operative decision making associated with NeuroSAFE in clinical practice.

Percentage Gleason pattern 4 and PI-RADS score predict upgrading in biopsy Grade Group 2 prostate cancer patients without cribriform pattern.

PURPOSE: To identify parameters to predict upgrading in biopsy Grade Group (GG) 2 prostate cancer patients without cribriform and intraductal carcinoma (CR/IDC) on biopsy. METHODS: Preoperative biopsies from 657 men undergoing radical prostatectomy (RP) for prostate cancer were reviewed for GG, presence of CR/IDC, percentage Gleason pattern 4, and tumor length. In men with biopsy GG2 without CR/IDC (n = 196), clinicopathologic features were compared between those with GG1 or GG2 without CR/IDC on RP (GG ≤ 2-) and those with GG2 with CR/IDC or any GG > 2 (GG ≥ 2+). Logistic regression analysis was used to predict upgrading in the biopsy cohort. RESULTS: In total 283 men had biopsy GG2 of whom 87 (30.7%) had CR/IDC and 196 (69.3%) did not. CR/IDC status in matched biopsy and RP specimens was concordant in 179 (63.3%) and discordant in 79 (27.9%) cases (sensitivity 45.1%; specificity 92.6%). Of 196 biopsy GG2 men without CR/IDC, 106 (54.1%) had GG ≥ 2+ on RP. Multivariable logistic regression analysis showed that age [odds ratio (OR): 1.85, 95% confidence interval (CI)1.09-3.20; p = 0.025], percentage Gleason pattern 4 (OR 1.54, 95% CI 1.17-2.07; p = 0.003), PI-RADS 5 lesion (OR 2.17, 95% CI 1.03-4.70; p = 0.045) and clinical stage T3 (OR 3.60; 95% CI 1.08-14.50; p = 0.049) were independent parameters to predict upgrading to GG ≥ 2+ on RP in these men. CONCLUSIONS: Age, clinical stage T3, percentage Gleason pattern 4 and presence of PI-RADS 5 lesions are independent predictors for upgrading in men with biopsy GG2 without CR/IDC. These findings allow for improved clinical decision-making on surveillance eligibility in intermediate-risk prostate cancer patients.

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.

Intraoperative assessment and reporting of radical prostatectomy specimens to guide nerve-sparing surgery in prostate cancer patients (NeuroSAFE).

AIMS: Radical prostatectomy for prostate cancer is frequently complicated by urinary incontinence and erectile dysfunction. Nerve-sparing surgery reduces the risk of postoperative complications and can be optimised by the use of intraoperative frozen sections of the adjacent neurovascular structure (NeuroSAFE). The aims of this study were to evaluate the pathological outcomes of the NeuroSAFE technique and to develop a comprehensive algorithm for intraoperative clinical decision-making. METHODS AND RESULTS: Between September 2018 and May 2019, 491 NeuroSAFE procedures were performed in 258 patients undergoing radical prostatectomy; 74 of 491 (15.1%) NeuroSAFE specimens had positive surgical margins. As compared with the corresponding paraffin sections, NeuroSAFE had a positive predictive value and negative predictive value of 85.1% and 95.4%, respectively. In 72.2% of secondary neurovascular bundle resections prompted by a NeuroSAFE positive surgical margin, no tumour was present. These cases more often had a positive surgical margin of ≤1 mm (48.7% versus 20.0%; P = 0.001) and only one positive slide (69.2% versus 33.3%; P = 0.008). None of the nine patients with Gleason pattern 3 at the surgical margin, a positive surgical margin length of ≤1 mm and one positive slide had tumour in the secondary resection. CONCLUSIONS: This study provides a systematic reporting template for pathological intraoperative NeuroSAFE evaluation, supporting intraoperative clinical decision-making and comparison between prostate cancer operation centres.

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.

Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics.

Oncological applications of Raman spectroscopy have been contemplated, pursued, and developed at academic level for at least 25 years. Published studies aim to detect pre-malignant lesions, detect cancer in less invasive stages, reduce the number of unnecessary biopsies and guide surgery towards the complete removal of the tumour with adequate tumour resection margins. This review summarizes actual clinical needs in oncology that can be addressed by spontaneous Raman spectroscopy and it provides an overview over the results that have been published between 2007 and 2017. An analysis is made of the current status of translation of these results into clinical practice. Despite many promising results, most of the applications addressed in scientific studies are still far from clinical adoption and commercialization. The main hurdles are identified, which need to be overcome to ensure that in the near future we will see the first Raman spectroscopy-based solutions being used in routine oncologic diagnostic and surgical procedures.

Lymphoceles after pelvic lymph node dissection during robot-assisted radical prostatectomy.

Background: Lymphoceles, lymph fluid-filled collections within the body lacking epithelial lining, are a common complication after pelvic lymph node dissection (PLND) during robot-assisted radical prostatectomy (RARP). In this study, we investigate the incidence of imaging confirmed symptomatic lymphoceles (SLC) in a centralized high-volume operating centre and assess predictive factors and treatment. Methods: We retrospectively analysed the incidence, risk factors and treatment of a consecutive series of patients who underwent PLND during RARP between September 2018 and January 2021 in a specialised operation clinic. We compared baseline patients' characteristics and pathological data between men who developed an SLC and those who did not. A multivariable model for the occurrence of an SLC was created using predetermined, clinically relevant variables to investigate predictive factors. Results: We analysed the records of 404 patients. The median follow-up length was 29 months. A total of 30 (7.4%) patients with an SLC were identified. The median time until SLC presentation was 12 weeks [interquartile range (IQR), 4-31 weeks], one-third of SLCs presented after 180 days. Percutaneous drainage was performed in 17 patients (57%). On multivariable analysis, only body mass index (BMI) significantly increased the odds of an SLC [per 5 odds ratio (OR) =1.7; 95% confidence interval (CI): 1.0-3.0, P=0.04]. Conclusions: SLCs present significant consequences, as more than half of patients with an SLC were treated with percutaneous drainage. Many patients presented later than the centralized surgeons' postoperative follow-up, a drawback of centralized care. An increased BMI was a significant predictor for SLC.

Urinary Incontinence and Sexual Function After the Introduction of NeuroSAFE in Radical Prostatectomy for Prostate Cancer.

BACKGROUND: Nerve-sparing (NS) radical prostatectomy (RP) results in better functional outcomes. Intraoperative neurovascular structure-adjacent frozen section examination (NeuroSAFE) significantly increases the frequency of NS surgery. The effect of NeuroSAFE on postoperative erectile function (EF) and continence is not yet clear. OBJECTIVE: To describe EF and continence outcomes for men undergoing RP with the NeuroSAFE technique. DESIGN, SETTING, AND PARTICIPANTS: Between September 2018 and February 2021, 1034 men underwent robot-assisted RP. Data for patient-reported outcomes were collected via validated questionnaires. INTERVENTION: NeuroSAFE technique for RP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Continence was assessed using the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) or Expanded Prostate Cancer Index Composite short form (EPIC-26) and defined as use of 0-1 pads/d. EF was evaluated using EPIC-26 or the International Index of Erectile Function short form (IIEF-5), with data converted according to the Vertosick method and categorized. Descriptive statistics were used to asses and describe tumor characteristics and continence and EF outcomes. RESULTS AND LIMITATIONS: Of the 1034 men who underwent RP after introduction of the NeuroSAFE technique, 63% and 60% completed a preoperative and at least one postoperative questionnaire on continence and EF, respectively. Of the men who underwent unilateral or bilateral NS surgery, use of 0-1 pads/d was reported by 93% after 1 yr and 96% after 2 yr; the corresponding rates for men who underwent non-NS surgery were 86% and 78%. Overall, use of 0-1 pads/d was reported by 92% of the men at 1 yr and by 94% at 2 yr after RP. Men in the NS group had a good or intermediate Vertosick score after RP more often than the non-NS group. Overall, 44% of the men had a good or intermediate Vertosick score at 1 and 2 yr after RP. CONCLUSIONS: After introduction of the NeuroSAFE technique, the continence rate was 92% at 1 yr and 94% at 2 yr after RP. The NS group had a greater percentage of men with an intermediate or good Vertosick score and a higher continence rate after RP in comparison to the non-NS group. PATIENT SUMMARY: Our study shows that after introduction of the NeuroSAFE technique during removal of the prostate, the continence rate among patients was 92% at 1 year and 94% at 2 years after surgery. Some 44% of the men had a good or intermediate score for erectile function 1 and 2 years after surgery.

Does Centralization of Radical Prostatectomy Reduce the Incidence of Postoperative Urinary Incontinence?

Background: On the basis of previous analyses of the incidence of urinary incontinence (UI) after radical prostatectomy (RP), the hospital RP volume threshold in the Netherlands was gradually increased from 20 per year in 2017, to 50 in 2018 and 100 from 2019 onwards. Objective: To evaluate the impact of hospital RP volumes on the incidence and risk of UI after RP (RP-UI). Design setting and participants: Patients who underwent RP during 2016-2020 were identified in the claims database of the largest health insurance company in the Netherlands. Incontinence was defined as an insurance claim for ≥1 pads/d. Outcome measurements and statistical analysis: The relationship between hospital RP volume (HV) and RP-UI was assessed via multivariable analysis adjusted for age, comorbidity, postoperative radiotherapy, and lymph node dissection. Results and limitations: RP-UI incidence nationwide and by RP volume category did not decrease significantly during the study period, and 5-yr RP-UI rates varied greatly among hospitals (19-85%). However, low-volume hospitals (≤120 RPs/yr) had a higher percentage of patients with RP-UI and higher variation in comparison to high-volume hospitals (>120 RPs/yr). In comparison to hospitals with low RP volumes throughout the study period, the risk of RP-UI was 29% lower in hospitals shifting from the low-volume to the high-volume category (>120 RPs/yr) and 52% lower in hospitals with a high RP volume throughout the study period (>120 RPs/yr for 5 yr). Conclusions: A focus on increasing hospital RP volumes alone does not seem to be sufficient to reduce the incidence of RP-UI, at least in the short term. Measurement of outcomes, preferably per surgeon, and the introduction of quality assurance programs are recommended. Patient summary: In the Netherlands, centralization of surgery to remove the prostate (RP) because of cancer has not yet improved the occurrence of urinary incontinence (UI) after surgery. Hospitals performing more than 120 RP operations per year had better UI outcomes. However, there was a big difference in UI outcomes between hospitals.

Detailed Evaluation of Androgen Deprivation Overtreatment in Prostate Cancer Patients Compared to the European Association of Urology Guidelines Using Long-term Data from the European Randomised Study of Screening for Prostate Cancer Rotterdam.

Background: Guidelines on androgen deprivation therapy (ADT) for prostate cancer (PCa) arise from a critical appraisal of scientific evidence, which is a costly effort. Despite these efforts and the side effects of ADT, guidelines may not always be adhered to. Objective: To determine ADT overtreatment in PCa patients compared to the European Association of Urology (EAU) guidelines, and to identify predictors and physicians' motivations for this overtreatment. Design setting and participants: Men were included from the European Randomised study of Screening for Prostate Cancer (ERSPC) Rotterdam who were diagnosed with PCa between 2001 and 2019, and received ADT <1 yr after diagnosis. Outcome measurements and statistical analysis: Patients were categorised into the concordant ADT or discordant ADT group following the EAU guidelines. Physicians' motivations for discordancy were reported. Multivariable logistic regression was performed to identify predictors for guideline-discordant ADT including the nonlinear fit of the year of diagnosis. Results and limitations: Of 3608 PCa patients, 1037 received ADT <1 yr after diagnosis. Adherence improved gradually over the study period, resulting in overall discordancy of 15%. A patient diagnosed in 2011 had 3.3 times lower risk on guideline-discordant ADT than a patient diagnosed in 2004 (odds ratio [OR] 0.30; 95% confidence interval [CI] 0.18-0.50). The most common reason for discordancy was unwillingness or unfitness for curative treatment of asymptomatic patients. Age (OR 1.19; 95% CI 1.15-1.24) and Gleason score ≥4 + 3 (OR 1.70; 95% CI 1.06-2.74) were associated with guideline-discordant ADT. Conclusions: In a Dutch cohort, slow adaptation of the EAU guidelines on ADT for PCa patients between 2001 and 2019 resulted in overall overtreatment of 15%, mostly in asymptomatic patients who were unfit or unwilling for curative treatment. Clear, structured presentation, or integration of these tailored guidelines into the electronic health record might accelerate the adaptation of future guidelines. Patient summary: Slow adaptation of the guidelines on hormonal therapy resulted in overtreatment in 15% of prostate cancer patients, mostly in asymptomatic patients who were unfit or unwilling for curative treatment.

A Prospective Multicenter Comparison Study of Risk-adapted Ultrasound-directed and Magnetic Resonance Imaging-directed Diagnostic Pathways for Suspected Prostate Cancer in Biopsy-naïve Men.

BACKGROUND: European Association of Urology guidelines recommend a risk-adjusted biopsy strategy for early detection of prostate cancer in biopsy-naïve men. It remains unclear which strategy is most effective. Therefore, we evaluated two risk assessment pathways commonly used in clinical practice. OBJECTIVE: To compare the diagnostic performance of a risk-based ultrasound (US)-directed pathway (Rotterdam Prostate Cancer Risk Calculator [RPCRC] #3; US volume assessment) and a magnetic resonance imaging (MRI)-directed pathway. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective multicenter study (MR-PROPER) with 1:1 allocation among 21 centers (US arm in 11 centers, MRI arm in ten). Biopsy-naïve men with suspicion of prostate cancer (age ≥50 yr, prostate-specific antigen 3.0-50 ng/ml, ± abnormal digital rectal examination) were included. INTERVENTION: Biopsy-naïve men with elevated risk of prostate cancer, determined using RPCRC#3 in the US arm and Prostate Imaging Reporting and Data System scores of 3-5 in the MRI arm, underwent systematic biopsies (US arm) or targeted biopsies (MRI arm). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the proportion of men with grade group (GG) ≥2 cancer. Secondary outcomes were the proportions of biopsies avoided and GG 1 cancers detected. Categorical (nonparametric) data were assessed using the Mann-Whitney U test and χ2 tests. RESULTS AND LIMITATIONS: A total of 1965 men were included in the intention-to-treat population (US arm n = 950, MRI arm n = 1015). The US and MRI pathways detected GG ≥2 cancers equally well (235/950, 25% vs 239/1015, 24%; difference 1.2%, 95% confidence interval [CI] -2.6% to 5.0%; p = 0.5). The US pathway detected more GG 1 cancers than the MRI pathway (121/950, 13% vs 84/1015, 8.3%; difference 4.5%, 95% CI 1.8-7.2%; p < 0.01). The US pathway avoided fewer biopsies than the MRI pathway (403/950, 42% vs 559/1015, 55%; difference -13%, 95% CI -17% to -8.3%; p < 0.01). Among men with elevated risk, more GG ≥2 cancers were detected in the MRI group than in the US group (52% vs 43%; difference 9.2%, 95% CI 3.0-15%; p < 0.01). CONCLUSIONS: Risk-adapted US-directed and MRI-directed pathways detected GG ≥2 cancers equally well. The risk-adapted US-directed pathway performs well for prostate cancer diagnosis if prostate MRI capacity and expertise are not available. If prostate MRI availability is sufficient, risk assessment should preferably be performed using MRI, as this avoids more biopsies and detects fewer cases of GG 1 cancer. PATIENT SUMMARY: Among men with suspected prostate cancer, relevant cancers were equally well detected by risk-based pathways using either ultrasound or magnetic resonance imaging (MRI) to guide biopsy of the prostate. If prostate MRI availability is sufficient, risk assessment should be performed with MRI to reduce unnecessary biopsies and detect fewer irrelevant cancers.

Radiolabeled Bombesin Analogs.

The gastrin-releasing peptide receptor (GRPR) is expressed in high numbers in a variety of human tumors, including the frequently occurring prostate and breast cancers, and therefore provides the rationale for directing diagnostic or therapeutic radionuclides on cancer lesions after administration of anti-GRPR peptide analogs. This concept has been initially explored with analogs of the frog 14-peptide bombesin, suitably modified at the N-terminus with a number of radiometal chelates. Radiotracers that were selected for clinical testing revealed inherent problems associated with these GRPR agonists, related to low metabolic stability, unfavorable abdominal accumulation, and adverse effects. A shift toward GRPR antagonists soon followed, with safer analogs becoming available, whereby, metabolic stability and background clearance issues were gradually improved. Clinical testing of three main major antagonist types led to promising outcomes, but at the same time brought to light several limitations of this concept, partly related to the variation of GRPR expression levels across cancer types, stages, previous treatments, and other factors. Currently, these parameters are being rigorously addressed by cell biologists, chemists, nuclear medicine physicians, and other discipline practitioners in a common effort to make available more effective and safe state-of-the-art molecular tools to combat GRPR-positive tumors. In the present review, we present the background, current status, and future perspectives of this endeavor.

Comparison of 68Ga-labeled Prostate-specific Membrane Antigen Ligand Positron Emission Tomography/Magnetic Resonance Imaging and Positron Emission Tomography/Computed Tomography for Primary Staging of Prostate Cancer: A Systematic Review and Meta-analysis.

CONTEXT: In December 2020, the US Food and Drug Administration approved a 68Ga-labeled prostate-specific membrane antigen ligand (68Ga-PSMA-11) for positron emission tomography (PET) in patients with suspected prostate cancer (PCa) metastasis who are candidates for initial definitive therapy. 68Ga-PSMA PET is increasingly performed for these patients and is usually combined with computed tomography (CT). In recent years, 68Ga-PSMA PET has been combined with high-resolution magnetic resonance imaging (MRI), which is beneficial for T staging and may further enhance the staging of primary PCa. OBJECTIVE: To compare the diagnostic accuracy of 68Ga-PSMA PET/MRI with 68Ga-PSMA PET/CT for staging of primary PCa. EVIDENCE ACQUISITION: A comprehensive literature search was performed using Embase, PubMed/Medline, Web of Science, Cochrane Library, and Google Scholar up to June 24, 2021 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Risk of bias was assessed using the QUADAS-2 tool. EVIDENCE SYNTHESIS: The search identified 2632 articles, of which 27 were included. The diagnostic accuracy of 68Ga-PSMA PET/MRI, measured as the pooled natural logarithm of diagnostic odds ratio (lnDOR), was 2.27 (95% confidence interval [CI] 1.21-3.32) for detection of extracapsular extension (ECE), 3.50 (95% CI 2.14-4.86) for seminal vesicle invasion (SVI), and 4.73 (95% CI 2.93-6.52) for lymph node metastasis (LNM). For 68Ga-PSMA PET/CT, the analysis showed lnDOR of 2.45 (95% CI 0.75-4.14), 2.94 (95% CI 2.26-3.63), and 2.42 (95% CI 2.07-2.78) for detection of ECE, SVI, and LNM, respectively. The overall risk of bias and applicability concerns were assessed as moderate and low, respectively. CONCLUSIONS: 68Ga-PSMA PET/MRI shows high diagnostic accuracy equivalent to that of 68Ga-PSMA PET/CT for detection of ECE, SVI, and LNM in staging of PCa. There is an urgent need for direct comparison of the two diagnostic tests in future research. PATIENT SUMMARY: The use of radioactively labeled molecules that bind to prostate-specific membrane antigen (68Ga-PSMA) for positron emission tomography (PET) scans combined with either computed tomography (CT) or magnetic resonance imaging (MRI) is increasing for prostate cancer diagnosis. There is a need for direct comparison of the two tests to demonstrate the benefit of 68Ga-PSMA PET/MRI for determining tumor stage in prostate cancer. TAKE HOME MESSAGE: After the recent US Food and Drug Administration approval of 68Ga-labeled prostate-specific membrane antigen ligand (68Ga-PSMA) positron emission tomography (PET) for staging of primary prostate cancer (PCa), it is expected that the use of this imaging modality will increase rapidly. Our review of the literature shows that 68Ga-PSMA PET/magnetic resonance imaging has high diagnostic accuracy equivalent to that of 68Ga-PSMA PET/computed tomography in primary PCa staging. There is an urgent need for direct head-to-head comparison of the two diagnostic tests in future research.

GRPr Antagonist 68Ga-SB3 PET/CT Imaging of Primary Prostate Cancer in Therapy-Naïve Patients.

The gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer (PCa) cells, making it an excellent tool for targeted imaging. The 68Ga-labeled GRPr antagonist SB3 has shown excellent results in preclinical and clinical studies and was selected for further clinical investigation. The aims of this phase I study were to investigate 68Ga-SB3 PET/CT imaging of primary PCa tumors and assess safety. More aims included an investigation of biodistribution and dosimetry and a comparison with pathology and GRPr expression. Methods: Ten therapy-naïve, biopsy-confirmed PCa patients planned for prostatectomy were included. A 3-h extensive PET/CT imaging protocol was performed within 2 wk before prostatectomy. Prostate tissue was evaluated for tumor localization and Gleason score, and in vitro autoradiography was performed to determine GRPr expression. Available MRI scans performed within 3 mo before the study were matched. For dosimetry, residence times were estimated and effective dose to the body as well as absorbed doses to organs were calculated using the IDAC dose model, version 2.1. Results: Administration of 68Ga-SB3 (187.4 ± 40.0 MBq, 40 ± 5 µg) was well tolerated; no significant changes in vital signs or laboratory results were observed. 68Ga-SB3 PET/CT showed lesions in 8 of 10 patients. Pathologic analysis revealed a total of 16 tumor lesions, of which PET/CT showed 14, resulting in a sensitivity of 88%. 68Ga-SB3 PET/CT imaging showed uptake in 2 large prostatic intraepithelial neoplasia foci, considered a precursor to PCa, resulting in an 88% specificity. Autoradiography of tumor lesions revealed heterogeneous GRPr expression and was negative in 4 patients. Both PET/CT-negative patients had a GRPr-negative tumor. In autoradiography-positive tumors, the level of GRPr expression showed a significant correlation to tracer uptake on PET/CT. Dosimetry calculations estimated the effective dose to be 0.0144 mSv/MBq, similar to other 68Ga-labeled radiopeptides. The highest absorbed dose was detected in the physiologic GRPr-expressing pancreas (0.198 mGy/MBq), followed by the bladder wall and kidneys. Conclusion:68Ga-SB3 PET/CT is a safe imaging method and a promising tool for early PCa imaging.