The Safety, Tolerability, and Preliminary Efficacy of a Gemcitabine-releasing Intravesical System (TAR-200) in American Urological Association-defined Intermediate-risk Non-muscle-invasive Bladder Cancer Patients: A Phase 1b Study.

Background and objective: Patients with intermediate-risk non-muscle-invasive bladder cancer (IR NMIBC) have a high risk of recurrence and need effective therapies to reduce the risk of disease recurrence or progression. This phase 1b study (NCT02720367) assessed the safety and tolerability of TAR-200, an intravesical drug delivery system, in participants with IR NMIBC. Methods: Participants with recurrent IR NMIBC were eligible. Participants received either two 7-d or two 21-d TAR-200 dosing cycles over a 4-6-wk period in a marker lesion/ablation design. TAR-200 was placed in the window between the cystoscopy showing recurrent papillary disease and the subsequent complete transurethral resection of the bladder tumour. The primary endpoint was TAR-200 safety. The secondary endpoints included TAR-200 tolerability, pharmacokinetics, and preliminary efficacy. Key findings and limitations: Twelve participants received TAR-200 treatment. No TAR-200-related serious or grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred. Nine participants had grade ≤ 2 TAR-200-related TEAEs, with urgency, dysuria, and haematuria being most common. Two participants refused a second dosing cycle due to urinary urgency and frequency. Insertion and removal of TAR-200 was successful in all cases. Plasma gemcitabine concentrations remained below the lower limit of detection. Five participants (42%) had complete response (CR): four had pathological CR and one had CR based on visual assessment. Conclusions and clinical implications: TAR-200 appears to be safe and well tolerated, with encouraging preliminary efficacy in participants with IR NMIBC. This study lays the groundwork for the multiple phase 2 and 3 global studies that are currently on-going for TAR-200. Patient summary: In this study, researchers evaluated the safety of the novel drug delivery system TAR-200 in participants with intermediate-risk non-muscle-invasive bladder cancer. They concluded that TAR-200 was safe and well tolerated with promising antitumour activity.

Extended pelvic lymph node dissection in robot-assisted radical prostatectomy is an independent risk factor for major complications.

The aim of this study is to evaluate the major postoperative complication rate after robot-assisted radical prostatectomy (RARP) and to identify related risk factors. A consecutive series of patients who underwent RARP between September 2016 and May 2021, with or without extended pelvic lymph node dissection (ePLND) were analyzed for postoperative complications that occurred within 30 days following surgery. Potential risk factors related to complications were identified by means of a multivariate logistic analysis. Electronic medical records were retrospectively reviewed for the occurrence of major complications (Clavien-Dindo grade III or higher) on a per patient level. A multivariate logistic regression with risk factors was performed to identify contributors to complications. In total, 1280 patients were included, of whom 79 (6.2%) experienced at least 1 major complication. Concomitant ePLND was performed in 609 (48%) of patients. The majority of all complications were likely related to the surgical procedure, with anastomotic leakage and lymphoceles being the most common. Upon multivariate analysis, performing ePLND remained the only significant risk factor for the occurrence of major complications (OR 2.26, p = 0.001). In contrast to robot-assisted radical prostatectomy alone, the combination with extended pelvic lymph node dissection (ePLND) has a substantial risk of serious complications. Since the ePLND is performed mainly for staging purpose, the clinical contribution of the ePLND has to be reconsidered with the present use of the PSMA-PET/CT.

A Prospective Randomised Trial to Determine the Effect of a Reduced Versus Standard Dose of Enzalutamide on Side Effects in Frail Patients with Prostate Cancer.

BACKGROUND AND OBJECTIVE: Enzalutamide is a potent androgen receptor signalling inhibitor, effectively used for the treatment of different stages of prostate cancer. Side effects occur frequently at the registered dose, whilst a lower dose might be equally effective. Therefore, the aim of this study is to determine the effect of a reduced dose of enzalutamide on side effects in frail patients with prostate cancer. METHODS: This multicentre randomised trial compared the standard enzalutamide dose of 160 mg once daily (OD) with a reduced dose of 120 mg OD in frail patients with prostate cancer. Fatigue, cognitive side effects, and depressive symptoms were measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire, Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire, and Geriatric Depression Scale-15 (GDS-15). Linear mixed-effect models were used to study differences in side effects over time between both groups. KEY FINDINGS AND LIMITATIONS: In total, 52 patients were included in the analysis (25 reduced dose and 27 standard dose). Patients treated with the reduced dose had significantly lower fatigue after 24 wk than those with the standard dose (difference FACIT-Fatigue 6.2; 95% confidence interval 1.4-11.0; p = 0.01). Patients treated with the reduced dose showed stable fatigue, cognitive side effects, and depressive symptoms over time, whilst patients with the standard dose showed significantly worse side effects after 24 wk than at baseline. CONCLUSIONS AND CLINICAL IMPLICATIONS: A reduced dose of enzalutamide results in less fatigue, cognitive side effects, and depressive symptoms in frail patients with prostate cancer than the standard dose, without any indication of interference with efficacy endpoints. PATIENT SUMMARY: In this report, we looked at the side effects of enzalutamide at two dose levels. We found that, in frail patients, three tablets a day result in less fatigue than four tablets a day. Patients treated with four tablets a day showed an increase in fatigue, cognitive side effects, and depression. We conclude that a lower dose of three tablets can be used to alleviate side effects without indications for less efficacy.

The Impact of Baseline PSMA PET/CT Versus CT on Outcomes of 223Ra Therapy in Metastatic Castration-Resistant Prostate Cancer Patients.

Imaging before 223Ra-dichloride (223Ra) therapy is crucial for selecting metastatic castration-resistant prostate cancer (mCRPC) patients with bone-only disease. The purpose of this study was to evaluate if baseline prostate-specific membrane antigen (PSMA) PET/CT (bPSMA) versus CT is associated with outcomes of 223Ra therapy. Methods: A secondary analysis of the data of a prospective observational study (NCT04995614) was performed. Patients received a maximum of 6 223Ra cycles and were retrospectively divided into the bPSMA or baseline CT (bCT) groups. All patients received baseline bone scintigraphy. Primary endpoints were alkaline phosphatase and prostate-specific antigen response. Secondary endpoints were overall survival (OS) and radiologic response. Results: Between 2017 and 2020, 122 mCRPC patients were included: 18 (14.8%) in the bPSMA group and 104 (85.2%) in the bCT group. All baseline characteristics were comparable. No significant differences in alkaline phosphatase or prostate-specific antigen response were found. The bCT group showed an OS significantly shorter than that of the bPSMA group (12.4 vs. 19.9 mo, P = 0.038). In 31 of 76 patients (40.1%) in the bCT group who also received posttherapy CT, lymph node or visceral metastases (soft-tissue involvement [STI]) were detected after 223Ra therapy, compared with 0 of 15 patients in the bPSMA group who received posttherapy PSMA PET/CT or CT. No significant difference in OS was found between patients in the bCT or posttherapy CT subgroup without STI (46/76) and the bPSMA group. Conclusion: bPSMA versus CT does not seem to impact biochemical response during 223Ra therapy in mCRPC patients. Nevertheless, patients in the bCT group had a significantly shorter OS, most likely due to underdetection of STI in this group. Therefore, replacing bCT with PSMA PET/CT appears to be a valuable screening method for identifying patients who will benefit most from 223Ra therapy.

Short-term Changes in Health-related Quality of Life of Patients Undergoing Radical Surgery for Upper Urinary Tract Urothelial Carcinoma: Results from a Prospective Phase 2 Clinical Trial.

Background and objective: The possible negative impact of radical surgery on patients' health-related quality of life (HRQoL) plays an important role in preoperative counseling. Here, we analyzed the HRQoL of patients treated for upper urinary tract urothelial carcinoma (UTUC) in the context of a single-arm phase 2 multicenter study, in which the safety and efficacy of a single preoperative intravesical instillation with mitomycin C were investigated. Our objective was to investigate early changes in HRQoL in patients undergoing radical surgery for UTUC and identify factors associated with these outcomes. Methods: Patients with pTanyN0-1M0 UTUC were prospectively included. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) questionnaire at baseline, and at 1 and 3 mo after surgery. A linear mixed model was used to evaluate the changes in HRQoL over time and identify the variables associated with these outcomes. The clinical effect size was used to assess the clinical impact and level of perceptibility of HRQoL changes for clinicians and/or patients based on given thresholds. Key findings and limitations: Between 2017 and 2020, 186 patients were included. At baseline, 1 mo after surgery, and 3 mo after surgery, response rates were 91%, 84%, and 78%, respectively. One month after surgery, a statistically significant and clinically relevant deterioration was observed in physical, role, and social functioning, and for the included symptom scales: constipation, fatigue, and pain. An improvement in emotional functioning was observed. At 3 mo, HRQoL returned to baseline levels, except emotional functioning, which improved at 1 mo and persisted to be better than that before surgery. Age >70 yr was associated with worse physical functioning, but better social and emotional functioning. Male patients reported better emotional functioning than females. Postoperative complications were negatively associated with social functioning. Conclusions and clinical implications: UTUC patients treated with radical surgery experienced a significant, albeit temporary, decline in HRQoL. Three months following surgery, HRQoL outcomes returned to baseline levels. This information can be used to counsel UTUC patients before undergoing radical surgery and contextualize recovery after surgery. Patient summary: We investigated the changes in quality of life as reported by patients who underwent surgery for upper tract urothelial carcinoma (UTUC). We found that patients experienced a decline in quality of life 1 mo after surgery, but this was temporary, with full recovery of quality of life 3 mo after surgery. These findings can help doctors and other medical staff in counseling UTUC patients before undergoing radical surgery.

Prostate-Specific Membrane Antigen-Targeted Radioguided Pelvic Lymph Node Dissection in Newly Diagnosed Prostate Cancer Patients with a Suspicion of Locoregional Lymph Node Metastases: The DETECT Trial.

Prostate-specific membrane antigen (PSMA)-targeted radioguided surgery (RGS) aims to optimize the peroperative detection and removal of PSMA-avid lymph node (LN) metastases (LNMs) and has been described in patients with recurrent prostate cancer (PCa). In newly diagnosed PCa patients undergoing pelvic LN dissections, PSMA RGS could guide the urologist toward PSMA-expressing LNMs as identified on preoperative 18F-PSMA PET/CT imaging. The objective was to evaluate the safety and feasibility of 111In-PSMA RGS in primary PCa patients with one or more suggestive LNs on preoperative 18F-PSMA PET/CT. Methods: This prospective, phase I/II study included 20 newly diagnosed PCa patients with at least 1 suggestive LN on preoperative 18F-PSMA PET/CT. PSMA RGS was performed 24 h after 111In-PSMA-I&T administration, and postoperative 18F-PSMA PET/CT was performed to verify successful removal of the suggestive lesions. The primary endpoint was determination of the safety and feasibility of 111In-PSMA RGS. Safety was assessed by monitoring adverse events. Feasibility was described as the possibility to peroperatively detect suggestive LNs as identified on preoperative imaging. Secondary outcomes included the accuracy of 111In-PSMA RGS compared with histopathology, tumor- and lesion-to-background ratios, and biochemical recurrence. Results: No tracer-related adverse events were reported. In 20 patients, 43 of 49 (88%) 18F-PSMA PET-suggestive lesions were successfully removed. 111In-PSMA RGS facilitated peroperative identification and resection of 29 of 49 (59%) RGS-target lesions, of which 28 (97%) contained LNMs. Another 14 of 49 (29%) resected LNs were not detected with 111In-PSMA RGS, of which 2 contained metastases. Conclusion: 111In-PSMA RGS is a safe and feasible procedure that allows peroperative detection of 18F-PSMA PET/CT-suggestive lesions in newly diagnosed PCa patients. The use of a radioactive PSMA tracer and a detection device (γ-probe) during surgery helps in identifying LNs that were suggestive of PCa metastases on the 18F-PSMA PET/CT before surgery and thus may improve the peroperative identification and removal of these LNs.

Validation of Claims Data for Absorbing Pads as a Measure for Urinary Incontinence after Radical Prostatectomy, a National Cross-Sectional Analysis.

The use of healthcare insurance claims data for urinary incontinence (UI) pads has the potential to serve as an objective measure for assessing post-radical prostatectomy UI rates, but its validity for this purpose has not been established. The aim of this study is to correlate claims data with Patient Reported Outcome Measures (PROMs) for UI pad use. Patients who underwent RP in the Netherlands between September 2019 and February 2020 were included. Incontinence was defined as the daily use of ≥1 pad(s). Claims data for UI pads at 12-15 months after RP were extracted from a nationwide healthcare insurance database in the Netherlands. Participating hospitals provided PROMS data. In total, 1624 patients underwent RP. Corresponding data of 845 patients was provided by nine participating hospitals, of which 416 patients were matched with complete PROMs data. Claims data and PROMs showed 31% and 45% post-RP UI (≥1 pads). UI according to claims data compared with PROMs had a sensitivity of 62%, specificity of 96%, PPV of 92%, NPV of 75% and accuracy of 81%. The agreement between both methods was moderate (κ = 0.60). Claims data for pads moderately align with PROMs in assessing post-prostatectomy urinary incontinence and could be considered as a conservative quality indicator.

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.

Subnodal Correspondence of PSMA Expression and USPIO-MRI in Metastatic Pelvic Lymph Nodes in Prostate Cancer.

OBJECTIVES: Two advanced imaging modalities used to detect lymph node (LN) metastases in prostate cancer patients are prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography and ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI). As these modalities use different targets, a subnodal comparison is needed to interpret both their correspondence and their differences. The aim of this explorative study was to compare ex vivo 111In-PSMA µSPECT images with high-resolution 7 T USPIO µMR images and histopathology of resected LN specimens from prostate cancer patients to assess the degree of correspondence at subnodal level. MATERIALS AND METHODS: Twenty primary prostate cancer patients who underwent pelvic LN dissection were included and received USPIO contrast and 111In-PSMA. A total of 41 LNs of interest (LNOIs) were selected for ex vivo imaging based on γ-probe detection or palpation. µSPECT and µMRI acquisition were performed immediately after resection. Overlay of µSPECT images on MR images was performed, and the level of correspondence (LoC) between µSPECT and µMR findings was assessed according to a 4-point Likert classification scheme. RESULTS: Forty-one LNOIs could be matched to an LN on ex vivo µMRI. Coregistration of µSPECT and USPIO-enhanced water-selective multigradient echo MR images was successful for all 41 LNOIs. Ninety percent of the lesions showed excellent correspondence regarding the presence of metastatic tissue and affected subnodal site (LoC 4; 37/41). In only 1 of 41 LNOIs, a small metastasis was misclassified by both techniques. Three LNOIs were classified as LoC 3 (7%) and 1 LNOI as LoC 2. All LoC 2 and LoC 3 lesions had PSMA-expressing metastases on final histopathology. CONCLUSIONS: Coregistration of µSPECT and USPIO-µMRI showed excellent subnodal correspondence in the majority (90%) of LNs. Ex vivo imaging may thus help localize small cancer deposits within resected LNs and could contribute to improved interpretation of in vivo imaging of LNs.

Diagnostic Performance and Safety of Positron Emission Tomography with 18F-rhPSMA-7.3 in Patients with Newly Diagnosed Unfavourable Intermediate- to Very-high-risk Prostate Cancer: Results from a Phase 3, Prospective, Multicentre Study (LIGHTHOUSE).

BACKGROUND: Radiohybrid (rh) 18F-rhPSMA-7.3 is a novel high-affinity prostate-specific membrane antigen (PSMA)-targeting radiopharmaceutical for prostate cancer (PCa) imaging. OBJECTIVE: To evaluate the diagnostic performance and safety of 18F-rhPSMA-7.3 in newly diagnosed PCa patients planned for prostatectomy. DESIGN, SETTING, AND PARTICIPANTS: Data on 18F-rhPSMA-7.3 were reported from the phase 3 prospective, multicentre LIGHTHOUSE study (NCT04186819). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients underwent positron emission tomography/computed tomography (PET/CT) 50-70 min after an injection of 296 MBq 18F-rhPSMA-7.3. Images were interpreted locally and by three blinded independent readers. The coprimary endpoints were patient-level sensitivity and specificity for the detection of pelvic lymph node (PLN) metastases, validated using histopathology at PLN dissection. Prespecified statistical thresholds (lower bounds of 95% confidence interval [CI]) were set at 22.5% for sensitivity and 82.5% for specificity. RESULTS AND LIMITATIONS: Of 372 patients screened, 352 had evaluable 18F-rhPSMA-7.3-PET/CT and 296 (99 [33%] with unfavourable intermediate-risk [UIR] and 197 [67%] with high-/very-high-risk [VHR] PCa) subsequently underwent surgery. As per the independent reads, 23-37 (7.8-13%) patients had 18F-rhPSMA-7.3-positive PLN. Seventy (24%) patients had one or more positive PLNs on histopathology. The sensitivity for PLN detection was 30% (95% CI, 19.6-42.1%) for reader 1, 27% (95% CI, 17.2-39.1%) for reader 2, and 23% (95% CI, 13.7-34.4%) for reader 3, not meeting the prespecified threshold. Specificity was 93% (95% CI, 88.8-95.9%), 94% (95% CI, 89.8-96.6%), and 97% (95% CI, 93.7-98.7%), respectively, exceeding the threshold for all readers. Specificity was high (≥92%) across both risk stratifications. Sensitivity was higher among high-risk/VHR (24-33%) than among UIR (16-21%) patients. Extrapelvic (M1) lesions were reported for 56-98/352 (16-28%) patients who underwent 18F-rhPSMA-7.3-PET/CT irrespective of surgery. Verification of these (predominantly by conventional imaging) gave a verified detection rate of 9.9-14% (positive predictive value, 51-63%). No serious adverse events were observed. CONCLUSIONS: Across all risk stratifications, 18F-rhPSMA-7.3-PET/CT had high specificity, meeting the specificity endpoint. The sensitivity endpoint was not met, although higher sensitivity was noted among high-risk/VHR than among UIR patients. Overall, 18F-rhPSMA-7.3-PET/CT was well tolerated, and identified N1 and M1 disease prior to surgery in newly diagnosed PCa patients. PATIENT SUMMARY: In order to select the most appropriate treatment for patients with prostate cancer, it is critical to diagnose the disease burden accurately at initial diagnosis. In this study, we investigated a new diagnostic imaging agent in a large population of men with primary prostate cancer. We found it to have an excellent safety profile and to provide clinically useful information regarding the presence of disease beyond the prostate.

Clinical Pharmacokinetics and Pharmacodynamics of the Next Generation Androgen Receptor Inhibitor-Darolutamide.

Darolutamide is a next-generation androgen receptor signaling inhibitor (ARSI) currently approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone sensitive prostate cancer (mHSPC). Studies suggest that darolutamide also has the potential to be used to treat other stages of prostate cancer (PC), suggesting that its indications will broaden in the near future. Since ARSIs show similar efficacy for the treatment of PC, pharmacokinetic properties of these drugs and patient characteristics could help physicians decide which drug to select. This review provides an overview of the pharmacokinetic and pharmacodynamic properties of darolutamide. One of the most important pharmacological advantages of darolutamide is its low brain distribution and therefore limited seizure potential and central nervous system adverse effects. In addition, darolutamide has little drug-drug interaction potential and is unlikely to alter the exposure of other cytochrome P450 or P-glycoprotein substrates. Nevertheless, it may significantly increase the exposure of breast cancer resistant protein (BCRP) substrates. The limited solubility and bioavailability of darolutamide increases when taken together with food, regardless of the fat content. Darolutamide is excessively metabolized by oxidation and glucuronidation and excreted in the urine and feces. For this reason, dose reduction is required in patients with moderate and severe renal or severe hepatic impairment. Although no exposure-response relationship was observed with darolutamide, less advanced stages of PC showed better PSA response on treatment. Overall, darolutamide has some advantageous pharmacological properties that may lead to its preferred use, when broader registered, in selected patients across different disease stages.

Immunohistochemical and histopathological validation of 18 F-PSMA-1007 PET/CT for intraprostatic cancerous lesions.

INTRODUCTION: Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer (PCa). In this study, we aim to immunohistochemically and histopathological validate the fluorine-18 (18 F)-PSMA-1007 positron emission tomography/computed tomography (PET/CT) for intraprostatic PCa lesions. METHODS: Between February 2019 and October 2020, patients with biopsy-proven, treatment-naïve intermediate-to-high-risk PCa undergoing an 18 F-PSMA-1007 PET/CT before robot-assisted radical prostatectomy (RARP) were prospectively enrolled. For all PCa lesions found on whole-mount histopathology, location, size, International Society of Urological Pathology (ISUP) grade group (GG), and immune reactive score (IRS) were assessed after PSMA staining. ISUP GG ≥ 3 PCa was defined as clinically significant (cs) PCa. All lesions were matched on PSMA PET/CT and the maximum standardized uptake value (SUVmax) was measured. RESULTS: A total of 125 lesions were analyzed in the 80 RARP specimens, of which 49 (40%) were csPCa and 76 (60%) non-csPCa. Linear multivariable regressions showed that an increase in SUVmax significantly correlated with a higher ISUP GG (p values between 0.021 and 0.001) and a higher IRS (p = 0.017). Logistic multivariable regression showed that csPCa significantly correlated with a higher SUVmax (odds ratio, OR: 1.17 [95% confidence interval, CI: 1.04-1.21, p = 0.005]), an increase in tumor length (OR: 1.05 [95% CI 1.01-1.10, p = 0.020]) and a higher IRS (OR; 1.24 [95% CI 1.07-1.47, p = 0.006]). A SUVmax threshold of 4 would have resulted in one (2%) missed lesion with csPCa. CONCLUSION: This prospective study revealed that 18 F-PSMA-1007 PET/CT SUVmax is correlated with the ISUP GG and IRS, and thereby could be a tool to characterize intraprostatic PCa lesions.

Head-to-Head Comparison of 18F-PSMA-1007 Positron Emission Tomography/Computed Tomography and Multiparametric Magnetic Resonance Imaging with Whole-mount Histopathology as Reference in Localisation and Staging of Primary Prostate Cancer.

BACKGROUND: Accurate local staging is critical for treatment planning and prognosis in prostate cancer (PCa). Although multiparametric magnetic resonance imaging (mpMRI) has high specificity for detection of extraprostatic extension (EPE) and seminal vesicle invasion (SVI), its sensitivity remains limited. 18F-PSMA-1007 positron emission tomography/computed tomography (PET/CT) may be more accurate in determining T stage. OBJECTIVE: To assess the diagnostic performance of 18F-PSMA-1007 PET/CT in comparison to mpMRI for intraprostatic tumour localisation and detection of EPE and SVI in men with primary PCa undergoing robot-assisted radical prostatectomy (RARP). DESIGN, SETTING, AND PARTICIPANTS: Between February 2019 and October 2020, 105 treatment-naïve patients with biopsy-proven intermediate- or high-risk PCa undergoing mpMRI and 18F-PSMA-1007 PET/CT before RARP were prospectively enrolled. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The diagnostic accuracy of 18F-PSMA-1007 PET/CT and mpMRI for intraprostatic tumour localisation and detection of EPE and SVI was assessed via histopathological examination of whole-mount RP specimens. The sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were calculated. The McNemar test was used to compare outcomes between imaging modalities. RESULTS AND LIMITATIONS: In 80 RP specimens, 129 PCa lesions were found, of which 96 were clinically significant PCa (csPCa). Per-lesion sensitivity for localisation of overall PCa was 85% (95% confidence interval [CI] 77-90%) with PSMA PET/CT and 62% (95% CI 53-70%) with mpMRI (p < 0.001). Per-lesion sensitivity for csPCa was 95% (95% CI 88-98%) with PSMA PET/CT and 73% (95% CI 63-81%) with mpMRI (p < 0.001). The diagnostic accuracy of PSMA PET/CT and mpMRI for detection of EPE per lesion did not significantly differ (sensitivity 45%, 95% CI 31-60% vs 55%, 95% CI 40-69%; p = 0.3; specificity 85%, 95% CI 75-92% vs 90%, 95% CI 81-86%; p = 0.5). The sensitivity and specificity of PSMA PET/CT and mpMRI for detection of SVI did not significantly differ (sensitivity 47%, 95% CI 21-73% vs 33%, 95% CI 12-62; p = 0.6; specificity 94%, 95% CI 88-98% vs 96%, 95% CI 90-99%; p = 0.8). CONCLUSIONS: 18F-PSMA-1007 is a promising imaging modality for localising intraprostatic csPCa but did not show additional value in assessing EPE and SVI in comparison to mpMRI. PATIENT SUMMARY: A new imaging technique called PET/CT (positron emission tomography/computed tomography) with the radioactive tracer 18F-PSMA-1007 shows promise in identifying the location of clinically significant prostate cancer. However, it does not seem to be of additional value over magnetic resonance imaging (MRI) for determining the local tumour stage.

Using Existing Clinical Information Models for Dutch Quality Registries to Reuse Data and Follow COUMT Paradigm.

BACKGROUND: Reuse of health care data for various purposes, such as the care process, for quality measurement, research, and finance, will become increasingly important in the future; therefore, "Collect Once Use Many Times" (COUMT). Clinical information models (CIMs) can be used for content standardization. Data collection for national quality registries (NQRs) often requires manual data entry or batch processing. Preferably, NQRs collect required data by extracting data recorded during the health care process and stored in the electronic health record. OBJECTIVES: The first objective of this study was to analyze the level of coverage of data elements in NQRs with developed Dutch CIMs (DCIMs). The second objective was to analyze the most predominant DCIMs, both in terms of the coverage of data elements as well as in their prevalence across existing NQRs. METHODS: For the first objective, a mapping method was used which consisted of six steps, ranging from a description of the clinical pathway to a detailed mapping of data elements. For the second objective, the total number of data elements that matched with a specific DCIM was counted and divided by the total number of evaluated data elements. RESULTS: An average of 83.0% (standard deviation: 11.8%) of data elements in studied NQRs could be mapped to existing DCIMs . In total, 5 out of 100 DCIMs were needed to map 48.6% of the data elements. CONCLUSION: This study substantiates the potential of using existing DCIMs for data collection in Dutch NQRs and gives direction to further implementation of DCIMs. The developed method is applicable to other domains. For NQRs, implementation should start with the five DCIMs that are most prevalently used in the NQRs. Furthermore, a national agreement on the leading principle of COUMT for the use and implementation for DCIMs and (inter)national code lists is needed.

Imaging and photodynamic therapy of prostate cancer using a theranostic PSMA-targeting ligand.

PURPOSE: Incomplete resection of prostate cancer (PCa) results in increased risk of disease recurrence. Combined fluorescence-guided surgery with tumor-targeted photodynamic therapy (tPDT) may help to achieve complete tumor eradication. We developed a prostate-specific membrane antigen (PSMA) ligand consisting of a DOTA chelator for 111In labeling and a fluorophore/photosensitizer IRDye700DX (PSMA-N064). We evaluated the efficacy of PSMA-tPDT using PSMA-N064 in cell viability assays, a mouse xenograft model and in an ex vivo incubation study on fresh human PCa tissue. METHODS: In vitro, therapeutic efficacy of PSMA-N064 was evaluated using PSMA-positive LS174T cells and LS174T wild-type cells. In vivo, PSMA-N064-mediated tPDT was tested in immunodeficient BALB/c mice-bearing PSMA-positive LS174T xenografts. Tumor growth and survival were compared to control mice that received either NIR light or ligand injection only. Ex vivo tPDT efficacy was evaluated in excised fresh human PCa tissue incubated with PSMA-N064. RESULTS: In vitro, tPDT led to a PSMA-specific light- and ligand dose-dependent loss in cell viability. In vivo, tPDT-induced tumor cell apoptosis, delayed tumor growth, and significantly improved survival (p = 0.004) of the treated PSMA-positive tumor-bearing mice compared with the controls. In fresh ex vivo human PCa tissue, apoptosis was significantly increased in PSMA-tPDT-treated samples compared to non-treated control samples (p = 0.037). CONCLUSION: This study showed the feasibility of PSMA-N064-mediated tPDT in cell assays, a xenograft model and excised fresh human PCa tissue. This paves the way to investigate the impact of in vivo PSMA-tPDT on surgical outcome in PCa patients.

Cost Effectiveness of Rectal Culture-based Antibiotic Prophylaxis in Transrectal Prostate Biopsy: The Results from a Randomized, Nonblinded, Multicenter Trial.

Background: Culture-based antibiotic prophylaxis is a plausible strategy to reduce infections after transrectal prostate biopsy (PB) related to fluoroquinolone-resistant pathogens. Objective: To assess the cost effectiveness of rectal culture-based prophylaxis compared with empirical ciprofloxacin prophylaxis. Design setting and participants: The study was performed alongside a trial in 11 Dutch hospitals investigating the effectiveness of culture-based prophylaxis in transrectal PB between April 2018 and July 2021 (trial registration number: NCT03228108). Intervention: Patients were 1:1 randomized for empirical ciprofloxacin prophylaxis (oral) or culture-based prophylaxis. Costs for both prophylactic strategies were determined for two scenarios: (1) all infectious complications within 7 d after biopsy and (2) culture-proven Gram-negative infections within 30 d after biopsy. Outcome measurements and statistical analysis: Differences in costs and effects (quality-adjusted life-years [QALYs]) were analyzed from a healthcare and societal perspective (including productivity losses, and travel and parking costs) using a bootstrap procedure presenting uncertainty surrounding the incremental cost-effectiveness ratio in a cost-effectiveness plane and acceptability curve. Results and limitations: For the 7-d follow-up period, culture-based prophylaxis (n = 636) was €51.57 (95% confidence interval [CI] 6.52-96.63) more expensive from a healthcare perspective and €16.95 (95% CI -54.29 to 88.18) from a societal perspective than empirical ciprofloxacin prophylaxis (n = 652). Ciprofloxacin-resistant bacteria were detected in 15.4%. Extrapolating our data, from a healthcare perspective, 40% ciprofloxacin resistance would lead to equal cost for both strategies. Results were similar for the 30-d follow-up period. No significant differences in QALYs were observed. Conclusions: Our results should be interpreted in the context of local ciprofloxacin resistance rates. In our setting, from a healthcare perspective, culture-based prophylaxis was significantly more expensive than empirical ciprofloxacin prophylaxis. From a societal perspective, culture-based prophylaxis was somewhat more cost effective against the threshold value customary for the Netherlands (€80.000). Patient summary: Culture-based prophylaxis in transrectal prostate biopsy was not associated with reduced costs compared with empirical ciprofloxacin prophylaxis.

Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Androgen receptor pathway inhibitors (ARPI) are standard of care for treatment-naïve metastatic castration-resistant prostate cancer (mCRPC), but rapid resistance is common. Early identification of resistance will improve management strategies. We investigated whether changes in circulating tumor DNA (ctDNA) fraction during ARPI treatment are linked with mCRPC clinical outcomes. EXPERIMENTAL DESIGN: Plasma cell-free DNA was collected from 81 patients with mCRPC at baseline and after 4 weeks of first-line ARPI treatment during two prospective multicenter observational studies (NCT02426333; NCT02471469). ctDNA fraction was calculated from somatic mutations in targeted sequencing and genome copy-number profiles. Samples were classified into detected versus undetected ctDNA. Outcome measurements were progression-free survival (PFS) and overall survival (OS). Nondurable treatment response was defined as PFS ≤6 months. RESULTS: ctDNA was detected in 48/81 (59%) baseline and 29/81 (36%) 4-week samples. ctDNA fraction for samples with detected ctDNA was lower at 4 weeks versus baseline (median 5.0% versus 14.5%, P = 0.017). PFS and OS were shortest for patients with persistent ctDNA at 4 weeks (univariate HR, 4.79; 95% CI, 2.62-8.77 and univariate HR, 5.49; 95% CI, 2.76-10.91, respectively), independent of clinical prognostic factors. For patients exhibiting change from detected to undetected ctDNA by 4 weeks, there was no significant PFS difference versus patients with baseline undetected ctDNA. ctDNA change had a positive predictive value of 88% and negative predictive value of 92% for identifying nondurable responses. CONCLUSIONS: Early changes in ctDNA fraction are strongly linked to duration of first-line ARPI treatment benefit and survival in mCRPC and may inform early therapy switches or treatment intensification. See related commentary by Sartor, p. 2745.

Rectal Culture-Based Versus Empirical Antibiotic Prophylaxis to Prevent Infectious Complications in Men Undergoing Transrectal Prostate Biopsy: A Randomized, Nonblinded Multicenter Trial.

BACKGROUND: An increase in infections after transrectal prostate biopsy (PB), related to an increasing number of patients with ciprofloxacin-resistant rectal flora, necessitates the exploration of alternatives for the traditionally used empirical prophylaxis of ciprofloxacin. We compared infectious complication rates after transrectal PB using empirical ciprofloxacin prophylaxis versus culture-based prophylaxis. METHODS: In this nonblinded, randomized trial, between 4 April 2018 and 30 July 2021, we enrolled 1538 patients from 11 Dutch hospitals undergoing transrectal PB. After rectal swab collection, patients were randomized 1:1 to receive empirical prophylaxis with oral ciprofloxacin (control group [CG]) or culture-based prophylaxis (intervention group [IG]). Primary outcome was any infectious complication within 7 days after biopsy. Secondary outcomes were infectious complications within 30 days, and bacteremia and bacteriuria within 7 and 30 days postbiopsy. For primary outcome analysis, the χ2 test stratified for hospitals was used. Trial registration number: NCT03228108. RESULTS: Data from 1288 patients (83.7%) were available for analysis (CG, 652; IG, 636). Infection rates within 7 days postbiopsy were 4.3% (n = 28) (CG) and 2.5% (n = 16) (IG) (P value = .08; reduction: -1.8%; 95% confidence interval, -.004 to .040). Ciprofloxacin-resistant bacteria were detected in 15.2% (n = 1288). In the CG, the presence of ciprofloxacin-resistant rectal flora resulted in a 6.2-fold higher risk of early postbiopsy infection. CONCLUSIONS: Our study supports the use of culture-based prophylaxis to reduce infectious complications after transrectal PB. Despite adequate prophylaxis, postbiopsy infections can still occur. Therefore, culture-based prophylaxis must be weighed against other strategies that could reduce postbiopsy infections. Clinical Trials Registration. NCT03228108.

Incidence and survival of castration-resistant prostate cancer patients with visceral metastases: results from the Dutch CAPRI-registry.

BACKGROUND: The objective of this real-world population study is to investigate incidence and treatment of visceral metastases (VMs) in castration resistant prostate cancer (CRPC) patients and their survival. METHODS: CRPC-patients in the CAPRI-registry between 2010 and 2016 were included in the analyses and followed till 2017. Outcomes were proportion of patients radiologically screened for VMs and proportion of patients with VMs at CRPC-diagnosis and at the start of every treatment line. Groups have been created based on location of VMs (lung, liver, or both) at date of first VM diagnosis. The outcome for these groups was overall survival (OS). Statistics included descriptive analyses, Kaplan-Meier method, and Cox proportional hazard regression analysis for survival analyses. RESULTS: Of 3602 patients from the CAPRI registry, 457 patients (12.7%) were diagnosed with VMs during follow-up: 230 patients with liver, 161 with lung, and 66 with both liver and lung metastases. The proportion of patients radiologically screened for VMs increased per treatment line as did the occurrence rate of VMs. However, 80% of patients at CRPC diagnosis to 40% in the 6th line were not screened for VMs at the start of a systemic treatment. Median OS was 8.6 months for patients with liver, 18.3 with lung and 10.9 with both liver and lung metastases (p < 0.001) from date of first VM diagnosis. After correction for prognostic factors patients with lung metastases had significantly better OS than patients with liver metastases (HR 0.650, p = 0.001). CONCLUSION: This real-world analysis showed that despite the increased rate of radiological staging during follow-up, still 80% to 40% of the patients (CRPC diagnosis to 6th treatment line respectively) were not screened for VMs at the start of a systemic treatment. VMs and location of VMs are key prognostic patient characteristics, impacts survival and have implications for treatment decisions, so routine staging of CRPC-patients is warranted. CLINICAL TRIAL IDENTIFICATION: The CAPRI study is registered in the Dutch Trial Registry as NL3440 (NTR3591).