Biochemical Response of <0.1 ng/ml Predicts Therapy-free Survival of Prostate Cancer Patients following Prostate-specific Membrane Antigen-targeted Salvage Surgery.

BACKGROUND: In a subset of patients with oligorecurrent prostate cancer (PCa), salvage surgery with prostate-specific membrane antigen (PSMA) radioguided surgery (PSMA-RGS) seems to be of value. OBJECTIVE: To evaluate whether a lower level of postoperative prostate-specific antigen (PSA; <0.1 ng/ml) is predictive of therapy-free survival (TFS) following salvage PSMA-RGS. DESIGN, SETTING, AND PARTICIPANTS: This cohort study evaluated patients with biochemical recurrence after radical prostatectomy and oligorecurrent PCa on PSMA positron emission tomography treated with PSMA-RGS in three tertiary care centers (2014-2022). INTERVENTION: PSMA-RGS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Postsalvage surgery PSA response was categorized as <0.1, 0.1-<0.2, or >0.2 ng/ml. Kaplan-Meier and multivariable Cox regression models evaluated TFS according to PSA response. RESULTS AND LIMITATIONS: Among 553 patients assessed, 522 (94%) had metastatic soft tissue lesions removed during PSMA-RGS. At 2-16 wk after PSMA-RGS, 192, 62, and 190 patients achieved PSA levels of <0.1, 0.1-<0.2, and >0.2 ng/ml, respectively. At 2 yr of follow-up, TFS rate was 81.1% versus 56.1% versus 43.1% (p < 0.001) for patients with PSA <0.1 versus 0.1-<0.2 versus >0.2 ng/ml. In multivariable analyses, PSA levels of 0.1-0.2 ng/ml (hazard ratio [HR]: 1.9, confidence interval [CI]: 1.1-3.1) and ≥0.2 ng/ml (HR: 3.2, CI: 2.2-4.6, p < 0.001) independently predicted the need for additional therapy after PSMA-RGS. The main limitation is the lack of a control group. CONCLUSIONS: For patients after salvage PSMA-RGS, a lower biochemical response (PSA <0.1 ng/ml) seems to predict longer TFS. This insight may help in counseling patients postoperatively as well as guiding the timely selection of additional therapy. PATIENT SUMMARY: We studied what happened to prostate cancer patients in three European centers who had salvage surgery using a special method called prostate-specific membrane antigen-targeted radioguidance. We found that patients who had low prostate-specific antigen levels soon after surgery were less likely to need further treatment for a longer time.

EAU Biochemical Recurrence Risk Classification and PSA Kinetics Have No Value for Patient Selection in PSMA-Radioguided Surgery (PSMA-RGS) for Oligorecurrent Prostate Cancer.

OBJECTIVE: To assess the influence of biochemical recurrence (BCR) risk groups and PSA kinetics on the outcomes of radioguided surgery against prostate-specific membrane antigen (PSMA-RGS). Currently, neither BCR risk group nor PSA doubling time (PSA-DT), or PSA velocity (PSA-V) are actively assigned or relevant for counseling prior to PSMA-RGS. METHODS: We retrospectively analyzed PSMA-RGS cases for oligorecurrent prostate cancer between 2014 and 2023. BCR risk groups, PSA-DT, and PSA-V were analyzed as predictors for complete biochemical response (cBR, PSA < 0.2 ng/mL), BCR-free, and therapy-free survival (BCRFS, TFS). RESULTS: Of 374 included patients, only 21/374 (6%) and 201/374 (54%) were classified as low- and high-risk BCR (no group assignment possible in 152/374, 41%). A total of 13/21 (62%) patients with low- and 120/201 (60%) with high-risk BCR achieved cBR (p = 1.0). BCR classification was no predictor for BCRFS (HR:1.61, CI: 0.70-3.71, p = 0.3) or subsequent TFS (HR:1.07, CI: 0.46-2.47, p = 0.9). A total of 47/76 (62%) patients with PSA-DT ≤ 6 mo and 50/84 (60%) with PSA-DT > 6 mo achieved cBR (p = 0.4). PSA-DT was not associated with cBR (OR: 0.99, CI: 0.95-1.03, p = 0.5), BCRFS (HR: 1.00, CI: 0.97-1.03, p = 0.9), or TFS (HR: 1.02, CI: 0.99-1.04, p = 0.2). Consistent negative findings were recorded for PSA-V. CONCLUSIONS: The BCR risk groups and PSA kinetics do not predict the oncological success of PSMA-RGS performed at low absolute PSA values. Indolent low-risk BCR is rarely treated by PSMA-RGS.

Improved Quality of Life in Metastatic Castration-Resistant Prostate Cancer Patients Receiving Consecutive Cycles of 177Lu-PSMA I&T.

The aim of this retrospective analysis was to evaluate health-related quality of life (HRQoL) for patients with metastatic castration-resistant prostate cancer (mCRPC) receiving consecutive cycles of 177Lu-prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) using the reliable and validated European Organisation for Research and Treatment of Cancer core quality-of-life (QoL) questionnaire. In addition, differences in HRQoL between patients with early discontinuation of treatment because of disease progression and patients who were defined as eligible for treatment continuation were analyzed. Methods: In total, 60 mCRPC patients were included in this analysis. The European Organisation for Research and Treatment of Cancer core QoL questionnaire was completed at baseline, before each treatment cycle up to the sixth treatment cycle, and at the time of PSMA-ligand PET/CT scans after the second and fourth treatment cycles. QoL assessment included global health status, functional scales, and symptom burden during treatment. Results: Global health was significantly improved at the second and fourth cycles of 177Lu-PSMA RLT (P = 0.014 and P = 0.039, respectively). In line with this, role and emotional functioning showed significant improvements at the second and fourth treatment cycles (role functioning, P = 0.045 and P = 0.048, respectively, and emotional functioning, P = 0.035 and P = 0.007, respectively). In addition, compared with baseline, fatigue and pain were significantly alleviated at the second and fourth treatment cycles (pain, P = 0.035 and P = 0.034, respectively, and fatigue, P = 0.042 and P = 0.041, respectively). Other aspects of HRQoL, even if not significantly improved, remained stable over time, except for deterioration of fatigue at the study's end (P = 0.014) and reduction of dyspnea at the second treatment cycle (P = 0.012). Patients with early discontinuation of treatment showed a concordant decline in HRQoL. Conclusion: mCRPC patients showed significant improvement in HRQoL in the course of treatment with 177Lu-PSMA RLT. Furthermore, patients with early discontinuation of treatment showed an analogous decline in HRQoL.

Safety and efficiency of repeat salvage lymph node dissection for recurrence of prostate cancer using PSMA-radioguided surgery (RGS) after prior salvage lymph node dissection with or without initial RGS support.

BACKGROUND AND OBJECTIVE: Metastasis-directed therapy is a feasible option for low PSA, recurrent locoregional metastatic prostate cancer. After initial salvage surgery, patients with good response might consider a repeat salvage surgery in case of recurrent, isolated, and PSMA-positive metastases. This analysis aimed to evaluate the oncological outcome and safety of repeat PSMA-targeted radioguided surgery (RGS) after either prior RGS or "standard" salvage lymph node dissection (SLND). MATERIALS AND METHODS: We identified 37 patients undergoing repeat RGS after prior SLND (n = 21) (SLND-RGS) or prior RGS (n = 16) (RGS-RGS) between 2014 and 2021 after initial radical prostatectomy with or without pelvic radiation therapy at two German tertiary referral centers. Kaplan-Meier analyses and uni-/multivariable Cox regression models were used to investigate factors associated with biochemical recurrence-free survival (BRFS) and treatment-free survival (TFS) after repeat salvage surgery. RESULTS AND LIMITATIONS: Complete Biochemical Response (cBR, PSA < 0.2 ng/ml) was observed in 20/32 patients (5 NA). Median overall BRFS [95% confidence interval (CI)] after repeat salvage surgery was 10.8 months (mo) (5.3-22). On multivariable regression, only age (HR 1.09, 95% CI 1.01-1.17) and preoperative PSA (HR 1.23, 95% CI 1.01-1.50) were associated with shorter BRFS, although PSA (HR 1.16, 95% CI 0.99-1.36) did not achieve significant predictor status in univariable analysis before (p value = 0.07). Overall, one year after second salvage surgery, 89% of the patients (number at risk: 19) did not receive additional treatment and median TFS was not reached. Clavien-Dindo grade > 3a complications were observed in 8% (3/37 patients). Limitations are the retrospective evaluation, heterogeneous SLND procedures, lack of long-term follow-up data, and small cohort size. CONCLUSION: In this study, repeat RGS was safe and provided clinically meaningful biochemical recurrence- and treatment-free intervals for selected cases. Patients having low preoperative PSA seemed to benefit most of repeat RGS, irrespective of prior SLND or RGS or the time from initial RP/first salvage surgery.

Development and external validation of a multivariable [68Ga]Ga-PSMA-11 PET-based prediction model for lymph node involvement in men with intermediate or high-risk prostate cancer.

PURPOSE: To develop and evaluate a lymph node invasion (LNI) prediction model for men staged with [68Ga]Ga-PSMA-11 PET. METHODS: A consecutive sample of intermediate to high-risk prostate cancer (PCa) patients undergoing [68Ga]Ga-PSMA-11 PET, extended pelvic lymph node dissection (ePLND), and radical prostatectomy (RP) at two tertiary referral centers were retrospectively identified. The training cohort comprised 173 patients (treated between 2013 and 2017), the validation cohort 90 patients (treated between 2016 and 2019). Three models for LNI prediction were developed and evaluated using cross-validation. Optimal risk-threshold was determined during model development. The best performing model was evaluated and compared to available conventional and multiparametric magnetic resonance imaging (mpMRI)-based prediction models using area under the receiver operating characteristic curves (AUC), calibration plots, and decision curve analysis (DCA). RESULTS: A combined model including prostate-specific antigen, biopsy Gleason grade group, [68Ga]Ga Ga-PSMA-11 positive volume of the primary tumor, and the assessment of the [68Ga]Ga-PSMA-11 report N-status yielded an AUC of 0.923 (95% CI 0.863-0.984) in the external validation. Using a cutoff of ≥ 17%, 44 (50%) ePLNDs would be spared and LNI missed in one patient (4.8%). Compared to conventional and MRI-based models, the proposed model showed similar calibration, higher AUC (0.923 (95% CI 0.863-0.984) vs. 0.700 (95% CI 0.548-0.852)-0.824 (95% CI 0.710-0.938)) and higher net benefit at DCA. CONCLUSIONS: Our results indicate that information from [68Ga]Ga-PSMA-11 may improve LNI prediction in intermediate to high-risk PCa patients undergoing primary staging especially when combined with clinical parameters. For better LNI prediction, future research should investigate the combination of information from both PSMA PET and mpMRI for LNI prediction in PCa patients before RP.

Prostate-specific Membrane Antigen-radioguided Surgery Facilitates Pelvic Lymph Node Dissection During Radical Prostatectomy for the Treatment of Locally Advanced Prostate Cancer with Regional Lymph Node Metastases.

Lymph node metastases (LNMs) are common in intermediate- to high-risk prostate cancer (PC) and may be missed during extended pelvic lymph node dissection (ePLND). Here we report on the use of prostate-specific membrane antigen (PSMA)-radioguided surgery (RGS) during open radical prostatectomy (RP) with ePLND to resect locoregional LNMs identified on preoperative PSMA positron emission tomography (PET). Preoperative PSMA PET showed 78 LNMs in 35 patients undergoing RP with ePLND and RGS between January 2018 and June 2020. In 14 patients (40%), LNMs were located outside the ePLND template. RGS achieved resection of PSMA-positive LNMs in 33/35 patients (94%). On univariable analysis, lower metastatic burden with up to two PSMA-positive LNMs on preoperative PET was associated with better postoperative outcomes. Limitations include the retrospective analysis and the small sample size. RGS facilitates resection of PSMA-positive LNs in patients treated with RP. Our data indicate a favorable treatment outcome in patients with low metastatic LN burden on preoperative PSMA PET. PATIENT SUMMARY: We investigated the use of radioactive guidance to remove lymph nodes affected by prostate cancer during surgical removal of the prostate. This approach can help to identify cancerous lymph nodes that might otherwise be missed and could lead to better survival outcomes.

Cohort Study of Oligorecurrent Prostate Cancer Patients: Oncological Outcomes of Patients Treated with Salvage Lymph Node Dissection via Prostate-specific Membrane Antigen-radioguided Surgery.

BACKGROUND: In a subset of patients with recurrent oligometastatic prostate cancer (PCa) salvage surgery with prostate-specific membrane antigen (PSMA)-targeted radioguidance (PSMA-RGS) might be of value. OBJECTIVE: To evaluate the oncological outcomes of salvage PSMA-RGS and determine the predictive preoperative factors of improved outcomes. DESIGN, SETTING, AND PARTICIPANTS: A cohort study of oligorecurrent PCa patients with biochemical recurrence (BCR) after radical prostatectomy and imaging with PSMA positron emission tomography (PET), treated with PSMA-RGS in two tertiary care centers (2014-2020), was conducted. INTERVENTION: PSMA-RGS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier and multivariable Cox regression models were used to assess BCR-free (BFS) and therapy-free (TFS) survival. Postoperative complications were classified according to Clavien-Dindo. RESULTS AND LIMITATIONS: Overall, 364 patients without concomitant treatment were assessed. At PSMA-RGS, metastatic soft-tissue PCa lesions were removed in 343 (94%) patients. At 2-16 wk after PSMA-RGS, 165 patients reached a prostate-specific antigen (PSA) level of <0.2 ng/ml. Within 3 mo, 24 (6.6%) patients suffered from Clavien-Dindo complications grade III-IV. At 2 yr, BFS and TFS rates were 32% and 58%, respectively. In multivariable analyses, higher preoperative PSA (hazard ratio [HR]: 1.07, 95% confidence interval [CI]: 1.02-1.12), higher number of PSMA-avid lesions (HR: 1.23, CI: 1.08-1.40), multiple (pelvic plus retroperitoneal) localizations (HR: 1.90, CI: 1.23-2.95), and retroperitoneal localization (HR: 2.04, CI: 1.31-3.18) of lesions in preoperative imaging were independent predictors of BCR after PSMA-RGS. The main limitation is the lack of a control group. CONCLUSIONS: As salvage surgery in oligorecurrent PCa currently constitutes an experimental treatment approach, careful patient selection is mandatory based on life expectancy, low PSA values, and low number of PSMA PET-avid lesions located in the pelvis. PATIENT SUMMARY: We looked at the outcomes from prostate cancer patients with recurrent disease after radical prostatectomy. We found that surgery may be an opportunity to prolong treatment-free survival, but patient selection criteria need to be very narrow.

Lessons learned after one year of COVID-19 from a urologist and radiotherapist view: A German survey on prostate cancer diagnosis and treatment.

INTRODUCTION: Since the beginning of the pandemic in 2020, COVID-19 has changed the medical landscape. International recommendations for localized prostate cancer (PCa) include deferred treatment and adjusted therapeutic routines. MATERIALS AND METHODS: To longitudinally evaluate changes in PCa treatment strategies in urological and radiotherapy departments in Germany, a link to a survey was sent to 134 institutions covering two representative baseline weeks prior to the pandemic and 13 weeks from March 2020 to February 2021. The questionnaire captured the numbers of radical prostatectomies, prostate biopsies and case numbers for conventional and hypofractionation radiotherapy. The results were evaluated using descriptive analyses. RESULTS: A total of 35% of the questionnaires were completed. PCa therapy increased by 6% in 2020 compared to 2019. At baseline, a total of 69 radiotherapy series and 164 radical prostatectomies (RPs) were documented. The decrease to 60% during the first wave of COVID-19 particularly affected low-risk PCa. The recovery throughout the summer months was followed by a renewed reduction to 58% at the end of 2020. After a gradual decline to 61% until July 2020, the number of prostate biopsies remained stable (89% to 98%) during the second wave. The use of RP fluctuated after an initial decrease without apparent prioritization of risk groups. Conventional fractionation was used in 66% of patients, followed by moderate hypofractionation (30%) and ultrahypofractionation (4%). One limitation was a potential selection bias of the selected weeks and the low response rate. CONCLUSION: While the diagnosis and therapy of PCa were affected in both waves of the pandemic, the interim increase between the peaks led to a higher total number of patients in 2020 than in 2019. Recommendations regarding prioritization and fractionation routines were implemented heterogeneously, leaving unexplored potential for future pandemic challenges.

Radical Prostatectomy Without Prior Biopsy Following Multiparametric Magnetic Resonance Imaging and Prostate-specific Membrane Antigen Positron Emission Tomography.

A biopsy-free diagnostic pathway in prostate cancer (PC) is limited by the diagnostic accuracy of multiparametric magnetic resonance imaging (mpMRI). The improved accuracy of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) raises the question whether this imaging modality can complement mpMRI to safely avoid biopsy prior to radical prostatectomy (RP). In this case series, we report the feasibility of primary RP without prior biopsy based on a high suspicion of significant PC in both mpMRI (Prostate Imaging Reporting and Data System [PI-RADS] score ≥4) and PSMA-PET (PET score ≥4 on a five-point Likert scale and maximum standardized uptake value ≥4.0) in 25 patients. All patients showed International Society of Urological Pathology (ISUP) grade ≥2 PC in postoperative histopathology. We report patient- and lesion-based comparisons with histopathology of the prostate specimen. Results of our case series may trigger the discussion about RP without prior biopsy as a possible option in well-selected patients. Our case series is limited by retrospective design and small sample size. We want to emphasize clearly that this practice should not be regarded as a standard procedure at the moment. Future studies with larger cohorts only inside a prospective, ethically approved study design are necessary to confirm these results.

Narrative review: prostate-specific membrane antigen-radioligand therapy in metastatic castration-resistant prostate cancer.

Radioactive-labelled ligands targeting the prostate-specific membrane antigen (PSMA), a transmembrane protein overexpressed in prostate cancer (PC), have shown promising activity in treatment of metastatic castration-resistant prostate cancer (mCRPC). PSMA-617 and PSMA-I&T (imaging and therapy), both labeled to the beta-emitter lutetium-177 (Lu177), are most frequently used in clinical routine and have shown a favorable side-effect profile. Common side effects are transient xerostomia. Severe side effects, e.g., treatment-associated myelosuppression, are rare. Currently treatment with Lu177-PSMA outside clinical trials is available for compassionate use for patients who exhausted conventional therapies. Previous retro- and prospective studies reported promising results with ≥50% PSA declines observed in at least one third of patients. Retrospective data suggests worse biochemical response in patients with visceral metastases. Preliminary data from the randomized phase II (TheraP) trial showed an improved biochemical response rate of Lu177-PSMA as compared to cabazitaxel in patients progressing after docetaxel. Following these promising data, the results of the randomized, prospective phase III VISION study are eagerly anticipated. A major challenge remains resistance to radioligand therapy with Lu177-PSMA. As an alternative, a PSMA-ligand labeled to the alpha-emitter Actinium-225 (Ac-225) may be offered to patients, which shows promising activity in patients developing progression under Lu177-PSMA at the cost of higher toxicity. Mostly permanent xerostomia is a relevant side effect resulting in treatment discontinuation in up to a quarter of patients. This review summarizes the literature on activity and toxicity of PSMA-targeted radioligand therapy in mCRPC.

Outcomes of palliative cystectomy in patients with locally advanced pT4 bladder cancer.

BACKGROUND: Radical cystectomy (Cx) is the standard of care for muscle-invasive bladder cancer (BCa). In locally advanced pT4 BCa the oncologic outcome is inexplicit but Cx may be necessary for palliation. OBJECTIVES: The aim of this retrospective study was to evaluate the outcomes of Cx performed in patients with locally advanced pT4 BCa and to identify patient subgroups with improved outcome. METHODS: Between 2008 and 2017, we identified 76 of 905 patients who underwent Cx for pT4 BCa at a single tertiary referral center. The physical patients' status was estimated according to the American Society of Anesthesiologists (ASA) classification. For the classification of postoperative complication rates, the Clavien-Dindo grading was used. Time-to-event variables with log-rank statistics were calculated with the use of the Kaplan-Meier method. RESULTS: Median age was 74 years (range 42-90). Preoperatively, the physical status was estimated poor in 40 (52%) patients (ASA-score of ≥3). Overall, 19 (25%) patients had pT4b BCa, 41 (54%) patients were lymph node positive (c/pN+) and 14 (18%) patients had distant metastases (c/pM+). Within 30 and 90 days after surgery, 21% and 30% of the patients, respectively, developed severe complications (Clavien-Dindo grade ≥3). Overall, 30- and 90-day mortality rates were 9% and 11%, respectively. Moreover, 86% and 75% of patients who died within 30 and 90 days after surgery, respectively, had an ASA-score ≥3. At a median postoperative follow-up of 8 months (range 0-85), 53 (70%) patients have died. During the follow-up period, 46% of the patients died due to progressive disease, 16% died of a noncancer-specific cause, and for 8% of the patients, the reason remains unknown. Median overall survival (OS) and cancer-specific survival were 13.0 and 16.0 months, respectively. In subgroup analyses ASA-score ≥3 and hemoglobin <11.7 g/dl was significantly associated with poor OS. No statistically significant differences were detected between subgroups. CONCLUSION: Cx performed in patients with locally advanced pT4 BCa is associated with an increased mortality rate within 90 days postoperatively. Our study revealed that the ASA-score is a relevant and easily available tool to rate the patient´s condition and estimate postoperative outcome.

KLK3 and TMPRSS2 for molecular lymph-node staging in prostate cancer patients undergoing radical prostatectomy.

BACKGROUND: Lymph-node (LN) metastasis in prostate cancer (PC) is a main risk factor for tumor recurrence after radical prostatectomy (RP). Molecular analysis facilitates detection of small-volume LN metastases with higher sensitivity than histopathology. We aimed to prospectively evaluate six candidate gene markers for detection of pelvic LN metastases and to determine their ability to predict biochemical recurrence-free survival (bRFS) in patients treated with RP. METHODS: The expression of kallikrein 2, 3, and 4 (KLK2, KLK3, and KLK4), prostate-specific membrane antigen (PSMA), transmembrane serine protease 2 (TMPRSS2) and transient receptor potential cation channel subfamily M member 8 (TRPM8) was assessed using qPCR. We analyzed LNs from 111 patients (intermediate PC, n = 32 (29%); high-risk PC, n = 79 (71%)) who underwent RP and extended pelvic lymph-node dissection without neoadjuvant treatment. RESULTS: Overall, 2411 LNs were examined by molecular and histopathologic examination. Histopathology detected 69 LN metastases in 28 (25%) patients. KLK2 and KLK3 diagnostically performed best and classified all pN1-patients correctly as molecular node-positive (molN1/pN1). The concordance on LN level was best for KLK3 (96%). KLK2, KLK3, KLK4, PSMA, TMPRSS2, and TRPM8 reclassified 27 (24%), 32 (29%), 29 (26%), 8 (7%), 13 (12%), and 23 (21%) pN0-patients, respectively, as node-positive (pN0/molN1). On multivariable cox regression analysis molecular LN status (molN1 vs. molN0) using KLK3 (HR 4.0, p = 0.04) and TMPRSS2 (HR 5.1, p = 0.02) were independent predictors of bRFS. Median bRFS was shorter in patients with only molecular positive LNs (molN1/pN0) for KLK3 (24 months, p = 0.001) and for TMPRSS2 (12 months, p < 0.001) compared to patients with negative nodes (molN0/pN0) (median bRFS not reached). CONCLUSIONS: For diagnostic purposes, KLK3 showed highest concordance with histopathology for detection of LN metastases in PC patients undergoing RP. For prognostic purposes, KLK3 and TMPRSS2 expression were superior to histopathologic LN status and other transcripts tested for molecular LN status. We suggest a combined KLK3/TMPRSS2 panel as a valuable diagnostic and prognostic tool for molecular LN analysis.

PSMA-PET/CT-based Lymph Node Atlas for Prostate Cancer Patients Recurring After Primary Treatment: Clinical Implications for Salvage Radiation Therapy.

BACKGROUND: Many patients experience recurrence of prostate cancer after radical prostatectomy. OBJECTIVE: The aim of this study was to visually analyze typical patterns of lymph node (LN) involvement for prostate cancer (PC) patients with biochemical recurrence after radical prostatectomy and lymphadenectomy by creating a color-coded heat map using gallium-68 prostate-specific membrane antigen positron emission tomography (68Ga-PSMA-PET) imaging. Further, we evaluated which LNs were covered by the Radiation Therapy Oncology Group (RTOG) clinical target volume (CTV) contouring guidelines. DESIGN, SETTING, AND PARTICIPANTS: A total of 1653 68Ga-PSMA-PET/computed tomography (CT) datasets were screened retrospectively. After meeting the eligibility criteria, 233 patients with 799 LN metastases were included in our study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We created a comprehensive three-dimensional color-coded LN atlas. Further, the coverage of LN metastases by RTOG CTV was assessed and stratification for risk factors was performed. RESULTS AND LIMITATIONS: In the overall, mainly high risk, collective, complete coverage by the standard RTOG CTV was accomplished in 31.0% of all LN metastases. The vast majority of uncovered LNs are situated in the para-aortal, pararectal, paravesical, preacetabular, presacral, and inguinal regions. Concerning examined stratification factors, prostate-specific antigen (PSA) levels at the time of PET/CT imaging had the highest predictive value for extrapelvic metastatic LN spread. Every increase of 1 ng/mL in PSA raises the risk of metastases outside the CTV by a factor of 1.43. CONCLUSIONS: We developed the first LN atlas for patients with recurrent PC using a heat map technique, in order to illustrate hot spots of LN recurrence. The vast majority of detected LNs are not covered by a standard CTV as recommended by the RTOG. Application of the standard RTOG CTV for pelvic irradiation in the salvage setting for high-risk PC patients seems to be inappropriate. PATIENT SUMMARY: We visualized typical lymph node recurrence sites for patients after prostate cancer surgery.

Positive Predictive Value and Correct Detection Rate of 18F-rhPSMA-7 PET in Biochemically Recurrent Prostate Cancer Validated by Composite Reference Standard.

The objective of this retrospective study was to assess the detection rate (DR), positive predictive value (PPV), and correct detection rate (CDR) of 18F-rhPSMA-7 PET/CT in biochemical recurrence (BCR) of prostate cancer (PCa) after radical prostatectomy (RP) using composite validation. Methods:18F-rhPSMA-7 PET/CT scans of patients with BCR between July 2017 and June 2018 were retrospectively reviewed. All suspicious lesions were recorded. The reference standard was histopathology or combinations of histopathology, imaging, or prostate-specific antigen (PSA) follow up, defined as composite reference standard. DR was calculated as the proportion of PSMA PET-positive patients to all patients independent of the reference standard, whereas the CDR was the percentage of patients who had at least 1 true-positive PSMA PET lesion localized that corresponded with the reference standard. The PPV was defined as the proportion of patients who had true-positive to all positive findings. The correlation between DR and patient characteristics was evaluated. Results: A total of 532 patients with a median PSA level of 0.97 ng/mL (interquartile range: 0.41-2.46 ng/mL) were included. Of these, 162 patients had composite follow-up at a median duration of 5.6 mo (range: 1.1-14.2 mo). The proportion of patients who had no lesion visualized on PET/CT, localized disease, and any distant metastases (M1) were 20%, 43%, and 37%, respectively. PET DR among all patients was 80%. On a per-patient basis, the PPV of 18F-rhPSMA-7 PET/CT in the composite cohort was 88%, and the CDR was 70%. The PPV in the histopathology-proven cohort was 91%, and the CDR in this subgroup was 73%. In patients with PSA levels ≥ 1 ng/mL the DR and PPV were 90% and 91%, respectively, resulting in a CDR of 82%. In patients with PSA levels < 1 ng/mL, the DR and PPV were 69% and 85%, respectively, resulting in a CDR of 59%. There was a significant positive correlation between 18F-rhPSMA-7 PET/CT detection efficacy and stratified PSA levels (P = 0.005), as well as PSA nadir after prostatectomy (P < 0.001). Conclusion:18F-rhPSMA-7 PET/CT offers high PPV in BCR after RP. Its CDR is dependent on the prescan PSA value with excellent CDR in patients with PSA ≥ 1 ng/mL.

Salvage Surgery in Patients with Local Recurrence After Radical Prostatectomy.

BACKGROUND: Since the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, isolated local recurrence after radical prostatectomy (RP) can be delineated accurately. OBJECTIVE: To describe and evaluate surgical technique, biochemical response, and therapy-free survival (TFS) after salvage surgery in patients with local recurrence in the seminal vesicle bed. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively assessed 40 patients treated with open salvage surgery in two centres (11/2014-02/2020). All patients presented with biochemical recurrence (BCR) after RP with a singular local recurrence at PSMA PET imaging. Thirty-three (82.5%) patients received previous salvage radiation therapy. SURGICAL PROCEDURE: Open salvage surgery with PSMA radioguidance. MEASUREMENTS: Prostate-specific antigen (PSA) nadir and percentage of patients with complete biochemical response (cBR) without further treatment (PSA < 0.2 ng/ml) after 6-16 wk were assessed. BCR-free survival and TFS were calculated using Kaplan-Meier estimates. Clavien-Dindo complications were evaluated. RESULTS AND LIMITATIONS: Prior to salvage surgery, median PSA was 0.9 ng/ml (interquartile range [IQR]: 0.5-1.7 ng/ml). Postoperatively, median PSA nadir was 0.1 ng/ml (IQR: 0-0.4 ng/ml). In 31 (77.5%) patients, cBR was observed. During the median follow-up of 24.4 months, 22 (55.0%) patients experienced BCR and 12 (30.0%) received further therapy. At 1 yr of follow-up, BCR-free survival rate was 62.2% and TFS rate was 88.3%. Three (7.5%) Clavien-Dindo grade III complications were observed. The main limitations are the retrospective design, short follow-up, and lack of a control group. CONCLUSIONS: Salvage surgery of local recurrence within the seminal vesicle bed is feasible. It may present an opportunity in selected, locally recurrent patients to prolong BCR-free survival and increase TFS. Further studies are needed to confirm our findings. PATIENT SUMMARY: We looked at the outcomes from prostate cancer patients with locally recurrent disease after radical prostatectomy and radiotherapy. We found that surgery in well-selected patients may be an opportunity to prolong treatment-free survival.

Molecular lymph node staging for bladder cancer patients undergoing radical cystectomy with pelvic lymph node dissection.

OBJECTIVE: Presence of lymph node (LN) metastasis in bladder cancer (BCa) is a main risk factor for tumor recurrence after radical cystectomy (RC). Molecular analysis facilitates detection of small-volume LN metastases with higher sensitivity than standard histopathology. The aim of the present study was to establish molecular LN analysis in BCa patients undergoing RC with lymph node dissection (LND) and to determine its ability to predict tumor recurrence. PATIENTS AND METHODS: Five transcripts with overexpression in BCa (FXYD3, KRT17, KRT20, SPINK1, UPKII) were evaluated for molecular LN analysis. We included 76 BCa patients from the prospective, randomized surgical phase-III trial (LEA AUO AB 25/02, NCT01215071) investigating extended vs. limited LND at RC. The primary endpoint was recurrence-free survival (RFS). As control, 136 LNs from 45 patients without BCa were analyzed to determine a threshold for pathologic gene expression. RESULTS: About 1,319 LNs were investigated with molecular and histopathologic examination. Histopathology detected 39 LN metastases in 17 (22%) patients. Of the tested genes FXYD3 performed best and classified all pN+-patients correctly as node-positive (pN+/molN+). In addition, FXYD3 reclassified 43 histopathologic negative LNs and 7 (9%) pN0-patients as molecular node-positive (pN0/molN+). Molecular and histopathologic LN status (pN0/molN0 vs. pN0/molN+ vs. pN+/molN+) was significantly associated with locally advanced disease (P = 0.006) and poor RFS (P < 0.001). Median RFS was not reached in LN-negative patients (pN0/molN0), 45 months (95%CI 8-83) in exclusively molecular positive patients (pN0/molN+) and 9 months (95%CI 5-13) in patients with histopathologic and molecular positive LNs (pN+/molN+). CONCLUSIONS: Molecular LN analysis with FXYD3 identified additional LN metastases in histopathologic negative LNs and identified patients with elevated risk of tumor recurrence after RC. Thus, molecular LN analysis improves LN staging and might serve as a tool to guide adjuvant treatment.

Early Prostate-Specific Antigen Changes and Clinical Outcome After 177Lu-PSMA Radionuclide Treatment in Patients with Metastatic Castration-Resistant Prostate Cancer.

Prostate-specific antigen (PSA) is widely used to monitor treatment response in patients with metastatic castration-resistant prostate cancer. However, PSA measurements are considered only after 12 wk of treatment. We aimed to evaluate the prognostic value of early PSA changes after 177Lu-labeled prostate-specific membrane antigen (177Lu-PSMA) radionuclide treatment in metastatic castration-resistant prostate cancer patients. Methods: Men who were treated with 177Lu-PSMA under a compassionate-access program at our institution and had available PSA values at baseline and at 6 wk after treatment initiation were included in this retrospective analysis. Patients were assigned to 3 groups on the basis of PSA changes: response (≥30% decline), progression (≥25% increase), and stable (<30% decline and <25% increase). The coprimary endpoints were overall survival and imaging-based progression-free survival. The secondary endpoints were PSA changes at 12 wk and PSA flare-up. Results: We identified 124 eligible patients with PSA values at 6 wk. A greater than or equal to 30% decline in PSA at 6 wk was associated with longer overall survival (median, 16.7 mo; 95% CI, 14.4-19.0) than stable PSA (median, 11.8 mo; 95% CI, 8.6-15.1) (P = 0.007) or PSA progression (median, 6.5 mo; 95% CI, 5.2-7.8) (P < 0.001). Patients with a greater than or equal to 30% decline in PSA at 6 wk also had a lower risk of imaging-based progression than patients with stable PSA (hazard ratio, 0.60; 95% CI, 0.38-0.94) (P = 0.02), whereas patients with PSA progression had a higher risk of imaging-based progression than patients with stable PSA (hazard ratio, 3.18; 95% CI, 1.95-5.21) (P < 0.001). The percentage changes in PSA at 6 and 12 wk were highly associated (r = 0.90; P < 0.001). Of 31 patients who experienced early PSA progression at 6 wk, 29 (94%) showed biochemical progression at 12 wk. Overall, only 1 (3%) of 36 patients with PSA progression at 6 wk achieved any PSA decline at 12 wk (1% of the entire cohort). The limitations of the study included its retrospective nature and the single-center experience. Conclusion: PSA changes at 6 wk after 177Lu-PSMA initiation are an early indicator of long-term clinical outcome. Patients with PSA progression after 6 wk of treatment could benefit from a very early decision to switch treatment. PSA flare-up during 177Lu-PSMA treatment is very uncommon. Prospective studies are now warranted to validate our findings and potentially inform clinicians earlier on the effectiveness of 177Lu-PSMA.

Treatment of non-metastatic castration resistant prostate cancer in 2020: What is the best?

Lately the development of 3 novel second-generation androgen receptor antagonists (enzalutamide, apalutamide, and darolutamide) chanced the treatment landscape of nonmetastatic castration-resistant prostate cancer. After proofing their clinical efficacy in large phase III registration trials with good compatibilities and tolerable side effects currently all 3 substances are Food and Drug Administration-approved in nonmetastatic castration-resistant prostate cancer. The present short review article provides an overview about these new treatment options and discusses their use in daily routine focusing on patient selection as well as on the impact of novel sensitive imaging modalities like prostate-specific membrane antigen-positron-emission tomography for detection of this stage of disease.

Extended Lymph Node Dissection for Bladder Cancer: Do Clinical Trials Rule Out a Benefit?

Although previous studies indicated a therapeutic benefit from superextended or extended lymph node dissection in bladder cancer patients undergoing radical cystectomy, the first prospective randomized trial could not confirm a significant survival benefit. With multimodal approaches including neoadjuvant or adjuvant chemotherapy as a gold standard, demonstrating any benefit may become even more difficult.