The habits of European urologists in the field of cryopreservation before the urological cancers treatment.

INTRODUCTION: Treatments against urogenital cancers frequently have fertility side-effects. The strategy to preserve fertility after oncologic treatments is still a matter of debate with a lack of evidence and international guidelines. The aim of this study is to investigate fertility preservation practices before urogenital cancer treatments and to compare national habits. MATERIAL AND METHODS: An online anonymous survey was submitted from January to June 2021 to six European urological societies. The 31-items questionnaire included questions about demography, habits of evaluation, and management of fertility preservation in case of urogenital cancer treatments. RESULTS: Two hundred twenty-eight urologists from six urological societies in five different countries (Belgium, The Netherlands, Luxembourg, France, Finland) filled out the survey. Three quarter (74%; n = 166) usually propose a cryopreservation before orchidectomy. In case of oligo/azoo-spermia, the technique performed for the sperm extraction during orchidectomy varies among the sample: 70.5% (n = 160) of the responders do not perform a Testicular Sperm Extraction (TESE) nor a Percutaneous Epididymal Sperm Aspiration (PESA). The cryopreservation for prostate cancer treatments is never proposed in 48.17% (n = 105) of responders but conversely it is always proposed in 5.05% (n = 11). The cryopreservation before bladder cancer treatments is not commonly proposed (67.5%, n = 154). CONCLUSION: Our study showed variable country specific tendencies in terms of fertility preservation in the period of treatment of urological cancers. These differences seem to be related to national guidelines recommendations. Standardization of international guidelines is urgently needed in the field of fertility for urological cancer patients.

ARNEO: A Randomized Phase II Trial of Neoadjuvant Degarelix with or Without Apalutamide Prior to Radical Prostatectomy for High-risk Prostate Cancer.

BACKGROUND: High-risk prostate cancer (PCa) patients have a high risk of biochemical recurrence and metastatic progression following radical prostatectomy (RP). OBJECTIVE: To determine the efficacy of neoadjuvant degarelix plus apalutamide before RP compared with degarelix with a matching placebo. DESIGN, SETTING, AND PARTICIPANTS: ARNEO was a randomized, placebo-controlled, phase II neoadjuvant trial before RP performed between March 2019 and April 2021. Eligible patients had high-risk PCa and were amenable to RP. INTERVENTION: Patients were randomly assigned at a 1:1 ratio to degarelix (240-80-80 mg) + apalutamide (240 mg/d) versus degarelix + matching placebo for 3 mo followed by RP. Prior to and following neoadjuvant treatment, pelvic 18F-PSMA-1007 positron emission tomography (PET)/magnetic resonance imaging (MRI) was performed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the difference in proportions of patients with minimal residual disease (MRD; = residual cancer burden (RCB) ≤0.25 cm3 at final pathology). Secondary endpoints included differences in prostate-specific antigen responses, pathological staging, and change in TNM stage on prostate-specific membrane antigen (PSMA) PET/MRI following hormonal treatment. Biomarkers (immunohistochemical staining on prostate biopsy [PTEN, ERG, Ki67, P53, GR, and PSMA] and PSMA PET/MRI-derived characteristics) associated with pathological response (MRD and RCB) were explored. RESULTS AND LIMITATIONS: Patients were randomized to neoadjuvant degarelix + apalutamide (n = 45) or degarelix + matching placebo (n = 44) for 12 wk and underwent RP. Patients in the degarelix + apalutamide arm achieved a significantly higher rate of MRD than those in the control arm (38% vs 9.1%; relative risk [95% confidence interval] = 4.2 [1.5-11], p = 0.002). Patients with PTEN loss in baseline prostate biopsy attained significantly less MRD (11% vs 43%, p = 0.002) and had a higher RCB at final pathology (1.6 vs 0.40 cm3, p < 0.0001) than patients without PTEN loss. Following neoadjuvant hormonal therapy, PSMA PET-estimated tumor volumes (1.2 vs 2.5 ml, p = 0.01) and maximum standardized uptake value (SUVmax; 4.3 vs 5.7, p = 0.007) were lower in patients with MRD than in patients without MRD. PSMA PET-estimated volume and PSMA PET SUVmax following neoadjuvant treatment correlated significantly with RCB at final pathology (both p < 0.001). CONCLUSIONS: In high-risk PCa patients, neoadjuvant degarelix plus apalutamide prior to RP results in a significantly improved pathological response (MRD and RCB) compared with degarelix alone. Our trial results provide a solid hypothesis-generating basis for neoadjuvant phase 3 trials, which are powered to detect differences in long-term oncological outcome following neoadjuvant androgen receptor signaling inhibitor therapy. PATIENT SUMMARY: In this study, we looked at the difference in pathological responses in high-risk prostate cancer patients treated with degarelix plus apalutamide or degarelix plus matching placebo prior to radical prostatectomy. We demonstrated that patients treated with degarelix plus apalutamide achieved a significantly better tumor response than patients treated with degarelix plus matching placebo. Long-term follow-up is required to determine whether improved pathological outcome translates into better oncological outcomes.

Radium-223 in patients with prostate specific antigen (PSA) progression and without clinical metastases following maximal local therapy: A pilot study.

BACKGROUND: Despite the curative intent of radical prostatectomy (RP) (+/- radiotherapy (RT)), 30% of the clinically localized prostate cancer (CaP) patients will develop rising PSA (prostate specific antigen). In absence of clinical recurrence, there is a lack of effective treatment strategies in order to control the disease at its earliest (micro)metastatic stage. The aim of this study was to assess safety, tolerability, and biochemical response of off-label Radium-223 (Xofigo) treatment in CaP patients with PSA relapse following maximal local therapy. METHODS: We conducted a prospective, single arm, single center open-label, pilot study with Radium-223 in CaP patients with rising PSA (>0.2 ng/ml) following RP + adjuvant/salvage RT. Negative staging with 68Ga-PSMA-11 PET/CT and whole-body MRI was mandatory at time of inclusion. Patients were eligible if they exhibited adverse clinico-pathological features predictive of significant recurrence. Safety, tolerability, biochemical progression (defined as PSA increase >50% from PSA nadir) and clinical recurrence were assessed. RESULTS: In total, 23 patients were screened of whom 8 patients were included is the study. Radium-223 treatment was safe with no serious treatment related adverse events. One patient developed grade 3 lymphopenia. All patients rapidly developed PSA progression (median PSA progression-free survival: 5.5 months). Eventually all patients experienced clinical recurrence (median clinical recurrence-free survival 11.0 months) of whom only 2 patients developed skeletal recurrence. CONCLUSIONS: Radium-223 in patients with PSA relapse following maximal local treatment without clinical metastases is safe. However, the clinical benefit of Ra-223 in this setting is doubtful as significant oncological benefit is lacking.

Minimally Invasive Buccal Mucosa Dorsal Graft for Female Distal Urethroplasty.

BACKGROUND: Female urethral stricture (FUS) represents a sporadic condition. There is a lack of data and standardized guidelines on diagnostics and therapeutics. Several surgical techniques have been described for FUS urethroplasty, among which the flap-based or graft-based ones are most reported. Buccal mucosa graft (BMG) represents the gold standard for male urethroplasty, and this can theoretically be applied also to FUS treatment. OBJECTIVE: To describe and present preliminary results of a novel minimally invasive technique for buccal mucosa dorsal graft (mini-dorsal BMG) urethroplasty for the treatment of FUS. DESIGN SETTING AND PARTICIPANTS: This is a retrospective study on buccal mucosa dorsal graft urethroplasty for the treatment of FUS. SURGICAL PROCEDURE: Every patient was placed in lithotomic position. Two stiches were placed at 10 and 2 o'clock positions to facilitate the dorsal median urethrotomy. The margins of the incised dorsal urethra at the 12 o'clock position are then dissected from the periurethral tissue. This dissection results in an elliptical raw area between the edges of the urethra over the periurethral tissue. The harvested BMG was fixed with several quilting sutures, using 5-0 and 4-0 absorbable sutures, to cover the raw area. The margins of the graft were sutured to the edges of the incised urethra. MEASUREMENTS: A chart review was performed. RESULTS AND LIMITATIONS: Thirteen patients underwent the mini-dorsal-BMG technique. The median preoperative uroflow was 5.6 (3-13) ml/s, and the median postoperative value was 23.4 (14-58) ml/s. CONCLUSIONS: The mini-dorsal-BMG technique for the treatment of FUS gives good results with low complication rates. Other series and long-term follow-up are necessary to confirm the reproducibility of this technique. PATIENT SUMMARY: We present the technical aspects and the promising preliminary results of a novel surgical technique for the treatment of female urethral stricture by using the buccal mucosa to correct this invalidating disease.

Prostate-Specific Antigen Modulatory Effect of a Fermented Soy Supplement for Patients with an Elevated Risk of Prostate Cancer: a Non-Randomized, Retrospective Observational Registration.

OBJECTIVE: To investigate the efficacy of a 6-month fermented soy supplement (equol-containing), measured by prostate-specific antigen (PSA) stabilization or PSA decrease from baseline (PSA modulatory effect) in men with an elevated risk of prostate cancer (PCa), with a WHO performance 0-2 and a follow-up of 12 months. METHODS: The patient population consisted of men with an elevated risk of PCa and a prior negative prostate biopsy within 1 year from starting therapy. Serum PSA values were recorded at inclusion (iPSA), at 6 months (1PSA), and optionally at 12 months (2PSA). Statistical analysis was carried out using the Wilcoxon rank sum test (p < 0.05). RESULTS: In total, 137 men used fermented soy for any prostatic reason. After inclusion criteria for an elevated risk of PCa and a prior negative prostate biopsy, we selected 58 patients. Among these, there was a significant PSA modulatory effect (iPSA-1PSA, p = 0.003). This modulatory effect was more strongly evident in the subgroup of patients with an elevated iPSA (≥ 4 ng/ml) (n = 33, iPSA-1PSA, p = 0.003, iPSA-2PSA, p = 0.002). CONCLUSIONS: We demonstrated a significant PSA modulatory effect of a 6-month fermented soy supplement in men with an elevated risk of PCa and a prior negative prostate biopsy. This positive effect is currently being investigated in a prospective study. Further evaluation of the role of fermented soy supplements is warranted in a preventive and therapeutic setting of men at an elevated risk of PCa.

Pushing the limits of metastasis-directed treatment in metastatic renal cell carcinoma in the era of targeted therapy.

OBJECTIVE: To assess the role of metastasis directed therapy and in particular surgical metastasectomy (MxT) in metastatic renal cell carcinoma (mRCC) in the era of targeted therapy. METHOD: The files of all patients who underwent MxT for treatment of mRCC in University Hospitals Leuven between 1989 and 2015 were reviewed. RESULTS: One hundred and thirty eight patients met the inclusion criteria. Mean age at MxT was 59.3 (IQR: 57.5-61.0) years. Median follow-up was 50.1 (42.3-63.8) months. Due to adequate patient selection, 91.9% of MxT achieved no evidence of disease status, which resulted in long median overall survival of 87.8 (63.8-113.4) months and median cancer specific survival of 92.8 (69.5-123.4) months. On multivariate analysis, primary tumor stage >pT2 (hazard ratio [HR] 2.79 [1.47-5.28] P= 0.002), unreached no evidence of disease status (HR 8.62 [3.19-23.32] P< 0.001), presence of nonpulmonary metastasis (HR 2.29 [1.02-5.10] P= 0.0449) and sarcomatoid dedifferentiation in the primary tumor (HR 4.52 [1.15-17.69] P= 0.03) significantly impacted overall survival. Survival did not differ for MxT performed before and after the advent of vascular endothelial growth factor receptor-tyrosine kinase inhibitors. DISCUSSION: Our study confirms the validity of MxT in mRCC in the tyrosine kinase inhibitors era. MxT should be considered in mRCC whenever the patient is fit enough to undergo surgery and complete removal of metastasis is considered possible, independent of number, location, and chronology of appearance of metastasis. Patients with pulmonary metastasis only, seem to be the best candidates for surgical MxT.

Correction to: Metastasectomy for visceral and skeletal oligorecurrent prostate cancer.

The authors have requested the removal of the Excel file in Electronic Supplementary Material to protect patient's privacy.

Development and external validation of a nomogram to predict lymph node invasion after robot assisted radical prostatectomy.

BACKGROUND: Prediction of lymph node invasion (LNI) after radical prostatectomy has been rarely assessed in robotically assisted laparoscopic radical prostatectomy (RALP) series. We aimed to develop and externally validate a pretreatment nomogram for the prediction of LNI following RALP in patients with high- and intermediate-risk prostate cancer. METHODS: 1654 RALP patients were prospectively collected between 2009 and 2016 from academic and community hospitals. We included patients with intermediate- and high-risk prostate cancer who underwent pelvic lymph node dissection (e-PLND). Logistic regression analysis was applied to construct a nomogram to predict LNI. Centers were randomly assigned to the training cohort (80%) and validation cohort (20%). The discriminative accuracies were evaluated by the areas under the curve and by the calibration plot. The net benefit of the nomogram to predict LNI was assessed by decision curve analysis and a cut-off was proposed. RESULTS: In total, 14% of the patients in our cohort had pN1 disease. Applying logistic regression analysis, the following covariates were chosen to develop the nomogram: initial PSA, clinical T stage, biopsy Gleason sum, and proportion of positive biopsy cores. The nomogram showed a median discriminative accuracy of 73% and excellent calibration. The net benefit of the model ranged between 7% and 51% predicted risk of LNI. A cut-off to perform e-PLND was set at 7%. This would permit a 29% of avoidable e-PLND, missing 9.4% of patients with LNI. CONCLUSIONS: We developed and externally validated a nomogram to predict LNI in patients treated with RALP from a prospective, multi-institutional, nationwide series. A risk of LNI > 7% is proposed as cut-off above which e-PLND is recommended.

Anatomical mapping of lymph nodes in patients receiving salvage lymphadenectomy based on a positive 11C-choline positron emission tomography/computed tomography scan.

INTRODUCTION: This paper aims to assess the diagnostic accuracy of an 11C-choline positron emission tomography/computed tomography (PET/CT) scan in the detection of lymph node (LN) metastases in patients with biochemical recurrence after radically treated prostate cancer (PCa), as compared to histology. The secondary goal is to depict spreading patterns of metastatic LNs in recurrent PCa. MATERIAL AND METHODS: A single center retrospective study comprising of 30 patients who underwent retroperitoneal and/or pelvic salvage lymph node dissection (LND) due to 11C-choline PET/CT-positive nodal recurrences after radical treatment (median Prostate Specific Antigen (PSA) 1.5 ng/ml, range 0.2-11.4). Positive nodes on the preoperative PET/CT scans were mapped and compared to post-operative pathology results.LNs were marked as true positive, false positive, true negative and false negative and a patient- and a region-based analysis was performed. Sensitivity, specificity and positive/negative predictive value (PPV/NPV) were calculated. RESULTS: Sixty positive LNs were detected on PET/CT with a median number of two positive nodes per patient (range 1-6). In 29 patients, a super-extended pelvic LND (PLND) was performed combined with a retroperitoneal LND (RPLND) in 13 of those cases. One patient underwent an inguinal LND. One hundred thirty-seven of 644 resected LNs contained metastases. The 11C-choline PET/CT scan correctly predicted 31 positive nodes (55%) while 25 nodes were falsely positive (45%). One hundred and six histologically proven metastatic nodes were not detected on the 11C-choline PET/CT scan (77%). Sensitivity, specificity, PPV and NPV of the 11C-choline PET/CT were 23%, 95%, 55% and 82%, respectively. CONCLUSIONS: 11C-choline PET/CT has a relatively low detection rate and a moderate PPV for metastatic LNs in patients with biochemical recurrence after radically treated PCa.

Validation of the Decipher Test for Predicting Distant Metastatic Recurrence in Men with High-risk Nonmetastatic Prostate Cancer 10 Years After Surgery.

BACKGROUND: Decipher is a genomic classifier designed to predict the development of distant metastases after surgical treatment of prostate cancer (PC). Its long-term prognostic role in a high-risk PC population has not been investigated previously. OBJECTIVE: To determine the prognostic role of the Decipher genomic classifier in two high-risk PC case-control studies. DESIGN, SETTING, AND PARTICIPANTS: Patients who developed distant metastases after surgery for high-risk, nonmetastatic PC in a European tertiary referral center from 1991 to 2011 were matched to patients not developing distant metastases (n=54). A validation study (n=298) was performed using a similar US case-control cohort. Formalin-fixed, paraffin-embedded tissue blocks from the index PC lesion were used for RNA extraction and gene expression analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome investigated was the development of distant metastasis within 10-yr follow-up. Multivariable logistic regression analysis was performed, with statistical significance considered at p<0.05. RESULTS AND LIMITATIONS: In both the European and US case-control studies, the median Decipher scores were higher in the population that developed metastases. In the multivariable analysis, each 10% increase in Decipher score translated to an increase in the risk of distant metastases within 10-yr follow-up, with an odds ratio of 1.53 (95% confidence interval [CI] 1.06-2.22; p=0.025) and 1.58 (95% CI 1.31-1.92; p<0.001) for the European and US cohorts, respectively. Median follow-up for the European cohort was 12yr (interquartile range 8-12). The study limitation is the small size of the European cohort. CONCLUSIONS: Our study validates Decipher as a predictor for metastatic recurrence even in patients with high-risk, nonmetastatic PC within 10-yr follow-up. PATIENT SUMMARY: Decipher is a test based on gene expression profiles in primary tumors in prostate cancer. It has already been proven to predict cancer recurrence after surgery, but this has not yet been shown for patients with high-risk prostate cancer. This is the first study confirming that Decipher predicts a patient's risk of developing cancer recurrence after surgery for high-risk prostate cancer.

Open and robotic radical prostatectomy.

Open retropubic radical prostatectomy has been the "gold standard" treatment for locally confined prostate cancer (PCa) but in recent years minimal invasive techniques as laparoscopy and robot-assisted prostatectomy have become widely available. The trifecta of the surgical treatment of PCa is cancer control, the preservation of continence, and erectile potency. Over the years the complication rates of radical prostatectomy have become very limited with improved cancer control and better functional results. We review the indications and the surgical technique of radical prostatectomy, be it open or laparoscopic, eventually robot-assisted as well as the pre- and postoperative measures and the surgery-related consequences.

Novel Insights into the Management of Oligometastatic Prostate Cancer: A Comprehensive Review.

CONTEXT: The current standard of care for metastatic prostate cancer (PCa) is androgen deprivation therapy (ADT) plus either docetaxel or abiraterone. Growing evidence suggests that metastasis-directed therapy (MDT) and/or local therapy targeted to the primary tumour (ie, prostate) may be of benefit in the setting of oligometastatic disease. Several prospective studies are underway; however, until robust evidence is available to guide treatment decisions, physicians are challenged with how best to manage patients with oligometastases. OBJECTIVE: This comprehensive review aims to collate the available evidence to date for a role of MDT and/or prostate-targeted therapy in the setting of oligometastatic PCa, as well as discuss ongoing trials in this setting. EVIDENCE ACQUISITION: We searched PubMed for the combination of "prostate cancer" and "oligometastatic", "oligometastases", "oligometastasis", "solitary metastases", "stereotactic body radiotherapy", "SBRT", "stereotactic ablative radiotherapy", "SABR", "salvage lymphadenectomy", or "metastasectomy" in publications over the last 20yr. We also searched ClinicalTrials.gov to identify relevant ongoing trials. EVIDENCE SYNTHESIS: The studies were divided according to the timing of metastasis into synchronous (ie, detected at the time of primary PCa diagnosis) and metachronous (ie, detected after treatment of the primary tumour), and according to treatment modality into MDT (including salvage lymph node dissection [sLND]) and prostate-targeted treatment. For MDT of synchronous/metachronous metastases, we included 16 completed studies and 11 ongoing prospective studies. In the case of sLND for nodal-only recurrence after primary treatment with curative intent, we included 11 completed studies. Finally, for prostate-targeted treatment of synchronous metastatic PCa, we included 25 completed studies and 11 ongoing prospective studies. In selected patients with oligorecurrent disease, early detection and aggressive treatment of metastatic lesions (surgery or radiotherapy) appears to be a feasible strategy and may delay the use of systemic therapies. MDT is a promising option in oligometastatic PCa patients, but more robust data are needed. In the setting of synchronous oligometastatic disease, aggressive cytoreductive treatment needs further data to confirm the benefits. CONCLUSIONS: In this review, we provide a comprehensive overview of the current literature on the treatment of patients with oligometastatic PCa. The data suggest that although ADT plus either docetaxel or abiraterone remains the mainstay of treatment for mPCa, in oligometastatic PCa, improved outcomes may be achieved with metastasis- and prostate-targeted therapies. The studies included in this review are mainly retrospective in nature, limiting the strength of the evidence they provide. Prospective studies are ongoing, and their results are eagerly awaited. PATIENT SUMMARY: We reviewed the treatment of patients with prostate cancer that has spread to five sites or fewer. We conclude that while androgen deprivation plus either docetaxel or abiraterone should remain the standard of care, there is evidence that treatment targeted at the metastases and the primary tumour may improve the outcome for the patient and potentially delay the use of systemic treatment.

Metastasectomy for visceral and skeletal oligorecurrent prostate cancer.

OBJECTIVES: Metastasis direct therapy (MDT) is a common practice in different fields of oncology. However, there is a lack of data on surgical MDT in visceral/skeletal oligometastatic prostate cancer (PCa). We aimed to assess the role of surgical excision of visceral and skeletal PCa recurrence. METHODS: Seventeen PCa patients experienced metachronous visceral or skeletal oligometastatic recurrence following maximal local treatment. Oligometastatic recurrence was defined as 1-3 lesions, detected with the best imaging technique available at the time of diagnosis. All patients underwent metastasectomy and were followed for a median of 43 months. Postoperative complications were graded using the Clavien-Dindo classification of surgical complications. Kaplan-Meier plots were used to assess overall survival. RESULTS: Fourteen patients (82%) had visceral lesions, two had bone lesions (12%), and one had an abdominal wall metastasis (6%). Four patients (24%) were under active ADT at the time of metastasectomy. PSA decreased after metastasectomy in 16 (94%) patients. Ten (77%) of the 13 ADT-naïve patients had a PSA decrease of ≥ 50%. Following metastasectomy, 16 (94.1%) patients developed metastatic recurrence of which 11 (64.7%) were again oligometastatic, amenable for repeated MDT. The median time to metastatic recurrence was 14 months (range 6.4-40). We observed 8% Clavien-Dindo grade 3-4 complications in 21 procedures. CONCLUSIONS: In this report, we analyzed the outcomes of surgical excision of visceral and skeletal PCa recurrence following primary treatment. We found that removing metastasis to the bone and viscera can be associated with long-term disease-free periods at a low rate of serious complications. These exploratory results should be confirmed in prospective studies.

Systematic Review of Systemic Therapies and Therapeutic Combinations with Local Treatments for High-risk Localized Prostate Cancer.

CONTEXT: Systemic therapies, combined with local treatment for high-risk prostate cancer, are recommended by the international guidelines for specific subgroups of patients; however, for many of the clinical scenarios, it remains a research field. OBJECTIVE: To perform a systematic review, and describe current evidence and perspectives about the multimodal treatment of high-risk prostate cancer. EVIDENCE ACQUISITION: We performed a systematic review of PubMED, Embase, Cochrane Library, European Society of Medical Oncology/American Society of Clinical Oncology Annual proceedings, and clinicalTrial.gov between January 2010 and February 2018 following the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. EVIDENCE SYNTHESIS: Seventy-seven prospective trials were identified. According to multiple randomized trials, combining androgen deprivation therapy (ADT) with external-beam radiotherapy (EBRT) outperforms EBRT alone for both relapse-free and overall survival. Neoadjuvant ADT did not show significant improvement compared with prostatectomy alone. The role of adjuvant ADT after prostatectomy in patients with high-risk disease is still debated, with lack of data from phase 3 trials in pN0 patients. Novel androgen pathway inhibitors have been tested only in early-phase trials in addition to primary treatment. GETUG 12, RTOG 0521, and nonmetastatic subgroup of the STAMPEDE trial showed improved relapse-free survival for docetaxel in patients treated with EBRT plus ADT, although mature metastasis-free survival data are still pending. Both the SPCG-12 and the VACSP#553 trial showed no improvement in relapse-free survival for adjuvant docetaxel after prostatectomy. CONCLUSIONS: In contrast to the clearly demonstrated survival benefits of long-term adjuvant ADT when used with EBRT, its role after prostatectomy remains unclear especially in pN0 patients. Adding docetaxel to EBRT-ADT improves relapse-free survival, with immature results on overall survival. Novel androgen receptor pathway inhibitors are currently being tested in the neoadjuvant and adjuvant setting. PATIENT SUMMARY: Treatment of high-risk prostate cancer is based on a multimodality approach that includes systemic treatments. The best treatment or therapy combination remains to be defined.

Neoadjuvant degarelix with or without apalutamide followed by radical prostatectomy for intermediate and high-risk prostate cancer: ARNEO, a randomized, double blind, placebo-controlled trial.

BACKGROUND: Recent retrospective data suggest that neoadjuvant androgen deprivation therapy can improve the prognosis of high-risk prostate cancer (PCa) patients. Novel androgen receptor pathway inhibitors are nowadays available for treatment of metastatic PCa and these compounds are promising for early stage disease. Apalutamide is a pure androgen antagonist with a very high affinity with the androgen receptor. The combination of apalutamide with degarelix, an LHRH antagonist, could increase the efficacy compared to degarelix alone. OBJECTIVE: The primary objective is to assess the difference in proportions of minimal residual disease at prostatectomy specimen between apalutamide + degarelix vs placebo + degarelix. Various secondary endpoints are assessed: variations of different biomarkers at the tumour level (tissue microarrays to evaluate DNA-PKs, PARP, AR and splice variants, PSMA, etc.), whole transcriptome sequencing, exome sequencing and clinical (PSA and testosterone kinetics, early biochemical recurrence free survival, quality of life, safety, etc.) and radiological endpoints. METHODS: ARNEO is a single centre, phase II, randomized, double blind, placebo-controlled trial. The plan is to include at least 42 patients per each of the two study arms. Patients with intermediate/high-risk PCa and who are amenable for radical prostatectomy with pelvic lymph node dissection can be included. After signing an informed consent, every patient will undergo a pelvic 68Ga -PSMA-11 PSMA PET/MR and receive degarelix at standard dosage and start assuming apalutamide/placebo (60 mg 4 tablets/day) for 12 weeks. Within thirty days from the last study medication intake the same imaging will be repeated. Every patient will undergo PSA and testosterone testing the day of randomization, before the first drug intake, and after the last dose. Formalin fixed paraffin embedded tumour samples will be collected and used for transcriptome analysis, exome sequencing and immunohistochemistry. DISCUSSION: ARNEO will allow us to answer, first, whether the combined treatment can result in an increased proportion of patients with minimal residual disease. Secondly, It will enable the study of the molecular consequences at the level of the tumour. Thirdly, what the consequences are of new generation androgen receptor pathway inhibitors on 68Ga -PSMA-11 PET/MR. Finally, various clinical, safety and quality of life data will be collected. TRIAL REGISTRATION: EUDRaCT number: 2016-002854-19 (authorization date 3rd August 2017). clinicalTrial.gov: NCT03080116 .

Molecular Subtypes of Clear-cell Renal Cell Carcinoma are Prognostic for Outcome After Complete Metastasectomy.

BACKGROUND: Metastasectomy is routinely performed in selected patients with metastatic clear-cell renal cell carcinoma (ccRCC) as an alternative to systemic therapy. In the absence of randomized trials, the benefit and best way of patient selection remain unclear. Earlier, we described four molecular ccRCC-subtypes (ccrcc1-4) that have a prognostic and predictive value upon first-line sunitinib or pazopanib. OBJECTIVE: Assess the prognostic value of ccrcc1-4 subtypes after complete metastasectomy. (1) Compare outcomes of good-prognosis ccrccc2&3-tumors with intermediate/poor-prognosis ccrcc1&4-tumors. (2) Compare outcomes of the four subtypes separately. DESIGN, SETTING, AND PARTICIPANTS: Single-center retrospective study (1995-2017), assessing 43 ccRCC patients undergoing complete metastasectomy without systemic treatment. INTERVENTION: Molecular subtype determined with established 35-gene expression classifier. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Median disease-free survival (DFS), time to systemic therapy, cancer-specific (CSS) and overall survival (OS) from metastasectomy, estimated with Kaplan-Meier method and tested against other predictors with multivariable Cox regression. RESULTS AND LIMITATIONS: Median DFS was 23 mo for ccrcc2&3-tumors versus 9 mo for ccrcc1&4-tumors (p=0.011, hazard ratio [HR]=2.6). Median time to systemic therapy was 92 mo versus 28 mo (p=0.003, HR=3.3). Median CSS was 133 mo versus 50 mo (p<0.001, HR=2.7). Median OS was 127 mo versus 50 mo (p=0.011, HR=2.5). The classification remained independent upon multivariable analysis. Outcomes remained significantly different when comparing four subtypes separately. The intrinsic heterogeneity of expression profiles is a limitation of this approach. CONCLUSION: Even after clinical patient selection, patients with a ccrcc1- or ccrcc4-tumor are at a higher risk of relapse after complete metastasectomy. Patients with a ccrcc2- or ccrcc3-tumor usually experience a long DFS. These results need validation in a larger cohort to establish the subtypes as prognostic marker. PATIENT SUMMARY: Metastasectomy is recommended for some patients with metastatic clear-cell kidney cancer; however, we do not know who will benefit the most. We show that molecular subtypes increase the possibility to predict which patients are at risk for early relapse after metastasectomy and who may benefit more from other treatment options.

Development and External Validation of Nomograms To Predict Adverse Pathological Characteristics After Robotic Prostatectomy: Results of a Prospective, Multi-institutional, Nationwide series.

BACKGROUND: The possibility of predicting pathologic features before surgery can support clinicians in selecting the best treatment strategy for their patients. We sought to develop and externally validate pretreatment nomograms for the prediction of pathological features from a prospective multicentre series of robotic-assisted laparoscopic prostatectomy (RALP) procedures. DESIGN, SETTING, AND PARTICIPANTS: Between 2009 and 2016, data from 6823 patients undergoing RALP in 25 academic and community hospitals were prospectively collected by the Belgian Cancer Registry. Logistic regression models were applied to predict extraprostatic extension (EPE; pT3a,b-4), seminal vesicle invasion (SVI; pT3b), and high-grade locally advanced disease (HGLA; pT3b-4 and Gleason score [GS] 8-10) using the following preoperative covariates: prostate-specific antigen, clinical T stage, biopsy GS, and percentage of positive biopsy cores. Internal and external validation was performed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The stability of the model was assessed via tenfold cross-validation using 80% of the cohort. The nomograms were independently externally validated using the test cohort. The discriminative accuracy of the nomograms was quantified as the area under the receiver operating characteristic curve and graphically represented using calibration plots. RESULTS AND LIMITATION: The nomograms predicting EPE, SVI, HGLA showed discriminative accuracy of 77%, 82%, and 88%, respectively. Following external validation, the accuracy remained stable. The prediction models showed excellent calibration properties. CONCLUSIONS: We developed and externally validated multi-institutional nomograms to predict pathologic features after RALP. These nomograms can be implemented in the clinical setting or patient selection in clinical trials. PATIENT SUMMARY: We developed novel nomograms using nationwide data to predict postoperative pathologic features and lethal prostate cancer.

The EMPaCT Classifier: A Validated Tool to Predict Postoperative Prostate Cancer-related Death Using Competing-risk Analysis.

BACKGROUND: Accurate prediction of survival after radical prostatectomy (RP) is important for making decisions regarding multimodal therapies. There is a lack of tools to predict prostate cancer-related death (PCRD) in patients with high-risk features. OBJECTIVE: To develop and validate a prognostic model that predicts PCRD combining pathologic features and using competing-risks analysis. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective multi-institutional observational cohort study of 5876 patients affected by high-risk prostate cancer. Patients were treated using RP and pelvic lymph node dissection (PLND) in a multimodal setting, with median follow-up of 49 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: For PCRD prediction, a multivariate model with correction for competing risks was constructed to evaluate pathologic high-risk features (pT3b-4, Gleason score ≥8, and pN1) as predictors of mortality. All possible associations of the predictors were combined, and then subgroups with similar risk of PCRD were collapsed to obtain a simplified model encoding subgroups with significantly differing risk. Eightfold cross-validation of the model was performed. RESULTS AND LIMITATIONS: After applying exclusion criteria, 2823 subjects were identified. pT3b-4, Gleason score ≥8, and pN1 were all independent predictors of PCRD. The simplified model included the following prognostic groups: good prognosis, pN0 with 0-1 additional predictors; intermediate prognosis, pN1 with 0-1 additional predictors; poor prognosis, any pN with two additional predictors. The cross-validation yielded excellent median model accuracy of 88%. The retrospective design and the short follow-up could limit our findings. CONCLUSIONS: We developed and validated a novel and easy-to-use prognostic instrument to predict PCRD after RP+PLND. This model may allow clinicians to correctly counsel patients regarding the intensity of follow-up and to tailor adjuvant treatments. PATIENT SUMMARY: Prediction of mortality after primary surgery for prostate cancer is important for subsequent treatment plans. We present an accurate postoperative model to predict cancer mortality after radical prostatectomy for high-risk prostate cancer.

Comparison of Functional Outcome after Extended versus Super-Extended Pelvic Lymph Node Dissection during Radical Prostatectomy in High-Risk Localized Prostate Cancer.

BACKGROUND: Urinary continence and erectile function (EF) are best preserved when meticulous dissection of prostate and nerve sparing technique are used during radical prostatectomy (RP). However, extent of lymph node dissection (LND) may also adversely affect functional results. OBJECTIVE: To determine whether performing a super-extended LND (seLND) has a significant effect on recovery of urinary continence and EF after RP. DESIGN SETTING AND PARTICIPANTS: All patients who underwent RP from January 2007 until December 2013 were handed questionnaires assessing continence and EF. All patients in whom at least an extended LND (eLND) was performed were selected. This search yielded 526 patients. 172 of these patients had filed out 2 or more questionnaires and were included in our analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All questionnaires were reviewed. We used Kaplan-Meier analyses and multivariate Cox analysis to assess the difference in recovery of continence and EF over time for eLND/seLND. Primary endpoints were full recovery of continence (no loss of urine) and full recovery of EF (successful intercourse possible). Patients who did not reach the endpoint when the last questionnaire was filled out were censored at that time. Median follow-up was 12.43 months for continence, and 18.97 months for EF. RESULTS AND LIMITATIONS: Patients undergoing seLND have a lower chance of regaining both urinary continence [hazard ratio (HR) 0.59, 95% CI 0.39-0.90, p = 0.026] and EF (HR 0.28, 95% CI 0.13-0.57, p = 0.009). Age at surgery had a significant influence on both continence and EF in multivariate analysis. Major limitation of the study was that no formal preoperative assessment of continence and potency was done. CONCLUSION: Extending the LND template beyond the eLND template may cause at least a significant delay in recovery of urinary continence and leads to less recovery of EF.

Long-term Impact of Adjuvant Versus Early Salvage Radiation Therapy in pT3N0 Prostate Cancer Patients Treated with Radical Prostatectomy: Results from a Multi-institutional Series.

BACKGROUND: Three prospective randomised trials reported discordant findings regarding the impact of adjuvant radiation therapy (aRT) versus observation for metastasis-free survival (MFS) and overall survival (OS) among patients with pT3N0 prostate cancer treated with radical prostatectomy (RP). None of these trials systematically included patients who underwent early salvage radiation therapy (esRT). OBJECTIVE: To test the hypothesis that aRT was associated with better cancer control and survival compared with observation followed by esRT. DESIGN, SETTING, AND PARTICIPANTS: Using a multi-institutional cohort from seven tertiary referral centres, we retrospectively identified 510 pT3pN0 patients with undetectable prostate-specific antigen (PSA) after RP between 1996 and 2009. Patients were stratified into two groups: aRT (group 1) versus observation followed by esRT in case of PSA relapse (group 2). Specifically, esRT was administered at a PSA level ≤0.5ng/ml. INTERVENTION: We compared aRT versus observation followed by esRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The evaluated outcomes were MFS and OS. Multivariable Cox regression analyses tested the association between groups (aRT vs observation followed by esRT) and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), surgical margin status (negative vs positive), and year of surgery. An interaction with groups and baseline patient risk was tested for the hypothesis that the impact of aRT versus observation followed by esRT was different by pathologic characteristics. The nonparametric curve fitting method was used to explore graphically the relationship between MFS and OS at 8 yr and baseline patient risk (derived from the multivariable analysis). RESULTS AND LIMITATIONS: Overall, 243 patients (48%) underwent aRT, and 267 (52%) underwent initial observation. Within the latter group, 141 patients experienced PSA relapse and received esRT. Median follow-up after RP was 94 mo (interquartile range [IQR]: 53-126) and 92 mo (IQR: 70-136), respectively (p=0.2). MFS (92% vs 91%; p=0.9) and OS (89% vs 92%; p=0.9) at 8 yr after surgery were not significantly different between the two groups. These results were confirmed in multivariable analysis, in which observation followed by esRT was not associated with a significantly higher risk of distant metastasis (hazard ratio [HR]: 1.35; p=0.4) and overall mortality (HR: 1.39; p=0.4) compared with aRT. Using the nonparametric curve fitting method, a comparable proportion of MFS and OS at 8 yr among groups was observed regardless of pathologic cancer features (p=0.9 and p=0.7, respectively). Limitations consisted of the retrospective nature of the study and the relatively small size of the patient population. CONCLUSIONS: At long-term follow-up, no significant differences between aRT and esRT were observed for MFS and OS. Our study, although based on retrospective data, suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT. PATIENT SUMMARY: At long-term follow-up, no significant differences in terms of distant metastasis and mortality were observed between immediate postoperative adjuvant radiation therapy (aRT) and initial observation followed by early salvage radiation therapy (esRT) in case of prostate-specific antigen relapse. Our study suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT.