Short-term Darolutamide (ODM-201) Concomitant to Radiation Therapy for Patients with Unfavorable Intermediate-risk Prostate Cancer: The Darius (AFU-GETUG P15) Phase 2 Trial Protocol.

BACKGROUND: Combination of androgen deprivation therapy (ADT) with external beam radiation therapy (EBRT) is a standard of care for patients with intermediate-risk prostate cancer (PCa). However, 6 months of ADT generates multiple side effects impacting quality of life (QoL). Darolutamide (an androgen receptor targeting agent [ARTA]) is associated with low blood-brain barrier penetrance and less drug-drug interaction. OBJECTIVE: To assess the efficacy of a combination of 6 months of darolutamide with EBRT to treat patients with unfavorable intermediate-risk PCa. DESIGN, SETTING, AND PARTICIPANTS: The DARIUS trial is a multicenter randomized non comparative phase 2 trial, randomizing the 6-months darolutamide + EBRT arm versus 6-months ADT + EBRT in patients with unfavorable intermediate-risk PCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint is a biological response defined as prostate-specific antigen ≤0.1 ng/ml at month six of darolutamide or ADT. The key secondary endpoints are biochemical recurrence-free survival, disease-free survival, safety, and QoL. Ancillary studies using radiomics and genomic classifier are planned. Sixty-two patients will be included. RESULTS AND LIMITATIONS: In this population of patients requiring ADT combined with EBRT, the use of an ARTA alone, such as darolutamide, may demonstrate antitumoral efficacy while minimizing toxicity and maintaining QoL. Limitations are mainly inherent to the open-label design of this study. CONCLUSIONS: Six months of darolutamide + EBRT compared with 6 months of ADT + EBRT may be efficient in terms of a biological response, avoiding toxicity and altered QoL attributable to ADT in patients with unfavorable intermediate-risk PCa. PATIENT SUMMARY: The ongoing DARIUS clinical trial assesses short-term (6 months) darolutamide treatment in association with external beam radiation therapy in men with localized prostate cancer. The trial investigates whether single-agent darolutamide can improve the biological response while maintaining a favorable tolerability profile.

Outcomes of lateral approach in robot-assisted radical prostatectomy: insights from a single-surgeon experience.

In the era of robotic prostate surgery, various techniques have been developed to improve functional outcomes. Urinary continence has shown satisfactory results, but the preservation of lateral nerves to the periprostatic capsule is only achievable by sparing the pubovesical complex. This study aims to present the first cases of lateral-approach robot-assisted radical prostatectomy (LRRP) performed by a novice surgeon. We conducted a retrospective analysis of 70 prostate cancer patients who underwent LRRP between October 2019 and September 2021, analyzing the perioperative and functional outcomes. The median operative time and intraoperative blood loss were 102 (92-108) minutes and 150 (130-180) mL, respectively. Five minor postoperative complications were reported, and the median hospital stay was 2 (1-2) days. Eleven positive surgical margins occurred. Potency and urinary continence recovery were achieved in 59 (84%) and 66 (94%) patients, respectively, 12 months after surgery. Our analysis shows that LRRP is a safe and effective procedure for prostate cancer surgery. Continence and potency recovery required a short learning curve, with an acceptable recovery rate even in the initial cases.

Prognostic value of programmed death ligand-1 and programmed death-1 expression in patients with upper tract urothelial carcinoma.

OBJECTIVE: To evaluate the prognostic value of programmed death ligand-1 (PD-L1) and programmed death-1 (PD-1) expression in patients with upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: A retrospective multicentre study was conducted in 283 patients with UTUC treated with radical nephroureterectomy (RNU) between 2000 and 2015 at 10 French hospitals. Immunohistochemistry analyses were performed using 2 mm-core tissue microarrays with NAT105® and 28.8® antibodies at a 5% cut-off for positivity on tumour cells and tumour-infiltrating lymphocytes to evaluate PD-L1 and PD-1 expression, respectively. Multivariable Cox regression models were used to determine the independent predictors of recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). RESULTS: Overall, 63 (22.3%) and 220 (77.7%) patients with UTUC had PD-L1-positive and -negative disease, respectively, while 91 (32.2%) and 192 (67.8%) had PD-1-positive and -negative disease, respectively. Patients who expressed PD-L1 or PD-1 were more likely to have pathological tumour stage ≥pT2 (68.3% vs 49.5%, P = 0.009; and 69.2% vs 46.4%, P < 0.001, respectively) and high-grade (90.5% vs 70.0%, P = 0.001; and 91.2% vs 66.7%, P < 0.001, respectively) disease with lymphovascular invasion (52.4% vs 17.3%, P < 0.001; and 39.6% vs 18.2%, P < 0.001, respectively) as compared to those who did not. In multivariable Cox regression analysis adjusting for each other, PD-L1 and PD-1 expression were significantly associated with decreased RFS (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.09-3.08, P = 0.023; and HR 1.59, 95% CI 1.01-2.54, P = 0.049; respectively), CSS (HR 2.73, 95% CI 1.48-5.04, P = 0.001; and HR 1.96, 95% CI 1.12-3.45, P = 0.019; respectively) and OS (HR 2.08, 95% CI 1.23-3.53, P = 0.006; and HR 1.71, 95% CI 1.05-2.78, P = 0.031; respectively). In addition, multivariable Cox regression analyses evaluating the four-tier combination of PD-L1 and PD-1 expression showed that only PD-L1/PD-1-positive patients (n = 38 [13.4%]) had significantly decreased RFS (HR 3.07, 95% CI 1.70-5.52; P < 0.001), CSS (HR 5.23, 95% CI 2.62-10.43; P < 0.001) and OS (HR 3.82, 95% CI 2.13-6.85; P < 0.001) as compared to those with PD-L1/PD-1-negative disease (n = 167 [59.0%]). CONCLUSIONS: We observed that PD-L1 and PD-1 expression were both associated with adverse pathological features that translated into an independent and cumulative adverse prognostic value in UTUC patients treated with RNU.

First case-series of robot-assisted pudendal nerve release: technique and outcomes.

OBJECTIVE: Pudendal Nerve Entrapment (PNE) may determine chronic pelvic pain associated with symptoms related to its innervation area. This study aimed to present the technique and report the outcomes of the first series of robot-assisted pudendal nerve release (RPNR). PATIENTS AND METHODS: 32 patients, who were treated with RPNR in our centre between January 2016 and July 2021, were recruited. Following the medial umbilical ligament identification, the space between this ligament and the ipsilateral external iliac pedicle is progressively dissected to identify the obturator nerve. The dissection medial to this nerve identifies the obturator vein and the arcus tendinous of the levator ani, which is cranially inserted into the ischial spine. Following the cold incision of the coccygeous muscle at the level of the spine, the sacrospinous ligament is identified and incised. The pudendal trunk (vessels and nerve) is visualized, freed from the ischial spine and medially transposed. RESULTS: The Median duration of symptoms was 7 (5, 5-9) years. The median operative time was 74 (65-83) minutes. The median length of stay was 1 (1-2) days. There was only a minor complication. At 3 and 6 months after surgery, a statistically significant pain reduction has been encountered. Furthermore, the Pearson correlation coefficient reported a negative relationship between the duration of pain and the improvement in NPRS score, - 0.81 (p = 0.01). CONCLUSIONS: RPNR is a safe and effective approach for the pain resolution caused by PNE. Timely nerve decompression is suggested to enhance outcomes.

StomaCare: quality of life impact after enhanced follow-up of ostomy patients by a home healthcare nursing service-a multicentre, randomized, controlled trial.

AIM: A stoma exposes patients to several complications which could impair their quality of life (QoL). In the last decade, the market for stoma therapy in France has evolved, with a significant increase in the activities of home health providers, meeting a need for patient follow-up and companionship. International studies have demonstrated the impact of the stoma therapist (ST) follow-up on the improvement of an ostomy patient's QoL. However, the impact of home stoma nurse management has not been analysed. In this context we would like to assess the added value on health-related QoL from the enhanced follow-up of ostomy patients by STs. METHODS: This is a randomized, controlled, open, national and multicentre trial (12 centres) which includes patients with an ostomy who benefit from either standard follow-up or from an enhanced and personalized follow-up with, in particular, regular consultations with an ST after discharge. The primary end-point is the 3-month QoL score obtained from the Stoma-QoL questionnaire. The secondary end-points are satisfaction of the care, comparison of QoL scores (Stoma-QoL and EuroQuol EQ-5D) and the economic gains by calculating the consumption of resources between the two arms. There will be a modified intention-to-treat analysis with 6-month follow-up in both study arms. DISCUSSION: The StomaCare trial will be the first randomized controlled study in France to evaluate the impact on QoL of an enhanced follow-up at home of ostomy patients by an ST.

Single-Center Experience of Focal Thermo-Ablative Therapy After Pelvic Radiotherapy for In-Field Prostate Cancer Oligo-Recurrence.

PURPOSE: In-field prostate cancer (PCa) oligo-recurrence after pelvic radiotherapy is a challenging situation for which metastasis-directed treatments may be beneficial, but options for focal therapies are scarce. METHODS: We retrospectively reviewed data for patients with three or less in-field oligo-recurrent nodal, bone and/or locally recurrent (prostate, seminal vesicles, or prostatic bed) PCa lesions after radiation therapy, identified with molecular imaging (PET and/or MRI) and treated by focal ablative therapy (cryotherapy or radiofrequency) at the Institut Bergonié between 2012 and 2020. Chosen endpoints were the post-procedure PSA response (partially defined as a >50% reduction, complete as a PSA <0.05 ng/ml), progression-free survival (PFS) defined as either a biochemical relapse (defined as a rise >25% of the Nadir and above 2 ng/ml), radiological relapse (on any imaging technique), decision of treatment modification (hormonotherapy initiation or line change) or death, and tolerance. RESULTS: Forty-three patients were included. Diagnostic imaging was mostly 18F-Choline positron emission tomography/computerized tomography (PET/CT) (75.0%), prostate specific membrane antigen (PSMA) PET/CT (9.1%) or a combination of pelvic magnetic resonance imaging (MRI), CT, and 99 mTc-bone scintigraphy (11.4%). PSA response was observed in 41.9% patients (partial in 30.3%, complete in 11.6%). In the hormone-sensitive exclusive focal ablation group (n = 31), partial and complete PSA responses were 32.3 and 12.9% respectively. Early local control (absence of visible residual active target) on the post-procedure imaging was achieved with 87.5% success. After a median follow-up of 30 months (IQR 13.3-56.8), the median PFS was 9 months overall (95% CI, 6-17), and 17 months (95% CI, 11-NA) for PSA responders. Complications occurred in 11.4% patients, with only one grade IIIb Dindo-Clavien event (uretral stenosis requiring endoscopic uretrotomy). CONCLUSION: In PCa patients showing in-field oligo-recurrence after pelvic radiotherapy, focal ablative treatment is a feasible option, possibly delaying a systemic treatment initiation or modification. These invasive strategies should preferably be performed in expert centers and discussed along other available focal strategies in multi-disciplinary meetings.

Standardizing immunohistochemistry methodology for evaluation of PD-1 and PDL-1 expression in upper tract urothelial carcinoma.

INTRODUCTION: Controversy regarding the prognostic and/or predictive role of PD-1 and PD-L1 expression for upper tract urothelial carcinoma (UTUC) could partly be explained by inconsistencies in the immunohistochemistry (IHC) methodology. Objective is to standardize the methodology for routine evaluation of PD-1 and PD-L1 expression in UTUC patients. MATERIALS AND METHODS: Twenty-two cases treated with radical nephroureterectomy between 1996 and 2015 at 11 French hospitals were randomly selected to compare different methodologies for evaluation of PD-1 and PD-L1 expression. IHC was carried out on whole tissue sections and 0.6 mm- or 2 mm-core tissue micro-arrays (TMAs) using PD-1 NAT105 and PD-L1 28.8 or E1L3N on both tumor cells and tumor-infiltrating immune cells (TILs). Results obtained with whole tissue sections (WTS) were compared to those obtained with 0.6 mm- and 2 mm-core TMAs. Concordance was evaluated using Kappa coefficient. RESULTS: For evaluation of PD-1 and PD-L1 expression, the best concordance with WTS was observed using the PD-1 NAT105 and PD-L1 28.8 antibody on 2 mm-core TMAs, with 5% cut off for positivity on TILs and tumor cells, respectively (Kappa = 0.8). CONCLUSIONS: The most accurate methodology for routine evaluation of PD-1 and PD-L1 expression in UTUC may be based on 2 mm-core TMAs using NAT105 and 28.8 antibodies with a 5% cut off for positivity on TILs and tumor cells, respectively.

Prostate cancer and PARP inhibitors: progress and challenges.

Despite survival improvements achieved over the last two decades, prostate cancer remains lethal at the metastatic castration-resistant stage (mCRPC) and new therapeutic approaches are needed. Germinal and/or somatic alterations of DNA-damage response pathway genes are found in a substantial number of patients with advanced prostate cancers, mainly of poor prognosis. Such alterations induce a dependency for single strand break reparation through the poly(adenosine diphosphate-ribose) polymerase (PARP) system, providing the rationale to develop PARP inhibitors. In solid tumors, the first demonstration of an improvement in overall survival was provided by olaparib in patients with mCRPC harboring homologous recombination repair deficiencies. Although this represents a major milestone, a number of issues relating to PARP inhibitors remain. This timely review synthesizes and discusses the rationale and development of PARP inhibitors, biomarker-based approaches associated and the future challenges related to their prescription as well as patient pathways.

Robot-assisted versus open surgery for radical nephrectomy with level 1-2 vena cava tumor thrombectomy: a French monocenter experience (UroCCR study #73).

BACKGROUND: The aim of this paper was to assess the feasibility of robot-assisted radical nephrectomy (RN) with inferior vena cava thrombectomy (RRVCT) and compare perioperative and oncological outcomes of this approach to open surgery for renal tumors with level 1-2 inferior vena cava (IVC) thrombus. METHODS: We performed a retrospective analysis of patients surgically treated for renal cancer with IVC level 1-2 thrombus in the Urology department of Bordeaux University Hospital between December 2015 and December 2019. Patients were stratified by surgical approach in two groups: open vs. robotic procedures. Pre-, per- and postoperative data were collected within the framework of the UroCCR project (NCT03293563). Univariate and multivariate analysis using regression models were performed. RESULTS: A total of 40 patients underwent RN with IVC tumor thrombus. Open and robotic surgery represented respectively 30 and 10 cases. The two groups were comparable regarding pre-operative tumor and patient characteristics. Robotic procedures were associated with lower estimated blood loss (EBL) (500 vs. 1250 mL, P=0.02), shorter Intensive Care Unit stay (2 vs. 4 days, P=0.03) and decrease of global length of stay (LOS) (7 vs. 10 days, P<0.01). Operative Time (OT) was significantly longer in the robotic group (350.5 vs. 208 min, P<0.01). No difference were observed between the two approaches regarding complications and oncological outcomes. CONCLUSIONS: Robotic approach induced lower bleeding and shorter LOS but required longer OT. This technique is feasible and safe for selected cases and experimented surgical teams. Complications rate and oncological outcomes are not different compared to standard open procedures.

Localized chromophobe carcinomas treated by nephron-sparing surgery have excellent oncologic outcomes.

OBJECTIVE: To evaluate the oncologic outcomes of nephron-sparing surgery (NSS) for localized chromophobe renal cell carcinoma (cRCC). MATERIAL AND METHODS: We performed a multicenter international study involving the French Network for Research on Kidney Cancer (UroCCR) and 5 international teams. Data from 808 patients treated with NSS between 2004 and 2014 for non-clear cell RCCs were analyzed. RESULTS: We included 234 patients with cRCC. There were 123 (52.6%) females. Median age was 61 (23-88) years. Median tumor size was 3 (1-11)cm. A positive surgical margin was identified in 14 specimens (6%). Pathologic stages were T1, T2, and T3a in 202 (86.3%), 9 (3.8%), and 23 (9.8%) cases, respectively. After a mean follow-up of 46.6 ± 36 months, 2 (0.8%) patients experienced a local recurrence. No patient had metastatic progression, and no patient died from cancer. Three-years estimated cancer-free survival and cancer-specific survival were 99.1% and 100%, respectively. CONCLUSION: Oncological results of NSS for localized cRCC are excellent. In this series, only 2 patients had a local recurrence, and no patient had metastatic progression or died from cancer.

The subclassification of papillary renal cell carcinoma does not affect oncological outcomes after nephron sparing surgery.

OBJECTIVES: To evaluate the oncological outcomes of papillary renal cell carcinoma (pRCC) following nephron sparing surgery (NSS) and to determine whether the subclassification type of pRCC could be a prognostic factor for recurrence, progression, and specific death. MATERIALS AND METHODS: An international multicentre retrospective study involving 19 institutions and the French network for research on kidney cancer was conducted after IRB approval. We analyzed data of all patients with pRCC who were treated by NSS between 2004 and 2014. RESULTS: We included 486 patients. Tumors were type 1 pRCC in 369 (76 %) cases and type 2 pRCC in 117 (24 %) cases. After a mean follow-up of 35 (1-120) months, 8 (1.6 %) patients experienced a local recurrence, 12 (1.5 %) had a metastatic progression, 24 (4.9 %) died, and 7 (1.4 %) died from cancer. Patients with type I pRCC had more grade II (66.3 vs. 46.1 %; p < 0.001) and less grade III (20 vs. 41 %; p < 0.001) tumors. Three-year estimated cancer-free survival (CFS) rate for type 1 pRCC was 96.5 % and for type 2 pRCC was 95.1 % (p = 0.894), respectively. Three-year estimated cancer-specific survival rate for type 1 pRCC was 98.4 % and for type 2 pRCC was 97.3 % (p = 0.947), respectively. Tumor stage superior to pT1 was the only prognostic factor for CFS (HR 3.5; p = 0.03). CONCLUSION: Histological subtyping of pRCC has no impact on oncologic outcomes after nephron sparing surgery. In this selected population of pRCC tumors, we found that tumor stage is the only prognostic factor for cancer-free survival.