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Background : Cisplatin-based combination chemotherapy before surgery is the standard of care for muscle-invasive bladder cancer. However, the optimal chemotherapy modalities have not been precisely defined to date. Patients and Methods : In the VESPER trial, patients received after randomization either gemcitabine and cisplatin (GC, 4 cycles) or methotrexate, vinblastine, doxorubicin and cisplatin (dose dense [dd]-MVAC, 6 cycles). Creatinine clearance (CrCl) was calculated before each cycle according to the Cockroft and Gault formula. Definition criteria for local control after neoadjuvant chemotherapy included pathological complete response (ypT0N0), pathological downstaging ( Results : A total of 2,128 cycles of chemotherapy were delivered, including 2,120 (99.6%) with cisplatin. Full doses of cisplatin were given in 1866 (88%) cycles. Twenty-three (4.7%) patients had to stop chemotherapy (12 GC, 11 dd-MVAC) because of renal failure. No difference in CrCl median values was observed between the two regimens during the first four cycles. A mild decrease occurred thereafter in patients treated with two additional cycles of dd-MVAC. A minimum total dose of 270 mg/m2 for cisplatin was mandatory to optimize pathological complete responses. Conclusion : At least 4 cycles of cisplatin-based chemotherapy should be delivered before cystectomy. Increasing the number of cycles beyond 4 cycles does not lead to a clinically significant deterioration in renal function but without obvious gain on local control. MicroAbstractCGC : A deep analysis of data from a randomized trial of perioperative chemotherapy in muscle-invasive bladder cancer shows that a minimum number of 4 cycles is required to optimize the chances of pathological complete response at cystectomy. Increasing the number beyond 4 cycles does not lead to a clinically significant deterioration in renal function without any obvious gain on pathological complete response.

This study looked at whether epidermal growth factor receptor inhibition by the monoclonal antibody panitumumab could increase the efficacy of standard chemotherapy in advanced urothelial cancer. Results were disappointing, with higher toxicity and no improvement in efficacy in the combination arm. Background: Epidermal growth factor receptor (EGFR) overexpression is frequent and associated with poor outcome in urothelial carcinoma. EGFR inhibition could improve the antitumor activity of chemotherapy. Patients and Methods: Patients with advanced, treatment-naive, histologically confirmed advanced urothelial carcinoma and no HRAS or KRAS mutation in the primary tumor received dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) without or with the anti-EGFR monoclonal antibody panitumumab (Pmab). A randomized (1:2) phase II design was used with progression-free survival (PFS) as the primary endpoint. Results: Ninety-seven eligible patients were randomized; 96 patients were evaluable for toxicity and 87 for efficacy. The median PFS were 6.8 months (95% confidence interval [CI], 6.3-9.2) for dd-MVAC and 5.7 months (95% CI, 4.6-6.4 months) for dd-MVAC+Pmab. For both immunohistochemical and molecular definition of basal/squamous-like (BASQ) tumors, no difference was observed in objective response rates or PFS between the two arms in BASQ and non-BASQ tumors. Conclusion: dd-MVAC+Pmab was associated with more serious adverse events and no improvement in efficacy outcomes.

International audience; Basal cell carcinoma (BCC) is the most common human malignancy. In most cases, BCC has slow progression and can be definitively cured by surgery or radiotherapy. However, in rare cases, it can become locally advanced or, even more rarely, metastatic. The alternative recommended treatments are Sonic Hedgehog pathway inhibitors; however, the response is often short-lived.Methods: This was a phase 2 basket study (NCT03012581) evaluating the efficacy and safety of nivolumab in a cohort of 32 advanced BCC patients, enrolled after failure of Sonic Hedgehog inhibitors, including 29 laBCC (91%) and 3 mBCC (9%).Results: Compared to previously published studies, our population consisted of severe patients with a poor prognosis because they had already received multiple lines of treatment: all patients received previous Sonic Hedgehog inhibitors, 53% of patients already had chemotherapy and 75% radiotherapy. At 12 weeks, we reported 3.1% of complete responses, 18.8% of partial responses, and 43.8% of stable diseases. The best response rate to nivolumab reached 12.5% of complete responses (four patients), 18.8% of partial responses (three patients), and 43.8% of stable diseases (14 patients). Adverse events (AE) were mostly grade 2 or 3, slightly different to the adverse events observed in the treatment of metastatic melanoma (higher rate of diabetes, no thyroid dysfunction).Conclusion: Nivolumab is a relevant therapeutic option for patients with advanced relapsing/refractory BCC.

International audience; Background: We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups.Methods: This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment.Findings: Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6-18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25-1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0·78 [95% CI 0·20-3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumab-ipilimumab (OR 0·95 [95% CI 0·38-2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab-ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab-ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib.Interpretation: We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma.

126 Background: CABASTY trial investigated the benefit of an adapted schedule of cabazitaxel (16 mg/m2 bi-weekly versus 25 mg/m2 tri-weekly) in mCRPC patients previously treated with docetaxel and alternative androgen-targeted therapy. The study met its endpoints with a significantly decreased incidence of grade ≥ 3 neutropenia without a decrease in overall survival. This preplanned analysis evaluated the prognostic impact of neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-platelets ratio (NPR) myeloid derived suppressor cells (MDSC) and leukocyte subtypes counts in this setting. Methods: 44 patients treated with cabazitaxel were included. Peripheral blood mononuclear cells were isolated and myeloid compartment analysis were performed at baseline, week 6 (S6) and week 12 (S12) of treatment using a multi-parametric flow cytometry panel. We investigated at each timepoints the association of NPR, NLR, MDSC and leukocytes subtypes with PSA response rate (PSArr), Progression Free Survival, and Overall Survival with a preplanned uni- and multivariate analysis. Results: The NLR, NPR, MDSC subtypes and lymphocytes count at baseline were prognostic in the CABASTY trial regardless of the cabazitaxel regimen. Patients with a high lymphocyte count and/or a low NLR, NPR, and MDSC counts at baseline had a significantly improved PSAr, PFS and OS. In the multivariate analysis, a NPR > 1,84 and lymphocytes count < 1,2 G/L at baseline were significantly associated with OS [HR 2.007 (1.3 - 3.1)] and [HR 0.38 (0.20 - 0.73)]. Conclusions: High NLR, NPR, neutrophil and MDSC counts as well as a low lymphocyte count at baseline and during treatment predict poor outcomes in mCRPC patients treated with cabazitaxel. NPR and lymphocyte count are readily available biomarkers that may be useful for risk stratification in future clinical trials and could be incorporated into prognostic nomograms. Clinical trial information: NCT02961257 .

490 Background: Evaluation of Patient-Reported Outcomes (PROs) is a major element used by health authorities for treatment approval. Pembrolizumab is a validated second-line treatment for locally advanced or metastatic urothelial carcinoma (la/mUC). In this real-life study, we aimed to describe la/mUC patients’ health-related quality of life (HRQoL) and patient/clinician-reported symptoms before and after pembrolizumab initiation. Here, we present interim results to assess clinical relevance for further analysis. Methods: A multicenter prospective French study was designed. PROs were assessed before pembrolizumab initiation (baseline) and at each treatment visit for seven timepoints. We report the analyses of the first three timepoints. HRQoL was measured using the European Organization for Research and Treatment of Cancer Quality-of-life Questionnaire-Core 30 (EORTC QLQ-C30) and the EuroQoL 5-dimensions 5-level (EQ-5D-5L) questionnaires. PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE) and CTCAE were assessed for 20 selected symptoms by both patients and clinicians in a blinded manner. Agreement in severity between clinicians and patients for all grade ≥3 symptoms was calculated with Cohen's kappa coefficient. Results: 39 patients were analyzed. Baseline completion rates were 69%, 62%, 59% and 12.8% for EORTC QLQ-C30, EQ-5D-5L, PRO-CTCAE and CTCAE respectively. Baseline median EORTC QLQ-C30 global health and summary scores were respectively 66.7 [interquartile range; 54.2, 79.2] and 83.6 [73.9, 94]. Improvement in EORTC QLQ-C30 global health median score to cycle 2 was observed in 33.3% patients, while the remaining patients experienced worsening score. Baseline mean EQ-5D-5L Visual Analog Scale score was 65.3 (Standard deviation (SD), 21.6), and 63.5 (SD, 16.1) at cycle 2. EQ-5D-5L domains scored level 1 decreased between baseline and cycle 2 for mobility (16 vs 14 patients) (p=0.0143), self-care (16 vs 14 patients) (p=0.0048), and usual activities (15 vs 14 patients) (p=0.015). Of 17 severity assessed symptoms, the Cohen's kappa coefficient was fair ĸ=0.35 (95% confidence interval (CI) [-0.08; 0.78]) for general pain, and bad ĸ=-0.063 (95%CI [-0.17; -0, 04]) for abdominal pain. In terms of symptom frequency, patients reported 19 symptoms at each visit. However, clinicians reported 13 and 14 symptoms respectively at baseline and cycle 2. Conclusions: HRQoL for la/mUC patients after first pembrolizumab infusion showed contradictory results with previous reports with a trend for HRQoL degradation after one treatment cycle. Comparative symptom severity assessment showed poor agreement between patients and clinicians. Clinicians graded symptoms less severely than patients. The final analysis will provide more complete data with longitudinal analysis to strengthen our preliminary conclusions. Clinical trial information: NCT03584659 .

Pimasertib is a selective, potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor. The aim of this study was to describe the efficacy, safety, and pharmacodynamics of pimasertib at pharmacologically active doses in a cohort of patients with locally advanced/metastatic melanoma from a first-in-human study of pimasertib. This was a phase I, open-label, two-part, dose-escalation study. Part 1 was conducted in patients with solid tumors and identified the maximum tolerated dose, while Part 2 was restricted to patients with advanced/metastatic melanoma. Endpoints included safety, pharmacodynamics, and antitumor activity. We present data for patients with melanoma only from both parts of the study. In total, 93 patients with melanoma received pimasertib, 89 of whom received pharmacologically active doses (28–255 mg/day) across four dose regimens in the two parts of the study. The objective response rate was 12.4% (11/89): complete response (n = 1) and partial response (PR; n = 10). Six patients responded for > 24 weeks. Nine of the 11 responders had tumors with B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF; n = 6) and/or NRAS Proto-Oncogene, GTPase (NRAS; n = 3) mutations. Forty-six patients had stable disease (SD). In patients with ocular melanoma (n = 13), best overall response was PR (n = 1), SD (n = 11), and disease progression (n = 1). Phosphorylated extracellular signal-regulated kinase (pERK) levels were substantially reduced within 2 h of treatment and inhibition was sustained with continuous twice-daily dosing. Treatment-related, recurrent, grade 3 or higher adverse events were reported in eight patients, including diarrhea, and skin and ocular events. Results from this phase I study indicate that pimasertib has clinical activity in patients with locally advanced/metastatic melanoma, particularly BRAF- and NRAS-mutated tumors, at clinically relevant doses associated with pERK inhibition in peripheral blood mononuclear cells. ClinicalTrials.gov, NCT00982865

The Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Ras/Raf/MEK/ERK) signaling cascade is frequently constitutively activated in human cancers. Pimasertib is a selective and potent adenosine triphosphate non-competitive MEK1/2 inhibitor. Our objectives were to describe the results of a phase I, first-in-human, dose-escalation trial of pimasertib that investigated the maximum tolerated dose, recommended phase II dose, and safety, as well as other endpoints. Four dosing schedules of pimasertib (once daily [qd], 5 days on, 2 days off; qd, 15 days on, 6 days off; continuous qd; continuous twice daily [bid]) were evaluated in patients with advanced solid tumors. Each treatment cycle lasted 21 days. The primary objective was to determine the maximum tolerated dose based on dose-limiting toxicities (DLTs) evaluated during cycle 1, and the recommended phase II dose (RP2D). Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and antitumor activity. Overall, 180 patients received pimasertib (dose range 1–255 mg/day). DLTs were mainly observed at doses ≥ 120 mg/day and included skin rash/acneiform dermatitis and ocular events, such as serous retinal detachment. The most common drug-related adverse events were consistent with class effects, including diarrhea, skin disorders, ocular disorders, asthenia/fatigue, and peripheral edema. The median time to maximum pimasertib concentration was 1.5 h across dosing schedules, and the apparent terminal half-life was 5 h across qd dosing schedules. Pimasertib decreased ERK phosphorylation within 2 h of administration, which was maintained for up to 8 h at higher doses and prolonged with bid dosing. Based on the safety profile and efficacy signals, a continuous bid regimen was the preferred dosing schedule and the RP2D was defined as 60 mg bid. ClinicalTrials.gov, NCT00982865.

Summary Objective. - To update French guidelines for the management of bladder cancer specifically non-muscle invasive (NMIBC) and muscle-invasive bladder cancers (MIBC). Methods. - A Medline search was achieved between 2018 and 2020, notably regarding diagnosis, options of treatment and follow-up of bladder cancer, to evaluate different references with levels of evidence. Results. - Diagnosis of NMIBC (Ta, T1, CIS) is based on a complete deep resection of the tumor. The use of fluorescence and a second-look indication are essential to improve initial diagnosis. Risks of both recurrence and progression can be estimated using the EORTC score. A stratification of patients into low, intermediate and high risk groups is pivotal for recommending adjuvant treatment: instillation of chemotherapy (immediate post-operative, standard schedule) or intravesical BCG (standard schedule and maintenance). Cystectomy is recommended in BCG-refractory patients. Extension evaluation of MIBC is based on contrast-enhanced pelvic-abdominal and thoracic CT-scan. Multiparametric MRI can be an alternative. Cystectomy associated with extended lymph nodes dissection is considered the gold standard for non-metastatic MIBC. It should be preceded by cisplatin-based neoadjuvant chemotherapy in eligible patients. An orthotopic bladder substitution should be proposed to both male and female patients with no contraindication and in cases of negative frozen urethral samples; otherwise transileal ureterostomy is recommended as urinary diversion. All patients should be included in an Early Recovery After Surgery (ERAS) protocol. For metastatic MIBC, first-line chemotherapy using platin is recommended (GC or MVAC), when performans status (PS 60 mL/min) allow it (only in 50% of cases). In second line treatment, immunotherapy with pembrolizumab demonstrated a significant improvement in overall survival. Conclusion. - These updated French guidelines will contribute to increase the level of urological care for the diagnosis and treatment of patients diagnosed with NMIBC and MIBC.

summary Introduction. –The purpose was to propose an update of the French guidelines from the national committee ccAFU on upper tract urothelial carcinomas (UTUC). Methods. – A systematic Medline search was performed between 2018 and 2020, as regards diagnosis, options of treatment and follow-up of UTUC, to evaluate different references with levels of evidence. Results. – The diagnosis of this rare pathology is based on CT-scan acquisition during excretion and ureteroscopy with histological biopsies. Radical nephroureterectomy (RNU) remains the gold standard for surgical treatment, nevertheless a conservative endoscopic approach can be proposed for low risk lesion: unifocal tumor, possible complete resection and low grade and absence of invasion on CT-scan. Close monitoring with endoscopic follow-up (flexible ureteroscopy) in compliant patients is therefore necessary. After RNU, bladder instillation of chemotherapy is recommended to reduce risk of bladder recurrence. A systemic chemotherapy is recommended after RNU in pT2–T4 N0–3 M0 disease. Conclusion. – These updated guidelines will contribute to increase the level of urological care for diagnosis and treatment for UTUC.

International audience; Nivolumab and cabozantinib are approved agents in mRCC patients after sunitinib/pazopanib (TKI) failure. However, the optimal sequence, cabozantinib then nivolumab (CN) or nivolumab then cabozantinib (NC), is still unknown. The CABIR study aimed to identify the optimal sequence between CN and NC after frontline VEGFR-TKI. In this multicenter retrospective study, we collected data from mRCC pts receiving CN or NC, after frontline VEGFR-TKI. A propensity score (PrS) was calculated to manage bias selection, and sequence comparisons were carried out with a cox model on a matched sample 1:1. The primary endpoint was progression-free survival (PFS) from the start of second line to progression in third line (PFS2-3 ). Key secondary endpoints included overall survival from second line (OS2 ). Out of 139 included mRCC patients, 38 (27%) and 101 (73%) received CN and NC, respectively. Overlap in PrS allowed 1:1 matching for each CN pts, with characteristics well balanced. For both PFS2-3 and OS2 , NC sequence was superior to CN (PFS2-3 : HR = 0.58 [0.34-0.98], P = .043; OS2 : 0.66 [0.42-1.05], P = .080). Superior PFS2-3 was in patients treated between 6 and 18 months with prior VEGFR-TKI (P = .019) and was driven by a higher PFSL3 with cabozantinib when given after nivolumab (P

Resume Objectif L’objectif de cet article est de faire une mise au point des donnees actuelles sur l’immunotherapie en uro-oncologie. Materiel et methodes Synthese des donnees de la litterature recente et des donnees presentees en congres nationaux et internationaux sur l’immunotherapie dans les cancers urologiques. Resultats Les nouvelles immunotherapies agissent en restaurant l’immunite antitumorale, en bloquant les points de retrocontrole negatif. Dans les cancers du rein et de la vessie, aux stades metastatiques, l’immunotherapie a montre un benefice en survie globale en deuxieme ligne, et plus recemment en premiere ligne de traitement pour le rein. Des essais sont actuellement en cours en situation adjuvante et neoadjuvante. Dans le cancer de la prostate, les donnees sont encore preliminaires et peu de patients semblent en beneficier. Conclusion L’immunotherapie a fait ses preuves dans les cancers du rein et de la vessie. L’identification de marqueurs predictifs devrait nous permettre a l’avenir de mieux selectionner les patients potentiellement repondeurs.

INTRODUCTION AND OBJECTIVE:Although HIFU treatment showed promising oncological results in several retrospective studies, large and comparative prospective studies are yet missing. The HiFi study (...

Simple Summary Many kinase inhibitors have been tested as potential alternatives for the treatment of castration-resistant prostate cancers. However, none of these clinical trials led to drug approval despite interesting responses. Our study reveals that genes involved in drug metabolism and their master regulator PXR (Pregnane X Receptor) could be responsible, at least in part, for these disappointing results as they can modulate tumor cell response to specific kinase inhibitors. We found that stable expression of PXR sensitized prostate cancer cells to erlotinib, dabrafenib, and afatinib, while it rendered cells resistant to dasatinib and had no effect for other inhibitors tested. We also report for the first time that sensitization to afatinib is due to an alteration in drug transport that involves the SLC16A1 monocarboxylate transporter. Together, our results further indicate that PXR might be considered as a biomarker of response to kinase inhibitors in castration-resistant prostate cancers. Abstract Resistance to castration is a crucial issue in the treatment of metastatic prostate cancer. Kinase inhibitors (KIs) have been tested as potential alternatives, but none of them are approved yet. KIs are subject of extensive metabolism at both the hepatic and the tumor level. Here, we studied the role of PXR (Pregnane X Receptor), a master regulator of metabolism, in the resistance to KIs in a prostate cancer setting. We confirmed that PXR is expressed in prostate tumors and is more frequently detected in advanced forms of the disease. We showed that stable expression of PXR in 22Rv1 prostate cancer cells conferred a resistance to dasatinib and a higher sensitivity to erlotinib, dabrafenib, and afatinib. Higher sensitivity to afatinib was due to a ~ 2-fold increase in its intracellular accumulation and involved the SLC16A1 transporter as its pharmacological inhibition by BAY-8002 suppressed sensitization of 22Rv1 cells to afatinib and was accompanied with reduced intracellular concentration of the drug. We found that PXR could bind to the SLC16A1 promoter and induced its transcription in the presence of PXR agonists. Together, our results suggest that PXR could be a biomarker of response to kinase inhibitors in castration-resistant prostate cancers.

PURPOSE Nivolumab is standard of care for patients with metastatic clear cell renal cell carcinoma (ccRCC) after failure of antiangiogenic therapies, but its activity on brain metastases from ccRCC remains unknown, because these patients were excluded from pivotal studies. We aimed to assess the activity of nivolumab in this population. METHODS The GETUG-AFU 26 NIVOREN phase II trial assessed the activity and safety of nivolumab in patients with metastatic ccRCC who failed vascular endothelial growth factor–directed therapies ( ClinicalTrials.gov identifier: NCT03013335 ). Patients with asymptomatic brain metastases were prospectively identified and underwent dedicated brain evaluation. Two cohorts were constituted: cohort A comprised patients with previously untreated brain metastases, and cohort B comprised patients whose brain metastases underwent prior therapy. The primary end point was intracranial response rate in cohort A. RESULTS Seventy-three patients with brain metastases were included: 39 in cohort A and 34 in cohort B. Intracranial response rate was 12% in cohort A; no objective response was reported in patients with brain lesions that were multiple or larger than 1 cm. Median intracranial progression-free survival was 2.7 months (95% CI, 2.3 to 4.6 months) in cohort A and 4.8 months (95% CI, 3.0 to 8.0 months) in cohort B, with adjusted hazard ratio of 2.04 (95% CI, 1.08 to 3.83). Overall survival rate at 12 months was 67% (95% CI, 49.6% to 79.1%) in cohort A and 59% (95% CI, 40.6% to 73.2%) in cohort B. Most patients in cohort A (72%) needed subsequent focal brain therapy. Nivolumab was well tolerated, with no unexpected toxicity. CONCLUSION Nivolumab activity is limited in patients with untreated brain metastases from ccRCC. Brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC.

Resume A ce jour les traitements systemiques incluant les hormonotherapies ou les chimiotherapies sont utilises a differents stades de la maladie cancereuse prostatique. Plusieurs types de complications peuvent survenir au cours d’un traitement systemique dans le cancer de la prostate, en fonction de la gamme therapeutique. Les plus frequents avec l’hormonotherapie sont la fatigue, la perte musculaire, la perte osseuse, l’hypertension arterielle et les syndromes metaboliques. Sous chimiotherapie, le risque le plus important est lie a la toxicite hematologique, mais il peut egalement survenir des neuropathies peripheriques, une mucite, de la diarrhee et des reactions d’hypersensibilite. La qualite du bilan pretherapeutique et la rigueur du suivi des patients permettent d’anticiper la plupart de ces evenements, de les prevenir ou de les prendre en charge a un stade precoce lorsqu’ils se manifestent. Le volet le plus important est l’education du patient, qui passe par une information complete et la mise en place de soins de support des l’initiation du traitement. Un avis specialise (cardiologique ou endocrinologique par exemple) est recommande en cas de symptomatologie non controlee. La reprise d’un traitement ayant entraine une complication majeure doit faire l’objet d’une discussion multidisciplinaire prenant en compte la gravite de l’evenement, sa reversibilite, l’esperance de vie du patient ainsi que l’efficacite attendue de la molecule.

Urothelial carcinoma of the bladder are rare but aggressive tumors with a high metastatic potential. The prognosis of these tumors has not drastically changed over the past 30 years, with an overall survival of less than two years in advanced or metastatic situations. Even though immune checkpoints inhibitors have changed this picture, it is beneficial for less than 30% of patients and there is no reliable biomarkers to identify this specific population of responders. Vinflunine is a vinca-alkaloid that was specifically developed as second line treatment post-platinum. As of today, it is the sole anticancer agent for which clinical trials have been pushed to phase III and that was approved for patients in good conditions. Unfortunately, it has been withdrawn from the list of reimbursed drugs, which impairs its prescription. Based on the results of phase III clinical trials with immunotherapies, this review provides the reader with argumentations in favor of patients' and clinicians' request to reimburse vinflunine for the treatment of advanced or metastatic urothelial carcinoma of the bladder.

Upper Tract Urothelial Carcinomas (UTUC) are extremely aggressive tumors of ureter or renal pelvis. UTUC present less tumor mutational burden and low tumor immune infiltrate compared to bladder cancer. Despite this they are treated with the same protocol than bladder cancer with more than 50% of relapses justifying the need of new therapeutic options. To improve patient care, we suggest stimulating the immune system by platinum-based chemotherapies (Cisplatin-Gemcitabine (CisGem) or Carboplatin-Gemcitabine (CarboGem)) in order to potentiate the effect of an anti-PD-L1, the Durvalumab. We launched a phase II clinical trial called “iNDUCT” which studies these combinations in UTUC patients. In parallel, we conduct an in vitro project that aims to determine if chemotherapies could transform cold tumor into a hot tumor, and if so by which mechanisms? Using UTUC cell lines (UM-UC-14,UCC03,UCC17,UCC14,UCC47) we have evaluated the cytotoxicity effects of the chemotherapies combinations in 2D and 3D cell cultures. We have assessed their potential (i) to induce DNA damage using image cytometry, (ii) to induce PD-L1 expression using flow cytometry, (iii) to induce immune cell death using ELISA kits, (iv) to activate the cGAS/STING pathway using qPCR and Western-Blot, and finally (v) to attract immune cells by using heterotypic spheroids model (tumoral cells+PBMCs).Our results demonstrate that CisGem and CarboGem present synergistic effects in UTUC spheroid cultures. These treatments also induce DNA damage pathway demonstrated by an increase of γH2AX, P-ATM, P-CHK1 and P-CHK2 positive cells. We found an increase of PD-L1 membrane expression after treatment in UTUC cell lines. RNA Seq analyses indicates that the major pathways upregulated by these combinations are inflammatory pathways (TNF-α signaling via NFkB, interferon alpha response, inflammatory response, interferon gamma response). We could observe an immune cell death induction demonstrated by an increase of ATP and HMGB1 release and calreticulin translocation. We showed cGAS/STING pathway activation as evidenced by an increase of P-IRF3 and interferon stimulated genes (ISGs) expression. We demonstrated an inhibition of the ISGs induction after treatment by our chemotherapies when cells are treated with an ATM inhibitor or in UMUC-14 deleted for STING. And we finally showed that CisGem and CarboGem can increase immune infiltration in the heterotypic tumor spheroids. These results indicate that the combination of platinum salts + gemcitabine induces inflammatory pathways via a non-canonical STING pathway dependent on ATM activation in UTUC model. Furthermore, these combination induce an upregulation of PD-L1 expression and allow immune cells attraction at the tumor. All these data support that a combination CisGem or CarboGem with an anti-PD-L1 will be efficient for UTUC patients. Citation Format: Alexandra Fauvre, Nadia Vie, Mathilde Robin, Clara Taffoni, Nadine Laguette, Julien Faget, Laurent Gros, Aurélie Garcin, Celine Gongora, Nadine Houede. Platinum-based chemotherapy immunomodulatory effects and immunotherapy association in upper tract urothelial carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1294.

Resume Introduction Proposer une mise a jour des recommandations du comite de cancerologie de l’Association francaise d’urologie pour la prise en charge des tumeurs de la voie excretrice urinaire superieure (TVES). Methodes Une revue systematique de la litterature (Medline) de 2016 a 2018 sur les elements du diagnostic, les options de traitement et la surveillance des TVES en evaluant les references avec leur niveau de preuve. Resultats Le diagnostic de cette pathologie rare repose sur l’uro-TDM avec acquisition au temps excreteur et l’ureteroscopie avec prelevements biopsiques. Le traitement chirurgical de reference est la nephroureterectomie totale (NUT), mais un traitement conservateur peut etre discute pour les lesions dites a bas risque : tumeur unifocale, resection complete potentielle, faible grade et absence d’infiltration sur l’imagerie, necessitant alors une surveillance endoscopique (ureteroscopie souple) rapprochee chez un patient compliant. Une instillation postoperatoire de chimiotherapie est recommandee et permet de diminuer le risque de recidive vesicale apres NUT. La chimiotherapie adjuvante a demontre son benefice clinique comparee a la surveillance apres NUT pour les tumeurs (pT2-T4 N0-3 M0). Conclusion Ces nouvelles recommandations doivent contribuer a ameliorer non seulement la prise en charge des patients, mais aussi le diagnostic et la decision therapeutique des TVES.

Introduction To propose an update of the French guidelines from the national committee ccAFU on upper tract urothelial carcinomas (UTUC). Methods A systematic Medline search was performed between 2016 and 2018, with regards to the diagnosis, the options of treatment and the follow-up of UTUC, to evaluate the different studies with levels of evidence. Results The diagnosis of this rare disease is based on CT-scan acquisition during excretion and ureteroscopy with histological biopsies. Radical nephroureterectomy (RNU) remains the gold standard for surgical treatment, nevertheless a conservative endoscopic approach can be proposed for low-risk diseases: unifocal tumour, possible complete resection low-grade and lack of invasion on CT-scan. Close monitoring with endoscopic follow-up (flexible ureteroscopy) in compliant patients is therefore necessary. After RNU, bladder instillation of chemotherapy is recommended in order to reduce the risk of bladder recurrence. An adjuvant chemotherapy is recommended after RNU in pT2-T4 N0-3 M0 disease. Conclusion These updated guidelines will contribute to increase the level of urological care for diagnosis and treatment of UTUC.

International audience; Bcl-2-associated athanogen-6 (BAG6) is a nucleocytoplasmic shuttling protein involved in protein quality control. We previously demonstrated that BAG6 is essential for autophagy by regulating the intracellular localization of the acetyltransferase EP300, and thus, modifying accessibility to its substrates (TP53 in the nucleus and autophagy-related proteins in the cytoplasm). Here, we investigated BAG6 localization and function in the cytoplasm. First, we demonstrated that BAG6 is localized in the mitochondria. Specifically, BAG6 is expressed in the mitochondrial matrix under basal conditions, and translocates to the outer mitochondrial membrane after mitochondrial depolarization with carbonyl cyanide m-chlorophenyl hydrazine, a mitochondrial uncoupler that induces mitophagy. In SW480 cells, the deletion of BAG6 expression abrogates its ability to induce mitophagy and PINK1 accumulation. On the reverse, its ectopic expression in LoVo colon cancer cells, which do not express endogenous BAG6, reduces the size of the mitochondria, induces mitophagy, leads to the activation of the PINK1/PARKIN pathway and to the phospho-ubiquitination of mitochondrial proteins. Finally, BAG6 contains two LIR (LC3-interacting Region) domains specifically found in receptors for selective autophagy and responsible for the interaction with LC3 and for autophagosome selectivity. Site-directed mutagenesis showed that BAG6 requires wild-type LIRs domains for its ability to stimulate mitophagy. In conclusion, we propose that BAG6 is a novel mitophagy receptor or adaptor that induces PINK1/PARKIN signaling and mitophagy in a LIR-dependent manner.

International audience; Objectifs : étude prospective multicentrique ouverte comparant l’efficacité carcinologique d’un traitement conservateur par ultrasons focalisés de haute intensité (HIFU) à la prostatectomie totale (PT) pour adénocarcinome prostatique localisé de stades ISUP 1 (non éligibles à la surveillance active) et ISUP 2. Nous communiquons des données carcinologiques intermédiaires à 18 mois.Méthodes : de février 2015 à septembre 2019, 3 364 patients (HIFU : 1 988, PT : 1 376) ont été inclus de façon prospective dans 42 centres. Âge médian : 74,6 vs 65 ; PSA médian : 7,11 vs 6,97 (p = 0,4) ; ISUP 1 : 0,39 ; ISUP 2 : 0,61. Objectif principal : survie sans traitement de rattrapage. Objectifs secondaires : bras HIFU : récidive biologique (RB) = PSA > Nadir + 2, PBP contrôle ; bras PT : R1, RB = PSA > 0,2 ng/mL.Résultats : objectif principal : à 18 mois, la probabilité de survie sans traitement de rattrapage est plus importante dans le bras HIFU comparé au bras prostatectomie HR = 0,31 IC95 % [0,23–0,42] soit un risque 3 fois plus élevé dans le groupe prostatectomie (p < 0,01). Objectifs secondaires : bras HIFU : récidives biologiques : 141 (10,6 %), PBP positives : 99 (7 %) ; bras PT : R1 = 25 % ; RB : 77 (9 %) à 18 mois.Conclusion : ces données intermédiaires à 18 mois ne permettent pas encore une comparaison équitable des deux bras en raison d’un profil évolutif spécifique à chaque groupe. Concernant l’objectif principal, la radiothérapie de rattrapage est probablement indiquée plus précocement après PT en raison de décisions de principe en RCP face à des marges positives. Le suivi des données carcinologiques pendant 30 mois, prévu dans l’étude, est justifié.

Background Currently, oral targeted therapies are known to be effective and are frequently used to treat metastatic cancer patients, but fatigue is a frequently reported early side effect of these treatments. This fatigue may impact the patient’s treatment adherence and result in a negative impact on quality of life. Physical exercise significantly improved the general well-being and quality of life of advanced cancer patients. However, there is no specific physical activity program adapted for patients with advanced disease. Methods QUALIOR is a two-part, randomized, open-label, and multicenter with two arms phase II/III trial. Patients (phase II: n = 120; phase III: n = 312) with metastatic cancer (breast cancer, kidney cancer, lung cancer, and other cancers [including but not limited to colon cancer, melanoma, sarcoma, or hepatocarcinoma]) treated with a first- or second-line oral targeted therapy without chemotherapy will be included. Patients will be randomized (2:1) to a 3-month supervised home-based standardized physical activity program or to a recommended adapted physical activity (via a booklet). The primary objective of the phase II is to evaluate the feasibility of the supervised program. The primary objective of the phase III is the evaluation of the benefit of the supervised home-based program compare to the recommended program in terms of fatigue and quality of life at 3 months. The secondary objectives aim to evaluate the impact of the supervised program on fatigue over time, pain, physical capacities, psychosocial and cognitive functions, general quality of life, frequency of dose reduction and patients’ adherence to the targeted therapy, overall survival, and progression-free survival. This study will also evaluate the medico-economic impact of supervised program compared to the recommended adapted physical activity program. Discussion The aim of this study is to evaluate home-based physical exercise program for metastatic cancer patients treated with oral targeted therapies to help patients to cope with fatigue and improve quality of life. Trial registration This trial was registered in ClinicalTrials.gov since May 2017 (NCT03169075).

International audience; Purpose: To assess the association between PD-L1 expression and disease-free survival (DFS) in High-Risk Non-Muscle Invasive Bladder Cancer (HR-NMIBC) patients treated with intravesical Bacillus Calmette-Guerin (BCG) instillations (IBI).Methods: Retrospective study in five French centres between 2001 and 2015. Participants were 140 patients with histologically confirmed HR-NMIBC. All patients received induction and maintenance IBI. Pathological stage/grade, concomitant carcinoma in situ, lesion number and tumour size were recorded. CD3, CD8 and PD-L1 expression in tumour cells and in T cells in the tumour microenvironment (TME) was determined immunohistochemically. Median follow-up was 54.2 months. The primary outcome measure was DFS. Univariable and multivariable analyses were performed using the log rank test and Cox proportional hazards model.Results: Of the 140 NMIBC, 52 (37.1%) were Ta, 88 (62.9%) were T1 and 100% were high grade. Median number of maintenance IBI was six (range 1-30). Twenty-five (17.9%) patients had recurrence/progression. In multivariable analysis, age (HR 1.07 [95% CI 1.02-1.13], p = 0.009), PD-L1 expression in tumour cells (HR per 10 units = 1.96 [95% CI 1.28-3.00], p = 0.02) and CD3/CD8 ratio (HR per 10 units = 3.38 [95% CI 1.61-7.11], p = 0.01) were significantly associated with DFS. However, using the cut-off corresponding for each PD-L1 antibodies, PD-L1 + status was not associated with DFS.Conclusion: Despite an association between PD-L1 expression and BCG failure in HR-NMIBC, the PD-L1 + status was not a prognostic factor in the response of BCG. Moreover, we confirmed the key role played by the IC within the microenvironment in BCG treatment. These findings highlighted the rationale to combine BCG and PD-L1/PD-1 antibodies in early bladder cancer.

Background Prostate cancer patients are known to suffer from poor sexual and urinary long-term side-effects following treatment, potentially impacting quality of life. The purpose of our study was to compare health-related quality of life at 3 years between prostate cancer patients and healthy controls according to key life-style characteristics. Secondary objectives were to compare urological dysfunction, sexual function, anxiety and depression. Methods Multicentric, case-control, observational prospective, open, follow-up study including 819 prostate cancer patients Results In total, 564 participants were included (mean age 67.9 years): 376 patients and 188 controls. Treatment breakdown was: 258 underwent RP, 90 received EBRT, 52 brachytherapy or HIFU, 15 CT, 26 ADT and 61 AS. There was no difference in median global quality of life between patients and controls (94.87 vs 94.15, p = 0.71). Multivariate analysis showed poorer social functioning in patients (24.3% vs. 16.3%, p = 0.0209), more dyspnea (22% vs. 12.4%, p = 0.0078), and yet less current pain (23% vs 33%, p = 0.0151). Conclusions Global health status score at 3 years after diagnosis was similar between patients and controls, though patients showed a significantly worse social functioning. Prostate cancer diagnosis per se does not seem to impact the quality of life of patients Trial registration clinicaltrials.gov, NCT02854982. Registered 4 August 2016, retrospectively registered.

BACKGROUND: The phase 3 trial CA184-043 evaluated radiotherapy to bone metastases followed by Ipilimumab or placebo in men with metastatic castrate-resistant prostate cancer (mCRPC) who had received docetaxel previously. In a prior analysis, the trial's primary endpoint (overall survival [OS]) was not improved significantly.OBJECTIVE: To report the final analysis of OS.DESIGN, SETTING, AND PARTICIPANTS: A total of 799 patients were randomized to receive a single dose of radiotherapy to one or more bone metastases followed by either Ipilimumab (n = 399) or placebo (n = 400).OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS was analyzed in the intention-to-treat population. Prespecified and exploratory subset analyses based on Kaplan-Meier/Cox methodology were performed.RESULTS AND LIMITATIONS: During an additional follow-up of approximately 2.4 yr since the primary analysis, 721/799 patients have died. Survival analysis showed crossing of the curves at 7-8 mo, followed by persistent separation of the curves beyond that point, favoring the ipilimumab arm. Given the lack of proportional hazards, a piecewise hazard model showed that the hazard ratio (HR) changed over time: the HR was 1.49 (95% confidence interval 1.12, 1.99) for 0-5 mo, 0.66 (0.51, 0.86) for 5-12 mo, and 0.66 (0.52, 0.84) beyond 12 mo. OS rates were higher in the ipilimumab versus placebo arms at 2 yr (25.2% vs 16.6%), 3 yr (15.3% vs 7.9%), 4 yr (10.1% vs 3.3%), and 5 yr (7.9% vs. 2.7%). Disease progression was the most frequent cause of death in both arms. In seven patients (1.8%) in the ipilimumab arm and one (0.3%) in the placebo arm, the primary cause of death was reported as study drug toxicity. No long-term safety signals were identified.CONCLUSIONS: In this preplanned long-term analysis, OS favored ipilimumab plus radiotherapy versus placebo plus radiotherapy for patients with postdocetaxel mCRPC. OS rates at 3, 4, and 5 yr were approximately two to three times higher in the ipilimumab arm.PATIENT SUMMARY: After longer follow-up, survival favored the group of men who received ipilimumab, with overall survival rates being two to three times higher at 3 yr and beyond.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) is recommended for localized muscle-invasive bladder cancer when patients are fit for cisplatin-based chemotherapy. A pathological complete response can be observed, corresponding to ypT0N0 stage on the radical cystectomy specimen. This review discusses the incidence, prognosis and potential therapeutic impact of complete response on pathological specimen in NAC treated patients. METHODS: A comprehensive review of the literature was conducted using Medline database, with no time frame. The articles were selected using the following keywords association: "Bladder cancer" (Mesh) AND "Neoadjuvant chemotherapy" (Mesh) AND "pT0" (Mesh). RESULTS: After NAC, ypT0N0 rates vary from 9 to 46% among the series, reported rates that are higher compared to those of pT0 without NAC administration. The incidence depends on the chemotherapy regimen (maximal local effect with cisplatin-based chemotherapy) and the pathological type of the disease (presence of variant histologies). Molecular analyses of bladder cancer could probably help in the near future to identify and predict NAC responders. Pathological complete response is associated with a favorable prognosis in terms of recurrence-free and overall survival. Nevertheless, disease recurrences are still observed in 10-15% of cases, which underlies the importance of local treatment and close follow-up even in these patients. CONCLUSION: ypT0N0 rate is approximately 25% after NAC, that is 4.3 higher than after bladder resection alone. The prognosis is better than that with residual tumor on specimen and is comparable to that of pT0 without NAC administration.

International audience; BACKGROUND:Neuroendocrine carcinoma of the urinary bladder (NCUB) is rare, accounting for < 1% of bladder cancer cases, with scarce reported data available.MATERIALS AND METHODS:We retrospectively reviewed the data from patients with NCUB treated at French institutions. The objectives were to describe the patient characteristics, treatments received, and outcomes (ie, disease-free survival [DFS], progression-free survival, overall survival [OS]) and investigate the prognostic factors.RESULTS:From 1997 to 2017, we included 236 patients, 173 with early-stage NCUB and 63 with advanced-stage NCUB. For those with early-stage disease, the median DFS was better for the patients who had received cisplatin-based chemotherapy compared with carboplatin (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.1-3.46), with no difference found between the neoadjuvant and adjuvant settings (HR, 1.1; 95% CI, 0.61-1.97). The median OS was 36 months (95% CI, 29-43 months) for stage I and II, 26 months (95% CI, 18 months to not reached) for stage IIIA, 16 months (95% CI, 12-21 months) for stage IIIB. The HR for stage IIIB compared with stage I/II was 2.6 (95% CI, 1.5-4.4). The DFS at 6 months was associated with OS (HR, 7.8; 95% CI, 4.1-15.0). For patients with metastases at diagnosis who had received chemotherapy, the median progression-free survival was 9 months (95% CI, 8-11) for first-line cisplatin and 6 months (95% CI, 4-13 months) for carboplatin; the median OS was 13 months (95% CI, 9-15 months). A high-risk Bajorin score (HR, 11.5; 95% CI, 1.2-112.6) and the use of carboplatin (HR, 2.26; 95% CI, 1.03-4.96) were associated with worse outcomes.CONCLUSIONS:In early-stage disease, a shorter DFS was associated with worse OS, and the use of cisplatin was associated with better OS. For the patients with metastases at diagnosis, a high-risk Bajorin score and the use of carboplatin were associated with worse outcomes.

e16512 Background: Immune-checkpoint-inhibitors (ICI) provide durable antitumor activity even for recurrent and/or metastatic disease. As illustrated in the Keynote-045 study (pembrolizumab (pembro.) in second line metastatic urothelial carcinoma; Fradet, 2019), improvement in long-term responder fraction does not always translate into progression-free survival (PFS) improvement. Despite a long-term benefit improvement (2 years PFS: 12.4% vs 3%), there was no significant difference in PFS (HR 0.98; 95% CI, 0.81-1.19; p=0.42). Benefits in terms of OS were not deemed sufficient by the French health authorities in charge of health technology assessment and reimbursement of medicinal products to consider that pembro. brought a significant improvement upon existing drugs in urothelial carcinoma. Thus, although recommended by scientific societies, this treatment has only been available in France since January 2020. The main objective is to illustrate the importance of using complementary statistical approaches when evaluating ICI phase III trials. Methods: PFS curves of the Keynote-045 study available in publications (Bellmunt, 2017; Fradet, 2019) were digitized to reconstruct pseudo individual patient data as per established methods. Survival rates were estimated using Kaplan-Meier method and comparison between groups were performed using Cox model. Flexible parametric survival models with cure (FPCM) were then used to estimate the treatment benefit in terms of long-term responder fraction and evaluate the treatment effect on PFS in the non–long-term responder population. Results: In both first and updated data, there were no significant between-group difference in the duration of PFS in the total population (2017: HR=0.95, 95%CI 0.79–1.15; 2019: HR=0.93, 95%CI 0.77–1.11). Using FPCM, we demonstrated that the long-term responder fraction (LRF) was higher with pembro. compared to chemotherapy (2017: Pembro 14.0% 95%CI 10.2-18.3; Chemo.: 7.7% 95%CI 4.9-11.2; 2019: Pembro 11.0% 95%CI 7.8-14.9; Chemo.: 4.6% 95%CI 2.7-7.3). Differences in LRF were estimated to 6.3% (95%CI 1.5–11.13) and 6.4% (95%CI 2.4-10.4]) in the first and updated analysis, respectively. In the non–long-term responder population, ICI was first associated with a higher risk of progression or death and then a lower risk. Conclusions: While ICIs show a substantial shift towards long-term benefit in terms of PFS, greater emphasis should be placed on rigorously evaluating this quantity instead of only reporting Kaplan-Meier estimation or comparing PFS curves using classical Cox model. Despite the long-term responder fraction improvement was constant between analysis, relative variations in LRFs were observed. This suggests that the follow-up of this study was not long enough to properly characterize long term responders.

Objectifs Evaluer l’association entre la survie sans maladie des tumeurs de vessie n’infiltrat pas le muscle (TVNIM) de haut risque (HR) traitees par BCG et l’expression de PD-L1. Methodes Les TVNIM de HR provenant de 5 centres universitaires Francais ayant recu du BCG en induction et en entretien etaient retrospectivement inclues. Les informations suivantes etaient colligees : stade pathologique, le grade, la presence de CIS concomitante, le nombre de lesion et la taille tumorale. Une analyse immunohistochimique centralisee sur echantillons de paraffine a permis la quantification de l’expression de CD3, CD8, PD-L1 (anticorps SP263/SP142, E1L3 N, 28 8) dans les cellules tumorales et immunitaires. Resultats Cent quarante patients (median âge 66,5 ans, male vs female : 6 :1) etaient inclus. Les TVNIM etaient toutes de haut grade, les stades Ta/T1 etaient repartis respectivement Ta37,1 % (n = 52) T162,9 % (n = 88). Le nombre median d’instillation delivrees pendant le schema d’entretien etait 6 (range 1–30) ( Tableau 1 ). Durant un suivi median etait de 54,24 mois (IC95 % = 49,91–58,68), 25 patients (17,9 %) avaient une recidive ou progression. Le taux de survie sans maladie a 72 mois etait de 81,11 %. L’âge (HR = 1,07 [1,02–1,13] p = 0,009), l’expression de PD-L1 (Ac E1N3L) dans les cellules tumorales (HRdivpar 10 = 1,96 [1,28–3,00] p = 0,02) et le ratio CD3/CD8 (HR = 3,38 [1,61–7,11] p = 0,01) etaient en analyse multivariee associes a la survie sans maladie ( Tableau 2 ). Par contre, le statut PD-L1+ dans les cellules tumorales, defini dans les etudes precedentes comme SP142 ≥ 5 %/SP263 ≥ 25 %, n’etait pas un facteur predictif de l’echec du BCG ( Fig. 1 ). Conclusion L’expression de PD-L1 et la population lymphocytairesT sont 2 facteurs predictifs de la reponse au BCG. Par contre, les seuils definissant le statut PD-L1+ issus des etudes sur les TVIMM+ ne sont pas associes au pronostic. Les resultats des essais sur la combinaison BCG + inhibiteur check-point permettront de confirmer l’hypothese du role cle joue par PD-L1 dans la resistance au BCG.

Background From 10% to 26% of patients with metastatic renal cell carcinoma (mRCC) experience rapidly progressive disease (PD) on treatment with sunitinib. Objective To investigate the benefit of subsequent treatment with another tyrosine kinase inhibitor (TKI) or a mammalian target of rapamycin (mTOR) inhibitor in such primary refractory patients. Design, setting, and participants A total of 150 mRCC patients with rapidly PD on first-line sunitinib (within two cycles, n = 93, or four cycles, n = 57) were identified: median age 59 yr; nephrectomy 86%; histological subtypes: clear cell (77.8%), papillary (14%), and sarcomatoid features (18%); according to the Memorial Sloan-Kettering Cancer Center and French classifications: good risk (11% and 7%, respectively), intermediate (68% and 63%, respectively), and poor (21% and 29%, respectively). Outcome measurements and statistical analysis Data were retrospectively collected by a questionnaire from 19 European oncology centers between March 2005 and March 2011. Progression-free survival (PFS) and overall survival (OS) were calculated (Kaplan-Meier method). Results and limitations Median OS from the start of first-line treatment was 7.4 mo. Second-line treatment was administered to 86 (57%) patients (44 mTOR inhibitors: 23 everolimus and 21 temsirolimus; 39 TKIs alone or in combination; three chemotherapy). Second-line PFS was not significantly different between TKIs and mTOR inhibitors (2.0 vs 0.9 mo; p = 0.536). Median OS from the start of second-line treatment was 5.0 mo for mTOR inhibitors and 6.6 mo for TKIs (p = 0.15). Conclusions Treatment with further TKIs or mTOR inhibitors for mRCC patients primarily refractory to first-line sunitinib in the observed time period achieved very minimal benefit, suggesting avoiding TKI rechallenge and possibly preferring alternative strategies, such as immune checkpoint inhibitors, after PD to a treatment line including a TKI in this setting. Patient summary The present work collected data about 150 patients affected by metastatic renal cell carcinoma, who received one of the current standard of care as first-line treatment, namely, the antiangiogenic drug sunitinib, and experienced rapid worsening of the disease. We investigated and described the subsequent outcome of such patients treated with two different types of drug, administered as second-line therapy, to better understand the best strategy to adopt for patients who got no benefit from sunitinib and to describe the current therapeutic approach in such cases.

Background About one-third of patients with renal cell carcinoma (RCC) have detectable metastases at diagnosis. Among them, bone is the second most frequent metastatic site. Treatment of metastatic RCC mostly relies on anti-angiogenic (AA) therapies and, more recently, immunotherapy. Skeletal-related events (SREs) can be prevented with bone-targeted therapies such as denosumab (Dmab), which has demonstrated superiority when compared with zoledronic acid in solid tumors. However, there is limited available data on Dmab toxicity in combination with AA therapies in patients with kidney cancer. The objective of this study was to retrospectively analyze the toxicity profile (mainly osteonecrosis of the jaw [ONJ] and hypocalcemia) in patients with metastatic renal cell carcinoma (mRCC) treated with Dmab and AA therapy combination. Patients and Methods We conducted a multicenter retrospective study among centers from the French Groupe d’Etudes des Tumeurs Uro Genitales (GETUG). Patients with bone metastases who received concurrently or sequentially AA therapy and Dmab were included in this study. Results A total of 41 patients with mRCC were enrolled. Although no patient presented with severe hypocalcemia, ONJ occurred in 7 (17%) of 41 patients. Interestingly, all patients with ONJ received the Dmab and AA combination in the first line of treatment; among these patients, 3 patients had no risk factor other than the Dmab and AA combination. Conclusion The incidence of ONJ was high in this real-life population of patients with mRCC treated with AA therapies combined with Dmab. This toxicity signal should warn physicians about this combination in the mRCC population.

Importance Androgen-deprivation therapy (ADT) plus docetaxel is the standard of care in hormone-naive metastatic prostate cancer but is of uncertain benefit in a nonmetastatic, high-risk prostate cancer setting. Objective To assess the benefit of ADT plus docetaxel in patients presenting with rising prostate-specific antigen (PSA) levels after primary local therapy and high-risk factors but no evidence of metastatic disease. Design, Setting, and Participants This open-label, phase 3, randomized superiority trial comparing ADT plus docetaxel vs ADT alone enrolled patients from 28 centers in France between June 4, 2003, and September 25, 2007; final follow-up was conducted April 12, 2017, and analysis was performed May 2 to July 31, 2017. Patients had undergone primary local therapy for prostate cancer, were experiencing rising PSA levels, and were considered to be at high risk of metastatic disease. Stratification was by prior local therapy and PSA-level doubling time (≤6 vs >6 months), and intention-to-treat analysis was used. Interventions Patients were randomly assigned to receive ADT (1 year) plus docetaxel, 70 mg/m2(every 3 weeks [6 cycles]), or ADT alone (1 year). Main Outcomes and Measures The primary outcome was PSA progression-free survival (PSA-PFS). Secondary end points were PSA response, radiologic PFS, overall survival, safety, and quality of life. Results Overall, 254 patients were randomized (1:1) to the trial; median age, 64 years in the ADT plus docetaxel arm, 66 years in the ADT alone arm. At a median follow-up of 30.0 months, the median PSA-PFS was 20.3 (95% CI, 19.0-21.6) months in the ADT plus docetaxel arm vs 19.3 (95% CI, 18.2-20.8) months in the ADT alone arm (hazard ratio [HR], 0.85; 95% CI, 0.62-1.16;P = .31). At a median follow-up of 10.5 years, there was no significant between-arm difference in radiologic PFS (HR, 1.03; 95% CI, 0.74-1.43;P = .88). Overall survival data were not mature. The most common grade 3 or 4 hematologic toxic effects in the ADT plus docetaxel arm were neutropenia (60 of 125 patients [48.0%]), febrile neutropenia (10 [8.0%]), and thrombocytopenia (4 [3.0%]). There was no significant between-arm difference in overall quality of life. Conclusions and Relevance Compared with ADT alone, combined ADT plus docetaxel therapy with curative intent did not significantly improve PSA-PFS in patients with high-risk prostate cancer and rising PSA levels and no evidence of metastatic disease. Trial Registration French Health Products Safety Agency identifier:030591; ClinicalTrials.gov identifier:NCT00764166

International audience; The National Cancer Institute Common Terminology Criteria for Adverse Events classification is the standard classification used by the physicians in oncology for reporting adverse events. This classification has evolved over the last years according to the emergence of new therapies. Reporting symptoms, quality of life (QoL) and toxicities via patient-reported outcomes (PROs) in clinical practice is not yet a standard of care, nevertheless many studies have been conducted recently to assess feasibility and impact of routine monitoring of PROs, which should enable for better management of toxicities and earlier detection of disease progression in a more patient-centered health care delivery system. The aim of this article was to discuss the advantages and limitations of both approaches, clinicians-reported outcomes and PROs. Growing evidence supports that the routine collection of PROs leads to improvement of QoL and overall survival of cancer patients.

Objective:To propose updated French guidelines for non-muscle invasive (NMIBC) and muscle-invasive (MIBC) bladder cancers.Methods:A Medline search was achieved between 2015 and 2018, as regards diagnosis, options of treatment and follow-up of bladder cancer, to evaluate different references with levels of evidence.Results:Diagnosis of NMIBC (Ta, T1, CIS) is based on a complete deep resection of the tumor. The use of fluorescence and a second-look indication are essential to improve initial diagnosis. Risks of both recurrence and progression can be estimated using the EORTC score. A stratification of patients into low, intermediate and high risk groups is pivotal for recommending adjuvant treatment: instillation of chemotherapy (immediate post-operative, standard schedule) or intravesical BCG (standard schedule and maintenance). Cystectomy is recommended in BCG-refractory patients. Extension evaluation of MIBC is based on contrast-enhanced pelvic-abdominal and thoracic CT-scan. Multiparametric MRI can be an alternative. Cystectomy associated with extended lymph nodes dissection is considered the gold standard for non-metastatic MIBC. It should be preceded by cisplatin-based neoadjuvant chemotherapy in eligible patients. An orthotopic bladder substitution should be proposed to both male and female patients with no contraindication and in cases of negative frozen urethral samples; otherwise transileal ureterostomy is recommended as urinary diversion. All patients should be included in an Early Recovery After Surgery (ERAS) protocol. For metastatic MIBC, first-line chemotherapy using platin is recommended (GC or MVAC), when performans status (PS < 1) and renal function (creatinine clearance > 60 mL/min) allow it (only in 50 % of cases). In second line treatment, immunotherapy with pembrolizumab demonstrated a significant improvement in overall survival.Conclusion:These updated French guidelines will contribute to increase the level of urological care for the diagnosis and treatment for NMIBC and MIBC., ObjectifProposer une mise à jour des recommandations dans la prise en charge des tumeurs de la vessie n’infiltrant pas le muscle vésical (TVNIM) et infiltrant le muscle vésical (TVIM).MéthodesUne revue systématique (Medline) de la littérature de 2015 à 2018 a été conduite par le ccAFU concernant les éléments du diagnostic, les options de traitement et la surveillance des TVNIM et TVIM, en évaluant les références avec leur niveau de preuve.RésultatsLe diagnostic de TVNIM (Ta, T1, CIS) se fait après une résection tumorale complète et profonde. L’utilisation de la fluorescence vésicale et l’indication d’un second look (4 à 6 semaines) contribuent à améliorer le diagnostic initial. Le risque de récidive et/ou progression tumorale est évalué en utilisant le score EORTC. La stratification des patients en faible, intermédiaire et haut risque permet de proposer le traitement adjuvant : instillations endovésicales de chimiothérapie (postopératoire immédiate, schéma d’attaque) ou de BCG (schéma d’attaque et d’entretien), voire l’indication d’une cystectomie pour les patients résistant au BCG. Le bilan d’extension d’une TVIM repose sur l’uro-scanner couplé au scanner thoracique. L’IRM pelvienne multiparamétrique peut être une alternative. La cystectomie associée à un curage ganglionnaire étendu est le traitement de référence des TVIM non métastatiques. Elle doit être précédée d’une chimiothérapie néoadjuvante à base de sels de platine chez les patients en bon état général avec une fonction rénale satisfaisante. Une entérocystoplastie est proposée chez l’homme et la femme en l’absence de contre-indications et lorsque la recoupe urétrale est négative à l’examen extemporané ; sinon l’urétérostomie cutanée transiléale est le mode de dérivation urinaire recommandé. L’inclusion de tous les patients dans un protocole de RAAC (récupération améliorée après chirurgie) est recommandée. Pour les TVIM métastatiques, une première ligne de chimiothérapie à base de sels de platine (GC ou MVAC) est recommandée, si l’état général (PS > 1) et la fonction rénale (clairance >60 mL/min) l’autorisent (50 % seulement des cas). En deuxième ligne de traitement, l’immunothérapie par pembrolizumab a démontré un bénéfice en survie globale.ConclusionCette actualisation des recommandations françaises doit contribuer à améliorer non seulement la prise en charge des patients, mais aussi le diagnostic et la décision thérapeutique des TVNIM et TVIM.

International audience; OBJECTIVE:To propose updated French guidelines for non-muscle invasive (NMIBC) and muscle-invasive (MIBC) bladder cancers.METHODS:A Medline search was achieved between 2015 and 2018, as regards diagnosis, options of treatment and follow-up of bladder cancer, to evaluate different references with levels of evidence.RESULTS:Diagnosis of NMIBC (Ta, T1, CIS) is based on a complete deep resection of the tumor. The use of fluorescence and a second-look indication are essential to improve initial diagnosis. Risks of both recurrence and progression can be estimated using the EORTC score. A stratification of patients into low, intermediate and high risk groups is pivotal for recommending adjuvant treatment: instillation of chemotherapy (immediate post-operative, standard schedule) or intravesical BCG (standard schedule and maintenance). Cystectomy is recommended in BCG-refractory patients. Extension evaluation of MIBC is based on contrast-enhanced pelvic-abdominal and thoracic CT-scan. Multiparametric MRI can be an alternative. Cystectomy associated with extended lymph nodes dissection is considered the gold standard for non-metastatic MIBC. It should be preceded by cisplatin-based neoadjuvant chemotherapy in eligible patients. An orthotopic bladder substitution should be proposed to both male and female patients with no contraindication and in cases of negative frozen urethral samples; otherwise transileal ureterostomy is recommended as urinary diversion. All patients should be included in an Early Recovery After Surgery (ERAS) protocol. For metastatic MIBC, first-line chemotherapy using platin is recommended (GC or MVAC), when performans status (PS60 mL/min) allow it (only in 50% of cases). In second line treatment, immunotherapy with pembrolizumab demonstrated a significant improvement in overall survival.CONCLUSION:These updated French guidelines will contribute to increase the level of urological care for the diagnosis and treatment for NMIBC and MIBC.

International audience; Objectifs : étude prospective multicentrique ouverte comparant l’efficacité carcinologique et les conséquences fonctionnelles d’un traitement conservateur par ultrasons focalisés de haute intensité (HIFU) à la prostatectomie totale (PT) pour adénocarcinome prostatique localisé de stades ISUP 1 (non éligibles à la surveillance active) et ISUP 2. Nous rapportons ici les EIG et résultats fonctionnels à 12 mois.Méthodes : de février 2015 à septembre 2019, 3364 patients (HIFU : 1988, PT : 1376) ont été inclus de façon prospective dans 42 centres. Âge médian : 74,6 vs 65 ; PSA médian : 7,11 vs 6,97 (p = 0,4). Les EIG ont été transmis à l’Agence nationale selon les standards internationaux.Objectifs fonctionnels de l’étude : IPSS, continence (USP), fonction érectile (IIEF5), qualité de vie (EORTC QLQ-C30) à 12 mois.Résultats : les durées médianes d’hospitalisation initiale ont été respectivement de 1 et 4 jours. Cinquante-trois EIG Clavien–Dindo ≥ IIIa : 32 HIFU (1,6 %) et 21 PT (1,5 %). Aucun risque préalablement inconnu n’a été mis en évidence. Onze cas de fistules ont été rapportés : bras HIFU : 3/1988 (1,5/1000) fistules (2 uro-digestives, 1 urinaire) ; bras PT : 8/1376 (5,8/1000) fistules (7 urinaires, 1 digestive). Tous les cas ont été guéris. Vingt-trois décès ont été enregistrés et sont non imputables. Résultats fonctionnels (HIFU vs PT) : IPSS médian : 4 vs 3, IPSS QdV médian : 1 vs 1 ; continence score médian : 0 vs 1 (p < 0,005) ; IIEF5 (Δ médianes pré- et postopératoires) 1 vs −9 (p < 0,0001) ; EORTC QLQ-C30 : 90,7 vs 93,4.Conclusion : une proportion supérieure de réhospitalisations a été constatée après HIFU. Plusieurs explications sont suggérées : l’âge plus élevé des patients, la durée d’hospitalisation initiale très brève et la gestion non standardisée des accidents rétentionnels. En dehors de l’IPSS, les conséquences fonctionnelles (incontinence, dysfonction érectile) sont significativement moins importantes pour l’HIFU que pour la prostatectomie à 12 mois postopératoires. La qualité de vie post-thérapeutique des deux groupes reste élevée, et malgré une différence d’âge de près de dix ans, est comparable.

The National Cancer Institute Common Terminology Criteria for Adverse Events classification is the standard classification used by the physicians in oncology for reporting adverse events. This classification has evolved over the last years according to the emergence of new therapies. Reporting symptoms, quality of life (QoL) and toxicities via patient-reported outcomes (PROs) in clinical practice is not yet a standard of care, nevertheless many studies have been conducted recently to assess feasibility and impact of routine monitoring of PROs, which should enable for better management of toxicities and earlier detection of disease progression in a more patient-centered health care delivery system. The aim of this article was to discuss the advantages and limitations of both approaches, clinicians-reported outcomes and PROs. Growing evidence supports that the routine collection of PROs leads to improvement of QoL and overall survival of cancer patients.

International audience; BACKGROUND:Enterocolitis is a rare, but serious gastrointestinal complication associated with docetaxel-based chemotherapy in patients with cancer. The incidence, clinical presentation and outcome of enterocolitis in patients with cancer treated with docetaxel-based chemotherapy was assessed in this study Patients and Methods: All patients treated with docetaxel for cancer between January 2010 and December 2014 at the University Hospital of Besançon were identified and their medical records reviewed.RESULTS:During this period, 1,227 patients received docetaxel chemotherapy and gastrointestinal events occurred in 381 (31.1%) patients. In multivariate analysis, a higher risk of gastrointestinal events was associated with a higher dose of docetaxel (≥75 mg/m2) (odds ratio(OR)=46.2; 95% confidence interval(CI)=5.4-397.0, p=0.0005) and the first cycle of docetaxel (OR=4.2; 95% CI=1.8-10.1, p=0.001). Among the 381 patients with gastrointestinal events, grade 3/4 neutropenia, diarrhea, febrile neutropenia, mucositis, nausea/vomiting, and rectal bleeding were diagnosed in 65 (17.1%), 51 (13.4%), 37 (9.7%); 12 (3.1%), seven (1.8%) and three (0.8%) patients, respectively; 54 patients (14.2%) were hospitalized. Computed tomographic scan was performed for 39 patients (10.2%). Twenty-seven patients presented radiological signs of enterocolitis. Three deaths (0.8%) related to enterocolitis were recorded. Docetaxel was resumed in 261 patients (68.5%) and the dose was reduced in 89 patients (23.4%). Docetaxel was discontinued in 120 patients (31.5%).CONCLUSION:Gastrointestinal events in patients treated with docetaxel may be a potential sign of fatal enterocolitis and require particular attention. Dose reduction at the first cycle may reduce the risk of such events.

International audience; PURPOSE:Over the past 3 decades, no major treatment breakthrough has been reported for advanced bladder cancer. Recent Food and Drug Administration (FDA) approval of five immune checkpoint inhibitors in the management of advanced bladder cancer represent new therapeutic opportunities. This review examines the available data of the clinical trials leading to the approval of ICIs in the management of metastatic bladder cancer and the ongoing trials in advanced and localized settings.METHODS:A literature search was performed on PubMed and ClinicalTrials.gov combining the MeSH terms: 'urothelial carcinoma' OR 'bladder cancer', and 'immunotherapy' OR 'CTLA-4' OR 'PD-1' OR 'PD-L1' OR 'atezolizumab' OR 'nivolumab' OR 'ipilimumab' OR 'pembrolizumab' OR 'avelumab' OR 'durvalumab' OR 'tremelimumab'. Prospectives studies evaluating anti-PD(L)1 and anti-CTLA-4 monoclonal antibodies were included.RESULTS:Evidence-data related to early phase and phase III trials evaluating the 5 ICIs in the advanced urothelial carcinoma are detailed in this review. Anti-tumour activity of the 5 ICIs supporting the FDA approval in the second-line setting are reported. The activity of PD(L)1 inhibitors in the first-line setting in cisplatin-ineligible patients are also presented. Ongoing trials in earlier disease-states including non-muscle-invasive and muscle-invasive bladder cancer are discussed.CONCLUSIONS:Blocking the PD-1 negative immune receptor or its ligand, PD-L1, results in unprecedented rates of anti-tumour activity in patients with metastatic urothelial cancer. However, a large majority of patients do not respond to anti-PD(L)1 drugs monotherapy. Investigations exploring the potential value of predictive biomarkers, optimal combination and sequences are ongoing to improve such treatment strategies.

Resume Introduction Le Comite de cancerologie de l’Association francaise d’urologie (CCAFU) a realise une revue de la litterature concernant la surveillance des carcinomes urotheliaux et propose des recommandations de suivi. Materiel et methode Une recherche bibliographique en langue francaise et anglaise a partir de PubMed » a ete effectuee de 1990 a 2014 en utilisant les mots cles « carcinome urothelial », « suivi », « pronostic », et « recidive ». Resultats Le rythme et les moyens de surveillance (cytologie, fibroscopie, uro-TDM) des tumeurs de la vessie non infiltrant le muscle (TVNIM) doivent etre adaptes aux risques de recidive et de progression definis selon les tables de l’EORTC. Apres traitement radical d’une tumeur de la vessie infiltrant le muscle (TVIM), la surveillance est basee sur la fibroscopie, la cytologie et la realisation d’une imagerie de coupe avec temps tardifs. La surveillance de l’uretre doit etre adaptee aux facteurs de recidive et poursuivie au moins 5 ans. La surveillance du haut appareil est a poursuivre a vie. En cas de traitement conservateur d’une TVIM, une reevaluation precoce par imagerie et fibroscopie est necessaire. Apres traitement radical d’une tumeur des voies excretrices superieures (TVES), la surveillance par cystoscopie et cytologie est essentielle en raison de la frequence des recidives vesicales au cours des trois premieres annees. Le traitement conservateur des TVES necessite une surveillance stricte notamment par uretero-renoscopie. Conclusion La surveillance des carcinomes urotheliaux est a adapter en fonction des stades et grades tumoraux, de la localisation et de la modalite de traitement definissant ainsi le risque de recidive dans le temps.