[Intravesical adjuvant regimen of epitubicin for intermediate risk NMIBC: Feasability study from CC-AFU vessie]. / Instauration du traitement adjuvant endovésical par épirubicine des tumeurs de vessie n'infiltrant pas le muscle : premier retour national d'expérience du CC-AFU vessie.

INTRODUCTION: Mitomycin C is the gold standard intravesical adjuvant therapy for intermediate-risk non-muscle-invasive bladder cancer (NMIBC). Tensions in the supply of mitomycin have emerged in France since late 2019. The ANSM in agreement with the AFU proposed to use epirubicin, already available in other European countries in this indication. The objective of our study was to report the initial French experience with the use of epirubicin in adjuvant treatment of NMIBC. MATERIALS AND METHODS: We undertook a French multicenter retrospective descriptive study to collect, from the centers of the members of the CC-AFU bladder, the clinico-pathological data of the patients, the indications, the modalities of use (dose, indication, circuit in the pharmacy) and the tolerance data of epirubicin. The impact of the COVID-19 epidemic on treatment interruptions was also identified. Of the 20 centers contacted, 5 (25%) had implemented the epirubicin administration protocol developed by the CC-AFU bladder subcommittee. A total of 61 patients were treated with endovesical instillations of epirubicin between November 2019 and November 2020 for NMIBC at a single dose of 50mg. RESULTS: A total of 61 patients (mean age 67 years, 64-77 years) were treated with epirubicin, of which 45 (73.8%) were male. The patients had intermediate-risk NMIBC in 88.5%, the rest had high-risk disease. Induction therapy without or with maintenance was planned for 48 (78.7%) and 13 patients (21.3%), respectively. The preparation and administration of epirubicin was similar to that of mitomycin: central pharmacy preparation for same-day dispensing with immediate outpatient instillation. Unlike mitomycin, urinary alkalinization was not required. Of the 498 total instillations scheduled, 345 were performed (69.3%). The COVID-19 epidemic significantly impacted epirubicin delivery: one patient could not start treatment (1.6%), 8 patients (13.1%) had to discontinue it permanently; the rest of the patients underwent delayed instillations (18%). Other causes of discontinuation included infectious complications (9.8%). No major toxicities were reported. CONCLUSION: The implementation of an adjuvant epirubicin treatment protocol presented a good feasibility with low toxicity, without modifying the organization of the patients' care pathway. In the context of unpredictable mitomycin shortage, epirubicin represents a good therapeutic alternative in the endovesical adjuvant treatment of intermediate-risk NMIBC. LEVEL OF PROOF: 3.

[French ccAFU guidelines - update 2020-2022: bladder cancer]. / Recommandations françaises du Comité de cancérologie de l'AFU ­ actualisation 2020­2022 : tumeurs de la vessie.

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 <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 of patients diagnosed with NMIBC and MIBC.

[French ccAFU guidelines - update 2020-2022: upper urinary tract urothelial carcinoma]. / Recommandations françaises du Comité de cancérologie de l'AFU - actualisation 2020­2022 : tumeurs de la voie excrétrice urinaire supérieure.

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.

Recommandations françaises du Comité de cancérologie de l'AFU - actualisation 2020­2022: tumeurs de la voie excrétrice urinaire supérieure / French ccAFU guidelines - update 2020­2022: upper urinary tract urothelial carcinoma

The purpose was to propose an update of the French guidelines from the national committee ccAFU on upper tract urothelial carcinomas (UTUC). 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.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 pT2­T4 N0­3 M0 disease. These updated guidelines will contribute to increase the level of urological care for diagnosis and treatment for UTUC.

L'objectif était de proposer une mise à jour des recommandations du Comité de cancérologie de l'Association française d'urologie (AFU) pour la prise en charge des tumeurs de la voie excrétrice supérieure (TVES). Une revue systématique de la littérature (Medline) a été effectuée de 2018 à 2020 sur les éléments du diagnostic, les options de traitement et la surveillance des TVES en évaluant les références avec leur niveau de preuve. Le diagnostic de cette pathologie rare repose sur l'uro-TDM avec acquisition au temps excréteur et l'urétérorénoscopie souple avec prélèvements biopsiques. Le traitement chirurgical de référence est la néphro-urétérectomie totale (NUT), mais un traitement conservateur peut être discuté pour les lésions dites « à bas risque ¼ : tumeur de bas grade, sans infiltration sur l'imagerie, unifocale < 2 cm, accessible à un traitement complet et nécessitant alors une surveillance endoscopique rapprochée par urétéroscopie souple chez un patient compliant. Une instillation postopératoire de chimiothérapie est recommandée et permet de diminuer le risque de récidive vésicale après NUT. La chimiothérapie adjuvante a démontré son bénéfice clinique comparée à la surveillance après NUT pour les tumeurs (pT2­T4 N0­3 M0). Ces nouvelles recommandations doivent contribuer à améliorer non seulement la prise en charge des patients, mais aussi le diagnostic et la décision thérapeutique des TVES.

[Immunotherapy in urology: Concept and results]. / Immunothérapie en urologie : principes et résultats.

OBJECTIVE: The purpose of this article is to update current data on immunotherapy in uro-oncology. MATERIAL AND METHODS: Synthesis of data from recent literature and data presented at national and international conferences on immunotherapy in urological cancers. RESULTS: Current immunotherapies restore the anti-tumor immunity, by blocking immunity-negative feedback checkpoints. In metastatic renal cell carcinoma and bladder carcinoma, immunotherapy has first shown a significant survival benefit in second-line, and more recently in first-line for kidney cancer. Trials are currently ongoing in adjuvant and neoadjuvant settings. In prostate cancer, there is little data and immunotherapy seems to benefit a limited subgroup of patients. CONCLUSION: Immunotherapy is a key treatment in kidney and bladder cancer. In the future, the identification of predictive markers should allow us to better select patients responding to immunotherapy.

[Management of patients with systemic treatments]. / Prise en charge des patients sous traitement systémique.

To date, systemic treatments, including hormone therapies or chemotherapy, are used at different stages of prostate cancer disease. Several types of complications can occur during systemic treatment in prostate cancer, depending on the therapeutic range. The most common with hormone therapy are fatigue, muscle loss, bone loss, high blood pressure and metabolic syndromes. For chemotherapy, the most significant risk is related to hematological toxicity, but peripheral neuropathies, mucositis, diarrhea and hypersensitivity reactions may also occur. The quality of the pre-treatment assessment and the rigorousness of patient follow-up make it possible to anticipate most of these events, to prevent them or to manage them at an early stage when they occur. The most important aspect is patient education, which involves comprehensive information and the implementation of supportive care as soon as the treatment is initiated. Specialized advice (e. g. cardiological or endocrinological) is recommended in the event of uncontrolled symptomatology. The resumption of treatment leading to a major complication should be the subject of a multidisciplinary discussion taking into account the severity of the event, its reversibility, the patient's life expectancy and the expected efficacy of the molecule.

[Short version of recommendations for enhanced recovery program (ERP) for cystectomy: Technical measures]. / Version courte des recommandations de la récupération ameliorée après chirurgie (RAAC) pour la cystectomie : mesures techniques.

INTRODUCTION: The enhanced recovery program (ERP) is a management mode whose objective is to reduce the risk of complications and allow the patient to recover more quickly all its functional capacities and to reintegrate at most quickly and safely in his usual environment. This intentionally synthetic document aims to disseminate in the urological community the main points of the ERP recommendations for cystectomy. This work, coordinated by AFU, involves several other partners. The full document is available on the "Urofrance" website. Another article will follow on organizational measures. METHOD: The development of the recommendations is based on the method "formalized consensus of experts" proposed by the HAS. The report is based on a systematic review of the literature (January 2006-May 2017), two rounds of iterative quotations and a national proofreading. Levels of proof of conclusions and gradation of recommendations are based on the HAS grid. RESULTS: The bibliographic strategy made it possible to retain 298 articles. Only the recommendations that obtained a strong agreement after the two rounds of iterative listing were retained. The recommendations presented here are in chronological form (before, during, after hospitalization). Twenty-six key points on the technical and organizational measures of ERP have been identified. CONCLUSION: The result of the literature review, supplemented by expert opinion, suggests a significant clinical interest in the application and dissemination of ERP for cystectomy, despite the limited data available for this indication.

French ccAFU guidelines ­ Update 2018­2020: Bladder cancer / Recommandations françaises du Comité de Cancérologie de l'AFU ­ Actualisation 2018­2020 : tumeurs de la vessie

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.

RETRACTED: Recommandations françaises du Comité de Cancérologie de l'AFU ­ Actualisation 2018­2020 : tumeurs de la voie excrétrice supérieure French ccAFU guidelines ­ Update 2018­2020: Upper tract urothelial carcinoma / Recommandations françaises du Comité de Cancérologie de l'AFU ­ Actualisation 2018­2020 : tumeurs de la voie excrétrice supérieure.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). Cet article est retiré de la publication à la demande des auteurs car ils ont apporté des modifications significatives sur des points scientifiques après la publication de la première version des recommandations. Le nouvel article est disponible à cette adresse: doi:10.1016/j.purol.2019.01.005. C'est cette nouvelle version qui doit être utilisée pour citer l'article. This article has been retracted at the request of the authors, as it is not based on the definitive version of the text because some scientific data has been corrected since the first issue was published. The replacement has been published at the doi:10.1016/j.purol.2019.01.005. That newer version of the text should be used when citing the article.

RETRACTED: Recommandations françaises du Comité de Cancérologie de l'AFU ­ Actualisation 2018­2020 : tumeurs de la vessie French ccAFU guidelines ­ Update 2018­2020: Bladder cancer / Recommandations françaises du Comité de Cancérologie de l'AFU ­ Actualisation 2018­2020 : tumeurs de la vessie.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). Cet article est retiré de la publication à la demande des auteurs car ils ont apporté des modifications significatives sur des points scientifiques après la publication de la première version des recommandations. Le nouvel article est disponible à cette adresse: doi:10.1016/j.purol.2019.01.006. C'est cette nouvelle version qui doit être utilisée pour citer l'article. This article has been retracted at the request of the authors, as it is not based on the definitive version of the text because some scientific data has been corrected since the first issue was published. The replacement has been published at the doi:10.1016/j.purol.2019.01.006. That newer version of the text should be used when citing the article.

[ypT0N0 after neoadjuvant chemotherapy and cystectomy for muscle-invasive bladder cancer: Incidence and prognosis. A review from the Bladder group of the French Committee of Oncology]. / Pièce opératoire ypT0N0 après séquence chimiothérapie néo-adjuvante ­ cystectomie pour TVIM : épidémiologie et impact pronostique. Une mise au point du CCAFU Vessie.

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.

[French ccAFU guidelines - Update 2018-2020: Upper tract urothelial carcinoma]. / Recommandations françaises du Comité de Cancérologie de l'AFU ­ Actualisation 2018­2020 : tumeurs de la voie excrétrice supérieure.

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.

[CCAFU french national guidelines 2016-2018 on upper tract tumors]. / Recommandations en onco-urologie 2016-2018 du CCAFU : Tumeurs de la voie excrétrice supérieure.

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 2013 and 2016, 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 tumour, possible complete resection and low grade and absence of invasion on CT-scan. Close monitoring with endoscopic follow-up (flexible ureteroscope) in compliant patients is therefore necessary. After RNU, bladder instillation of chemotherapy is recommended to reduced risk of baldder recurrence. The place of systemic therapy (adjuvant and neoadjuvant chemotherapy) remains to define. CONCLUSION: These updated guidelines will contribute to increase the level of urological care for diagnosis and treatment for UTUC. © 2016 Elsevier Masson SAS. All rights reserved.

[CCAFU french national guidelines 2016-2018 on bladder cancer]. / Recommandations en onco-urologie 2016-2018 du CCAFU : Tumeurs de la vessie.

OBJECTIVE: The purpose of the guidelines national committee CCAFU on bladder cancer was to propose updated french guidelines for non-muscle invasive (NMIBC) and invasive (MIBC) bladder cancers. METHODS: A Medline search was achieved between 2013 and 2016, 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 tumour. 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 pelvic-abdominal and thoracic CT-scan; MRI and FDG-PET remain optional. Cystectomy associated with extensive pelvic lymph nodes resection is considered the gold standard for non metastatic MIBC. An orthotopic bladder substitution should be proposed to both male and female patients lacking any contraindications and in cases of negative frozen urethral samples. The interest of neoadjuvant chemotherapy is well known for all MIBC, wathever the stage. Thus, neoadjuvant chemotherapy is recommended for all eligible patients according PS (PS <2) and renal function (clearance > 60ml/mn). As regards metastatic MIBC, first-line chemotherapy using platin is recommended (GC or MVAC). In second line treatment, only chemotherapy using vinflunine has been validated to date, even if results of immunotherapy clinical trials are encouraging. CONCLUSION: These updated french guidelines will contribute to increase the level of urological care for the diagnosis and treatment for NMIBC and MIBC. © 2016 Elsevier Masson SAS. All rights reserved.

Epicure: a European epidemiological study of patients with an advanced or metastatic Urothelial Carcinoma (UC) having progressed to a platinum-based chemotherapy.

BACKGROUND: Platinum-based systemic chemotherapy is considered the backbone for management of advanced urothelial carcinomas. However there is a lack of real world data on the use of such chemotherapy regimens, on patient profiles and on management after treatment failure. METHODS: Fifty-one randomly selected physicians from 4 European countries registered 218 consecutive patients in progression or relapse following a first platinum-based chemotherapy. Patient characteristics, tumor history and treatment regimens, as well as the considerations of physicians on the management of urothelial carcinoma were recorded. RESULTS: A systemic platinum-based regimen had been administered as the initial chemotherapy in 216 patients: 15 in the neoadjuvant setting, 61 in adjuvant therapy conditions, 137 in first-line advanced setting and 3 in other conditions. Of these patients, 76 (35 %) were initially considered as cisplatin-unfit, mainly because of renal impairment (52 patients). After platinum failure, renal impairment was observed in 44 % of patients, ECOG Performance Status ≥ 2 in 17 %, hemoglobinemia < 10 g/dL in 16 %, hepatic metastases in 13 %. 80 % of these patients received further anticancer therapy. Immediately after failure of adjuvant/neoadjuvant chemotherapy, most subsequent anticancer treatments were chemotherapy doublets (35/58), whereas after therapy failure in the advanced setting most patients receiving further anticancer drugs were treated with a single agent (80/114). After first progression to chemotherapy, treatment decisions were mainly driven by Performance Status and prior response to chemotherapy (>30 % patients). The most frequent all-settings second anticancer therapy regimen was vinflunine (70 % of single-agent and 42 % of all subsequent treatments), the main reasons evoked by physicians (>1 out of 4) being survival benefit, safety and phase III evidence. CONCLUSION: In this daily practice experience, a majority of patients with urothelial carcinoma previously treated with a platinum-based therapy received a second chemotherapy regimen, most often a single agent after an initial chemotherapy in the advanced setting and preferably a cytotoxic combination after a neoadjuvant or adjuvant chemotherapy. Performance Status and prior response to chemotherapy were the main drivers of further treatment decisions.

Statistical controversies in clinical research: should schedules of tumor size assessments be changed?

BACKGROUND: Time to progression (TTP) is often used as a primary end point in phase II clinical trials. Since the actual date of nadir and progression is never known, most calculated TTP are overestimated. This study evaluates the imprecision on the estimate of TTP under two hypothetical tumor kinetic settings and various assessment schedules. DESIGN: A two-component tumor growth model was used to account for treatment effect assuming exponential decay for tumor shrinkage and linear growth for progression. Evolution of tumor burden (TB) was modelized according to two scenarios using either a cytotoxic or a cytostatic agent and several assessment schedules. TB, nadir, progression and TTP were simulated for each visit schedule. RESULTS: For cytotoxic agents, our model predicted response at 1.5 weeks, a TB at nadir of 40.2 mm (starting from 100 mm) occurring at 6.7 weeks and true progression at 11.2 weeks with a TB of 48.2 mm. For cytostatic agents, our model predicted no response, a TB at nadir of 77 mm occurring at 9.2 weeks and true progression at 19.4 weeks with a TB of 92 mm. Depending on the assessment schedule, estimated TTP was increased from 0.8 to 36.8 weeks and from 0.6 to 28.6 weeks when compared with the true TTP and varied from 5.2% to 298% and from 1.66 to 109.58% when compared with the true TB at progression for cytotoxic and cytostatic agents, respectively. Our model further shows that for cytotoxic agents, evaluation of TB every 6 weeks is optimal to capture the true nadir, the time to nadir, the true progression and the true TTP, whereas for cytostatic agents, this evaluation is optimal every 10 weeks. CONCLUSIONS: Our results emphasize the importance to estimate the effects of tested drugs on tumor shrinkage before design any phase II clinical trials to choose optimal TB evaluation's timing.

Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment.

BACKGROUND: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. PATIENTS AND METHODS: We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201). RESULTS: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type. CONCLUSIONS: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.

[Observational survey of the French Urological Association Oncology Committee (CCAFU) evaluating the practice of immediate postoperative instillation (IPOP) using mitomycin C for non-muscle invasive bladder cancer (NMIBC) treatment]. / Enquête observationnelle du Comité de cancérologie de l'association française d'urologie (CCAFU) sur la pratique des instillations postopératoires précoces (IPOP) de mitomycine C pour le traitement des tumeurs de vessie n'infiltrant pas le muscle (TVNIM).

OBJECTIVE: To evaluate the practice of immediate postoperative instillation (IPOP) using mitomycin C for non-muscle invasive bladder cancer (NMIBC) treatment by urologists members of the French Association of Urology (AFU). MATERIAL AND METHOD: Internet-based observational survey evaluating indications and practical modalities of IPOP in NMIBC treatment using questionnaire sent in May 2014 to 915 urologists. RESULTS: Two hundred ninety-eight urologists participated in the survey (response rate: 32.6%) and 57% prescribed the IPOP. The median frequency of IPOP prescription was 3.3%, and was higher in the academic public sector. The CASE recommendations were self-assessed as known or well-known in 67% of cases. The selections criteria for IPOP were adequately identified by 62% of urologists, without differences according to sectors of activity. The IPOP prescription modalities were declared as an obstacle to the completion for 41.9% of urologists, and especially in the private sector. Completion times of IPOP were declared <24h in 91% of cases. We see that 28.5% of urologists prescribed an urinary alkalization. The average frequency of complications of IPOP was 0.91 per urologist. CONCLUSIONS: The IPOP prescription frequency was higher among urologists practicing in the academic sector. Neither the level of knowledge of the recommendations nor the frequency of complications of IPOP had explained this difference. However, the prescription modalities were more frequently reported as an obstacle to their completion in the private sector. LEVEL OF EVIDENCE: 3.

[Molecular, preclinical, and clinical comparative data regarding different strains of bacillus Calmette-Guérin (BCG): Review by the French Urological Association Oncology Committee (CCAFU)]. / Données comparatives moléculaires, précliniques et cliniques des différentes souches de bacille de Calmette-Guérin (BCG) : revue de la littérature du Comité de cancérologie de l'Association française d'urologie (CCAFU).

OBJECTIVE: To review the differences between the BCG strains used for the treatment of non-muscle invasive bladder cancer (NMIBC) at the molecular level, regarding cytotoxicity, immunogenicity, clinical efficiency, and safety. MATERIAL AND METHOD: A systematic review of the literature search was performed from the database MedLine, focused on the following keywords: BCG; bladder; strain; genome; cytotoxicity; immune response; efficiency; safety. RESULTS: Genetic differences between BCG strains have been identified and correlated to their time to differentiation from their initial cultures start, assuming a lower resistance to the host immune defenses of Tice and Danish strains compared to the Connaught strain. Preclinical comparative data showed superior cytotoxic effect and immunogenicity of the Connaught strain compared to Tice and Danish strains. The phase III trials have shown superior efficiency of BCG Connaught compared to BCG Tice and BCG Danish compared to BCG Tice regarding recurrence-free survival. CONCLUSIONS: Among BCG strains used in France in NMIBC treatment, preclinical and clinical efficiency of Connaught strain was higher than that of the Tice strain. The limits of the currently available studies lie primarily in the lack of use of maintenance therapy.

Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.

BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.