Amir Sherif

Treatment of Muscle-Invasive and Metastatic Bladder Cancer: Update of the EAU Guidelines.

CONTEXTnNew data regarding treatment of muscle-invasive and metastatic bladder cancer (MiM-BC) has emerged and led to an update of the European Association of Urology (EAU) guidelines for MiM-BC.nnnOBJECTIVEnTo review the new EAU guidelines for MiM-BC with a specific focus on treatment.nnnEVIDENCE ACQUISITIONnNew literature published since the last update of the EAU guidelines in 2008 was obtained from Medline, the Cochrane Database of Systematic Reviews, and reference lists in publications and review articles and comprehensively screened by a group of urologists, oncologists, and a radiologist appointed by the EAU Guidelines Office. Previous recommendations based on the older literature on this subject were also taken into account. Levels of evidence (LEs) and grades of recommendations (GRs) were added based on a system modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence.nnnEVIDENCE SYNTHESISnCurrent data demonstrate that neoadjuvant chemotherapy in conjunction with radical cystectomy (RC) is recommended in certain constellations of MiM-BC. RC remains the basic treatment of choice in localised invasive disease for both sexes. An attempt has been made to define the extent of surgery under standard conditions in both sexes. An orthotopic bladder substitute should be offered to both male and female patients lacking any contraindications, such as no tumour at the level of urethral dissection. In contrast to neoadjuvant chemotherapy, current advice recommends the use of adjuvant chemotherapy only within clinical trials. Multimodality bladder-preserving treatment in localised disease is currently regarded only as an alternative in selected, well-informed, and compliant patients for whom cystectomy is not considered for medical or personal reasons. In metastatic disease, the first-line treatment for patients fit enough to sustain cisplatin remains cisplatin-containing combination chemotherapy. With the advent of vinflunine, second-line chemotherapy has become available.nnnCONCLUSIONSnIn the treatment of localised invasive bladder cancer (BCa), the standard treatment remains radical surgical removal of the bladder within standard limits, including as-yet-unspecified regional lymph nodes. However, the addition of neoadjuvant chemotherapy must be considered for certain specific patient groups. A new drug for second-line chemotherapy (vinflunine) in metastatic disease has been approved and is recommended.

The updated EAU guidelines on muscle-invasive and metastatic bladder cancer.

CONTEXTnNew data regarding diagnosis and treatment of muscle-invasive and metastatic bladder cancer (MiM-BC) has emerged and led to an update of the European Association of Urology (EAU) guidelines for MiM-BC.nnnOBJECTIVEnTo review the new EAU guidelines for MiM-BC.nnnEVIDENCE ACQUISITIONnA comprehensive workup of the literature obtained from Medline, the Cochrane central register of systematic reviews, and reference lists in publications and review articles was developed and screened by a group of urologists, oncologists, and radiologist appointed by the EAU Guideline Committee. Previous recommendations based on the older literature on this subject were taken into account. Levels of evidence and grade of guideline recommendations were added, modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence.nnnEVIDENCE SYNTHESISnThe diagnosis of muscle-invasive bladder cancer (BCa) is made by transurethral resection (TUR) and following histopathologic evaluation. Patients with confirmed muscle-invasive BCa should be staged by computed tomography (CT) scans of the chest, abdomen, and pelvis, if available. Adjuvant chemotherapy is currently only advised within clinical trials. Radical cystectomy (RC) is the treatment of choice for both sexes, and lymph node dissection should be an integral part of cystectomy. An orthotopic bladder substitute should be offered to both male and female patients lacking any contraindications, such as no tumour at the level of urethral dissection. Multimodality bladder-preserving treatment in localised disease is currently regarded only as an alternative in selected, well-informed, and compliant patients for whom cystectomy is not considered for clinical or personal reasons. An appropriate schedule for disease monitoring should be based on (1) natural timing of recurrence, (2) probability of disease recurrence, (3) functional deterioration at particular sites, and (4) consideration of treatment of a recurrence. In metastatic disease, the first-line treatment for patients fit enough to sustain cisplatin is cisplatin-containing combination chemotherapy. Presently, there is no standard second-line chemotherapy.nnnCONCLUSIONSnThese EAU guidelines are a short, comprehensive overview of the updated guidelines of (MiM-BC) as recently published in the EAU guidelines and also available in the National Guideline Clearinghouse.

Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer

BACKGROUNDnCharacterising responders to neoadjuvant chemotherapy (NAC) is important to minimise overtreatment and the unnecessary delay of definitive treatment of urothelial urinary bladder cancer.nnnOBJECTIVEnTo assess the effect of NAC on tumour downstaging and overall survival.nnnDESIGN, SETTING, AND PARTICIPANTSnA total of 449 patients from the randomised prospective Nordic Cystectomy Trials 1 and 2 were analysed retrospectively. Eligible patients were defined as T2-T4aNXM0 preoperatively and pT0-pT4aN0-N+M0 postoperatively. The median follow-up time was 5 yr.nnnINTERVENTIONnThe experimental arm consisted of cisplatin-based NAC; the control arm consisted of cystectomy only.nnnMEASUREMENTSnThe primary outcome was tumour downstaging defined as pathologic TNM less than clinical TNM. Different downstaging thresholds were applied: complete downstaging (CD) (pT0N0), noninvasive downstaging (NID) (pT0/pTis/pTaN0), and organ confinement (OC) (≤ pT3aN0). Downstaging rates and nodal status were compared between the study arms using the chi-square test. Secondary outcome was overall survival (OS) stratified by treatment arm, downstaging categories, and clinical stages, analysed by the Kaplan-Meier method. The following covariates were tested as prognostic factors in univariate and multivariate analyses using the Cox regression method: age, sex, clinical stage, pN status, NAC, CD, NID, and OC.nnnRESULTS AND LIMITATIONSnDownstaging rates increased significantly in the NAC arm independent of the downstaging threshold. The impact was more prominent in clinical T3 tumours, with a near threefold increase in CD tumours. The combination of CD and NAC showed an absolute risk reduction of 31.1% in OS at 5 yr compared with CD controls. The combination of NAC and CD revealed a hazard ratio of 0.32 compared with 1.0 for the combination of no NAC and no CD. Limitations were the retrospective approach and uncertain clinical TNM staging.nnnCONCLUSIONSnSurvival benefits of NAC are reflected in downstaging of the primary tumour. Chemo-induced downstaging might be a potential surrogate marker for OS.

FOXP3 and survival in urinary bladder cancer

Whats known on the subject? and What does the study add?

Feasibility of T-Cell-Based Adoptive Immunotherapy in the First 12 Patients with Advanced Urothelial Urinary Bladder Cancer. Preliminary Data on a New Immunologic Treatment Based on the Sentinel Node Concept

BACKGROUNDnExpected 2-yr survival for patients with urothelial urinary bladder cancer (UBC) with lymph node involvement (pN2) is 20%, regardless of standard neoadjuvant/adjuvant oncologic treatment. Tumor-reactive lymphocytes are present in sentinel nodes (SNs) draining human bladder cancer and display immunologic function on restimulation in vitro. Metinel nodes (MNs) drain secondarily from metastatic tumors and also possess tumor-reactive lymphocytes, which might be a source for adoptive T-cell immunotherapy.nnnOBJECTIVESnTo determine if MN detection and subsequent expansion of autologous T-helper cells with subsequent reinfusion was feasible and safe to perform in patients with metastatic UBC.nnnDESIGN, SETTING, AND PARTICIPANTSnIn an open trial, the first 12 included patients are described. Patients were prospectively selected from a single tertiary academic center and had metastatic UBC. All 12 patients were preoperatively staged as T2-T4b N1-2 and/or M0-M1 or MX.nnnINTERVENTIONSnMNs were excised in conjunction with intended cystectomy. T lymphocytes were extracted with enhancement and expansion of tumor specific T-helper cells, followed by reinfusion of expanded T cells.nnnMEASUREMENTSnAll patients were preoperatively staged with transurethral resection of the bladder and routine computed tomography scan. Intended detection of MNs was performed intraoperatively with intended cystectomy. Harvested T cells were evaluated and cell cultures were established. Assessment of reinfusion of expanded, autologous, tumor-specific T-helper cells to six of the patients was performed, focusing on adverse effects.nnnRESULTS AND LIMITATIONSnIn six patients, it was feasible to administer the treatment. Reinfusion of these T cells was performed without any major adverse effects. In six other patients, we encountered technical failures.nnnCONCLUSIONSnA novel adoptive immunotherapy based on T cells from tumor-draining lymph nodes is feasible in advanced UBC. Infusion of expanded, autologous, tumor-specific T-helper cells might be a future treatment option in metastasized UBC. Long-term overall survival remains to be determined.

Sentinel node detection in renal cell carcinoma. A feasibility study for detection of tumour-draining lymph nodes.

Study Type – Therapy (case series)

Update of the Clinical Guidelines of the European Association of Urology on muscle-invasive and metastatic bladder carcinoma

CONTEXTnNew data regarding diagnosis and treatment of muscle-invasive and metastatic bladder cancer (MiM-BC) has emerged and led to an update of the European Association of Urology (EAU) guidelines for MiM-BC.nnnOBJECTIVEnTo review the new EAU guidelines for MiM-BC.nnnEVIDENCE ACQUISITIONnA comprehensive workup of the literature obtained from Medline, the Cochrane central register of systematic reviews, and reference lists in publications and review articles was developed and screened by a group of urologists, oncologists, and radiologist appointed by the EAU Guideline Committee. Previous recommendations based on the older literature on this subject were taken into account. Levels of evidence and grade of guideline recommendations were added, modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence.nnnEVIDENCE SYNTHESISnThe diagnosis of muscle-invasive bladder cancer (BCa) is made by transurethral resection (TUR) and following histopathologic evaluation. Patients with confirmed muscle-invasive BCa should be staged by computed tomography (CT) scans of the chest, abdomen, and pelvis, if available. Adjuvant chemotherapy is currently only advised within clinical trials. Radical cystectomy (RC) is the treatment of choice for both sexes, and lymph node dissection should be an integral part of cystectomy. An orthotopic bladder substitute should be offered to both male and female patients lacking any contraindications, such as no tumour at the level of urethral dissection. Multimodality bladder-preserving treatment in localised disease is currently regarded only as an alternative in selected, well-informed, and compliant patients for whom cystectomy is not considered for clinical or personal reasons. An appropriate schedule for disease monitoring should be based on: a) natural timing of recurrence; b) probability of disease recurrence; c) functional deterioration at particular sites; and d) consideration of treatment of a recurrence. In metastatic disease, the first-line treatment for patients fit enough to sustain cisplatin is cisplatin-containing combination chemotherapy. Presently, there is no standard second-line chemotherapy.nnnCONCLUSIONSnThese EAU guidelines are a short, comprehensive overview of the updated guidelines of (MiM-BC) as recently published in the EAU guidelines and also available in the National Guideline Clearinghouse.

Treatment of muscle-invasive bladder cancer.

In the USA, the incidence of bladder cancer is three-times higher in men than in women and it is the fourth most common cancer in men after prostate, lung and colorectal cancer. Muscle-invasive urothelial urinary bladder cancer has a very high mortality rate. This is regardless of intensive therapeutic efforts such as radical surgery in combination with oncological treatment options. The development of treatments with better outcomes regarding disease-specific survival and treatment-inflicted morbidity is likely to occur over the next few years. The significance of meta-analyses on the effect of neoadjuvant chemotherapy, the development of sentinel node dissection and the impact of the introduction of robot-assisted surgery on the possibility of performing minimally invasive surgery in advanced bladder cancer patients is discussed.

Actualización de las Guías Clínicas de la Asociación Europea de Urología sobre el carcinoma vesical músculo-invasivo y metastásico

Contexto: la aparicion de nuevos datos relacionados con el diagnostico y tratamiento de cancer vesical musculo-invasivo y metastasico (CaV-MiM) ha obligado a una actualizacion de las Guias sobre el CaV-MiM de la Asociacion Europea de Urologia (EAU). Objetivo: revision de las nuevas guias de la EAU para el CAV-MiM. Evidencia adquirida: un grupo de urologos, oncologos y radiologos designados por el Comite de Guias Clinicas de la EAU ha realizado un exhaustivo trabajo de revision de la literatura procedente de Medline, el registro central Cochrane de revisiones sistematicas y las citas bibliograficas de publicaciones y articulos de revision. Se han tenido en cuenta las recomendaciones basadas en la literatura previa disponible sobre este aspecto. Ademas, han sido anadidos niveles de evidencia y grados de recomendacion, segun las modificaciones del Oxford Centre for Evidence-based Medicine. Evidencia sintetizada: el diagnostico de cancer vesical musculo-invasivo (CaVMI) se realiza mediante la reseccion transuretral y el consiguiente estudio histopatologico. Una vez confirmada la existencia de CaVMI es preciso realizar el estadiaje mediante tomografia computarizada toraco-abdomino-pelvica, si se dispone de ella. Actualmente, la quimioterapia adyuvante solamente se recomienda en el contexto de ensayos clinicos. La cistectomia radical es el tratamiento de eleccion en ambos sexos, y la linfadenectomia debe constituir una parte integral de la misma. Tanto a hombres como a mujeres se les debe ofrecer la sustitucion vesical ortotopica siempre que no existan contraindicaciones, tales como la existencia de tumor en el margen uretral. En la actualidad, los tratamientos multimodales para la conservacion vesical en casos de enfermedad localizada constituyen un alternativa terapeutica solamente en pacientes seleccionados, adecuadamente informados, y en aquellos en los que se desestima la cistectomia por motivos clinicos o personales. Los protocolos de seguimiento deben disenarse sobre la base de: a) historia natural de la recurrencia; b) probabilidades de recurrencia; c) deterioro funcional en localizaciones especificas; y d) consideraciones sobre el tratamiento de la recurrencia. En la enfermedad metastasica el tratamiento de primera linea para los pacientes con un estado general adecuado para tolerar el cisplatino es la quimioterapia combinada basada en este farmaco. Actualmente no existe una quimioterapia estandarizada de segunda linea. Conclusiones: estas guias de la EAU constituyen un resumen de la exhaustiva vision de conjunto de las guias recientemente actualizadas del CaV-MiM, publicadas en las guias clinicas de la EAU, tambien disponibles en la National Guideline Clearinghouse

MP-13.08: Detection of immune responses against urinary bladder cancer in sentinel lymph nodes

Objective: The lymphatic drainage from a tumour is received in the sentinel node where the immune system encounters tumour derived antigens. We investigated anti-tumoural lymphocyte function in sentinel nodes from patients with urinary bladder cancer. Methods: In 14 patients undergoing cystectomy due to bladder cancer, radioactive tracer and blue dye were used to identify the sentinel node. Cell suspensions from the tumour, sentinel- and non-sentinel nodes and peripheral blood were analyzed by flow cytometry with antibodies against lymphocyte surface antigens and against the tumour cell marker cytokeratin-20. Reactivity against autologous tumour extract and the mitogen Concanavalin A was tested in proliferation assays with 3 HThymidine incorporation. Lymphocytes were put in long-term culture with IL-2 and autologous tumour extract. Results: Sentinel nodes were detected in 12 of the 14 patients. Antigen dependent proliferation in response to autologous tumour extract was detected in 6 patients, in 5 cases in sentinel nodes, in the remaining case in a non-sentinel node. Proliferation against Concanavalin A was vigorous in lymph nodes from all patients, whereas tumour infiltrating lymphocytes were unresponsive. Lymphocytes from sentinel nodes could be expanded in vitro. Conclusion: Tumour reactive lymphocytes are present in sentinel nodes draining human bladder cancers. These cells display immunologic