Bladder Cancer. A Practical Guide

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Preface Contents Contributors Part I: Bladder Cancer 1: Bladder Cancer Screening, Signs and Symptoms, and Workup Introduction Screening Rationale for Screening Prior Screening Trials Identification of At-Risk Populations Signs and Symptoms Evaluation Conclusions References 2: Cystoscopy and Enhanced Diagnostics Introduction Photodynamic Diagnosis Blue Light Flexible Cystoscopy in the Clinic (Surveillance) Narrow-Band Imaging Storz Professional Image Enhancement System (IMAGE 1 S) Optical Coherence Tomography Confocal Laser Endomicroscopy Real-Time Multispectral Imaging Conclusion References 3: Using Urinary Biomarkers in Urothelial Carcinoma of the Bladder and Upper Tracts Introduction The Rationale for Urinary Markers Available Urinary Markers NMP22 BTA TRAK/BTA Stat ImmunoCyt/uCyt+ UroVysion FISH CxBladder Xpert BC Monitor DNA Methylation Markers When to Use Urinary Markers Practical Considerations What to Do with a Positive Urine Marker? How to Use a Negative Marker? Can a Marker Predict Outcomes? Urinary Markers in Upper Tract Urothelial Carcinoma The Guidelines The Optimal Trials for Use of Urinary Biomarkers Conclusion References 4: Pathology Introduction Flat Urothelial Carcinoma In Situ (CIS) Papillary Neoplasms Urothelial Papilloma Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP) Low-Grade Papillary Urothelial Carcinoma (LGPUC) High-Grade Papillary Urothelial Carcinoma (HGPUC) Invasive Urothelial Carcinoma Pathologic Features of Invasive Urothelial Carcinomas (Including Divergent Differentiation) En Bloc Resection Upper Urinary Tract Biopsies Pathology Report References 5: Risk Stratification of Patients: Risk Tables and Assessment – NMIBC and MIBC Introduction NMIBC RISK Groups Risk Scoring EORTC (European Organisation for Research and Treatment of Cancer) CUETO (Club Urologico Espanol de Tratamiento Oncologico) The Molecular Landscape of Non-Muscle Invasive Bladder Cancer MIBC Risk with Clinical Parameters Risk with Imaging Risk Via IHC Risk Via Genomic Classifiers References 6: Perioperative Preparation and Management of Cystoscopy Patient Preoperative Assessment OR Management Postoperative References 7: Transurethral Resection of Bladder Tumors (TURBT) Introduction Indications Patient Preparation Basics of Standard TURBT Blue Light TURBT Narrow Band Imaging Image1 S En Bloc Resection Handling of Specimens in the OR Special Circumstances Tumors at the Anterior Wall Tumors Located near the Ureteral Orifices Tumors Located at the Lateral Wall Tumors Located at the Bladder Dome Tumors Located in Bladder Diverticula Management of Common Complications Bladder Perforation Bleeding Postoperative Hydronephrosis References 8: Single Immediate Intravesical Instillation of Chemotherapy- Rationale and Practical Considerations What Is the Rationale of Single Immediate Instillation of Chemotherapy? What Is the Current Evidence for the Use of Single Immediate Instillation of Chemotherapy? Is Single Immediate Instillation of Chemotherapy Effective Per Se? Are there any Differences Between Chemotherapeutic Agents? Which Patients Profit Most? How Is Current Single Immediate Instillation of Chemotherapy Administered? In-a-Nutshell: A Practical Guide on Single Immediate Instillation of Chemotherapy References 9: Adjuvant Intravesical Therapy: Bacillus Calmette-Guerin Introduction Indications Oncological Outcomes: Recurrence Oncological Outcomes: Progression BCG for Carcinoma In Situ Factors Influencing BCG Outcomes BCG Strain Gender Age Smoking Genetic Variations BCG Administration: Pre-, Peri-, and Post-Instillation Management BCG Contraindications BCG Schedule BCG Dose Peri-Instillation Medical Therapy BCG Instillation and Dwell Time Management of Side Effects BCG Side Effects Rate BCG Local Side Effects BCG Systemic Side Effects Defining and Evaluating Recurrence Conclusion References 10: Adjuvant Intravesical Chemotherapy Traditional Induction Intravesical Chemotherapy (Mitomycin C/Epirubicin/Doxorubicin) Improving MMC Efficacy Urinary Alkalization & Dehydration Electromotive Drug Administration Chemohyperthermia Maintenance Therapy with Intravesical Chemotherapy BCG Shortage: New Chemotherapeutic Agents (Gemcitabine, Docetaxel, Gemcitabine/Docetaxel, Gemcitabine/MMC) Single-Dose Postoperative Intravesical Therapy Postoperative Intravesical Agents Toxicity Practical Application of Single-Dose Postoperative Intravesical Chemotherapy Salvage Intravesical Chemotherapy Valrubicin Chemohyperthermia Single-Agent Chemotherapy Multiagent Chemotherapy Practical Advice for Salvage Intravesical Treatment Choice and Administration References 11: Device-Assisted Therapies for Nonmuscle-Invasive Bladder Cancer: A Practical Approach Introduction Indications Synergo HIVEC EMDA Patient Preparation Administration Management of Side Effects and Evaluating Recurrence Discussion References 12: Intravesical Salvage Therapy After BCG/Regular Chemo Introduction Administration Prior to Administration After Administration Single-Agent Therapy BCG +/− Interferon Valrubicin Mitomycin C, Electromotive Mitomycin C, and Heated Mitomycin C Gemcitabine Docetaxel Multiagent Therapy Gemcitabine/Mitomycin C Gemcitabine/Docetaxol Quadruple Immunotherapy Current Clinical Trials and Future Therapy Patient Follow-Up Summary References 13: Oncological Monitoring of NonMuscle Invasive Bladder Cancer (NMIBC) Background Risk-Stratified Surveillance and Follow-up for NMIBC Risk Stratification Surveillance Algorithm First Surveillance Cystoscopy Low-Risk Patient Follow-Up Intermediate-Risk Patient Follow-Up High-Risk Patient Follow-Up Discontinuation of Follow-Up Cystoscopy and Recent Advances White Light Cystoscopy Blue Light Cystoscopy (Fluorescent Cystoscopy) Outcomes Drug Administration, Technique, and Safety Profile Key Clinical Uses Advantages and Disadvantages Summary Narrow-Band Imaging (NBI) Urine Cytology and Novel Urine Markers Interpreting the Statistics for Urinary Markers Sensitivity and Negative Predictive Value (NPV) Specificity and Positive Predictive Value (PPV) Urine Cytology Nuclear Matrix Protein 22 (NMP22®) Bladder Tumor Antigen (BTA®) UroVysion®FISH ImmunoCytTM Summary Cross-Sectional Imaging Computed Tomography Urography Magnetic Resonance Urography Bladder Biopsies Variant Histology Lifestyle Modifications Conclusion References 14: Radical Cystectomy Enhanced Recovery After Surgery Protocols Indications for Cystectomy and Morbidity of Surgery ERAS History and Use in Urology Components of ERAS Preoperative Measures Initial Assessment—Role of Prehabilitation and Nutrition Education No Bowel Preparation Venous Thromboembolism Prophylaxis Mu Opioid Antagonists Intraoperative Measures Fluid Management Minimization of Narcotic Pain Medications Minimally Invasive surgery Postoperative Measures No Nasogastric Tube Early Feeding Early Ambulation Modern Efforts in ERAS Conclusion Open Radical Cystectomy Male/Female Radical Cystectomy Male Cystectomy Male Nerve-Sparing Seminal Vesicle-Sparing Surgery Female Cystectomy Cysto-Hysterectomy Nerve-Sparing Female Cystectomy Individualized cystectomy Robot-Assisted Radical Cystectomy Preoperative Workup and Care Patient Positioning and Port Placement Robot-Assisted Radical Cystectomy in Males Periureteral Space Lateral Pelvic Space Anterior Rectal Space Control of Lateral Vascular Pedicle Anterior Vesical Space and Apical Dissection (DVC Control and Urethral Transection) Robot-Assisted Anterior Pelvic Exenteration in Females Control of the Ovarian Pedicles Anterior Rectal Space Apical Dissection (DVC Control and Urethral Transection) Closure of the Vagina Robot-Assisted Extended Pelvic Lymph Node Dissection Conclusion Organ-Sparing Approaches for Radical Cystectomy (Partial Cystectomy, Radical Cystectomy in Women with Reproductive Organ Preservation, Prostate-Sparing Radical Cystectomy) Introduction Preoperative Evaluation Partial Cystectomy Surgical Technique Outcomes of Partial cystectomy Radical Cystectomy in Women with Reproductive Organ Preservation Prostate-Sparing Radical Cystectomy Surgical Approaches Outcomes of Prostate-Sparing Cystectomy Cystectomy Surgical Technique – Pelvic Lymph Node Dissection Evidence for Pelvic Lymph Node Dissection Standard vs. Extended LND Lymphatic Drainage from Bladder Lymphadenectomy Boundaries and Surgical Technique Minimum Number of Lymph Nodes for Evaluation Complications of LND Prognostic Factor in Survival References 15: Surgical Technique: Urethrectomy Introduction Surgical Technique Preoperative Preparation Patient Positioning and Preparation Incision Dissection of the Distal Urethra Dissection of the Proximal Urethra Closure of the Surgical Site Postoperative Care References 16: Management of Common Complications After Radical Cystectomy, Lymph Node Dissection, and Urinary Diversion Introduction Gastrointestinal Complications Infectious Complications Wound Complications Genitourinary Complications Lymphatic Complications Cardiopulmonary Complications Thromboembolic Complications Stomal Complications Complications Specific to Continent Diversion Conclusion References 17: Incontinent Urinary Diversion Introduction Patient Preparation Surgical Techniques Cutaneous Ureterostomy Introduction Indications Limitations and Relative Contraindications Surgical Technique Steps Ureterocutaneous Anastomosis Variants Complications Follow-Up Ileal Conduit Indications Patient Selection Open Surgical Technique Intracorporeal Surgical Technique Complications Follow-Up Other Incontinent Diversions Jejunal Conduit Colonic Conduit Conclusions References 18: Continent Cutaneous Urinary Diversions Patient Selection Patient Preparation Surgical Techniques Indiana Pouch Robotic Approach for Continent Cutaneous Urinary Diversion Prevention and Management of Complications Urinary Tract Monitoring References 19: Orthotopic Bladder Substitution Introduction Indications and Contraindications Urethral Margin Age and Motivation Sphincter and Urethral Quality Gender Patient Preparation Surgical Technique Open Studer Neobladder Other Technical Issues Intracorporeal W-Neobladder Postoperative Management Complications Management of Complications Conclusion References 20: Neoadjuvant Chemotherapy Introduction Indications Patient Preparation Selection of Agent Administration Management of Side Effects Oncologic Monitoring References 21: Adjuvant Chemotherapy in Bladder Cancer Indications Patient Preparation Selection of Agent Administration Management of Side Effects Oncologic Monitoring Defining and Evaluating Recurrence References 22: Trimodal Therapy Indications for Trimodality Treatment Introduction The Case for TMT Patient Selection for TMT Patient Factors Baseline Bladder Function Contraindications to Chemotherapy or RT Patient Compliance Tumour Factors T Stage Nodal Disease Associated Widespread Carcinoma in Situ Tumour-Related Hydronephrosis Histological Type Treatment Factors Transurethral Resection of Bladder Tumour (TURBT) Neoadjuvant Chemotherapy The Ideal TMT Candidate TMT in Patients Unfit for RC Summary Patient Preparation for Trimodal Therapy Initial Workup Trimodality Bladder Preserving Strategy Radiotherapy Preparation Perioperative Chemotherapy – Concomitant Chemotherapy as Part of Bladder Preservation Therapy Introduction Choice of Agents Cisplatinum Fluoro-Uracil (5FU) Mitomycin C (MMC) Carbogen/Nicotinamide Gemcitabine Other Radio-Sensitisers COVID-19 Conclusions External Beam Irradiation for Trimodality Therapy in Bladder Cancer Introduction Radiotherapy Administration Simulation Treatment Field Design, Targets, and Dose Radiation Fields Radiation Dose Radiation Frequency Considerations/Controversies Normal Tissue Considerations Novel Techniques Management of Toxicities Acute Toxicities Late Toxicities Oncologic Monitoring References 23: Managing Urothelial Recurrences after Chemoradiation Therapy Overview Non-muscle-Invasive Bladder Recurrences Muscle-Invasive Bladder Recurrences The Role of Additional Radiation Therapy Upper Urinary Tract (Ureter, Renal Pelvis) Recurrences Urethral Recurrences Distant Recurrence References 24: Cytotoxic Chemotherapy for Advanced Bladder and Upper Tract Cancer Chemotherapy Indications First-Line Setting Second-Line Setting Patient Preparation Prognostic Selection of Agent Cisplatin-Based Regimens Carboplatin-Based Regimens Non-Platinum-Based Therapy Monotherapy Administration Management of Toxicity Oncologic Monitoring References 25: Immunotherapy for Metastatic Urothelial Carcinoma Introduction Indications Patient Preparation Selection of Agent Atezolizumab Pembrolizumab Nivolumab Avelumab Durvalumab Administration Management of Toxicity Oncologic Monitoring Defining and Evaluating Recurrence Conclusion References 26: Novel Therapies Novel Therapies Indications Patient Preparation Selection of Agent Anti-Angiogenic Pathways Antibody Drug Conjugates PARP Inhibitors Fibroblast Growth Factor Receptor Alterations Human Epidermal Growth Factor Receptor Inhibitors mTOR Inhibitors Administration Management of Toxicity Oncologic Monitoring Defining and Evaluating Recurrence References 27: Variant Histology: Management Pearls Introduction Identifying Variant Histology on Trans Urethral Resection (TUR) Specimens Distinguishing Features of Variants Urothelial Carcinoma with Divergent Differentiation Invasive Variants of Urothelial Carcinoma Non-urothelial Variants Molecular Features of Variants Intravesical Treatment for NMIBC with Variant Histology – Is There a Role? Muscle Invasive Variant Bladder Cancer: Treatment Paradigm The Role of Neoadjuvant Chemotherapy Radical Cystectomy: The Way to Go! The Role of Radiation Is Bladder Preservation Possible with Variant Histology (VH)? Prognostic Implications and Variations Follow-up and Surveillance Strategies Conclusion References 28: Clinical Trials in Bladder and Upper Tract Cancer – Bladder Cancer Disease States NMIBC Disease States MIBC Disease States Metastatic Disease States References 29: Practical Approaches to Clinical Trials in Non-muscle-Invasive Bladder Cancer Background Biases in Clinical Trials Key Elements in Clinical Trial Design Features of NMIBC That Influence Clinical Trial Designs Common Types of Trials in NMIBC Early-Phase Trials Adjuvant Trials Marker Lesion Studies Second-Line Trials Landmark Studies in NMIBC BCG Versus Doxorubicin [3] SWOG 8507 BCG Maintenance [4] Immediate Postoperative Intravesical Gemcitabine [5] References 30: Clinical Trials in Localized Muscle-Invasive Bladder Cancer Introduction Surgical Trials Neoadjuvant Trials Adjuvant Trials Bladder-Sparing Trimodality Trials Bladder-Sparing Genomically Selected Chemotherapy Trials Conclusions References 31: Clinical Trials in Metastatic Urothelial Carcinoma Introduction First Line, Cisplatin-Eligible First Line, Cisplatin-Ineligible Post-Platinum Post-Immune Checkpoint Inhibitor Additional Considerations References 32: Clinical Trials in Upper Tract Urothelial Carcinoma Specific Issues Relevant to Upper Tract Urothelial Cancer General Comments on UTUC Trial Design UTUC Surgical Trials UTUC Nonmetastatic Medical Oncology Trials References Part II: Upper Tract Urothelial Carcinoma 33: Patient Evaluation and Diagnosis – Screening, Evaluation, and Workup Epidemiology Diagnosis CT Urography MRI Plane Film Urography Renal/Bladder Ultrasound Imaging Appearance Urine-Based Studies Conclusion References 34: Risk Stratification of Upper Tract Urothelial Carcinoma for Kidney-Sparing Surgery Introduction Patient-Related Risk Factors Age and Sex Tobacco Consumption Preoperative Neutrophil-to-Lymphocytes Ratio (NLR) Ureteroscopy before RNU Tumor-Related Risk Factors Tumor Grade Urine Cytology Ureteroscopy and Biopsy Tumor Size, Location, and Multifocality Lymphovascular Invasion (LVI) Concomitant Carcinoma in Situ (CIS) Tumor Architecture (Sessile Vs. Papillary) Surgical Margins Lymph Node Status Tumor Necrosis PD-1 and PD-L1 Expression Conclusion Key Points References 35: Ureteroscopic Managment of Upper Tract Urothelial Carcinoma Indications Diagnostic Purpose Therapeutic Purpose Patient Preparation Surgical Technique Flexible Ureteroscopy: Instrument Characteristics Instrument Miniaturization Fiberoptic Versus Digital Ureteroscopes Narrow-Band Imaging 1-S Technology Photodynamic Diagnosis Flexible Ureteroscopy: A Step-by-Step Approach Cystoscopy Retrograde Ureteropyelography “No-Touch” Ureteroscopy Biopsy and Cytology Biopsy Techniques Cytology Handling Specimen in OR Endoscopic Treatment Laser Tumor Ablation Monopolar Bugbee Management of Common Complications Bleeding Complications Ureteral Wall Damages Conclusions References 36: Adjuvant Therapy for Upper Tract Urothelial Carcinoma after Endoscopic Management Introduction Pretreatment Management Topical Agents Efficacy of Intracavitary BCG Instillations Efficacy of Intracavitary Mitomycin C Instillations Instillation Techniques Anterograde Intracavitary Instillations Retrograde Intracavitary Instillations Transvesical Retrograde Approach Vesico-renal Reflux-Based Retrograde Approach Comparative Efficacy of Instillation Techniques Toxicity and Post-Instillation Management BCG MMC Both Defining and Evaluating Recurrence References 37: Novel Adjuvant Therapies for Upper Tract Urothelial Carcinoma After Endoscopic Management Introduction Epirubicin and Pirarubicin Thiotepa Gemcitabine BCG Combination Agents Checkpoint Inhibitors Conclusions References 38: Nephroureterectomy for Upper Tract Urothelial Carcinoma: Indications and Technique Introduction Indications and Preparation for RNU Surgical Technique Approach Management of the Bladder Cuff Management of Lymph Nodes Management of Common Complications Summary References 39: Selection, Administration and Description of Neoadjuvant versus Adjuvant Therapy for Upper Tract Urothelial Carcinoma Introduction Risk Prediction Tools Risk Factors for Relapse/Poor Prognosis Patient Factors Biochemical Factors Macroscopic Pathology Factors Microscopic Pathology Factors Molecular Markers Evidence for Perioperative Chemotherapy Recent Developments in the Adjuvant Setting Neoadjuvant Evidence Why Not Use Neoadjuvant Treatment? So What Should We Recommend? References 40: Oncologic Monitoring After Radical Nephroureterectomy Intravesical Recurrence Contralateral Upper Urinary Tract Recurrence Systemic Recurrence References Index