Gallbladder Cancer: Current Treatment Options

Description

The book discusses the recent progress in understanding the therapeutic targets for gallbladder cancer to provide opportunities for research and for developing innovative strategies that may enhance the benefit of conventional chemotherapy. The book focuses on identifying candidate molecules and the overall status of the targeted therapies available for gallbladder cancer, as there is an urgent need to discover new molecular targets that can guide the emergence of new treatment strategies to improve patient outcomes and act as biomarkers for the early detection of diseases. Recently, new treatment therapeutics targets for gallbladder cancer patients have been identified and the field is evolving rapidly. The book is relevant for the clinical researcher, surgeon, scientist and academician. Foreword Foreword Preface Contents Editors and Contributors About the Editors Contributors Part I: Introduction 1: Gallbladder Cancer: Current Treatment Options and Therapeutics 1.1 Introduction 1.2 Surgical Treatment 1.3 Chemotherapy and Radiotherapy of GBC 1.3.1 Adjuvant Chemotherapy in Resected Gallbladder Cancer 1.3.2 Chemotherapy in Unresectable Gallbladder Cancer 1.3.3 Adjuvant Chemoradiotherapy in Resected Gallbladder Cancer 1.3.4 Neoadjuvant Chemoradiotherapy in Resectable Gallbladder Cancer 1.3.5 Chemoradiotherapy in Unresectable Gallbladder Cancer 1.4 Chemoresistance and Gallbladder Cancer 1.5 Future Directions in the GBC Treatment 1.5.1 HER2 and EGFR Targeting Therapies 1.5.2 Other Therapeutic Targets 1.6 Noncoding RNAs as Therapeutic Targets in Gallbladder Cancer 1.7 Conclusion References Part II: Surgical Management, Adjuvant Chemotherapy and Palliative Chemotherapy in Gallbladder Cancer 2: Surgical Management of Gallbladder Cancer Patients 2.1 Introduction 2.1.1 Epidemiology and Risk Factors 2.2 Preoperative Planning 2.2.1 Clinical Presentation 2.2.2 Staging: Anatomy and Imaging 2.2.2.1 Anatomy 2.2.2.2 Imaging Ultrasonography Computed Tomography (CT) Magnetic Resonance Imaging Positron-Emission Tomography 2.2.3 Histopathological Diagnosis 2.2.4 Staging Laparoscopy 2.3 Management of Stage I-III GBC 2.3.1 T1a Disease 2.3.2 T1b Disease 2.3.3 T2/T3 Disease with or Without Lymphadenopathy 2.3.4 Survival and Prognostic Factors After (Re-)resection 2.4 Management of Stage IV GBC 2.5 Surgical Procedures for GBC 2.5.1 GBC Suspicion During Routine Cholecystectomy 2.5.1.1 Approach 2.5.2 GBC Suspicion Before Surgery 2.5.2.1 Open Approach 2.5.2.2 Lymphadenectomy 2.5.2.3 Assessment of Main Portal Vein and Common Hepatic Artery 2.5.2.4 Assessment of the Extrahepatic Biliary Tree 2.5.2.5 Assessment of Right Portal Vein and Right Hepatic Artery 2.5.2.6 Nonanatomical or Anatomical Segment 4b and 5 Resection 2.5.2.7 Laparoscopic and Robotic Approach 2.5.3 GBC Diagnosed at Histopathological Analysis After Routine Cholecystectomy 2.5.3.1 Re-resection: Timing and Open Versus Laparoscopic Approach 2.5.3.2 Extent of Re-resection 2.5.3.3 Port-Site Resection 2.6 Postoperative Management 2.6.1 Complications 2.6.2 Postoperative Surveillance 2.6.3 Adjuvant Therapy 2.7 Palliative Therapy 2.8 Conclusion and Future Perspectives References 3: Conventional Therapy in Gallbladder Cancer 3.1 Introduction 3.2 Diagnosis 3.2.1 Ultrasonography 3.2.2 CT Scan 3.2.3 PET/CT 3.2.4 MRI, MRA, and MRCP 3.3 Surgical Treatment 3.3.1 Preoperative Diagnosis 3.3.2 Intraoperative Diagnosis 3.3.3 Postoperative Diagnosis 3.4 Special Topics 3.4.1 Lymphadenectomy 3.4.2 Pancreaticoduodenectomy as Treatment of Gallbladder Cancer 3.4.3 Gallbladder Wall Perforation 3.4.4 Management of Advanced Tumors 3.4.5 Jaundice 3.4.6 Resection of Portal Sites 3.4.7 Laparoscopy: When and Where 3.4.8 Palliative Management 3.5 Chemotherapy and Radiotherapy 3.5.1 Chemotherapy in Advanced Cases 3.5.2 Neoadjuvant Chemotherapy 3.5.3 Adjuvant Chemotherapy 3.5.4 Chemoradiotherapy (CRT) 3.5.5 Radiotherapy (RT) References 4: Adjuvant Therapy of Gallbladder Cancer 4.1 Introduction 4.2 Rationale for Adjuvant Therapy and Risk Factors for Recurrence 4.3 Randomized Clinical Trials 4.3.1 ABC-02 4.3.2 PRODIGE-12/ACCORD-18 4.3.3 BILCAP 4.3.4 BCAT 4.3.5 TOSBIC01 (Tokyo Study Group for Biliary Cancer) 4.3.6 Chemoradiotherapy: SWOG0809 4.4 Future Directions 4.5 Conclusion References 5: Incidental Gallbladder Cancer: The Role of Routine Versus Selective Histopathological Examination of Gallbladder Specimens After Cholecystectomy 5.1 Introduction 5.2 Routine Versus Selective Histopathological Assessment 5.3 Histopathology 5.4 Personal Experience 5.5 Conclusions References 6: Minimally Invasive Surgery for Management of Gallbladder Cancer 6.1 Introduction 6.2 Operative Indications 6.2.1 Lymphatic Nodes Resection 6.2.2 Preoperative Evaluation 6.2.3 Imaging 6.2.4 Other Complementary Investigations 6.2.5 Preoperative Laparoscopy 6.3 Laparoscopic Radical Cholecystectomy 6.3.1 Patient Positioning 6.3.2 Positioning and Placement of Trocars 6.3.3 Exposure 6.3.4 Dissection 6.3.5 Resection 6.3.6 Choledochojejunostomy 6.3.7 Postoperative Care 6.4 Complications 6.4.1 Bleeding 6.4.2 Bile Leak 6.5 Discussion 6.6 Conclusions References 7: Thick-Walled Gallbladder: Differential Diagnosis and Surgical Approach to a Thickened Gallbladder 7.1 Introduction 7.2 Pathogenesis of the Thickened Wall 7.3 Differential Diagnosis 7.3.1 Xanthogranulomatous Cholecystitis 7.3.2 Chronic Cholecystitis 7.3.3 Gallbladder Polyps 7.3.4 Gallbladder Tuberculosis 7.3.5 IGG4-Related Cholecystitis 7.3.6 Vascular Lesions of the Gallbladder 7.3.7 Hydatid Cyst of the Gallbladder 7.3.8 Gallbladder Cancer 7.3.9 Gallbladder Gist 7.3.10 Neuroendocrine Tumors of Gallbladder 7.3.11 Mesenchymal Tumors of the Gallbladder 7.4 Approaches to a Thick-Walled GB 7.5 Conclusion References 8: Management of Incidentally Detected Gallbladder Cancer After Cholecystectomy 8.1 Introduction 8.2 Defining the Dilemma When Diagnosing an Incidental GBC 8.3 Pathology Notes for Incidental GBC 8.3.1 The Role of pT-Stage Category at Presentation 8.3.2 Is Sidedness Important in GBC? 8.3.3 Recording of Intraoperative Events at Primary Surgery 8.3.4 Timing of Reresection: Does It Matter if Early or Late? 8.4 Preoperative Cross-Sectional Imaging for Restaging before Resection 8.4.1 Role of PET Scan? 8.4.2 Role of Staging Laparoscopy and Laparoscopic Reresection 8.5 Type and Extent of Surgical Reresection 8.5.1 Biology Trumphs Surgery 8.5.2 Should Laparoscopic Port Sites be Resected? 8.5.3 Should the Common Bile Duct be Resected? 8.6 Outcome Prediction and Prognostic Score 8.7 Adjuvant Chemotherapy 8.8 Future Directions References 9: Adjuvant Therapy in Gallbladder Cancers 9.1 Adjuvant Treatment 9.2 Adjuvant Chemotherapy 9.3 Adjuvant Chemoradiation (CRT)/Radiation (RT) 9.3.1 Radiotherapeutic Considerations 9.3.2 Treatment Guidelines 9.3.3 Follow-Up References Part III: Targeted Therapies in Gallbladder Cancer 10: A Look at Emerging Therapeutic Targets for Gallbladder Cancer: A Multi-Omics Approach 10.1 Introduction 10.2 Genetic Biomarkers and Neoantigen Targets 10.3 MicroRNA Biomarkers in Gallbladder Carcinoma 10.4 Biomarkers in the Microbiome 10.5 Proteomic Biomarkers 10.6 Other Potential Biomarkers: Metabolites 10.7 Emerging Targets and Therapies: The Role of the Immune System 10.8 Conclusion and Future Perspectives References 11: MicroRNA and Their Role in Carcinoma Gallbladder 11.1 Introduction 11.2 What Are MicroRNAs? 11.2.1 miRNA Synthesis 11.2.2 miRNA Transcription 11.2.3 Nuclear Processing and Export 11.2.4 Cytoplasmic Processing 11.2.5 Mechanism of miRNA-Mediated Gene Silencing 11.3 MicroRNA and Cancers 11.3.1 miRNA and Cell Cycle Regulation 11.3.2 miRNA and Apoptosis 11.3.3 miRNA in Local Spread and Metastasis 11.3.4 miRNA and Angiogenesis 11.3.5 miRNA and Cancer Metabolism 11.3.6 Role of miRNA in Gallbladder Cancer 11.3.7 miRNAs Overexpression in GBC: Oncogenic miRNAs 11.3.8 miRNAs Downregulated in GBC: Tumor Suppressive miRNAs 11.3.9 Current Considerations in miRNA Therapeutics 11.3.10 Inhibition of miRNA 11.3.11 Replacement of miRNA 11.3.12 Delivering microRNA 11.3.12.1 Local Delivery Methods 11.3.12.2 Systemic Delivery Methods 11.3.12.3 Viral Vectors 11.3.12.4 Lipid Vectors 11.3.12.5 Nanoparticles 11.4 Conclusion References 12: Gallbladder Cancer: Epigenetic Landscape, Targeted Therapy, and Prospect of Epitherapy 12.1 Introduction 12.2 Epigenetics: Definition, Concept, and Mechanism 12.2.1 Epigenetic Regulation of Gene Expression and Cancer 12.2.2 Epigenetic Regulation of Coding Genes and Biomarkers in Gallbladder Cancer 12.2.3 Epigenetic Regulation of Non-coding Genes and Biomarkers in Gallbladder Cancer 12.2.3.1 MicroRNAs 12.2.3.2 Long Non-Coding RNAs 12.2.4 DNA Methylation Screening Techniques 12.3 Therapeutic Approaches in GBC: Epigenetics Regulators, Inhibitors, and Targeted Therapy 12.3.1 Epigenetic Regulators 12.3.2 Combination Therapy 12.3.3 Targeting DNA and Histone Modifications 12.3.3.1 Targeted Therapy in GBC 12.3.4 Targeting Non-Coding RNAs 12.4 Future Scope of Epitherapy in GBC and Conclusion References 13: Targeted Treatment of Gallbladder Cancer 13.1 Introduction 13.2 Treatment Category 13.2.1 Adjuvant 13.2.2 Neoadjuvant 13.2.3 Metastatic or Palliative 13.3 Targeted Therapy—Epithelial Growth Factor Receptor (EGFR/HER1) 13.3.1 Erlotinib 13.3.2 Gefitinib 13.4 BRCA 1 & 2 13.5 ERBB2 (HER-2-Neu) Amplification 13.6 BRAFV600E Mutation 13.7 FGFR Gene Rearrangement or Fusion 13.8 Vascular Endothelial Growth Factor Receptors (VEGFR) 13.9 Isocitrate Dehydrogenase 1 (IDH1) 13.10 NTRK Gene Fusion 13.11 Immunotherapy 13.11.1 Nivolumab Plus Ipilimumab 13.11.2 Nivolumab 13.11.3 Pembrolizumab 13.11.4 Combination of Immunotherapy and Chemotherapy 13.12 Cancer Vaccine 13.13 Conclusions References 14: Molecular Pathways in Gallbladder Cancer as Potential Therapeutic Target 14.1 Introduction 14.2 Gallbladder Carcinogenesis Pathways 14.3 Molecular Changes/Mutations Involved in Gallbladder Carcinogenesis 14.3.1 Tumor Suppressor Gene (TP53 Mutations) 14.3.2 HER-2/Neu 14.3.3 EGFR Mutations 14.3.4 VEGF Mutations 14.3.5 Mitochondrial DNA Mutations 14.3.6 Fragile Histidine Triad (FHIT) Gene Mutation 14.3.7 Proto-Oncogene KRAS Mutations 14.3.8 DNA Damage Repair (DDR) Pathway Mutations 14.3.9 PI3K/AKT/mTOR Pathway Mutations 14.3.10 Methylation and Gallbladder Cancer 14.4 Evolving Landscape of Molecular Targeted Therapy for GBC 14.4.1 Key Pathways Targeted for Therapy 14.4.1.1 HER-2/Neu 14.4.1.2 Epidermal Growth Factor Receptor 14.4.1.3 Vascular Endothelial Growth Factor (VEGF) 14.4.1.4 Fibroblast Growth Factor Receptor 14.4.1.5 MAPK (RAS/RAF/MEK/ERK) Pathway 14.4.1.6 PI3K-AKT-mTOR Pathway 14.4.1.7 C-Mesenchymal Epithelial Transition Factor (MET) 14.5 Immunotherapy 14.6 Future Perspectives 14.7 Conclusions References 15: Targeted Therapy: Molecular Pathology and Targets of Gallbladder Cancer 15.1 Introduction 15.2 Histopathological Features of Gallbladder Cancer 15.3 Molecular Pathogenesis of Gallbladder Cancer 15.4 Molecular Intended Therapy of Gallbladder Cancer 15.4.1 Herceptin (HER)-2 15.4.2 Vascular Endothelial Growth Factor (VEGF)/VEGF Receptor-(R) 15.4.3 EGFR (Epidermal Growth Factor Receptor) 15.4.4 MAPK/ERK (Also Called as RAS/RAF/MEK/ERK) Pathway 15.4.5 PI3K/AKT/mTOR Pathway 15.4.6 DNA Damage Repair (DDR) Pathway 15.4.7 TP53 15.4.8 C-Mesenchymal Epithelial Transition Factor (MET) 15.4.9 Cyclin Dependent Kinase Inhibitor (CDKN)-2A/B 15.4.10 KIT (A Protoncogene) 15.5 Future Perspective References 16: Targeted Therapies in Gallbladder Cancer: Current Status and Future Perspectives 16.1 Introduction 16.2 Potential Targets for Anticancer Therapy 16.2.1 Major Signaling Pathways in Gallbladder Cancer 16.2.1.1 PI3K/AKT/mTOR Signaling Pathway 16.2.1.2 MAPK/ERK Signaling Pathway 16.2.1.3 EGFR Pathway 16.2.1.4 Hedgehog Signaling Pathway 16.2.2 Major Signaling Molecules in Gallbladder Cancer 16.2.2.1 TP53 16.2.2.2 KRAS 16.2.2.3 HER2 16.2.2.4 HIF1A 16.2.2.5 VEGF 16.3 Conclusion References 17: Integrative Omics: The Roadmap for Gallbladder Biomarkers Identification 17.1 Introduction 17.1.1 Gallbladder Cancer 17.1.2 Overview of Current Therapies in GBC 17.1.3 Multi-Omics Approach to Identify the Potential Targets in GBC 17.1.4 Molecular Signatures and Therapeutic Perspective 17.2 Potential Biomarkers in GBC 17.2.1 With Genomics Studies 17.2.2 With Transcriptomics Studies 17.2.3 With Epigenomic Studies 17.2.4 With Proteomics Studies 17.2.5 Altered Pathways Identified in GBC 17.2.6 Liquid Biopsy for Molecular Diagnosis in GBC 17.2.6.1 Circulating Tumor Cells 17.2.6.2 Ct-DNA 17.3 Future Perspectives References 18: Anti-EGFR Therapy in Gallbladder Cancer 18.1 Introduction 18.2 What Are EGFR Inhibitors? 18.3 Anti-EGFR Tyrosine Kinase Inhibitor 18.3.1 First Generation 18.3.1.1 Erlotinib 18.3.1.2 Gefitinib 18.3.2 Second Generation 18.3.2.1 Afatinib 18.3.2.2 Dacomitinib 18.3.2.3 Lapatinib 18.4 Anti-EGFR Antibody 18.4.1 Cetuximab 18.4.2 Panitumumab 18.4.3 Vandetanib 18.4.4 Varlitinib 18.4.5 Neratinib 18.5 Role of Anti- EGFR Therapy in Gallbladder Cancer 18.6 Resistance to EGFR TKIs and Third-Generation TKIs 18.7 New Agents and Future Directions 18.8 Conclusion References