Gallbladder Cancer: Current Treatment Options

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