Critical Issues in Head and Neck Oncology Key Concepts from the Seventh THNO Meeting

Preface
Contents
Part I: Biomarkers in Head and Neck Squamous Cell Cancer (HNSCC)
	Chapter 1: Promising Biomarkers for Early Diagnosis and Prognosis Prediction
		Introduction
		Matrix Metalloproteinases
		Autophagy Biomarkers
		Intra-tumoural Immune Cells as Biomarkers
		References
	Chapter 2: Biomarkers for Hypoxia, HPVness, and Proliferation from Imaging Perspective
		Introduction
		Imaging Biomarkers for the Assessment of HPV-ness
		Imaging Biomarkers for Tumor Hypoxia
		Evaluation Treatment Response with RECIST 1.1
		The Potential for Automatic Head and Neck Segmentation and Volumetric RECIST Assessment as Surrogate Imaging Marker for Tumor Proliferation
		Conclusions and Future Directions
		References
	Chapter 3: Mechanisms of Cetuximab Resistance and How to Overcome It
		Introduction
		The Epidermal Growth Factor Receptor
		Cetuximab as Anti-EGFR Targeting Agent
		Mechanisms of Cetuximab Resistance
			Altered Response Elicited at the Level of EGFR
			Molecular Alterations in Effectors Downstream of EGFR
			Cross-talk with Other Receptor Tyrosine Kinases
			Alterations in Proteins Outside the EGFR Pathway
			Epithelial-to-Mesenchymal Transition
			Hypoxia and Angiogenesis
		Strategies to Overcome Cetuximab Resistance
			Irreversible and Multiple HER Receptor Inhibition to Overcome Resistance
			Identification of Drug Resistance Mechanisms and Predictive Biomarkers
		Conclusion and Future Perspectives
		References
	Chapter 4: The Role of Liquid Biopsies for Monitoring Disease Evolution
		Introduction
		Liquid Biopsies for Cancer Screening and Disease Monitoring
			Early Detection of Virally Associated HNSCC Based on Plasma DNA
			Cell-free DNA Analysis in Non-virally Related HNSCC
			DNA Methylation Analysis for Cancer Screening
		Cell-Free Circulating Tumor DNA for Mutation Profiling
			Concordance Between Liquid and Solid Tissue-Based Mutational Analysis
			ctDNA Versus CTCs: Which Is the Better Source for Mutation Analysis?
			Liquid Biopsies for Treatment Selection and the Analysis of Resistance Mechanisms
		Circulating Tumor Cells for Prognosis of Outcome in HNSCC
		Conclusions
		References
	Chapter 5: NK Cells in Immunotherapy: How Important Are They?
		Introduction
		NK Cells, Antitumor Effects and Antibody Dependent Cell Cytotoxicity
		Strategies to Enhance Antitumor NK Cell Function
			Reinforcement of NK Cell Activity
			Prevent NK Cell Inhibition
				Anti-PD-1
				Anti NKG2A
				Anti KIR2
				Anti TIM-3
				Anti LAG-3
				Anti-TIGIT
			Increase ADCC Through Engineering of Monoclonal Antibodies
			Improve NK Cells Trafficking and Homing in the Tumor
			CAR–NK
		Conclusions
		References
	Chapter 6: Biomarkers for Immune Modulatory Treatment in Head and Neck Squamous Cell Carcinoma (HNSCC)
		Background
		Potential Predictive Biomarkers for Immune Checkpoint Inhibitors
		PD-L1
		Gene Expression Profiling
		Tumour Mutation Burden
		Combination of Tumour Mutation Burden and Gene Expression Profiling
		Multidimensional Quantitative IHC/IF
		Tissue Resident Memory (TRM) Cells
		Conclusion
		References
Part II: Primary Disease
	Chapter 7: Novel Approaches in Surgical Management: How to Assess Surgical Margins
		Introduction
		Historical Background: The Concept of “Margin”
		Current Biological Rationale of Margins in Head and Neck Surgery
		Special Elements of Challenge in the Head and Neck Area
		Practical Determinants of Margin
		“Frailty” of Cutting Through Healthy Tissue
		Current Intraoperative Margin Evaluation
		Future Directions: “Know Your Enemy”
			Future Directions: Enhanced Tumor Visualization
			Future Directions: Augmented Mapping of the Surgical Bed
		Conclusions
		References
	Chapter 8: The Surgical Approach to Elderly Patients with HNSCC
		Introduction
		Functional Physiological Age Related Issues with Impact on Selection for Surgical Treatment
		Assessment of Comorbidity for Surgical Treatment
		Age and Special Surgical Procedures
		Conclusion
		References
	Chapter 9: Contemporary Opportunities in Nonsurgical Management of Locoregionally Advanced Head and Neck Squamous Cell Carcinoma
		Introduction
		Definition of LAHNSCC in HPV(+) HNC
		Trials on HPV(+) LAHNSCC
			Revisiting the Role of Cisplatin and Cetuximab in HPV(+) LAHNSCC
			Refining “Old Tools” for HPV(+) LAHNSCC: Dose, Fractionation, and Volumes
			Addressing Distant Metastasis Endpoint: Role of Induction Chemotherapy
			Quest for Additional Risk Stratification Parameters
			Emerging Role of Immunotherapy in HPV(+) LAHNSCC
		Research in HPV(−) LAHNSCC
			Window of Opportunity Trials Exploring Targeted Agents, Including immunotherapy
			Hypoxia Modification and Smoking Cessation
			Patients Unfit for Chemotherapy
		Conclusion
		References
	Chapter 10: High-Dose Three-Weekly or Low-Dose Weekly Cisplatin during Radiation, What to Prefer?
		Introduction
		High-Dose Three-Weekly Cisplatin
		Low-Dose Weekly Cisplatin
		High-Dose Three-Weekly Versus Low-Dose Weekly
			Level V Evidence
			Level IV Evidence
			Level III Evidence
			Level of Evidence II
			Level of Evidence I
		Immunotherapy Trials
		Concluding Remarks and Outlooks for the Future
		References
	Chapter 11: Where and when to Use Induction Chemotherapy in Head and Neck Squamous Cell Cancer
		Introduction
		Milestones in Systemic Therapies for Locoregionally Advanced HNSCC
		Comparison of the Practice Changing TPF Protocols (TAX 323/EORTC 24971 and TAX 324)
		When to Use Induction Chemotherapy in Head and Neck Squamous Cell Cancer
			For Larynx Preservation
			For Treatment Intensification
			For Borderline Resectable or Unresectable Oral Cavity Cancer
			As a Selection Tool for RT Dose de-Escalation in HPV-Positive OPSCC
			Oligometastatic Disease
		Where to Use Induction Chemotherapy
		Conclusions
		References
	Chapter 12: Prognostic Role of p16/HPV in Non-oropharyngeal Head and Neck Squamous Cell Cancer (HNSCC)
		Introduction
		HPV Life Cycle
		Risk Factors for HPV(+) Non-OPC
		p16 as a Surrogate Biomarker for a Transcriptionally Active HPV Infection in Non-OPC
		p16/HPV as a Prognostic Factor in Non-OPC
		Conclusions
		References
	Chapter 13: Is there a Role for Neoadjuvant Targeted Therapy and Immunotherapy?
		Introduction
		Induction Therapy with Targeted Therapy and Immune Checkpoint Inhibitors
		Window of Opportunity Trials with Targeted Therapy and Immune Checkpoint Inhibitors
		Conclusion
		References
	Chapter 14: Is there a Role for Adjuvant Targeted and Immunotherapies in Patients with Locoregionally-Advanced Head and Neck Cancer?
		Introduction
		Adjuvant Post-Operative Chemoradiotherapy Improves Outcomes in LA-SCCHN
		Adjuvant Chemotherapy Is Not Effective in LA-SCCHN
		Epidermal Growth Factor Receptor-Targeted Therapies in LA-SCCHN
		Anti-EGFR Monoclonal Antibodies Are Not Used as Adjuvant Therapies for LA-SCCHN
		Small Tyrosine Kinase Inhibitors Are Not Effective Adjuvant Therapies in LA-SCCHN
		Immune Checkpoint Inhibitors as Adjuvant Therapies in LA-SCCHN
		Summary and Conclusions
		References
	Chapter 15: Optimal Supportive Measures during Primary Treatment
		Introduction
		Reasons to Implement Supportive Care during Curative Treatment in Head and Neck Cancer
		Multiple Interventions for Different Aspects of Support
		The Example of Mucositis: An Early and up-to-Date Supportive Care Intervention
		Conclusion
		References
Part III: Recurrent and/or Metastatic Disease
	Chapter 16: Salvage Surgery in Head and Neck Cancer
		Introduction
		Evolution of Salvage Surgery
		Tumor Factors
		Patient Factors
		Reconstructive Surgery after Resection for Salvage
			Arterial and Venous Options for Reconstruction in a Salvage Neck
			Venous Options for Reconstruction in a Salvage Neck
			Advanced Options for Reconstruction in a Salvage Neck
		Complications in Salvage Surgery
		Ideal Candidates
		Conclusion
		References
	Chapter 17: Re-Irradiation for Local Relapses or Second Primaries: When and how?
		Introduction
		When to re-Irradiate?
			Previous Toxicity and Patient-Related Considerations
			Treatment Volume and Recurrent Stage
			Time Interval since Initial Radiotherapy
			Anatomical Site
			Second Primary vs Recurrent Tumors
			Re-Irradiation after Salvage Surgery
		How to re-Irradiate?
			Re-Irradiation Dose
			Re-Irradiation Volume
			Concurrent Systemic Therapy
		Radiation Techniques
			Intensity-Modulated Radiotherapy (IMRT)
			Stereotactic Body Radiotherapy (SBRT)
			Proton Therapy
			Brachytherapy
		Toxicities of re-Irradiation
		References
	Chapter 18: New and Promising Targeted Therapies in First and Second-Line Settings
		Introduction
		EGFR Pathway
			Cetuximab
			Other ErbB Antibodies
			TKIs against ErbB
			Future Research into ErbB Targeting
		PI3K/AKT/mTOR Pathway
		Cell Cycle Regulation
		DNA Repair Inhibitors
		Antiangiogenesis
		RAS-RAF-MEK-ERK Pathway
		FGFR
		Neurotrophic Tyrosine Kinase Receptor Family
		Implications for Clinical Trial Design
		Conclusions
		References
	Chapter 19: Update of Immune Therapies in Recurrent/Metastatic Head and Neck Cancer
		Background: Prior to the Emergence of Immune Therapies
		Emergence of Immune Therapies in HNSCC
		Second-Line Randomised Trials of Immune Checkpoint Inhibitors
		First-Line Randomised Trials of Immune Checkpoint Inhibitors
		Combination of Other Treatments with Anti-PD1 or PD-L1 Agents
		Anti-PD1/PD-L1 with Anti-CTLA4 Combinations
		Other Combinations
		Conclusion
		References
Part IV: Rare Head and Neck Cancers
	Chapter 20: Patients with Rare Head Neck Cancers: Do They Need a Different Approach?
		Introduction on Rare tumors
			Definition and Frequency of Rare Cancers
			Poor Prognosis of Rare Cancers
			Problems and Challenges in Rare Cancers
		Rare Cancers in the Head and Neck Region
			Salivary Gland Cancers
			Salivary Duct Cancer (as Example)
			NTRK Inhibition
		Future
		References
Part V: Nasopharynx Cancer
	Chapter 21: Epidemiological Aspects in Nasopharyngeal Cancer
		Introduction
		Incidence
		Survival
		Discussion
		References
	Chapter 22: New Developments in the Management of Nasopharyngeal Carcinoma
		Unique Characteristics of Nasopharyngeal Carcinoma
		Radiotherapy
		Chemotherapy and Radiotherapy Combinations
		EBV-DNA
		Immunotherapy and Chemoradiotherapy
		Conclusions
		References
	Chapter 23: New Drugs for Recurrent or Metastatic Nasopharyngeal Cancer
		Introduction
		Immuno-Oncology in RMNPC
			Immune Checkpoint Inhibitors (ICI)
			Adoptive Cell Therapy
			Therapeutic Vaccines
			Personalized Cancer Vaccines (PCV)
			Oncolytic Viruses (OV)
		Molecularly Targeted Agents
			Vascular Endothelial Growth Factor Receptor (VEGFR) Inhibitors
			Epidermal Growth Factor Receptor (EGFR) Inhibitors
		Epigenetic Therapy in RMNPC
		Conclusion and Future Approaches
		References
Part VI: Keynote Lecture
	Chapter 24: Innovation and Advances in Precision Medicine in Head and Neck Cancer
		Introduction
		The Current Landscape of Large Scale Genomics Based Data Research in HNSCC
		Biomarker-Based Treatment Strategies
		Innovative Clinical Trial Designs
		Adapting to the Evolution of Cancer
			Monitoring in Minimal Residual Disease (MRD)
			Selecting Patients for Personalized Treatment
			Prediction of Treatment Outcome
		Moving Beyond Genomics in HNSCC
			Transcriptomics
			Epigenomics
			Metabolomics
			Microbiome
			Artificial Intelligence/Radiomics
		Conclusion
		References