Hodgkin Lymphoma: A Comprehensive Overview

Preface
Contents
Part I: Epidemiology and Pathogenesis
	1: Epidemiology of Hodgkin Lymphoma
		1.1	 Introduction
		1.2	 Definition and Histological Classification (WHO)
		1.3	 Hodgkin Lymphoma Occurrence
			1.3.1	 Overall Incidence
			1.3.2	 Age-Specific Incidence Patterns Vary Geographically
				1.3.2.1	 Historical Patterns
				1.3.2.2	 Modern Age-Specific Incidence Patterns
				1.3.2.3	 Age-Specific Incidence Patterns for Hodgkin Lymphoma Subtypes
			1.3.3	 Incidence Trends
			1.3.4	 Classifications for Epidemiological Studies: Multi-disease Models
			1.3.5	 Classifications by Age at Diagnosis, Histology and Tumour Epstein-Barr Virus Status
			1.3.6	 Overlap Between Epidemiological Classifications of Hodgkin Lymphoma
		1.4	 Familial Accumulation of Hodgkin Lymphoma: Genetic Predisposition
			1.4.1	 Genetic Studies: Genome-Wide Association Studies
				1.4.1.1	 Hodgkin Lymphoma Subtype-Specific Associations in Genetic Analyses
		1.5	 Risk Factors
			1.5.1	 Prevailing Hypotheses in Hodgkin Lymphoma Epidemiology
				1.5.1.1	 Childhood Socio- Economic Environment
			1.5.2	 Anthropometry
			1.5.3	 Medical History
				1.5.3.1	 Infections
					Epstein-Barr Virus Infection: Infectious Mononucleosis
					Epstein-Barr Virus Infection: Serological Evidence
					Epstein-Barr Virus Infection: Variation in Tumour Prevalence
					A Four-Disease Model for Hodgkin Lymphoma
					Other Childhood Infections
				1.5.3.2	 Primary and Secondary Immune Deficiencies
				1.5.3.3	 Autoimmune and Allergic Disorders
					Autoimmune and Allergic/Atopic Diseases
				1.5.3.4	 Medications
			1.5.4	 Environmental Exposures
				1.5.4.1	 Ultraviolet Light
				1.5.4.2	 Tobacco
				1.5.4.3	 Alcohol
		1.6	 Conclusion
		References
	2: The Role of Viruses in the Genesis of Hodgkin Lymphoma
		2.1	 Introduction
		2.2	 Hodgkin Lymphoma and Epstein-Barr Virus
			2.2.1	 Epstein-Barr Virus and the Pathogenesis of Hodgkin Lymphoma
			2.2.2	 Risk Factors for Epstein-Barr Virus-Associated Hodgkin Lymphoma
			2.2.3	 Epstein-Barr Virus and Hodgkin Lymphoma: A Causative Association?
			2.2.4	 Epstein-Barr Virus and the Clinicopathological Features of Hodgkin Lymphoma
		2.3	 Epstein-Barr Virus-Negative Hodgkin Lymphoma Cases
			2.3.1	 Hodgkin Lymphoma and Herpesviruses Other Than Epstein-Barr Virus
			2.3.2	 Polyomaviruses and Hodgkin Lymphoma
			2.3.3	 Measles Virus and Hodgkin Lymphoma
			2.3.4	 The Virome, Anelloviruses, and Hodgkin Lymphoma
		2.4	 Conclusions
		References
	3: Pathology and Molecular Pathology of Hodgkin Lymphoma
		3.1	 Subclassification and Pathology
			3.1.1	 Nodular Lymphocyte-Predominant Hodgkin Lymphoma
			3.1.2	 Classical Hodgkin Lymphoma: The HRS Cells
				3.1.2.1	 Nodular Sclerosis Classical Hodgkin Lymphoma
				3.1.2.2	 Mixed Cellularity Classical Hodgkin Lymphoma
				3.1.2.3	 Lymphocyte-Depleted Classical Hodgkin Lymphoma
				3.1.2.4	 Lymphocyte-Rich Classical Hodgkin Lymphoma
		3.2	 Differential Diagnosis
		3.3	 Histogenesis of HRS and LP Cells
			3.3.1	 Cellular Origin of HRS and LP Cells
			3.3.2	 Relationship of Hodgkin Cells and Reed-Sternberg Cells and Putative HRS Cell Precursors
		3.4	 Genetic Lesions
		3.5	 Deregulated Transcription Factor Networks and Signaling Pathways
			3.5.1	 The Lost B Cell Phenotype
			3.5.2	 Constitutive Activation of Multiple Signaling Pathways
		3.6	 Anti-apoptotic Mechanisms
		References
	4: Microenvironment, Cross-Talk, and Immune Escape Mechanisms
		4.1	 Microenvironment
			4.1.1	 Hodgkin Lymphoma Subtypes
			4.1.2	 Epstein-Barr Virus
			4.1.3	 Human Immunodeficiency Virus
			4.1.4	 T Cell Subsets in cHL
			4.1.5	 T Cell Subsets in NLPHL
			4.1.6	 Fibrosis and Sclerosis
			4.1.7	 Eosinophils, Plasma Cells, Mast Cells, and B Cells
		4.2	 Cross-Talk between HRS Cells and Microenvironment (Fig. 4.4)
			4.2.1	 Factors Supporting Tumor Growth
			4.2.2	 Shaping the Environment
		4.3	 Immune Escape Mechanisms (Fig. 4.4)
			4.3.1	 Antigen Presentation
			4.3.2	 HLA Class I Expression
			4.3.3	 HLA Class II Expression
			4.3.4	 Immune Checkpoints
			4.3.5	 Immunosuppression
		4.4	 Prognostic Impact of the Microenvironment
		4.5	 Conclusion
		References
	5: What Have We Learnt from Genomics and Transcriptomics in Classic Hodgkin Lymphoma
		5.1	 Introduction
		5.2	 Genomics of Hodgkin and Reed-Sternberg Cells
			5.2.1	 Cytokine Signaling
			5.2.2	 NF-κB Signaling
			5.2.3	 PI3K/AKT/mTOR Signaling
			5.2.4	 Immune Escape
		5.3	 The Transcriptome of HRS Cells
		5.4	 Microenvironment Profiling
		5.5	 Biomarker-Driven Prognostication and Risk Stratification in cHL
		5.6	 Conclusions and Future Perspective
		References
Part II: Diagnosis and First-Line Treatment
	6: Clinical Evaluation
		6.1	 Presenting Manifestations
		6.2	 Physical Findings and Laboratory Abnormalities
		6.3	 Pathologic Diagnosis: The Biopsy
		6.4	 Staging Systems for Hodgkin Lymphoma
		6.5	 Imaging Evaluation of the Extent of Disease
		6.6	 Clinical Evaluation During Therapy
		6.7	 Definition of the Response to Treatment
		6.8	 Complete Remission
		6.9	 Follow-Up Management
		6.10	 Conclusion
		References
	7: Functional Imaging in Hodgkin Lymphoma
		7.1	 Introduction
		7.2	 History of Imaging in Hodgkin Lymphoma
		7.3	 Background of PET and the FDG Tracer
			7.3.1	 Basic Principles of PET
			7.3.2	 The FDG Tracer
		7.4	 PET in Clinical Management of Hodgkin Lymphoma
			7.4.1	 Staging
			7.4.2	 Early Assessment of Chemosensitivity
			7.4.3	 Final Response Assessment
			7.4.4	 Interpretation Criteria
				7.4.4.1	 Interim PET Scan
				7.4.4.2	 End-of-Treatment PET Scan
			7.4.5	 Treatment Response Assessment to Immune Checkpoint Inhibitors
			7.4.6	 PET in Radiotherapy Planning
			7.4.7	 PET for Response Prediction During Salvage Treatment
			7.4.8	 PET for Follow-Up of HL Patients in Complete Remission
		7.5	 PET Response-Adapted Therapy
			7.5.1	 Early-Stage HL
			7.5.2	 Advanced-Stage HL
			7.5.3	 Post-chemotherapy PET/CT-Driven Consolidation Radiotherapy
			7.5.4	 PET/CT-Adapted Therapy in Relapsed HL
		7.6	 Toward Revised Criteria for PET Scan Interpretation
			7.6.1	 Qualitative vs. Semiquantitative Assessment
				7.6.1.1	 From Anatomical to Functional Imaging
				7.6.1.2	 Toward New Criteria for Response Assessment of New Drugs
				7.6.1.3	 Biomarker Integration in Response Criteria
			7.6.2	 Interim PET
			7.6.3	 End-of-Treatment PET
		7.7	 FDG-PET/MRI
		7.8	 Future Perspectives
			7.8.1	 Other Tracers
			7.8.2	 Quantitative Methods for PET Reading (SUV, MTV, TLG)
				7.8.2.1	 Semiquantitative Assessment
				7.8.2.2	 Metabolic Tumor Volume
		7.9	 General Recommendations for the Use of PET in HL
		References
	8: Prognostic Factors
		8.1	 Historical Perspective
		8.2	 Prognostic Factors
			8.2.1	 Definition and Use
			8.2.2	 Types of Prognostic Factors
			8.2.3	 Different End Points
			8.2.4	 Types and Analyses of Prognostic Studies
			8.2.5	 Predictive Factors
		8.3	 Prognostic Factors across Stages
		8.4	 Early-Stage Hodgkin Lymphoma
		8.5	 Advanced-Stage Hodgkin Lymphoma
			8.5.1	 Pretreatment Prognostic Factors in Advanced-Stage Hodgkin Lymphoma
			8.5.2	 Interim PET as Prognostic Factor in Advanced-Stage Hodgkin Lymphoma
			8.5.3	 Prognostic Indices in Advanced-Stage Hodgkin Lymphoma
		8.6	 Prognostic Factors in Relapsed or Refractory Hodgkin Lymphoma
			8.6.1	 Patients Treated for r/r HL with Conventional Treatment
			8.6.2	 Treatment with High-Dose Chemotherapy and Autologous Stem Cell Transplantation
			8.6.3	 Patients’ Prognostic Indices or Scores in r/r HL Treated with Novel Agents
			8.6.4	 Prognostic Factors for Treatment with Novel Agents in r/r HL
		8.7	 Conclusion and Future Aspects
		References
	9: Principles of Radiation Therapy for Hodgkin Lymphoma
		9.1	 Principles of Radiation Therapy of Hodgkin Lymphoma
		9.2	 The Evolution of Radiotherapy for HL
		9.3	 Indications for Radiation Therapy in HL
			9.3.1	 Lymphocyte-Predominant HL
			9.3.2	 Classic Hodgkin: Stage I–II
			9.3.3	 Stage III–IV HL
			9.3.4	 RT in Salvage Programs for Refractory and Relapsed HL
		9.4	 Radiation Fields and Volumes: Principles and Design
			9.4.1	 Extended-Field Radiation Therapy
			9.4.2	 Involved-Field Radiation Therapy
			9.4.3	 Involved-Site Radiation Therapy (ISRT): The New Standard Volume for HL
				9.4.3.1	 ISRT When RT Is the Primary Treatment
				9.4.3.2	 ISRT When RT Is Part of Combined-Modality Treatment
			9.4.4	 Involved-Node Radiation Therapy (INRT): A Special Case of ISRT
			9.4.5	 Volume Definitions for Planning ISRT and INRT
				9.4.5.1	 Volume of Interest Acquisition
				9.4.5.2	 Determination of Gross Tumor Volume (GTV)
					Pre-chemotherapy (or Presurgery) GTV
					No Chemotherapy or Post-chemotherapy GTV
				9.4.5.3	 Determination of Clinical Target Volume (CTV)
				9.4.5.4	 Determination of Internal Target Volume (ITV)
				9.4.5.5	 Determination of Planning Target Volume (PTV)
			9.4.6	 Determination of Organs at Risk (OAR)
				9.4.6.1	 Lung
				9.4.6.2	 Heart
				9.4.6.3	 Thyroid
				9.4.6.4	 Second Cancers
			9.4.7	 Consolidation Volume Radiation Therapy (CVRT)
		9.5	 Dose Considerations and Recommendations
			9.5.1	 The Significance of Reducing the Radiation Dose
			9.5.2	 Dose Recommendations
		9.6	 New Aspects of Radiation Volume Definition and Treatment Delivery
			9.6.1	 New Technologies
			9.6.2	 Deep Inspiration Breath Hold
		9.7	 Proton Therapy
		9.8	 Common Side Effects and Supportive Care During Radiation Therapy
			9.8.1	 Common Acute Side Effects
			9.8.2	 Uncommon Early Side Effects
			9.8.3	 Supportive Care During Treatment
			9.8.4	 Follow-Up After Treatment
		References
	10: Principles of Chemotherapy in Hodgkin Lymphoma
		10.1	 Historical Introduction
		10.2	 Chemotherapy Applied to Advanced-Stage Hodgkin Lymphoma: Theories and Practice
			10.2.1	 Classes of Active Classical Agents in HL (Table 10.1)
			10.2.2	 Polychemotherapy: Models and Comparative Clinical Studies (Tables 10.2 and 10.3)
				10.2.2.1	 MOPP and Derivatives
				10.2.2.2	 ABVD and Derivatives
				10.2.2.3	 The Dose/Response Relationship: Norton and Simon Model
					Dose/Response Relationships and Treatment Tolerance: An Individual Characteristic?
				10.2.2.4	 Sustained/Weekly Regimens
				10.2.2.5	 Escalated-Dose Regimens
				10.2.2.6	 High-Dose Treatment and Autologous Stem Cell Transplantation as Part of Initial Therapy
				10.2.2.7	 Risk-Adapted Regimens Based on PET
				10.2.2.8	 Incorporation of Antibody-Drug Conjugate in Primary Treatment of Advanced-Stage cHL
		10.3	 Chemotherapy Treatment for Recurrent and Refractory Hodgkin Lymphoma
			10.3.1	 New Systemic Treatments
		10.4	 Conclusions
		References
	11: Treatment of Early Favorable Hodgkin Lymphoma
		11.1	 Introduction
		11.2	 Defining Favorable Early-Stage Disease
			11.2.1	 Staging
			11.2.2	 Prognostic Factors
		11.3	 Radiotherapy Alone
		11.4	 Late Treatment Effects and Mortality
		11.5	 Combined Modality Treatment
			11.5.1	 Radiotherapy Alone Versus CMT
			11.5.2	 Optimal Number of Cycles of Chemotherapy
			11.5.3	 Optimal Chemotherapy Combination
			11.5.4	 Optimal Radiation Dose
			11.5.5	 Optimal Radiation Field Size
		11.6	 Chemotherapy Alone
		11.7	 Treatment Adaptation Based on PET Scan Response
		11.8	 Recommendations and Future Directions
		References
	12: Treatment of Early Unfavorable Hodgkin Lymphoma
		12.1	 Prognostic Factors
			12.1.1	 Definition
			12.1.2	 New Prognostic Factors
		12.2	 Long-Term Side Effects
		12.3	 Non-PET-Adapted Treatment Strategies
			12.3.1	 Fields and Dose of Radiotherapy
			12.3.2	 Chemotherapy
			12.3.3	 Chemotherapy Alone
		12.4	 PET-Adapted Treatment Strategies
			12.4.1	 Interim PET
			12.4.2	 Clinical Trials
				12.4.2.1	 Rapid Study
				12.4.2.2	 H10 Study
				12.4.2.3	 Other Studies
				12.4.2.4	 Management of iPET-Positive Patients
		12.5	 ESMO and NCCN Recommendations
		12.6	 New Drugs
			12.6.1	 Brentuximab Vedotin
			12.6.2	 Checkpoint Inhibitors
		12.7	 Conclusions and Future Strategies
		References
	13: Treatment of Advanced-Stage Hodgkin Lymphoma
		13.1	 Introduction and Early History of Combination Chemotherapy
		13.2	 Fourth-Generation Regimens
			13.2.1	 Hybrid and Alternating Regimens
			13.2.2	 BEACOPP Escalated
		13.3	 ABVD or BEACOPP Escalated as Standard First-Line Treatment?
		13.4	 Outcome Prediction
			13.4.1	 The International Prognostic Score
			13.4.2	 Positron Emission Tomography
		13.5	 Response-Adapted Therapy
			13.5.1	 De-escalation of Therapy in Early Responders
			13.5.2	 Escalation of Therapy in Early Nonresponders
		13.6	 Introduction of Brentuximab Vedotin into First-Line Treatment
		13.7	 Introducing Programmed-Death-1 Inhibitors into First-Line Treatment
		13.8	 The Role of Radiotherapy
		13.9	 Summary
		References
	14: Optimizing Decision Making in Hodgkin Lymphoma
		14.1	 Treatment Choices and Individualized Care
		14.2	 Treatment-Related Late Effects and Associated Human Cost
		14.3	 Risk, Impact, and Variability of Treatment-Related Late Effects
		14.4	 Paucity of Harmonized Data to Guide Providers and Patients Towards Individualized Treatment Choices
		14.5	 Disease Classification and Prognostication
		14.6	 Simulation Modeling
			14.6.1	 Low-Dose CT Scan for Lung Cancer
			14.6.2	 Diffuse Large B-Cell Lymphoma (DLBCL)
		14.7	 Decision Models in Hodgkin Lymphoma (HL)
		14.8	 Conclusion
		References
Part III: Special Clinical Situations
	15: Pediatric Hodgkin Lymphoma
		15.1	 Introduction
			15.1.1	 Comparison of Pediatric/Adolescent Vs. Adult HL
			15.1.2	 Classical Pediatric Hodgkin Lymphoma (PHL)
				15.1.2.1	 Overall Strategies
				15.1.2.2	 Low-Risk (Early Favorable) Disease
				15.1.2.3	 Intermediate- and High-Risk (Advanced, Unfavorable) Disease
				15.1.2.4	 Future Considerations in Classical Pediatric and Adolescent HL
			15.1.3	 Nodular Lymphocyte-Predominant HL (NLPHL)
			15.1.4	 Recurrence, Relapse, and Salvage in PHL
				15.1.4.1	 Introduction
				15.1.4.2	 Standard-Dose Salvage Chemotherapy Regimens
				15.1.4.3	 Prognostic Factors at Relapse in Pediatric HL: Standard-Dose Chemoradiotherapy Vs. High-Dose Chemotherapy/Stem Cell Transplantation
				15.1.4.4	 Role of Radiotherapy in Relapsed Hodgkin Lymphoma
				15.1.4.5	 High-Dose Chemotherapy and Autologous Stem Cell Transplant
				15.1.4.6	 High-Dose Chemotherapy and Allogeneic Stem Cell Transplantation
				15.1.4.7	 Brentuximab Vedotin and Checkpoint Inhibitors
			15.1.5	 Late Effects
				15.1.5.1	 Cardiac Toxicities
				15.1.5.2	 Pulmonary Toxicities
				15.1.5.3	 Thyroid Toxicities
				15.1.5.4	 Secondary Malignancies
			15.1.6	 Summary/Future Directions
		References
	16: The Management of Older Patients with Hodgkin Lymphoma
		16.1	 Introduction
		16.2	 Epidemiology
		16.3	 Pathology
		16.4	 Clinical Presentation
		16.5	 Age Issues Affecting Treatment and Outcome
			16.5.1	 Comorbidity
			16.5.2	 Therapy-Associated Toxicity
		16.6	 Therapy
			16.6.1	 Early Stages
			16.6.2	 Advanced Stages
				16.6.2.1	 Earlier Data
				16.6.2.2	 Contemporary Data
			16.6.3	 Relapsed Patients
		16.7	 Conclusions and Perspectives
		References
	17: Nodular Lymphocyte-Predominant Hodgkin Lymphoma
		17.1	 Introduction
		17.2	 Pathology of NLPHL
		17.3	 Differential Diagnosis
		17.4	 Transformation to NHL
		17.5	 Clinical Characteristics
		17.6	 Treatment of Early Favorable NLPHL
		17.7	 Treatment of Early Unfavorable and Advanced NLPHL
		17.8	 Treatment of Relapsed NLPHL
		17.9	 Risk Factors
		17.10	 Summary and Conclusions
		References
	18: The Management of Hodgkin Lymphoma During Pregnancy
		18.1	 Introduction
		18.2	 Diagnostic Approach to HL during Pregnancy
		18.3	 Outcomes of Mother and Child in HL Coincident with Pregnancy
		18.4	 Treatment of Hodgkin Lymphoma during Pregnancy
			18.4.1	 General Therapeutic Principles
			18.4.2	 Early-Stage HL during Pregnancy
			18.4.3	 Use of Chemotherapy for Symptomatic or Advanced-Stage HL in Pregnant Patients
		18.5	 Fetal Outcomes
		18.6	 Planning the Delivery and Managing the Postpartum Period in Patients with HL
		18.7	 Relapsed HL and Concomitant Pregnancy
		18.8	 Conclusions
		References
	19: The Management of HIV-Hodgkin Lymphoma
		19.1	 Introduction
		19.2	 Epidemiology
			19.2.1	 CD4 T-Cell Counts and Risk of HIV-HL
		19.3	 Pathology
		19.4	 Clinical Presentation and Prognostic Factors
			19.4.1	 Prognostic Factors
		19.5	 Management
			19.5.1	 Primary Chemotherapy
				19.5.1.1	 Stage-Adapted Approach
				19.5.1.2	 PET-Adapted Approach
				19.5.1.3	 Brentuximab Vedotin with Chemotherapy
				19.5.1.4	 Combination Antiretroviral Therapy (cART)
			19.5.2	 Relapsed and Resistant Disease
				19.5.2.1	 Brentuximab Vedotin
				19.5.2.2	 Checkpoint Inhibitors
		References
Part IV: Relapsed and Refractory Disease
	20: Relapsed and Refractory Hodgkin Lymphoma
		20.1	 Introduction
		20.2	 Prognostic Factors in Relapsed and Refractory Hodgkin Lymphoma
		20.3	 Salvage Therapy
		20.4	 Pre-ASCT FDG-PET
		20.5	 Salvage Radiotherapy
		20.6	 HDCT Regimens
		20.7	 Tandem HDCT/ASCT
		20.8	 Posttransplant Therapy
		20.9	 Allogeneic Transplantation after Reduced Conditioning in Hodgkin Lymphoma
		References
	21: Allogeneic Transplantation for Relapsed Hodgkin Lymphoma
		21.1	 Introduction
		21.2	 Myeloablative Allogeneic Stem Cell Transplantation in Hodgkin Lymphoma: A Historical Perspective
		21.3	 Reduced-Intensity Regimens
		21.4	 Prognostic Factors of Long-Term Outcome for Allogeneic SCT
		21.5	 Evidence for Graft Versus Hodgkin Lymphoma
		21.6	 Role of Allogeneic SCT in Autograft Failures
		21.7	 Moving Allogeneic Stem Cell Transplantation to Earlier Stages of the Disease
		21.8	 Role of Allogeneic SCT in the Pediatric Population
		21.9	 Alternative Donor Transplants
		21.10	 Role of Allogeneic Stem Cell Transplantation in the Era of New Drugs
		References
	22: Targeting CD30 in Patients with Hodgkin Lymphoma
		22.1	 Introduction
		22.2	 Structure and Function of CD30
		22.3	 Therapeutic Targeting of CD30
		22.4	 Monoclonal Antibodies
		22.5	 Bispecific Monoclonal Antibodies
		22.6	 Radiolabeled Antibodies
		22.7	 Chimeric Antigen Receptor (CAR) T-Cell Therapy
		22.8	 Antibody-Drug Conjugates
			22.8.1	 Single-Agent Experience with Brentuximab Vedotin
		22.9	 Safety and Tolerability of Brentuximab Vedotin
			22.9.1	 Brentuximab Vedotin in Frontline Setting for HL
				22.9.1.1	 Early-Stage Disease
				22.9.1.2	 Advanced-Stage Disease
				22.9.1.3	 Elderly Patients
			22.9.2	 Brentuximab Vedotin Pre-ASCT
			22.9.3	 Brentuximab Vedotin Maintenance Post Autologous Stem Cell Transplant
			22.9.4	 Brentuximab Vedotin-Based Combinations in Posttransplant Settings
		22.10	 Conclusions
		References
	23: Hodgkin Lymphoma and PD-1 Blockade
		23.1	 Introduction
		23.2	 Early Clinical Trials
		23.3	 Measuring Response to PD-1 Blockade: Pseudoprogression and Treatment Beyond Progression
		23.4	 Minimal Residual Disease in cHL
		23.5	 Mechanisms of Response and Resistance
		23.6	 PD-1 Blockade-Based Combination Treatments and Use in Earlier Lines of Therapy
			23.6.1	 Frontline Therapy
			23.6.2	 First Relapse: Salvage Therapy
			23.6.3	 Maintenance Following ASCT
			23.6.4	 Combination Approaches in Multiply Relapsed/Refractory Patients
			23.6.5	 Impact of PD-1 Blockade on Subsequent Therapies
		23.7	 PD-1 Blockade and Allogeneic Stem Cell Transplantation
		23.8	 Conclusion
		References
	24: Other New Agents for Hodgkin Lymphoma
		24.1	 PI3K/Akt/mTOR Pathway
		24.2	 HDAC Inhibitors
		24.3	 Lenalidomide
		24.4	 Emerging Therapies
		24.5	 Conclusion
		References
Part V: Survivorship
	25: Quality of Life in Hodgkin Lymphoma
		25.1	 Quality of Life in Hodgkin Lymphoma
		25.2	 Health-Related Quality-of-Life Assessment
			25.2.1	 HRQoL Instruments
			25.2.2	 HRQoL in Special Patient Groups
		25.3	 HRQoL in Clinical Trials for Hodgkin Lymphoma
			25.3.1	 Lessons from Retrospective and Cross-Sectional Studies
			25.3.2	 Results from Prospective Trials
		25.4	 Conclusions
		References
	26: Second Malignancy Risk After Treatment of Hodgkin Lymphoma
		26.1	 Introduction
		26.2	 Methods of Assessing Second Cancer Risk
		26.3	 Magnitude of the Risk Increase of Second Malignancy, Temporal Patterns, and Age Effects
		26.4	 Contributors to Second Cancer Risk
			26.4.1	 Radiation Therapy
			26.4.2	 Chemotherapy
			26.4.3	 Genetic Factors
		26.5	 Risk of Selected Second Malignancies
			26.5.1	 Risk Factors for Leukemia
			26.5.2	 Risk Factors of Non-Hodgkin Lymphoma (NHL)
			26.5.3	 Risk Factors for Breast Cancer
			26.5.4	 Risk Factors for Lung Cancer
		26.6	 Clinical Implications
		References
	27: Cardiovascular and Pulmonary Late Effects
		27.1	 Cardiovascular Toxicity
			27.1.1	 Chemotherapy-Associated Cardiotoxicity
				27.1.1.1	 General Aspects of Chemotherapy-Associated Cardiotoxicity
				27.1.1.2	 Prevention of Chemotherapy-Associated Cardiotoxicity
				27.1.1.3	 Surveillance for and Management of Chemotherapy-Associated Cardiotoxicity
			27.1.2	 Radiation-Associated Cardiotoxicity
				27.1.2.1	 General Aspects of Radiation-Associated Cardiotoxicity
				27.1.2.2	 Dose-Response Relationships for Radiation-Associated Cardiotoxicity
				27.1.2.3	 Other Risk Factors for Radiation-Associated Cardiotoxicity
				27.1.2.4	 Imaging of and Screening for Radiation-Associated Cardiotoxicity
				27.1.2.5	 Prevention and Management of Radiation-Associated Cardiotoxicity
			27.1.3	 Radiation-Associated Cerebrovascular Toxicity
				27.1.3.1	 Radiation-Associated Stroke and Transient Ischemic Attack
				27.1.3.2	 Prevention and Screening for Radiation Damage to Carotid Arteries
				27.1.3.3	 Management of Radiation-Associated Carotid Artery Damage
			27.1.4	 Radiation-Associated Damage to Other Major Arteries
		27.2	 Late Pulmonary Toxicity
			27.2.1	 Chemotherapy-Associated Pulmonary Toxicity
				27.2.1.1	 General Aspects of Chemotherapy-Associated Pulmonary Toxicity
				27.2.1.2	 Bleomycin
				27.2.1.3	 Other Agents Leading to Pulmonary Toxicity
				27.2.1.4	 Prevention of Chemotherapy-Associated Pulmonary Toxicity
				27.2.1.5	 Management of Chemotherapy-Associated Pulmonary Toxicity
			27.2.2	 Radiation-Associated Pulmonary Toxicity
				27.2.2.1	 General Aspects of Radiation-Associated Pulmonary Toxicity
				27.2.2.2	 Prevention of Radiation-Associated Pulmonary Toxicity
				27.2.2.3	 Management of Radiation-Associated Pulmonary Toxicity
				27.2.2.4	 Combined Toxicity
		27.3	 Conclusion
		References
	28: Gonadal Dysfunction and Fertility Preservation in Hodgkin Lymphoma Patients
		28.1	 Introduction
		28.2	 Gonadal Dysfunction in Men
			28.2.1 Male Reproductive Physiology
			28.2.2 Hodgkin Lymphoma and Male Gonadal Dysfunction
			28.2.3 Treatment-Related Gonadal Dysfunction
			28.2.4 Predictive Factors for Gonadal Dysfunction and Damage
			28.2.5 Hormonal Analyses to Assess Testicular Function After Therapy
			28.2.6 Endocrine Hypogonadism After Chemotherapy in Men
			28.2.7 Fertility Preservation in Men: Preventative Pretreatment Strategies and Management After Chemotherapy
		28.3	 Gonadal Dysfunction in Women
			28.3.1 Female Reproductive Physiology
			28.3.2 Treatment-Related Infertility
			28.3.3 Posttreatment Assessment of Ovarian Reserve with Anti-Müllerian Hormone Levels
				28.3.3.1	 Reduced Ovarian Reserve Prior to Therapy
				28.3.3.2	 Hypogonadism in Women
			28.3.4 Radiation Therapy
			28.3.5 Preventative Treatment Strategies in Women
			28.3.6 Pharmacological Prevention of Gonadal Damage
				28.3.6.1	 GnRH Agonists (GnRHa) During Chemotherapy
			28.3.7 Cryopreservation of Oocytes/Ovarian Tissue
				28.3.7.1	 Ovarian Stimulation and Cryopreservation of Fertilized and Unfertilized Oocytes
				28.3.7.2	 Cryopreservation of Ovarian Tissue
					Combination of Different Fertility-Preserving Techniques
			28.3.8 Transposition of the Ovaries
			28.3.9 Premature Menopause
			28.3.10 Fertility and Late Effects in HL Survivors
		28.4	 Conclusions
		References
	29: Cancer-Related Fatigue in Hodgkin Lymphoma
		29.1	 Introduction
		29.2	 Assessment of CRF
		29.3	 Prevalence of CRF and Time of Occurrence
		29.4	 The Longitudinal Course of CRF
		29.5	 The Impact of Treatment Intensity on Long-Term CRF
		29.6	 Predictors of Long-Term CRF
		29.7	 Impact of Persistent CRF on Treatment Outcome and Social Reintegration
		29.8	 Management of CRF
		29.9	 Summary and Conclusion
		References