Front Cover 1
Melanoma 2
copyright 
3 
Contributors 4
Contents 8
Hematology/Oncology 
 
12 
Preface 14
State of Melanoma 16
Key points 16
Introduction 16
Historical perspectives 17
Pathogenesis 17
Risk factors 18
Diagnosis 18
Staging 19
Prognosis 19
Surgical treatment 20
Primary Tumor 20
Lymphadenectomy 21
LN Evaluation 21
Medical management 22
Immunology and Immunotherapy in Melanoma 23
Adjuvant Treatment 24
Neoadjuvant Treatment 25
Management of metastatic inoperable (advanced, systemic) disease 26
Chemotherapy 26
BCT 27
Immunotherapy 27
Targeted Therapy 28
Future directions 29
References 30
Understanding the Biology of Melanoma and Therapeutic Implications 38
Key points 38
Introduction 38
Melanoma development 39
Melanocyte Formation in Development 39
Role of Ultraviolet Radiation 39
Role of MITF 40
Molecular signaling in melanoma 40
MAPK Signaling 40
Phosphoinositol-3-Kinase Signaling 41
Oncogenic Mutations 42
BRAF 42
NRAS/NF1 43
CKIT 43
GNAQ/GNA11 44
Other mutations 44
Cell cycle regulation 44
PTEN loss 44
Oncogene-directed treatments 45
Interaction of immunology and molecular signaling 47
Summary 48
References 48
Surgical Management of Melanoma 56
Key points 56
Introduction 57
Surgical treatment of localized disease 57
Surgical Treatment of Primary Melanoma 57
Staging of the Clinically Negative Regional Lymph Nodes 59
Thickness 0.76 to 0.99 mm 61
Ulceration 61
Mitotic count 61
Surgical treatment of regional lymph node metastases 62
Arguments in Favor of Routine Completion Lymphadenectomy 62
Arguments Against Routine Completion Lymphadenectomy 63
Role of postoperative radiation after lymphadenectomy 63
Surgical treatment of metastatic melanoma 64
Incidence of Resectable Metastatic Melanoma 64
Outcomes with Surgery 65
Complete response rate and duration of response 65
Progression-free survival 65
Overall survival 66
Integration of Surgery and Systemic Therapy in Patients with Metastatic Melanoma 66
Summary 67
References 67
Melanoma Adjuvant Therapy 72
Key points 72
Introduction 72
Clinical Predictors of Risk in Patients with Melanoma 72
Indications for Adjuvant Therapy 73
Immunotherapy with Interferon-alfa 74
Mechanism 74
IFN-a: Regimens Testing High-dose IFN-a 74
IFN-a: Other ECOG and Intergroup Trials Testing HDI 76
E1690 76
E1694 76
E2696 76
IFN-a: Other Doses, Routes and Durations Tested 76
Hellenic trial 79
E1697 79
EORTC 18952 79
DeCOG 80
Pegylated IFN 80
EORTC 18991 80
IFN-a: Meta-analyses 80
Predictors of Benefit and Prognostic Markers 80
Adjuvant radiation therapy 81
Trials testing other adjuvant agents 82
Chemotherapy 82
Biochemotherapy 82
Immunotherapy with Vaccines 82
Modalities of the near future: under trial 84
Immunotherapy with Anti–Cytotoxic T-Lymphocyte Antigen 4 Antibodies 84
Other Future Concepts 85
Immunotherapy with anti–programmed death 1 and anti–programmed death L1 agents 85
Targeted therapy with inhibitors of BRAF 85
Neoadjuvant therapy 85
Summary 87
References 87
Targeted Therapies for Cutaneous Melanoma 92
Key points 92
Introduction 92
The mitogen-activated protein kinase pathway in cutaneous melanoma 93
Targeting BRAF in cutaneous melanoma 94
Early RAF-Inhibitor Studies 94
Efficacy of the Selective RAF Inhibitors 95
RAF Inhibitors in BRAF Non-V600E Mutant Melanoma 97
RAF Inhibitors in Patients with Brain Metastases 97
RAF-Inhibitor Toxicity 98
Development of RAF-Inhibitor Resistance 98
MEK-Inhibitor Monotherapy and Combination Therapy 99
Targeting NRAS in cutaneous melanoma 100
Targeting KIT-mutant melanoma 101
Current recommendations 101
Summary 101
References 102
Treatments for Noncutaneous Melanoma 108
Key points 108
Introduction 108
Biology and Epidemiology 108
Mucosal melanoma 109
Ocular melanoma 109
Clinical management of locoregional disease 110
Evaluation and Workup 110
Staging mucosal melanoma 110
Staging ocular melanoma 111
Treating Locoregional Mucosal Melanoma 111
Surgery 111
Radiotherapy 111
Adjuvant chemotherapy 112
Treating Locoregional Ocular Melanoma 112
Radiotherapy: brachytherapy 112
Radiotherapy: external beam radiation 113
Surgery 113
Other approaches 113
Adjuvant chemotherapy 114
Surveillance 114
Clinical management of advanced disease 114
Local Modalities for the Treatment of Systemic Disease 114
Surgery 114
Liver-directed therapy 114
Systemic Therapy 115
References 116
Targeted Therapy Resistance Mechanisms and Therapeutic Implications in Melanoma 124
Key points 124
Introduction 124
Reactivation of the MAPK signaling pathway in resistance 125
The PI3K/AKT pathway in resistance to BRAF and MEK inhibitors 128
Other mechanisms that may mediate BRAFi resistance 130
Activation of Receptor Tyrosine Kinases 130
Cell-Cycle Regulators 130
Amplification of Microphthalmia-Associated Transcription Factor 131
Potential Novel Resistance Mechanisms 131
Heterogeneity and resistance mechanisms 131
Therapeutic strategies to overcome BRAFi resistance 132
Summary 134
References 134
Introduction to the Role of the Immune System in Melanoma 138
Key points 138
Background 138
Inflammation and Immunosurveillance in Melanomagenesis 138
Prognostic Value of Studying the Immune Tumor Microenvironment 139
Inflammatory and Immune Gene Signatures in the Biology of Melanoma 141
Role of the Immune System in Dissemination of Melanoma to the Nodes and Distant Organs 144
Immunosurveillance Against Primary and Relapsing Melanoma 145
Immunosuppression, Tolerance Mechanisms, and Chronic Inflammation Induced by Melanoma 146
Clinical status of immunotherapy for melanoma: brief overview 150
Cancer Vaccines, Adoptive T-cell Therapies, and Antigen-specific Escape from Effector T-cell Response 150
Vaccines and Cytokines 152
Special Immunotherapy Designs Based on Modulation of the Tumor Microenvironment 153
Lesional immunotherapy 153
Radiation therapy 154
Summary 155
References 155
Vaccines and Melanoma 160
Key points 160
Introduction 160
Previous vaccine approaches in melanoma: some promise, but limited clinical activity 161
Immunogens 161
Clinical trials with TAA vaccines 162
Small, single-arm studies 162
Larger, comparative studies 163
Recombinant Viral Vector–Based Vaccines 163
Whole Cell–Based Vaccines 164
New strategies 164
NeoVax: A New Concept for Antigen Selection Coupled with an Effective Immune Adjuvant 165
Choice of antigen: neoantigens 165
Choice of delivery: long peptides 165
Choice of adjuvant: the TLR-3 agonist poly-ICLC 166
WDVAX: A Scaffold Vaccine Incorporating Autologous Whole Tumor Cells, GM-CSF, and CpG into a Unique Delivery System 167
Choice of antigen: autologous tumor cells 167
Choice of adjuvant: tumor cell–secreted GM-CSF in combination with the TLR-9 agonist oligodeoxynucleotide containing unmeth ... 167
Choice of delivery: a novel material engineered scaffold 167
Summary and outlook 168
References 168
Interferon, Interleukin-2, and Other Cytokines 172
Key points 172
Cytokines 172
Interferon 172
Initial Use in Melanoma 173
Adjuvant Testing 173
PEG-IFN 175
Toxicity 175
Adjuvant Dosing and Schedule 176
Predicting Response 176
Future Directions 176
IL-2 176
Initial Studies 177
Studies in Melanoma 177
IL-2 Combined with Chemotherapy 177
IL-2 Combined with Other Cytokines 178
IL-2 Combined with Vaccines 178
Other IL-2 Combinations 179
Toxicity 179
Patient Selection 179
Other cytokines 180
IL-21 180
GM-CSF 180
Summary 181
References 181
Immune Checkpoint Blockade 186
Key points 186
Introduction 186
CTLA-4 inhibitors 187
Preclinical Studies with CTLA-4 187
Ipilimumab 188
Tremelimumab 189
Adverse Events 189
Management of irAEs 189
Evaluating Response with CTLA-4 Inhibitors 190
Anti–PD-1 antibodies 191
Preclinical Studies 191
Nivolumab 191
MK-3475 192
Anti–PD-L1 antibodies 192
Preclinical Studies 192
MPDL3280A 192
MEDI4736 192
Mucosal melanoma 193
Uveal melanoma 193
Identifying a biomarker 194
Prognostic Markers 194
Predictive Biomarkers 194
Immunoprofiling 194
Novel immune checkpoints 195
Summary 195
References 196
Combinatorial Approach to Treatment of Melanoma 202
Key points 202
Introduction 202
Combination immunotherapy plus chemotherapy 203
Rationale 203
Clinical Trials 203
Combination immunotherapy plus targeted therapy 204
Rationale 204
Ipilimumab Plus Vemurafenib 204
Sequential therapy 205
Rationale 205
Experience and Next Directions 205
Sequential Therapy Versus Combination Therapy 205
Recent trials of other combinations across modalities or pathways 205
Rationale 205
Summary 209
References 209
Index 214