Lung Cancer	3
	Contents	7
	Contributors	10
	Preface	15
	CHAPTER 1 Smoking Prevention and Cessation	17
	Overview	17
	Introduction	17
	Tobacco and lung cancer	18
	Secondhand smoke andlung cancer	19
	Smoking among lungcancer patients	20
	Forms of tobacco	20
	Smoked tobacco	20
	Smokeless tobacco	22
	Recent developments on the tobacco market	22
	Factors explaining tobacco use	23
	Smoking initiation	23
	Smoking prevention	23
	Nicotine addiction	25
	Benefits of quitting	25
	Smoking cessation interventions	26
	Behavioral counseling	26
	Pharmaceutical aids for smoking cessation	28
	Nicotine replacement therapy	33
	Sustained-release bupropion	34
	Varenicline	34
	Combination therapy	35
	Use of medications in pregnancy	35
	Summary	35
	References	35
	CHAPTER 2 Lung Cancer Susceptibility and Risk Assessment Models	41
	Introduction	41
	Epidemiologic risk factors	41
	Family history	41
	Prior inflammatory diseases and disorders	42
	Diet and nutritional risk factors	43
	Genetic susceptibility	44
	Candidate gene approaches	45
	Genome-wide association studies	45
	6p21 and 12p13	47
	Intermediate phenotypic assays in measuring genetic susceptibility	49
	DNA damage and repair phenotypic assays	49
	Cell cycle phenotypic assays	51
	Phenotypic assays in apoptotic pathways	51
	Emerging novel biomarkers for LC risk and early detection	51
	LC risk assessment models	52
	An overview of cancer risk prediction models	52
	Concluding remarks	54
	References	55
	CHAPTER 3 Molecular Profiling	64
	Introduction	64
	Techniques used in molecular profiling	66
	DNA sequencing	66
	RNA profiling	67
	Proteomics	69
	Data analysis and statistics	71
	Clinical applications	74
	Early detection and diagnosis	74
	Molecular subclassification and staging	75
	Selection of therapy	76
	Future directions and conclusions	77
	Acknowledgments	78
	References	78
	CHAPTER 4 Somatic Genome Alterations in Human Lung Cancers	83
	Lung cancer genetics overview	83
	Lung adenocarcinoma genomics	84
	Molecular alteration spectra of lung adenocarcinoma	84
	Key genetic alterations in lung adenocarcinoma in a few selected pathways	85
	Genetic correlates of sensitivity and resistance	89
	Germline predisposition	89
	Future directions	90
	Lung squamous cell carcinoma genomics	90
	Introduction and overview of genomic alterations of lung SqCCs	90
	Somatic copy number alterations	91
	Genomic features of small cell lung cancers	93
	Previous molecular findings in SCLC	93
	Large-scale genome analysis studies of SCLC	94
	Biological and clinical implications of SCLC genome alterations	95
	References	96
	CHAPTER 5 Serum Proteomic Biomarkers	106
	Natural history of lung cancer progression and potential utility for biomarkers in the clinic	106
	The blood proteome	107
	Proteomic discovery platforms	108
	Proteomic approaches for discovery and validation of blood biomarkers	108
	MALDI-TOF MS serum analysis for diagnosis	108
	Serum proteomics for response to therapy	114
	Strategies to address serum proteome complexity	115
	Liquid chromatography (LC) tandem mass spectrometry (MS/MS)	115
	Targeted proteomics using multiple reaction monitoring (LC MRM MS)	117
	Bio-analytical validation of serum protein biomarkers	117
	Circulating autoantibodies	118
	Clinical validation of serum biomarkers	118
	Current challenges in lung cancer biomarker development and implementation	119
	Conclusions and future clinical implications	120
	References	121
	CHAPTER 6 Molecular Biology of Lung Preneoplasia	126
	Introduction	126
	Pathology of lung cancer preneoplastic lesions	127
	Squamous cell carcinoma preneoplasia	127
	Adenocarcinoma precursor lesions	129
	Precursor lesions of neuroendocrine tumors	129
	Molecular pathogenesis of lung cancer	130
	Pathogenesis of squamous cell carcinoma	131
	Pathogenesis of lung adenocarcinoma	132
	Pathogenesis of SCLC	134
	Field cancerization in lung cancer pathogenesis	134
	Smoking damaged epithelium and lung field cancerization	135
	Field cancerization transcriptome	135
	Field cancerization compartmentalization	136
	Inflammation and lung cancer	138
	Summary and perspectives	138
	References	139
	CHAPTER 7 Detection and Treatment of Preneoplastic Lesions	145
	Introduction	145
	Detection of preneoplastic lesions in central airways	145
	Principles of biophotonic imaging	145
	Autofluorescence bronchoscopy (AFB)	146
	Narrow band imaging (NBI)	147
	Optical coherence tomography (OCT)	147
	Indications for autofluorescence bronchoscopy	149
	Evaluation of patients with abnormal sputum cytology	149
	Evaluation of patients with suspected, known or previously completely resected lung cancer	149
	Assessment of patients with early central lung cancer prior to endobronchial therapy	150
	Surveillance of bronchial intraepithelial neoplasia	150
	Detection of preneoplastic lesions in peripheral lung	151
	Treatment of preinvasive bronchial lesions	152
	Endobronchial therapies	153
	Photodynamic therapy (PDT)	153
	Electrocautery	153
	Cryotherapy	154
	Brachytherapy	154
	Follow-up after endobronchial treatment	154
	References	154
	CHAPTER 8 Pathology of Adenocarcinoma	160
	Introduction	160
	Adenocarcinoma classification in resected specimens	161
	Preinvasive lesions	161
	Invasive adenocarcinoma	165
	Adenocarcinoma variants	165
	Prognosis of adenocarcinoma subtypes in resected specimens	165
	TNM staging: impact of 2011 adenocarcinoma classification	167
	Adenocarcinoma classification in small biopsies and cytology	168
	References	170
	CHAPTER 9 Management of Multifocal Bronchioloalveolar Carcinoma (BAC)	174
	Introduction	174
	Heterogeneity in the presentation with advanced BAC	175
	Evaluating Multifocal BAC	175
	Symptomatology	176
	Natural history and imaging findings	176
	Interventions to manage multifocal BAC	177
	Is the multifocal disease encompassed within a single lobe or lung?	177
	Is the patient symptomatic, or is there any progression at a clinically significant rate?	179
	If there is evidence of progression at a clinically significant pace, is this a unifocal (or arguably “oligo-focal”) or multifocal process?	179
	Approach to unifocal progression in the setting of multifocal disease	180
	Palliative surgery	181
	Systemic therapy for multifocal BAC	181
	Bronchorrhea	185
	Conclusions	186
	References	187
	CHAPTER 10 Radiology and Lung Cancer Screening	192
	Introduction	192
	Concept of screening	192
	Bias	193
	Historical perspectives	193
	Radiographic screening	194
	Computed tomography screening	194
	The National Lung Screening Trial	195
	Trial design	195
	Participant cohort	196
	Results	196
	Ongoing lung cancer screening trials and programs	197
	Lung cancer screening recommendations in the US	197
	Nodule detection and management	198
	Risks of LDCT screening	201
	Risks of radiation	201
	Psychological and procedural risks	202
	Cost effectiveness of LDCT screening	202
	Lung cancer screening and smoking cessation	202
	Translation from trial to practice	202
	Recruitment	202
	Academic center to community hospital	203
	Conclusion	203
	References	203
	CHAPTER 11 Imaging Lung Cancer	207
	Introduction	207
	Imaging of the primary tumor (T)	207
	Imaging of regional lymphnodes (N)	208
	Imaging of distant metastasis (M)	211
	Conclusion	215
	References	215
	CHAPTER 12 Staging of the Mediastinum	218
	Introduction	218
	Imaging	218
	Endoscopic evaluation	219
	Mediastinoscopy	221
	Anterior mediastinotomy, extended cervical mediastinoscopy, thoracoscopy and re-do mediatinoscopy	223
	Video Assisted Mediastinal Lymphadenectomy (VAMLA) – a staging procedure?	224
	Discussion	224
	References	227
	CHAPTER 13 Management of the Solitary Pulmonary Nodule	230
	Introduction	230
	Prevalence of lung nodules	230
	Risk of malignancy	231
	Clinical features	231
	Radiographic features	231
	Management	232
	Patient preference and shared decision-making	232
	Management plan	232
	Low probability	232
	Intermediate probability	233
	High probability	235
	Conclusion	237
	References	237
	CHAPTER 14 Minimally Invasive Resections for Lung Cancer	240
	Introduction	240
	Postoperative pain	242
	Estimated blood loss and chest tube duration	242
	Postoperative independence and return to pre-operative function	243
	Pulmonary function	243
	Operative time and length of stay	245
	Cost-effectiveness	245
	Administration of adjuvant chemotherapy	246
	Complications	248
	Special circumstances	248
	Reoperation	248
	Barriers to adoption	248
	Thoracoscopic segmentectomy	248
	Thoracoscopic pneumonectomy	249
	Thoracoscopic bronchoplasty	249
	Thoracoscopic chest wall resections	249
	Thoracoscopic lymphadenectomy	249
	Robotic-assisted lobectomy	249
	Conclusions	249
	References	250
	CHAPTER 15 Extended Resections for Lung Cancer	252
	Introduction	252
	General principles for all extended resections	252
	Chest wall invasion	254
	Superior sulcus tumor resection	258
	Vertebral body involvement	259
	Diaphragm Involvement	261
	Phrenic nerve involvement	261
	Recurrent laryngeal nerve involvement	262
	Pericardium	262
	Heart and great vessels	263
	Trachea	265
	Surgical perspectives for synchronous tumors	265
	Summary	266
	References	266
	CHAPTER 16 Bronchoscopic Interventions for Lung Cancer	269
	Introduction	269
	Central airway disease in lung cancer amenable to bronchoscopic treatment	269
	Mechanical bronchoscopic interventions in lung cancer	271
	Thermal bronchoscopic interventions in lung cancer	274
	Nonthermal, nonmechanical bronchoscopic interventions in lung cancer	277
	Conclusion	279
	References	279
	CHAPTER 17 Primary Tracheal Tumors	283
	Epidemiology	283
	Anatomy and physiology	283
	Symptoms	284
	Diagnosis and staging	284
	Tumor pathology and classification	286
	Management	288
	Surgical techniques	290
	Prognosis	292
	Conclusion	292
	References	292
	CHAPTER 18 Adjuvant Chemotherapy Following Surgery for Lung Cancer	294
	Introduction	294
	Clinical trials of adjuvant chemotherapy	294
	Japanese Clinical Oncology Group Trial 9304	295
	Adjuvant Lung Project Italy	296
	International Adjuvant Lung Cancer Trial	296
	Big Lung Trial	297
	JBR.10 Trial	298
	Adjuvant Navelbine International Trialist’s Association Study	298
	Cancer and Leukemia Group B-9633	299
	Pooled analyses of adjuvant chemotherapy trials	299
	Selection of patients to receive adjuvant chemotherapy	300
	Stage II and III disease	300
	Stage IA disease	300
	Stage IB disease	300
	Elderly patients	301
	Patients with poor performance status	301
	Selection of adjuvant chemotherapy regimen	301
	Cisplatin versus carboplatin	301
	Choice of a second agent	301
	Unanswered questions	302
	Predictive and prognostic biomarkers	302
	Use of targeted therapies with adjuvant chemotherapy	302
	Summary of recommendations	302
	References	303
	CHAPTER 19 Neoadjuvant Chemotherapy for Resectable Non-Small Cell Lung Cancer	306
	Introduction	306
	Phase II trials in resectable stage III disease	307
	Phase II trials in earlier stage disease	310
	Randomized phase II and phase III trials	311
	Meta-analyses of neoadjuvant chemotherapy	315
	Impact on surgical morbidity and mortality	316
	Surrogate efficacy endpoints in neoadjuvant trials	317
	Window of opportunity trials	318
	Conclusions	320
	References	321
	CHAPTER 20 Image-Guided Radiation Therapy	325
	Introduction	325
	Conventional versus CT-based simulation	326
	PET and PET-CT in radiation treatment planning	326
	Tumor motion	328
	Image guided radiation therapy	329
	Cone-beam CT	329
	Tomotherapy	330
	Markers and respiratory gating	330
	Orthogonal kV X-rays	331
	In-room CT	331
	The role of image guidance in stereotactic body radiotherapy (SBRT)	332
	Conclusions	332
	References	332
	CHAPTER 21 Stereotactic Ablative Radiotherapy for Lung Cancer	336
	Introduction	336
	History of SABR	337
	Radiobiology of SABR tumor biology	338
	Normal tissue biology and tolerance	339
	Defining SABR	340
	Immobilization and target motion issues related to SABR	341
	Physics and dosimetry of SABR	341
	Treatment experience in non-small cell lung cancer	343
	Medically inoperable stage I patients	343
	Operable stage I patients	347
	SABR for lung cancer metastases, multiple primary lung tumors, and recurrent lung cancer	348
	Summary	349
	References	349
	CHAPTER 22 Proton Therapy	354
	Introduction	354
	Relative biologic effectiveness and biological research on protons	355
	Rationale for proton therapy	356
	Proton treatment planning and delivery	357
	Physical characteristics of proton beams	357
	Passive scattering systems	357
	Dynamic spot scanning systems	359
	Planning proton therapy versus photon therapy	360
	Image-guided proton delivery	362
	Tumor motion considerations	362
	Adaptive proton therapy	363
	Normal-tissue doses from proton therapy versus other forms of radiation therapy	363
	Protons produce lower normal tissue doses than 3D CRT, IMRT, or SBRT	363
	Clinical trials	365
	References	366
	CHAPTER 23 Combinations of Radiation Therapy and Chemotherapy for Non-small Cell and Small-Cell Lung Carcinoma	369
	Introduction	369
	Rationale for combining radiation therapy and chemotherapy	369
	Sequential chemotherapy and radiation therapy	370
	Concurrent chemotherapy and radiation therapy	372
	Sequential versus concurrent chemoradiation therapy	372
	Concurrent chemoradiation therapy followed by surgical resection	373
	Radiation therapy	375
	The importance of radiation dose in local tumor control	375
	Designing the radiation volume and configuration	376
	Minimizing radiation-induced toxicity to normal tissues	378
	Novel radiation delivery techniques	382
	Chemoradiation for small-celllung cancer	383
	Sequencing of radiation and chemotherapy for limited-stage disease	383
	Chemotherapy regimens	384
	Radiation dose and fractionation schedule	384
	Radiation target volumes and dose constraints	386
	Consolidative thoracic radiation for extensive-stage disease	386
	Prophylactic cranial irradiation	386
	Conclusions	387
	References	387
	CHAPTER 24 Individualized Radiotherapy by Dose Escalation and Altered Fractionation in Non-small Cell Lung Cancer	395
	Introduction	395
	History of radiation dose escalation and altered fractionation	395
	Advances in technology and conformality	397
	Modern studies of dose-escalation for locally advanced disease	399
	Individualized radiation treatment planning	401
	Conclusions	402
	References	402
	CHAPTER 25 Molecular Target Treatment for Personalized Radiotherapy in Lung Cancer	406
	Technologic improvements in radiation delivery enhances therapeutic ratio	406
	Overcoming the plateau of radiation efficacy	407
	Targeted therapy with radiotherapy: past successes and failures	407
	Hypoxia targeting	407
	Vascular targeting	409
	EGFR targeting	409
	Guidelines for incorporating novel targeted agents in combination with radiation in lung cancer	410
	Potential targeted agents to combine with radiation therapy	411
	DNA damage repair targeting drugs	411
	Cell cycle checkpoint inhibitors	412
	Signal transduction inhibitors	412
	Epigenetic agents	412
	HSP90 inhibitors	413
	Considerations for bringing agents into clinical testing	414
	The synthetic lethality effect with radiation	414
	Prioritizing agents for clinical development	414
	Preclinical studies in the disease site of interest	414
	Biomarkers for patient selection	414
	Design of clinical trials	415
	Challenges and opportunities for the clinical development of targeted agents with radiation therapy	417
	Conclusion	417
	References	418
	CHAPTER 26 EGFR Tyrosine Kinase Inhibitors and Monoclonal Antibodies: Clinical Trial Review	422
	Background	422
	Front-line therapy: combination anti-EGFR therapy and chemotherapy for molecularly unselected NSCLC patients	422
	Front-line therapy: chemotherapy and intermittent anti-EGFR therapy	424
	Front-line therapy: anti-EGFR single agent	425
	Maintenance therapy	428
	Salvage therapy	429
	Other TKIs and MAbs	430
	Conclusions	432
	References	432
	CHAPTER 27 Mechanisms of Resistance to Epidermal Growth Factor Receptor (EGFR) in Non-small Cell Lung Cancer	437
	Introduction	437
	Primary resistance to EGFR TKIs	438
	EGFR-resistant mutations	438
	KRAS and BRAF mutations	440
	PIK3CA mutations and PTEN loss	440
	ErbB family members: mutation and amplification	441
	Acquired resistance to EGFR TKIs	441
	Acquired EGFR mutations	441
	HER2 amplification	443
	MAPK1 amplification	443
	MET amplification	443
	HGF overexpression	444
	IGF-1R signaling and other pathways	444
	Histological transformation	444
	Epithelial-mesenchymal transition (EMT)	444
	Pharmacologic interactions	444
	Tumor heterogeneity	445
	Conclusions	445
	References	445
	CHAPTER 28 Predictive Tumor Biomarkers for EGFR Inhibitors	451
	EGFR	452
	EGFR mutation	452
	Sensitizing EGFR mutations	452
	Resistant EGFR mutations	454
	Other rare mutations	455
	Role of EGFR mutations in clinical settings	456
	Mutation detection methods	456
	EGFR gene copy number	459
	EGFR protein expression	459
	Germline polymorphisms of EGFR	459
	KRAS mutations	460
	Other biomarkers	460
	EGFR testing in the clinical setting	461
	Perspectives for future development of the biomarkers	463
	References	464
	CHAPTER 29 Immunologic Approaches to Lung Cancer Therapy	470
	Cancer immunotherapy	470
	Targeting immune regulatory checkpoints for lung cancer therapy	470
	Tumor protein and peptide vaccines	471
	Dendritic cell vaccines	473
	Modified tumor cell vaccines	474
	Immune adjuvant vaccines	475
	Gene delivery vaccines	476
	Conclusion	476
	References	477
	CHAPTER 30 Novel and Emerging Agents in NSCLC	480
	Introduction	480
	Novel targeted agents	480
	HSP 90 inhibitors	480
	Met inhibitors/HCF inhibitors	481
	MEK inhibitors	482
	PI3K/AKT/mTOR pathway inhibitors	482
	PARP inhibitors	484
	Notch and hedgehog inhibitors	484
	Mitotic inhibitors	485
	Conclusion and future directions for novel targeted agents	486
	Targeted gene therapy for lung cancer	486
	p53 gene replacement	487
	Clinical trials of p53 gene replacement	487
	Gene replacement in combination with chemotherapy and radiation	488
	Systemic gene therapy for metastases	489
	Future directions for gene therapy	490
	References	490
	CHAPTER 31 Novel Clinical Trial Designs for Metastatic Lung Cancer	495
	Introduction	495
	Alternative endpoints in clinical trials	495
	The need for novel trial designs	496
	The impact of molecularly targeted agents in trial design	497
	The BATTLE trial	498
	Moving forward with innovative clinical trial designs	500
	References	502
	CHAPTER 32 Novel Statistical Models for NSCLC Clinical Trials	504
	Introduction	504
	Bayesian statistics and its relevance in clinical trials	507
	Adaptive designs	509
	Continual reassessment method (CRM)	509
	Predictive probability design (PPD)	509
	Biomarker stratified Bayesian adaptive randomization design (BSBARD)	510
	Comparison of standard and novel designs	510
	Challenges for adaptive designs	512
	The BATTLE trial: a case study	512
	Other novel designs	515
	Summary	518
	References	518
	CHAPTER 33 Tumor Microenvironment, Angiogenesis Biology, and Targeted Therapy	521
	Tumor angiogenesis	521
	Regulation of tumor angiogenesis	522
	Vascular endothelial growth factor receptor signaling	522
	Fibroblast growth factor receptor signaling	523
	Epidermal growth factor receptor signaling	523
	Platelet derived growth factor receptor signaling	523
	Therapeutic strategies to inhibit angiogenesis in lung cancer	524
	VEGF targeted therapies: FDA approved agents	524
	Combined VEGF/R and EGFR targeted therapies	525
	Tyrosine kinase inhibitors of VEGFR pathway	525
	Novel agents	528
	Vascular disrupting agents (VDAs)	528
	Antiangiogenic therapy in SCLC	529
	Biomarkers of response to antiangiogenic therapy	530
	High blood pressure	531
	Circulating cytokines	531
	VEGF single nucleotide polymorphisms (SNPs)	532
	Other biomarkers	532
	Tumor resistance to antiangiogenic therapies	532
	Conclusion	533
	References	534
	CHAPTER 34 Anti-angiogenic Agents in Metastatic NSCLC	543
	Introduction	543
	Monoclonal antibodies to VEGF/VEGFR	543
	Bevacizumab	543
	Ramucirumab	546
	Small molecule tyrosine kinase inhibitors	546
	Sorafenib	547
	Sunitinib	548
	Pazopanib	548
	Vandetanib	548
	Cediranib	549
	Motesanib	549
	Axitinib	549
	BIBF 1120	549
	Cabozantinib	550
	Vascular disrupting agents	550
	Other anti-angiogenic therapies	550
	Aflibercept	550
	Biomarkers for anti-angiogenic therapies	551
	Conclusion	552
	References	552
	CHAPTER 35 Targeting ALK Rearrangements	557
	Introduction	557
	The molecular biology of native ALK	557
	EML4-ALK: role in molecular pathogenesis	558
	Clinicopathologic features of patients with ALK rearrangements	559
	Prognostic implications of ALK rearrangements	560
	Diagnostic testing for ALK rearrangements	560
	ALK FISH	560
	RT-PCR	561
	Immunohistochemistry	561
	ALK Inhibitors: Crizotinib	562
	Clinical efficacy	562
	Safety profile	564
	Acquired resistance to crizotinib	564
	Other systemic therapies	565
	Future directions	565
	Next generation ALK inhibitors	565
	Heat shock protein 90 inhibitors	566
	Conclusion	566
	References	567
	CHAPTER 36 Non-small Cell Lung Cancers (NSCLC) with Mutations in BRAF	573
	Introduction	573
	Biology of BRAF mutant malignancies	573
	Molecular pathogenesis and frequency of BRAF mutations in human malignancies	574
	BRAF V600E mutant melanomas and colorectal cancers	574
	BRAF mutant NSCLC	575
	Diagnosis of BRAF mutations	575
	Clinical characteristics of BRAF mutated NSCLC	575
	The treatment of V600E BRAF mutant NSCLC	575
	The non-V600E BRAF mutants	576
	BRAF inactivating mutations	576
	Mechanisms of resistance to BRAF inhibitors	576
	Summary	577
	References	577
	CHAPTER 37 Prognostic and Predictive Biomarker Signatures	580
	Introduction	580
	Prognostic biomarker signatures	581
	Predictive biomarker signatures	583
	Future directions	584
	References	584
	CHAPTER 38 Brain Metastasis from Lung Cancer	588
	Introduction	588
	Pathophysiology of brain metastasis	588
	Treatment options	589
	Surgical resection	589
	Stereotactic radiosurgery	589
	Whole-brain radiation therapy	590
	WBRT as primary therapy for gross disease	590
	WBRT as an adjuvant after local therapy	592
	WBRT after surgery	592
	WBRT after stereotactic radiosurgery	593
	Prophylactic cranial irradiation	594
	Toxicity of radiation to the brain	597
	Biomarkers in non-small cell lung cancer and brain metastases	598
	Conclusions	599
	References	599
	Index	607
	Supplemental Images	619