Lung Cancer
Lung CancerEDITED BYJack A. Roth,             MD, F.A.C.S.Professor and Bud Johnson Clinical Distinguished ChairDepartment...
C 2008 by Blackwell PublishingBlackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USABlackwell ...
ContentsContributors, viiPreface, xi 1 Smoking Cessation, 1   Alexander V. Prokhorov, Kentya H. Ford,   and Karen Suchanek...
vi   Contents                14 Adjuvant Chemotherapy Following Surgery for Lung Cancer, 221                   Benjamin Be...
ContributorsMiguel Alvelo-Rivera, MD                                James D. Cox, MDAssistant Professor of Surgery,       ...
viii   ContributorsWilbur A. Franklin, MD                                  Michael Kent, MDProfessor, Department of Pathol...
Contributors       ixJin Soo Lee, MD                                        Sacha Mussot, MDDirector,                     ...
x   ContributorsLecia Sequist, MD, MPH                                   Robert D. Timmerman, MDInstructor in Medicine,   ...
PrefaceWhen the first edition of Lung Cancer was pub-           high risk for developing lung cancer. This will belished 14...
CHAPTER 1Smoking CessationAlexander V. Prokhorov, Kentya H. Ford, and Karen Suchanek HudmonOverview                       ...
2   Chapter 1Table 1.1 Health consequences of smoking.                     annual number of deaths from breast, colon, and...
Smoking Cessation      3same amount as men experience twice the risk of          Smoking among lungdeveloping lung cancer ...
4   Chapter 1Table 1.2 Percentage of current cigarette smokersa aged ≥18 years, by selected characteristics—National Healt...
Smoking Cessation       528.7% in Kentucky [51]. Twenty-three percent of           less tobacco than standard cigarettes, ...
6   Chapter 1of age and 70% of daily smokers have become              tine acts on the brain to produce a number of ef-reg...
Smoking Cessation      7studies, which are routinely limited to smokers of       smoked, number of cigarettes smoked per d...
8   Chapter 1   Recent advances in the mapping of the human             metabolism via the cytochrome P450 liver enzymesge...
Smoking Cessation      9congestion, fatigue, shortness of breath, and risk for    positive influence on survival rates. Alt...
10    Chapter 1     Social factors     • Culture     • Socio-economic status     • Media/peer/family influences     • Poli...
Smoking Cessation          11Table 1.3 The 5 A’s and 5 R’s for smoking cessation interventions.5 A’s      Ask about tobacc...
12Table 1.4 FDA-approved medications for smoking cessation.                                                               ...
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  1. 1. Lung Cancer
  2. 2. Lung CancerEDITED BYJack A. Roth, MD, F.A.C.S.Professor and Bud Johnson Clinical Distinguished ChairDepartment of Thoracic and Cardiovascular SurgeryProfessor of Molecular and Cellular OncologyDirector, W.M. Keck Center for Innovative Cancer TherapiesChief, Section of Thoracic Molecular OncologyThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USAJames D. Cox, MDProfessor and HeadDivision of Radiation OncologyThe University of Texas M. D. Anderson Cancer CenterHouston, Texas, USAWaun Ki Hong, MD, D.M.Sc. (Hon.)American Cancer Society ProfessorSamsung Distinguished University Chair in Cancer MedicineProfessor and Head, Division of Cancer MedicineProfessor, Department of Thoracic/Head and Neck Medical OncologyThe University of Texas M.D. Anderson Cancer CenterHouston, Texas, USATHIRD EDITION
  3. 3. C 2008 by Blackwell PublishingBlackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USABlackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UKBlackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, AustraliaThe right of the Author to be identified as the Author of this Work has been asserted in accordance withthe Copyright, Designs and Patents Act 1988.All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, ortransmitted, in any form or by any means, electronic, mechanical, photocopying, recording orotherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the priorpermission of the publisher.First published 1998Third edition 20081 2008Library of Congress Cataloging-in-Publication DataLung cancer / edited by Jack A. Roth, James D. Cox, Waun Ki Hong. – 3rd ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4051-5112-2 (alk. paper) 1. Lungs–Cancer. I. Roth, Jack A. II. Cox, James D. (James Daniel), 1938– III. Hong, Waun Ki. [DNLM: 1. Lung Neoplasms–therapy. 2. Lung Neoplasms–diagnosis. 3. Lung Neoplasms–genetics. WF 658 L9604 2008]RC280.L8L765 2008616.99 424–dc22ISBN: 978-1-4051-5112-2A catalogue record for this title is available from the British LibrarySet in 9.5/12pt Meridien by Aptara Inc., New Delhi, IndiaPrinted and bound in Singapore by Fabulous Printers Pte LtdFor further information on Blackwell Publishing, visit our website:http://www.blackwellpublishing.comThe publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy,and which has been manufactured from pulp processed using acid-free and elementary chlorine-freepractices. Furthermore, the publisher ensures that the text paper and cover board used have metacceptable environmental accreditation standards.Designations used by companies to distinguish their products are often claimed as trademarks. All brandnames and product names used in this book are trade names, service marks, trademarks or registeredtrademarks of their respective owners. The Publisher is not associated with any product or vendormentioned in this book.The contents of this work are intended to further general scientific research, understanding, anddiscussion only and are not intended and should not be relied upon as recommending or promoting aspecific method, diagnosis, or treatment by physicians for any particular patient. The publisher and theauthor make no representations or warranties with respect to the accuracy or completeness of thecontents of this work and specifically disclaim all warranties, including without limitation any impliedwarranties of fitness for a particular purpose. In view of ongoing research, equipment modifications,changes in governmental regulations, and the constant flow of information relating to the use ofmedicines, equipment, and devices, the reader is urged to review and evaluate the information providedin the package insert or instructions for each medicine, equipment, or device for, among other things,any changes in the instructions or indication of usage and for added warnings and precautions. Readersshould consult with a specialist where appropriate. The fact that an organization or Website is referred toin this work as a citation and/or a potential source of further information does not mean that the authoror the publisher endorses the information the organization or Website may provide or recommendationsit may make. Further, readers should be aware that Internet Websites listed in this work may havechanged or disappeared between when this work was written and when it is read. No warranty may becreated or extended by any promotional statements for this work. Neither the publisher nor the authorshall be liable for any damages arising herefrom.
  4. 4. ContentsContributors, viiPreface, xi 1 Smoking Cessation, 1 Alexander V. Prokhorov, Kentya H. Ford, and Karen Suchanek Hudmon 2 Lung Cancer Susceptibility Genes, 20 Joan E. Bailey-Wilson 3 Lung Cancer Susceptibility and Risk Assessment Models, 33 Xifeng Wu, Hushan Yang, Jie Lin, and Margaret R. Spitz 4 The Molecular Genetics of Lung Cancer, 61 David S. Shames, Mitsuo Sato, and John D. Minna 5 Molecular Biology of Preneoplastic Lesions of the Lung, 84 Ignacio I. Wistuba and Adi F. Gazdar 6 Detection of Preneoplastic Lesions, 99 Stephen Lam 7 Treatment of Preneoplastic Lesions of the Lung, 111 Annette McWilliams 8 The Pathology and Pathogenesis of Peripheral Lung Adenocarcinoma Including Bronchioloalveolar Carcinoma, 121 Wilbur A. Franklin 9 Treatment of Bronchioloalveolar Carcinoma, 144 Ji-Youn Han, Dae Ho Lee, and Jin Soo Lee10 Molecular Profiling for Early Detection and Prediction of Response in Lung Cancer, 153 Jacob M. Kaufman and David P. Carbone11 The Role for Mediastinoscopy in the Staging of Nonsmall Cell Lung Cancer, 169 Carolyn E. Reed12 Minimally Invasive Surgery for Lung Cancer, 180 Michael Kent, Miguel Alvelo-Rivera, and James Luketich13 Extended Resections for Lung Cancer, 194 Philippe G. Dartevelle, Bedrettin Yildizeli, and Sacha Mussot v
  5. 5. vi Contents 14 Adjuvant Chemotherapy Following Surgery for Lung Cancer, 221 Benjamin Besse and Thierry Le Chevalier 15 Induction Chemotherapy for Resectable Lung Cancer, 233 Katherine M.W. Pisters 16 Image-Guided Radiation Therapy, 247 Kenneth E. Rosenzweig and Sonal Sura 17 Stereotactic Body Radiation Therapy for Lung Cancer, 256 Robert D. Timmerman and Brian D. Kavanagh 18 Proton Therapy, 271 Joe Y. Chang, Alfred R. Smith, and James D. Cox 19 Combinations of Radiation Therapy and Chemotherapy for Nonsmall Cell Lung Carcinoma, 283 Zhongxing Liao, Frank V. Fossella, and Ritsuko Komaki 20 New Chemotherapeutic Agents in Lung Cancer, 315 Anne S. Tsao 21 Immunologic Approaches to Lung Cancer Therapy, 334 Jay M. Lee, Steven M. Dubinett, and Sherven Sharma 22 Epidermal Growth Factor Receptor Inhibitors, 352 Lecia V. Sequist and Thomas J. Lynch 23 Tumor Angiogenesis: Biology and Therapeutic Implications for Lung Cancer, 369 Emer O. Hanrahan, Monique Nilsson, and John V. Heymach 24 Retinoids and Rexinoids in Lung Cancer Prevention and Treatment, 386 Nishin Bhadkamkar and Fadlo R. Khuri 25 Proteasome Inhibition in Nonsmall Cell Lung Cancer Therapy, 400 Minh Huynh and Primo N. Lara Jr 26 Targeted Genetic Therapy for Lung Cancer, 411 Jack Roth 27 Screening for Early Detection, 421 James L. Mulshine 28 Natural Agents for Chemoprevention of Lung Cancer, 441 Amir Sharafkhaneh, Suryakanta Velamuri, Seyed Javad Moghaddam, Vladimir Badmaev, Burton Dickey, and Jonathan Kurie Index, 457 Color plates are found facing, 276
  6. 6. ContributorsMiguel Alvelo-Rivera, MD James D. Cox, MDAssistant Professor of Surgery, Professor and Head, Division of Radiation OncologyDivision of Thoracic Surgery The University of Texas,University of Pittsburgh Medical Center, M.D. Anderson Cancer Center,Pittsburgh, PA, USA Houston, TX, USAVladimir Badmaev, MD Philippe G. Dartevelle, MDVice President, Scientific and Medical Affairs Professor of Thoracic and Cardiovascular SurgerySabinsa Pharmaceutical, Inc., at Paris Sud UniversityNew Jersey, NJ, USA Head of the Department of Thoracic and Vascular Surgery and Heart Lung TansplantationJoan E. Bailey-Wilson, PhD ˆ Hopital Marie Lannelongue Le PlessisSenior Investigator and Co-Branch Chief, Robinson FranceNational Human Genome Research Institute,National Institutes of Health, Burton Dickey, MDBaltimore, MD, USA Professor and Chair, Department of Pulmonary MedicineBenjamin Besse, MD The University of TexasAssistant Professor, M. D. Anderson Cancer CenterDepartment of Medicine, Houston, TX, USAInstitut Gustave Roussy,Villejuif, France Steven M. Dubinett, MD Professor and ChiefNishin Bhadkamkar Division of Pulmonary and Critical Care Medicine,Resident, House Staff Doctor Department of Medicine,Emory University School of Medicine Director, UCLA Lung Cancer Research Program,Atlanta, GA, USA Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA,David P. Carbone, MD, PhD Los Angeles, CA, USAProfessor of Medicine and Cancer Biology,Vanderbilt-Ingram Cancer Center, Kentya H. Ford, PhDNashville, TN, USA Postdoctoral Fellow, Department of Behavioral Sicence,Joe Y. Chang, MD, PhD The University of Texas,Assistant Professor, M. D. Anderson Cancer Center,Director of Translation Research in Houston, TX, USA Thoracic Radiation Oncology,Department of Radiation Oncology, Frank Fosella, MDThe University of Texas M. D. Anderson Cancer Center, Medical Director, Thoracic OncologyHouston, TX, USA Multidisciplinary Care Center; Professor, Department of Thoracic/HeadThierry Le Chevalier, MD and Neck Medical OncologyDepartment of Medicine, The University of Texas,Institut Gustave Roussy, M.D. Anderson Cancer CenterVillejuif, France Houston, TX , USA vii
  7. 7. viii ContributorsWilbur A. Franklin, MD Michael Kent, MDProfessor, Department of Pathology, Surgical Resident, Department ofUniversity of Colorado Health Sciences Center, Thoracic Surgery,Aurora, CO, USA Beth Israel Deaconess Medical Center, Boston, MA, USAAdi F. Gazdar, MDProfessor of Pathology and Deputy Director, Fadlo R. Khuri, MDHamon Center for Therapeutic Oncology Research, Professor of Hematology and Oncology,The University of Texas Southwestern Medical Center, Winship Cancer Institute,Dallas, TX, USA Emory University, Atlanta, GA, USAJi-Youn Han, MD, PhDChief Scientist, Lung Cancer Branch, Ritsuko Komaki, MDNational Cancer Center Professor, Department of RadiationGoyang, Gyeonggi, Korea Oncology, Gloria Lupton Tennison DistinguishedEmer O. Hanrahan, MB, BCh, MRCPI Professorship for Lung Cancer ResarchMedical Oncology Fellow, The University of Texas,Department of Thoracic/Head and M. D. Anderson Cancer Center, Neck Medical Oncology, Houston, TX, USAThe University of Texas M.D. Anderson Cancer Center, Jonathan Kurie, MDHouston, TX, USA Professor, Department of Thoracic/Head and Neck Medical OncologyJohn Heymach, MD, PhD The University of Texas,Assistant Professor, M.D. Anderson Cancer CenterDepartment of Thoracic/Head and Neck Medical Oncology Houston, TX, USA and Cancer BiologyThe University of Texas,M.D. Anderson Cancer Center Stephen Lam, MD, FRCPC Professor of Medicine,Houston, TX , USA University of British Columbia; and Chair, Lung Tumor Group,Karen Suchanek Hudmon, Dr PH, MS, BS Pharm British Columbia Cancer Agency,Associate Professor, Vancouver, British Columbia, CanadaDepartment of Pharmacy Practice,Purdue University School of Pharmacy & Pharmaceutical Sciences, Primo N. Lara Jr, MDWest, Lafavette, Professor of Medicine,IN, USA University of California Davis Cancer Center, Sacramento, CA, USAMinh Huynh, MDStaff Oncologist Dae Ho Lee, MDKaiser Permanente Walnut Creek Medical Center, Assistant Professor,Walnut Creek, CA Division of Oncology, Department of Internal Medicine,Jacob M. Kaufman, MD, PhD College of Medicine,Candidate, Predoctoral Trainee University of Ulsan and Asan MedicalVanderbilt University School of Medicine Center,Vanderbilt University Cancer Center, Seoul, KoreaNashville, TN, USA Jay M. Lee, MDBrian D. Kavanagh, MD, MPH Surgical Director, Thoracic Oncology ProgramProfessor and Vice Chairman, Assistant Professor of SurgeryDepartment of Radiation Oncology, Division of Cardiothoracic SurgeryUniversity of Colorado Comprehensive Cancer Center, David Geffen School of Medicine at UCLAAurora, CO, USA Los Angeles, CA, USA
  8. 8. Contributors ixJin Soo Lee, MD Sacha Mussot, MDDirector, Thoracic and Vascular Surgeon and Staff MemberResearch Institute, Department of Thoracic and Vascular SurgeryNational Cancer Center, and Heart Lung TransplantationGoyang, Gyeonggi, Korea ˆ Hopital Marie Lannelongue – Le Plessis Robinson – FranceZhongxing Liao, MD Monique B. Nilsson, PhDAssociate Professor, Research Scientist,The University of Texas M.D. Department of Cancer Biology,Anderson Cancer Center, The University of Texas M.D. Anderson Cancer Center,Houston, TX, USA Houston, TX, USAJie Lin, PhD Katherine M.W. Pisters, MDInstructor, Department of Epidemiology, Professor of Medicine,The University of Texas M.D. Anderson Cancer Center, Department of Thoracic/Head & Neck MedicalHouston, TX, USA Oncology, Division of Cancer Medicine,James D. Luketich, MD The University of Texas M.D. Anderson CancerSampson Endowed Professor of Surgery; Center, and Chief, Heart, Houston, TX, USALung and Esophageal Surgery Institute,University of Pittsburgh Alexander V. Prokhorov, MD, PhDMedical Center, Professor, Department of Behavioral Science,Pittsburgh, PA, USA The University of Texas M.D. Anderson Cancer Center,Thomas J. Lynch Houston, TX, USAChief of Hematology–Oncology,Massachusetts General Hospital, Carolyn E. Reed, MDBoston, MA, USA Professor of Surgery and Chief,Annette McWilliams, MD, FRCPC Section of General Thoracic Surgery,Clinical Assistant Professor, Medical University of South Carolina,Department of Medicine, Charleston, SC, USAUniversity of British Columbia; and Respiratory Physician, Kenneth E. Rosenzweig, MDDepartment of Cancer Imaging, Associate Attending,BC Cancer Research Centre, Department of Radiation Oncology,Vancouver, BC, Canada Memorial Sloan–Kettering Cancer Center, New York, NY, USAJohn D. Minna, MDProfessor of Internal Medicine and Pharmacology; Jack Roth, MD and Director, Hamon Center for Therapeutic Professor and Bud Johnson Clinical Distinguished Chair Oncology Research, Department of Thoracic and Cardiovascular SurgeryThe University of Texas Southwestern Medical Center, Professor of Molecular and Cellular OncologyDallas, TX, USA Director, W.M. Keck Center for Innovative Cancer TherapiesSeyed Javad Moghaddam, MD Chief, Section of Thoracic Molecular OncologyInstructor, Department of Pulmonary Medicine The University of Texas,The University of Texas, M.D. Anderson Cancer CenterM.D. Anderson Cancer Center, Houston, TX, USAHouston, TX, USA Mitsuo Sato, MD, PhDJames L. Mulshine, MD Postdoctoral Researcher,Professor, Internal Medicine and Associate Provost Hamon Center for Therapeutic Oncology Research for Research, and the Simmons Cancer Center,Rush University Medical Center, The University of Texas Southwestern Medical Center,Chicago, IL, USA Dallas, TX, USA
  9. 9. x ContributorsLecia Sequist, MD, MPH Robert D. Timmerman, MDInstructor in Medicine, Professor and Vice Chairman,Harvard Medical School, Effie Marie Cain Distinguished ChairMGH Cancer Center, in Cancer Therapy Research,Boston, MA, USA Department of Radiation Oncology, University of TexasDavid S. Shames, PhD Southwestern Medical Center,Postdoctoral Fellow Dallas, TX, USAHamon Center for Therapeutic Oncology ResearchThe University of Texas Southwestern Medical Center, Anne S. Tsao, MDDallas, TX, USA Assistant Professor, Department of Thoracic/Head andAmir Sharafkhaneh, MD Neck Medical Oncology,Assistant Professor of Medicine at Baylor College The University of Texas of Medicine and Staff, M.D. Anderson Cancer Center,Physician at the Michael E. DeBakey VA Medical Center, Houston, TX, USAHouston, TX, USA Suryakanta Velamuri, MDSherven Sharma, PhD Assistant Professor of Medicine,Associate Professor, Balor College of Medicine;Division of Pulmonary and Critical and Staff Physician, Care Medicine, Michael E. Debakey VA Medical Center,Department of Medicine, Houston, TX, USAUCLA Lung Cancer Research Program,David Geffen School of Medicine at UCLA, Ignacio I. Wistuba, MDWest Los Angeles VA, Associate Professor of PathologyLos Angeles, CA, USA and Thoracic/Head & Neck Medical Oncology,Alfred R. Smith, PhD The University of TexasProfessor, The University of Texas M.D. Anderson Cancer Center,M.D. Anderson Proton Therapy Center, Houston, TX, USAHouston, TX, USA Xifeng Wu, MD, PhDMargaret R. Spitz, MD, MPH Professor, Department of Epidemiology,Professor and Chair, The University of TexasDepartment of Epidemiology, M.D. Anderson Cancer Center,The University of Texas Houston, TX, USAM.D. Anderson Cancer Center,Houston, TX, USA Bedrettin Yildizeli, MD Associated Professor of Thoracic Surgery,Sonal Sura, MD Department of Thoracic Surgery,Radiation Oncology Resident, Marmara University Hospital,New York City, NY, USA Istanbul, Turkey
  10. 10. PrefaceWhen the first edition of Lung Cancer was pub- high risk for developing lung cancer. This will belished 14 years ago, the editors were optimistic that important for implementing screening and preven-progress in reducing the mortality from this disease tion strategies. New techniques have emerged forwould result from insights in the biology of can- lung cancer staging that improve accuracy. A va-cer and new treatment strategies. Rapid progress in riety of surgical and radiation therapy techniquesthe biology, prevention, diagnosis, and treatment have been developed which will make local tumorof lung cancer convinced us that a third edition control more effective and less invasive. Combinedwas warranted. This book is not intended as a com- modality therapy and new chemotherapeutic agentsprehensive textbook, but as a concise summary of are yielding higher response rates and improved sur-advances in lung cancer clinical research and treat- vival when used in the adjuvant setting. The finalment for the clinician. section of the book describes novel approaches that Over 20 years of research on the biology of lung may emerge as important preventative, diagnostic,cancer has culminated in the clinical application and therapeutic modalities in the near future.of targeted therapies. These agents disable specific The editors emphasize that these advances areoncogenic pathways in the lung cancer cell and possible because of the work of those dedicatedcan mediate tumor regression with fewer adverse to translational research and rigorously conductedevents. Several chapters are devoted to summariz- clinical trials. We are optimistic that progress willing the most recent work in this field. Much research continue at a rapid pace and that deaths from lungis attempting to identify biomarkers to predict a cancer will continue to decrease. Jack A. Roth James D. Cox Waun Ki Hong xi
  11. 11. CHAPTER 1Smoking CessationAlexander V. Prokhorov, Kentya H. Ford, and Karen Suchanek HudmonOverview resulting in nearly 440,000 deaths each year [3]. The economic implications are enormous: moreTobacco use is a public health issue of enormous than $75 billion in medical expenses and over $81importance, and smoking is the primary risk factor billion in loss of productivity as a result of pre-for the development of lung cancer. Considerable mature death are attributed to smoking each yearknowledge has been gained with respect to biobe- [4–8]. While the public often associates tobacco usehavioral factors leading to smoking initiation and with elevated cancer risk, the negative health con-development of nicotine dependence. Smoking ces- sequences are much broader. The 2004 Surgeonsation provides extensive health benefits for every- General’s Report on the health consequences ofone. State-of-the-art treatment for smoking cessa- smoking [9] provides compelling evidence of the ad-tion includes behavioral counseling in conjunction verse impact of smoking and concluded that smok-with one or more FDA-approved pharmaceutical ing harms nearly every organ in the body (Tableaids for cessation. The US Public Health Service Clin- 1.1). In 2000, 8.6 million persons in the Unitedical Practice Guideline for Treating Tobacco Use and De- States were living with an estimated 12.7 mil-pendence advocates a five-step approach to smoking lion smoking-attributable medical conditions [10].cessation (Ask about tobacco use, Advise patients to There is convincing evidence that stopping smok-quit, Assess readiness to quit, Assist with quitting, ing is associated with immediate as well as long-and Arrange follow-up). Health care providers are term health benefits, including reduced cumulativeencouraged to provide at least brief interventions at risk for cancer. This is true even in older individu-each encounter with a patient who uses tobacco. als, and in patients who have been diagnosed with cancer [11].Introduction Smoking and lung cancerMore than two decades ago, the former US SurgeonGeneral C. Everett Koop stated that cigarette smok- In the United States, approximately 85% of alling is the “chief, single, avoidable cause of death in lung cancers are in people who smoke or whoour society and the most important public health have smoked [3]. Lung cancer is fatal for mostissue of our time” [1]. This statement remains true patients. The estimated number of deaths of lungtoday. In the United States, cigarette smoking is the cancer will exceed 1.3 million annually early in theprimary known cause of preventable deaths [2], third millennium [12]. Lung cancer is the leading cause of cancer-related deaths among AmericansLung Cancer, 3rd edition. Edited by Jack A. Roth, James D. Cox, of both genders, with 174,470 estimated newlyand Waun Ki Hong. c 2008 Blackwell Publishing, diagnosed cases and 162,460 deaths [13,14]. TheISBN: 978-1-4051-5112-2. number of deaths due to lung cancer exceeds the 1
  12. 12. 2 Chapter 1Table 1.1 Health consequences of smoking. annual number of deaths from breast, colon, and prostate cancer combined [15]. Recent advances inCancer Acute myeloid leukemia technology have enabled earlier diagnoses, and ad- Bladder vances in surgery, radiation therapy, imaging, and Cervical Esophageal chemotherapy have produced improved responses Gastric rates. However, despite these efforts, overall sur- Kidney vival has not been appreciably affected in 30 years, Laryngeal and only 12–15% of patients with lung cancer are Lung being cured with current treatment approaches Oral cavity and pharyngeal [16]. The prognosis of lung cancer depends largely Pancreatic on early detection and immediate, premetastasisCardiovascular Abdominal aortic aneurysm stage treatment [17]. Prevention of lung cancerdiseases Coronary heart disease (angina pectoris, is the most desirable and cost-efficient approach ischemic heart disease, myocardial to eradicating this deadly condition. Numerous infarction, sudden death) epidemiologic studies consistently define smoking Cerebrovascular disease (transient as the major risk factor for lung cancer (e.g. [18– ischemic attacks, stroke) 20]). The causal role of cigarette smoking in lung Peripheral arterial disease cancer mortality has been irrefutably establishedPulmonary Acute respiratory illnesses in longitudinal studies, one of which lasted as longdiseases Pneumonia as 50 years [21]. Tobacco smoke, which is inhaled Chronic respiratory illnesses either directly or as second-hand smoke, contains Chronic obstructive pulmonary an estimated 4000 chemical compounds, including disease over 60 substances that are known to cause cancer Respiratory symptoms (cough, [22]. Tobacco irritants and carcinogens damage the phlegm, wheezing, dyspnea) cells in the lungs, and over time the damaged cells Poor asthma control may become cancerous. Cigarette smokers have Reduced lung function in infants lower levels of lung function than nonsmokers exposed (in utero) to maternal [9,23], and quitting smoking greatly reduces smoking cumulative risk for developing lung cancer [24].Reproductive Reduced fertility in women The association of smoking with the developmenteffects Pregnancy and pregnancy outcomes of lung cancer is the most thoroughly documented Premature rupture of membranes causal relationship in biomedical history [25]. The Placenta previa Placental abruption link was first observed in the early 1950s through Preterm delivery the research of Sir Richard Doll, whose pioneering Low infant birth weight research has, perhaps more so than any other epi- Infant mortality (sudden infant death demiologist of his time, altered the landscape of dis- syndrome) ease prevention and consequently saved millions ofOther Cataract lives worldwide. In two landmark US Surgeon Gen-effects Osteoporosis (reduced bone density in erals’ reports published within a 20-year interval (in postmenopausal women, increased risk 1964 [26] and in 2004 [9]), literature syntheses fur- of hip fracture) ther documented the strong link between smoking Periodontitis and cancer. Compared to never smokers, smokers Peptic ulcer disease (in patients who are have a 20-fold risk of developing lung cancer, and infected with Helicobacter pylori) more than 87% of lung cancers are attributable to Surgical outcomes smoking [27]. The risk for developing lung cancer Poor wound healing increases with younger age at initiation of smoking, Respiratory complications greater number of cigarettes smoked, and greater number of years smoked [11]. Women smoking theSource: Reference [9].
  13. 13. Smoking Cessation 3same amount as men experience twice the risk of Smoking among lungdeveloping lung cancer [28,29]. cancer patients Tobacco use among patients with cancer is a se-Second-hand smoke and rious health problem with significant implicationslung cancer for morbidity and mortality [36–39]. Evidence in- dicates that continued smoking after a diagnosisWhile active smoking has been shown to be the with cancer has substantial adverse effects on treat-main preventable cause of lung cancer, second- ment effectiveness [40], overall survival [41], riskhand smoke contains the same carcinogens that are of second primary malignancy [42], and increasesinhaled by smokers [30]. Consequently, there has the rate and severity of treatment-related complica-been a concern since release of the 1986 US Sur- tions such as pulmonary and circulatory problems,geon General’s report [31] concluding that second- infections, impaired would healing, mucositis, andhand smoke causes cancer among nonsmokers and Xerostomia [43,44].smokers. Although estimates vary by exposure lo- Despite the strong evidence for the role of smok-cation (e.g., workplace, car, home), the 2000 Na- ing in the development of cancer, many cancer pa-tional Household Interview Survey estimates that a tients continue to smoke. Specifically, about onequarter of the US population is exposed to second- third of cancer patients who smoked prior to theirhand smoke [32]. Second-hand smoke is the third diagnoses continue to smoke [45] and among pa-leading cause of preventable deaths in the United tients received surgical treatment of stage I nonsmallStates [33], and it has been estimated that expo- cell lung cancer [46] found only 40% who were ab-sure to second-hand smoke kills more than 3000 stinent 2 years after surgery. Davison and Duffy [47]adult nonsmokers from lung cancer [34]. Accord- reported that 48% of former smokers had resumeding to Glantz and colleagues, for every eight smok- regular smoking after surgical treatment of lungers who die from a smoking-attributable illness, one cancer. Therefore, among patients with smoking-additional nonsmoker dies because of second-hand related malignancies, the likelihood of a positivesmoke exposure [35]. smoking history at and after diagnosis is high. Since 1986, numerous additional studies have Patients who are diagnosed with lung cancer maybeen conducted and summarized in the 2006 US face tremendous challenges and motivation to quitSurgeon General’s report on “The Health Conse- after a cancer diagnosis can be influenced by a rangequences of Involuntary Exposure of Tobacco Smoke.” The of psychological variables. Schnoll and colleaguesreport’s conclusions based on this additional ev- [48] reported that continued smoking among pa-idence are consistent with the previous reports: tients with head and neck and lung cancer is asso-exposure to second-hand smoke increases risk of ciated with lesser readiness to quit, having relativeslung cancer. More than 50 epidemiologic stud- who smoke at home, greater time between diag-ies of nonsmokers’ cigarette smoke exposure at noses and assessment, greater nicotine dependence,the household and/or in the workplace showed lower self-efficacy, lower risk perception, fewer per-an increased risk of lung cancer associated with ceived pros and greater cons to quitting, more fa-second-hand smoke exposure [34]. This means that talistic beliefs, and higher emotional distress. Lung20 years after second-hand smoke was first es- cancer patients should be advised to quit smoking,tablished as a cause of lung cancer in lifetime but once they are diagnosed, some might feel thatnonsmokers, the evidence supporting smoking ces- there is nothing to be gained from quitting [49].sation and reduction of second-hand smoke expo- Smoking cessation should be a matter of specialsure continues to mount. Eliminating second-hand concern throughout cancer diagnosis, treatment,smoke exposure at home, in the workplaces, and and the survival continuum, and the diagnosis ofother public places appears to be essential for re- cancer should be used as a “teachable moment”ducing the risk of lung cancer development among to encourage smoking cessation among patients,nonsmokers. family members, and significant others [37]. The
  14. 14. 4 Chapter 1Table 1.2 Percentage of current cigarette smokersa aged ≥18 years, by selected characteristics—National HealthInterview Survey, United States, 2005.Characteristic Category Men (n = 13,762) Women (n = 17,666) Total (n = 31,428)Race/ethnicityb White, non-Hispanic 24.0 20.0 21.9 Black, non-Hispanic 26.7 17.3 21.5 Hispanic 21.1 11.1 16.2 American Indian/Alaska Native 37.5 26.8 32.0 Asianc 20.6 6.1 13.3Educationd 0–12 years (no diploma) 29.5 21.9 25.5 GEDe (diploma) 47.5 38.8 43.2 High school graduate 28.8 20.7 24.6 Associate degree 26.1 17.1 20.9 Some college (no degree) 26.2 19.5 22.5 Undergraduate degree 11.9 9.6 10.7 Graduate degree 6.9 7.4 7.1Age group (yrs) 18–24 28.0 20.7 24.4 25–44 26.8 21.4 24.1 45–64 25.2 18.8 21.9 ≥65 8.9 8.3 8.6Poverty levelf At or above 23.7 17.6 20.6 Below 34.3 26.9 29.9 Unknown 21.2 16.1 18.4Total 23.9 18.1 20.9a Persons who reported having smoked at least 100 cigarettes during their lifetime and at the time of the interview reportedsmoking every day or some days; excludes 296 respondents whose smoking status was unknown.b Excludes 314 respondents of unknown or multiple racial/ethnic categories or whose racial/ethnic category was unknown.c Excludes Native Hawaiians or other Pacific Islanders.d Persons aged ≥25 years, excluding 339 persons with unknown level of education.e General Educational Development.f Calculated on the basis of US Census Bureau 2004 poverty thresholds.Source: Reference [7].medical, psychosocial, and general health benefits proportion of the population continues to smoke.of smoking cessation for cancer patients provide a In 2005, an estimated 45.1 million adult Americansclear rationale for intervention. (20.9%) were current smokers; of these, 80.8% re- ported to smoking every day, and 19.2% reported smoking some days [7]. The prevalence of smokingForms of tobacco varies considerably across populations (Table 1.2), with a greater proportion of men (23.9%) thanSmoked tobacco women (18.1%) reporting current smoking. Per-Cigarettes have been the most widely used form of sons of Asian or Hispanic origin exhibit the low-tobacco in the United States for several decades [51], est prevalence of smoking (13.3 and 16.2%, respec-yet in recent years, cigarette smoking has been de- tively), and American Indian/Alaska natives exhibitclining steadily among most population subgroups. the highest prevalence (32.0%). Also, the preva-In 2005, just over half of ever smokers reported be- lence of smoking among adults varies widely acrossing former smokers [3]. However, a considerable the United States, ranging from 11.5% in Utah to
  15. 15. Smoking Cessation 528.7% in Kentucky [51]. Twenty-three percent of less tobacco than standard cigarettes, bidis exposehigh school students report current smoking, and their smokers to considerable amounts of hazardousamong boys, 13.6% report current use of smoke- compounds. A smoking machine-based investiga-less tobacco, and 19.2% currently smoke cigars [52]. tion found that bidis deliver three times the amountThese figures are of particular concern, because of carbon monoxide and nicotine and almost fivenearly 90% of smokers begin smoking before the times the amount of tar found in conventionalage of 18 years [53]. cigarettes [63]. Other common forms of burned tobacco in theUnited States include cigars, pipe tobacco, and bidis. Smokeless tobaccoCigars represent a roll of tobacco wrapped in leaf to- Smokeless tobacco products, also commonly calledbacco or in any substance containing tobacco [54]. “spit tobacco,” are placed in the mouth to allow ab-Cigars’ popularity has somewhat increased over the sorption of nicotine through the buccal mucosa. Spitpast decade [55]. The latter phenomenon is likely tobacco includes chewing tobacco and snuff. Chew-to be explained by a certain proportion of smok- ing tobacco, which is typically available in loose leaf,ers switching cigarettes for cigars and by adoles- plug, and twist formulations, is chewed or parked incents’ experimentation with cigars [56]. In 1998, the cheek or lower lip. Snuff, commonly available asapproximately 5% of adults had smoked at least one loose particles or sachets (resembling tea bags), hascigar in the past month [57]. The nicotine content a much finer consistency and is generally held inof cigars sold in the United States ranged from 5.9 the mouth and not chewed. Most snuff productsto 335.2 mg per cigar [58] while cigarettes have a in the United States are classified as moist snuff.narrow range of total nicotine content, between 7.2 The users park a “pinch” (small amount) of snuffand 13.4 mg per cigarette [59]. Therefore, one large between the cheek and gum (also known as dip-cigar, which could contain as much tobacco as an ping) for 30 minutes or longer. Dry snuff is typicallyentire pack of cigarettes is able to deliver enough sniffed or inhaled through the nostrils; it is used lessnicotine to establish and maintain physical depen- commonly [64].dence [59]. In 2004, an estimated 3.0% of Americans 12 years Pipe smoking has been declining steadily over the of age and older had used spit tobacco in the pastpast 50 years [60]. It is a form of tobacco use seen month. Men used it at higher rates (5.8%) thanamong less than 1% of Americans [60]. Bidi smok- women (0.3%) [60]. The prevalence of spit tobaccoing is a more recent phenomenon in the United is the highest among 18- to 25-year-olds and is sub-States. Bidis are hand-rolled brown cigarettes im- stantially higher among American Indians, Alaskaported mostly from Southeast Asian countries. Bidis natives, residents of the southern states, and ru-are wrapped in a tendu or temburni leaf [61]. Visually, ral residents [61,66]. The consumption of chew-they somewhat resemble marijuana joints, which ing tobacco has been declining since the mid-1980s;might make them attractive to certain groups of conversely, in 2005, snuff consumption increased bythe populations. Bidis are available in multiple fla- approximately 2% over the previous year [66], pos-vors (e.g., chocolate, vanilla, cinnamon, strawberry, sibly because tobacco users are consuming snuff in-cherry, mango, etc.), which might make them par- stead of cigarettes in locations and situations whereticularly attractive to younger smokers. A survey smoking is banned.of nearly 64,000 people in 15 states in the UnitedStates revealed that young people (18–24 years ofage) reported higher rates of ever (16.5%) and Factors explaining tobacco usecurrent (1.4%) use of bidis then among older adults(ages 25 plus years). With respect to sociodemo- Smoking initiationgraphic characteristics, the use of bidis is most com- In the United States, smoking initiation typicallymon among males, African Americans, and con- occurs during adolescence. About 90% of adultcomitant cigarette smokers [62]. Although featuring smokers have tried their first cigarette by 18 years
  16. 16. 6 Chapter 1of age and 70% of daily smokers have become tine acts on the brain to produce a number of ef-regular smokers by that age [67,68]. Because most fects [77,78] and immediately after exposure, nico-adolescents who smoke at least monthly continue tine induces a wide range of central nervous sys-to smoke into adulthood, youth-oriented tobacco tem, cardiovascular, and metabolic effects. Nicotinepreventions and cessation strategies are warranted stimulates the release of neurotransmitters, in-[67,68]. Since the mid-1990s, by 2004, the past- ducing pharmacologic effects, such as pleasuremonth prevalence had decreased by 56% in 8th and reward (dopamine), arousal (acetylcholine,graders, 47% in 10th graders, and 32% in 12th norepinephrine), cognitive enhancement (acetyl-graders [69]. In recent years, however, this down- choline), appetite suppression (norepinephrine),ward trend has decelerated [69]. The downward learning and memory enhancement (glutamate),trend is unlikely to be sustained without steady and mood modulation and appetite suppression (sero-systematic efforts by health care providers in pre- tonin), and reduction of anxiety and tensionventing initiation of tobacco use and assisting young (β-endorphin and GABA) [78]. Upon entering thesmokers in quitting. brain, a bolus of nicotine activates the dopamine re- A wide range of sociodemographic, behavioral, ward pathway, a network of nervous tissue in thepersonal, and environmental factors have been ex- brain that elicits feelings of pleasure and stimulatesamined as potential predictors of tobacco exper- the release of dopamine.imentation and initiation of regular tobacco use Although withdrawal symptoms are not the onlyamong adolescents. For example, it has been sug- consequence of abstinence, most cigarette smok-gested that the prevalence of adolescent smok- ers do experience craving and withdrawal on ces-ing is related inversely to parental socioeconomic sation [79], and, therefore, relapse is common [80].status and adolescent academic performance [68]. The calming effect of nicotine reported by manyOther identified predictors of adolescent smoking users is usually associated with a decline in with-include social influence and normative beliefs, neg- drawal effects rather than direct effects on nicotineative affect, outcome expectations associated with [53]. This rapid dose-response, along with the shortsmoking, resistance skills (self-efficacy), engaging in half-life of nicotine (t 1/2 = 2 h), underlies tobaccoother risk-taking behaviors, exposure to smoking in users’ frequent, repeated administration, therebymovies, and having friends who smoke [70–75]. perpetuating tobacco use and dependence. Tobacco Although numerous studies have been successful users become proficient in titrating their nicotinein identifying predictors of smoking initiation, few levels throughout the day to avoid withdrawalstudies have identified successful methods for pro- symptoms, to maintain pleasure and arousal, andmoting cessation among youth, despite the finding to modulate mood. Withdrawal symptoms includethat in 2005, more than half of high school cigarette depression, insomnia, irritability/frustration/anger,smokers have tried to quit smoking in the past year anxiety, difficulty concentrating, restlessness, in-and failed [52]. These results confirm the highly creased appetite/weight gain, and decreased heartaddictive nature of tobacco emphasizing the need rate [81,82].for more effective methods for facilitating cessation The assumption that heavy daily use (i.e., 15–among the young. 30 cigarettes per day), is necessary for dependence to develop is derived from observations of “chip-Nicotine addiction pers,” adult smokers who have not developed de-Nicotine has come to be regarded as a highly addic- pendence despite smoking up to five cigarettes pertive substance. Judging by the current diagnostic cri- day for many years [83,84]. Chippers do not tendteria, tobacco dependence appears to be quite preva- to differ from other smokers in their absorption andlent among cigarette smokers; more than 90% of metabolism of nicotine, causing some investigatorssmokers meet the DSM-IV (Diagnostic and Statisti- to suggest that this level of consumption may be toocal Manual of Mental Disorders) criteria for nicotine low to cause nicotine dependence. However, thesedependence [76]. Research has shown that nico- atypical smokers are usually eliminated from most
  17. 17. Smoking Cessation 7studies, which are routinely limited to smokers of smoked, number of cigarettes smoked per day) willat least 10 cigarettes per day [83]. be more similar for persons who are related geneti- Signs of dependence on nicotine have been re- cally (i.e., biologically) than for persons who are notported among adolescent smokers, with approx- related genetically. Hence, one would expect to ob-imately one fifth of them exhibiting adult-like serve greater similarities between children and theirdependence [85]. Although, lengthy and regular biological parents and siblings than would be ob-tobacco use has been considered necessary for served between children and their adoptive parentsnicotine dependence to develop [68], recent re- or adopted siblings. Indeed, research has demon-ports have raised concerns that nicotine depen- strated stronger associations (i.e., higher correlationdence symptoms can develop soon after initiation, coefficients) between biologically-related individu-and that these symptoms might lead to smoking als, compared to nonbiologically-related individu-intensification [79,86]. Adolescent smokers, who als, for the reported number of cigarettes consumeduse tobacco regularly, tend to exhibit high craving [90]. In recent years, it has become more difficultfor cigarettes and substantial levels of withdrawal to conduct adoption studies, because of the reducedsymptoms [87]. number of intranational children available for adop- tion [91]. Additionally, delayed adoption (i.e., time elapsed between birth and entry into the new fam-Genetics of tobacco use and ily) is common with international adoptions anddependence might lead to an overestimation of genetic effects if early environmental influences are attributed toAs early as 1958, Fisher hypothesized that the link genetic influences [92].between smoking and lung cancer could be ex- In twin studies, identical (monozygotic) twinsplained at least in part by shared genes that predis- and fraternal (dizygotic) twins are compared. Iden-pose individuals to begin smoking as young adults tical twins share the same genes; fraternal twins,and to develop lung cancer later in adulthood [88]. like ordinary siblings, share approximately 50% ofMore recently, tobacco researchers have begun to their genes. If a genetic link exists for the phe-explore whether genetic factors do in fact contribute nomenon under study, then one would expect totoward tobacco use and dependence. see a greater concordance in identical twins than Tobacco use and dependence are hypothesized to in fraternal twins. Thus, in the case of tobaccoresult from an interplay of many factors (includ- use, one would expect to see a greater proportioning pharmacologic, environmental and physiologic) of identical twins with the same tobacco use be-[77]. Some of these factors are shared within fam- havior than would be seen with fraternal twins.ilies, either environmentally or genetically. Studies Statistically, twin studies aim to estimate the per-of families consistently demonstrate that, compared centage of the variance in the behavior that isto family members of nonsmokers, family members due to (1) genes (referred to as the “heritability”),of smokers are more likely to be smokers also. How- (2) shared (within the family) environmental ex-ever, in addition to shared genetic predispositions, periences, and (3) nonshared (external from theit is important to consider environmental factors family) environmental experiences [91]. A num-that promote tobacco use—siblings within the same ber of twin studies of tobacco use have been con-family share many of the same environmental in- ducted in recent years. These studies have largelyfluences as well as the same genes. To differentiate supported a genetic role [91,93]; higher concor-the genetic from the environmental influences, epi- dance of tobacco use behavior is evident in identicaldemiologists use adoption, twin, twins reared apart, twins than in fraternal twins. The estimated aver-and linkage study designs [89]. age heritability for smoking is 0.53 (range, 0.28– Key to the adoption studies is the assumption that 0.84) [93,94]; approximately half of the varianceif a genetic link for tobacco use exists, then tobacco in smoking appears to be attributable to geneticuse behaviors (e.g., smoking status, number of years factors.
  18. 18. 8 Chapter 1 Recent advances in the mapping of the human metabolism via the cytochrome P450 liver enzymesgenome have enabled researchers to search for (specifically, CYP2A6 and CYP2D6).genes associated with specific disorders, including In summary, each of these types of study designstobacco use. Using a statistical technique called link- supports the hypothesis that genetics influence theage analysis, it is possible to identify genes that pre- risk for a wide range of tobacco-related phenotypes,dict a trait or disorder. This process is not based on such as ever smoking, age at smoking onset, levelprior knowledge of a gene’s function, but rather it of smoking, ability to quit, and the metabolic path-is determined by examining whether the trait or ways of nicotine (e.g., see [45,89,95–99]). But givendisorder is coinherited with markers found in spec- that there are many predictors of tobacco use andified chromosomal regions. Typically, these types dependence, of which genetic predisposition is justof investigations involve collection of large family one piece of a complex puzzle, it is unlikely that so-pedigrees, which are studied to determine inheri- ciety will move toward widespread genotyping fortance of the trait or disorder. This method works early identification of individuals who are at riskwell when a single gene is responsible for the out- for tobacco use. Perhaps a more likely use of ge-come; however, it becomes more difficult when netics as related to tobacco use is its potential formultiple genes have an impact, such as with to- improving our treatment for dependence [91]. Ifbacco use. In linkage studies of smoking, it is com- genetic research leads to new knowledge regardingmon for investigators to identify families, ideally the mechanisms underlying the development andwith two or more biologically-related relatives that maintenance of dependence, it is possible that new,have the trait or disorder under study (referred to more effective medications might be created. Fur-as affected individuals, in this case, smokers) and thermore, through pharmacogenomics research weother unaffected relatives. For example, data from might gain improved knowledge as to which pa-affected sibling pairs with parents is a common de- tients, based on their genetic profiles, would be bestsign in linkage analysis. A tissue sample (typically treated with which medications. Researchers are be-blood) is taken from each individual, and the sample ginning to examine how DNA variants affect healthundergoes genotyping to obtain information about outcome with pharmacologic treatments, with athe study participant’s unique genetic code. If a goal of determining which genetic profiles respondgene in a specific region of a chromosome is as- most favorably to specific pharmaceutical aids forsociated with smoking, and if a genetic marker is cessation (e.g. [98,100–103]).linked (i.e., in proximity), then the affected pairs(such as affected sibling pairs) will have increasedodds for sharing the same paternal/maternal gene Benefits of quitting[91]. As genetic research moves forward, new clues The reports of the US Surgeon General on theprovide insight into which genes might be promis- health consequences of smoking, released in 1990ing “candidates” as contributors to tobacco use and and 2004, summarize abundant and significantdependence. Currently, there are two general lines health benefits associated with giving up tobaccoof research related to candidate genes for smoking. [9,104]. Benefits noticed shortly after quitting (e.g.,One examines genes that affect nicotine pharmaco- within 2 weeks to 3 months), include improvementsdynamics (the way that nicotine affects the body) in pulmonary function and circulation. Withinand the other examines genes that affect nicotine 1–9 months of quitting, the ciliary function ofpharmacokinetics (the way that the body affects the lung epithelium is restored. Initially, patientsnicotine). A long list of candidate genes are being might experience increased coughing as the lungsexamined—some of the most extensively explored clear excess mucus and tobacco smoke particu-involve (a) the dopamine reward pathway (e.g., lates. In several months, smoking cessation resultsthose related to dopamine synthesis, receptor acti- in measurable improvements of lung function. Overvation, reuptake, and metabolism) and (b) nicotine time, patients experience decreased coughing, sinus
  19. 19. Smoking Cessation 9congestion, fatigue, shortness of breath, and risk for positive influence on survival rates. Although manypulmonary infection and 1 year postcessation, the smoking cessation interventions are aimed at pri-excess risk for coronary heart disease is reduced to mary prevention of cancer, these results indicatehalf that of continuing smokers. After 5–15 years, that there can be substantial medical benefits forthe risk for stroke is reduced to a rate similar to individuals who quit smoking after they are diag-that of people who are lifetime nonsmokers, and nosed with cancer.10 years after quitting, an individual’s chance ofdying of lung cancer is approximately half that of Smoking cessation interventionscontinuing smokers. Additionally, the risk of devel-oping mouth, larynx, pharynx, esophagus, bladder, Effective and timely administration of smoking ces-kidney, or pancreatic cancer is decreased. Finally, sation interventions can significantly reduce the risk15 years after quitting, a risk for coronary heart dis- of smoking-related disease [110]. Recognizing theease is reduced to a rate similar of that of people who complexity of tobacco use is a necessary first stephave never smoked. Smoking cessation can also lead in developing effective interventions and trials forto a significant reduction in the cumulative risk for cessation and prevention. The biobehavioral modeldeath from lung cancer, for males and females. of nicotine addiction and tobacco-related cancers Smokers who are able to quit by age 35 can be presents the complex interplay of social, psycho-expected to live an additional 6–9 years compared logical, and biological factors that influence tobaccoto those who continue to smoke [105]. Ossip-Klein use and addiction (Figure 1.1). These factors in turnet al. [106] recently named tobacco use a “geriatric mediate dependence, cessation, and relapse in mosthealth issue.” Indeed, a considerable proportion of individuals, and treatment has been developed totobacco users continue to smoke well into their 70s address many of the factors noted in the model [38].and 80s, despite the widespread knowledge of thetobacco health hazards. Elderly smokers frequently The health care provider’s roleclaim that the “damage is done,” and it is “too late and responsibilityto quit;” however, a considerable body of evidence Health care providers are uniquely positioned torefutes these statements. Even individuals who assist patients with quitting, having both access topostpone quitting until age 65 can incur up to four quitting aids and commanding a level of respect thatadditional years of life, compared with those who renders them particularly influential in advising pa-continued to smoke [24,106]. Therefore, elderly tients on health-related issues. To date, physicianssmokers should not be ignored as a potential target have received the greatest attention in the scien-for cessation efforts. Health care providers ought to tific community as providers of tobacco cessationremember that it is never too late to advise their treatment. Although less attention has been paid toelderly patients to quit and to incur health benefits. other health care providers such as pharmacists and A growing body of evidence indicates that con- nurses, they too are in a unique position to servetinued smoking after a diagnosis of cancer has the public and situated to initiate behavior changesubstantial adverse effects. For example, these among patients or complement the efforts of otherstudies indicate that smoking reduces the over- providers [64,111].all effectiveness of treatment, while causing com- Fiore and associates conducted a meta-analysisplications with healing as well as exacerbating of 29 investigations in which they estimated thattreatment side effects, increases risk of developing compared with smokers who do not receive an in-second primary malignancy, and decreases over- tervention from a clinician, patients who receiveall survival rates [36–38,107–109]. On the other a tobacco cessation intervention from a physicianhand, the medical, health, and psychosocial bene- clinician or a nonphysician clinician are 2.2 andfits of smoking cessation among cancer patients are 1.7 times as likely to quit smoking at 5 or morepromising. Gritz et al. [37] indicated that stopping months postcessation, respectively [112]. Althoughsmoking prior to diagnosis and treatment can have a brief advice from a clinician has been shown to
  20. 20. 10 Chapter 1 Social factors • Culture • Socio-economic status • Media/peer/family influences • Politics Psychological factors • Comorbidity Tobacco use, • Personality Behavioral, Dependence, Cancer • Stress Neurochemical, Cessation, Relapse Physiological factors Biological factors • Genetics • NutritionFigure 1.1 Biobehavioral model of nicotine addiction and tobacco-related cancers. (Adapted from [38].)lead to increased likelihood of quitting, more in- from self-help materials to individual cognitive–tensive counseling leads to more dramatic increases behavioral therapy, enable individuals to more ef-in quit rates [112]. Because the use of pharma- fectively recognize high-risk smoking situations, de-cotherapy agents approximately doubles the odds velop alternative coping strategies, manage stress,of quitting [7,112], smoking cessation interventions improve problem-solving skills, and increase socialshould consider combining pharmacotherapy with support [113]. The Clinical Practice Guideline out-behavioral counseling. lines a five-step framework that clinicians can apply To assist clinicians and other health care providers when assisting patients with quitting. Health carein providing cessation treatment, the US Public providers should: (a) systematically identify all to-Health Service has produced a Clinical Practice Guide- bacco users, (b) strongly advise all tobacco users toline for the Treatment of Tobacco Use and Dependence quit, (c) assess readiness to make a quit attempt, (d)[112]. The Guideline is based on a systematic re- assist patients in quitting, and (e) arrange follow-upview and analysis of scientific literature which yields contact. The steps have been described as the 5 A’s:a series of recommendations and strategies to as- Ask, Advise, Assess, Assist, and Arrange follow-upsist health care providers in delivering smoking (Table 1.3). Due to the possibility of relapse, healthcessation treatment. The Guideline emphasizes the care providers should also provide patients withimportance of systematic identification of tobacco brief relapse prevention treatment. Relapse preven-users by health care workers and offering at least tion reinforces the patient’s decision to quit, reviewsbrief treatment interventions to every patient who the benefits of quitting, and assists the patient in re-uses tobacco. Among the most effective approaches solving any problems arising from quitting [112].for quitting are behavioral counseling and pharma- The outlined strategy has been termed the 5 R’scotherapy, used alone or, preferably, in combination (Table 1.3): Relevance, Risks, Rewards, Roadblocks,[112]. and Repetition. In the absence of time or expertise for providing more comprehensive counseling, clin-Behavioral counseling icians are advised to (at a minimum), ask about to-Behavioral interventions play an integral role in bacco use, advise tobacco users to quit, and refersmoking cessation treatment, either alone or in con- these patients to other resources for quitting, suchjunction with pharmacotherapy. These interven- as a toll-free tobacco cessation quitline (1-800-QUITtions, which include a variety of methods ranging NOW, in the US).
  21. 21. Smoking Cessation 11Table 1.3 The 5 A’s and 5 R’s for smoking cessation interventions.5 A’s Ask about tobacco use Identify and document tobacco use status for every patient at every visit Advise to quit Urge every tobacco user to quit in a clear, strong, and personalized manner Assess readiness to make a Assess whether or not the tobacco user is ready to make a quit attempt in quit attempt the next 30 days Assist in quit attempt Use counseling and/or pharmacotherapy with the patient willing to make a quit attempt to help him or her quit Arrange follow-up Schedule follow-up contact, preferably within the first week after the quit date5 R’s Relevance Encourage the patient to indicate why quitting is personally relevant, being specific as possible Risk Ask the patient to identify the negative consequences of tobacco use, including acute risks (e.g., short breath), long-term risks (e.g., cancer, and environmental risks, e.g., cancer among family) Rewards Request that the patient identify potential benefits of stopping tobacco use (e.g., improved health) Roadblocks Ask the patient to identify barriers or impediments to quitting and note the elements of treatment that could address such barriers (e.g., withdrawal symptoms, fear of failure, lack of support) Repetition Repeat the motivational intervention every time an unmotivated patient visits the clinic settingAdapted from [112].Pharmaceutical aids for nicotine oral inhaler), sustained-release bupropion,smoking cessation and varenicline tartrate. These are described in brief below, and summaries of the prescribing informa-According to the Clinical Practice Guideline [112], tion for each medication are provided in Table 1.4.all patients attempting to quit should be encour-aged to use one or more effective pharmacother- Nicotine replacement therapyapy agents for cessation except in the presence of In clinical trials, patients who use NRT products arespecial circumstances. These recommendations are 1.77 times as likely to quit smoking than are thosesupported by the results of more than 100 controlled who receive placebo [7]. The main mechanism oftrials demonstrating that patients receiving pharma- action of NRT products is thought to be a stimula-cotherapy are approximately twice as likely to re- tion of nicotine receptors in the ventral tegmentalmain abstinent long-term (greater than 5 mo) when area of the brain, which results in dopamine releasecompared to patients receiving placebo (Figure 1.2). in the nucleus accumbens. The use of NRT is to re-Although one would argue that pharmacotherapy duce the physical withdrawal symptoms and to al-is costly and might not be a necessary component leviate the physiologic symptoms of withdrawal, soof a treatment plan for each patient, it is the most the smoker can focus on the behavioral and psy-effective known method for maximizing the odds chological aspects of quitting before fully abstainingof success for any given quit attempt, particularly nicotine. Key advantages of NRT are that patientswhen combined with behavioral counseling [112]. are not exposed to the carcinogens and other toxic Currently, seven marketed agents have an FDA- compounds found in tobacco and tobacco smoke,approved indication for smoking cessation in the and NRT provides slower onset of action than nico-US: five nicotine replacement therapy (NRT) for- tine delivered via cigarettes, thereby eliminating themulations (nicotine gum, nicotine lozenge, trans- near-immediate reinforcing effects of nicotine ob-dermal nicotine patches, nicotine nasal spray, and tained through smoking (Figure 1.3). NRT products
  22. 22. 12Table 1.4 FDA-approved medications for smoking cessation. Nicotine replacement therapy (NRT) formulations Bupropion SR Varenicline Chapter 1 Gum Lozenge Transdermal preparations1 Nasal spray Oral inhaler 2 2 2 3 3 2 Nicorette , Generic Commit , Generic Nicoderm CQ Generic Patch Nicotrol NS Nicotrol inhaler Zyban , Generic Chantix3 OTC OTC OTC OTC/Rx Rx Rx Rx Rx 2 mg, 4 mg; 2 mg, 4 mg 24-hour release (formerly Habitrol) Metered spray 10 mg cartridge 150 mg sustained-release 0.5 mg, 1 mg tablet original, FreshMint2, Fruit Chill2, mint 7 mg, 14 mg, 21 mg 24-hour release 0.5 mg nicotine in 50 L delivers 4 mg inhaled tablet Product mint, orange2 7 mg, 14 m g, 21 mg aqueous nicotine solution nicotine vapor ≥25 cigarettes/day: 4 mg 1st cigarette ≤30 minutes after >10 cigarettes/day : >10 cigarettes/day: 1–2 doses/hour 6–16 cartridges/day; 150 mg po q AM × 3 days, Days 1–3: <25 cigarettes/day: 2 mg waking: 4 mg 21 mg/day × 6 weeks 21 mg/day × 4 weeks (8–40 doses/day) individualized dosing then increase to 150 mg 0.5 mg po q AM 1st cigarette >30 minutes after 14 mg/day × 2 weeks 14 mg/day × 2 weeks One dose = 2 sprays (one in pobid Days 4 –7: Week 1–6: waking: 2 mg 7 mg/day × 2 weeks 7 mg/day × 2 weeks each nostril); each spray • Initially, use at least 0.5 mg po bid 1 piece q 1–2 hours delivers 0.5 mg of nicotine to 6 cartridges/day • Do not exceed 300 mg/day Weeks 2–12: Week 7–9: Week 1–6: ≤10 cigarettes/day: ≤10 cigarettes/day: the nasal mucosa 1 mg po bid • Best effects with • Treatment should be 1 piece q 2–4 hours 1 lozenge q 1–2 hours 14 mg/day × 6 weeks 14 mg/day × 6 weeks continuous puffing for initiated while patient is Week 10–12: Week 7–9: 7 mg/day × 2 weeks 7 mg/day × 2 weeks • Maximum • Patients should begin 20 minutes still smoking 1 piece q 4–8 hours 1 lozenge q 2–4 hours – 5 doses/hour therapy 1 week prior to Week 10–12: • Nicotine in cartridge is • Set quit date 1–2 weeks quit date • May wear patch for 16 hours • May wear patch for 16 – 40 doses/day depleted after 20 minutes after initiation of therapy • Maximum, 24 pieces/day 1 lozenge q 4–8 hours • Take dose after eating if patient experiences hours if patient • For best results, initially use of active puffing Allow at least 8 hours • Chew each piece slowly sleep disturbances experiences sleep at least 8 doses/day • with a full glass of water • Maximum, 20 lozenges/day • Patient should inhale into between doses • Park between cheek and (remove at bedtime) disturbances Patients should not sniff, • Dose tapering is not • Allow to dissolve slowly • back of throat or puff in • Avoid bedtime dosing to gum when peppery or (remove at bedtime) swallow, or inhale through necessary (20–30 min) • Duration: 8–10 weeks short breaths minimize insomnia tingling sensation appears Nausea and insomnia are Dosing the nose as the spray is • Do not inhale into the • (~15–30 chews) • Nicotine release may cause • Duration: 8 weeks being administered • Dose tapering is not side effects that are a warm, tingling sensation lungs (like a cigarette) but necessary • Resume chewing when taste Duration: 3 –6 mo usually temporary • “puff’’ as if lighting a pipe or tingle fades • Do not chew or swallow • Can be used safely with • Duration: 12 weeks; an • Open cartridge retains NRT • Repeat chew/park steps until • Occasionally rotate to additional 12 week course potency for 24 hours most of the nicotine is gone different areas of the mouth • Duration: 7–12 weeks, may be used in selected (taste or tingle does not • Duration: up to 6 months with maintenance up to patients • No food or beverages 15 return; generally 30 min) minutes before or during use 6 months in selected • Park in different areas of Duration: up to 12 weeks patients • mouth • No food or beverages 15 min before or during use • Duration: up to 12 weeks • Mouth/jaw soreness • Nausea • Local skin reactions (erythema, pruritus, burning) • Nasal and/or throat irritation • Mouth and/or throat • Insomnia • Nausea • Hiccups • Hiccups • Headache (hot, peppery, or burning irritation • Dry mouth • Sleep disturbances • Dyspepsia • Cough • Sleep disturbances (insomnia) or abnormal/vivid sensation) • Unpleasant taste • Nervousness/difficulty (insomnia, abnormal • Hypersalivation • Heartburn dreams (associated with nocturnal nicotine • Rhinitis • Cough concentrating dreams) • Effects associated with • Headache absorption) • Tearing • Rhinitis • Rash • Constipation incorrect chewing • Flatulence • Sneezing • Dyspepsia • Constipation • Flatulence technique: • Insomnia • Cough • Hiccups • Seizures (risk is 1/1000 • Vomiting Adverse effects Lightheadedness • Headache • Headache [0.1%]) Nausea/vomiting Throat and mouth irritation

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