2. Lung Cancer

3. Lung Cancer
EDITED BY
Jack A. Roth, MD, F.A.C.S.
Professor and Bud Johnson Clinical Distinguished Chair
Department of Thoracic and Cardiovascular Surgery
Professor of Molecular and Cellular Oncology
Director, W.M. Keck Center for Innovative Cancer Therapies
Chief, Section of Thoracic Molecular Oncology
The University of Texas M.D. Anderson Cancer Center
Houston, Texas, USA
James D. Cox, MD
Professor and Head
Division of Radiation Oncology
The University of Texas M. D. Anderson Cancer Center
Houston, Texas, USA
Waun Ki Hong, MD, D.M.Sc. (Hon.)
American Cancer Society Professor
Samsung Distinguished University Chair in Cancer Medicine
Professor and Head, Division of Cancer Medicine
Professor, Department of Thoracic/Head and Neck Medical Oncology
The University of Texas M.D. Anderson Cancer Center
Houston, Texas, USA
THIRD EDITION

4. C 2008 by Blackwell Publishing
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First published 1998
Third edition 2008
1 2008
Library of Congress Cataloging-in-Publication Data
Lung 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]
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5. Contents
Contributors, vii
Preface, 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 Lee
10 Molecular Profiling for Early Detection and Prediction of Response
in Lung Cancer, 153
Jacob M. Kaufman and David P. Carbone
11 The Role for Mediastinoscopy in the Staging of Nonsmall Cell
Lung Cancer, 169
Carolyn E. Reed
12 Minimally Invasive Surgery for Lung Cancer, 180
Michael Kent, Miguel Alvelo-Rivera, and James Luketich
13 Extended Resections for Lung Cancer, 194
Philippe G. Dartevelle, Bedrettin Yildizeli, and Sacha Mussot
v

6. 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

7. Contributors
Miguel Alvelo-Rivera, MD James D. Cox, MD
Assistant Professor of Surgery, Professor and Head, Division of Radiation Oncology
Division of Thoracic Surgery The University of Texas,
University of Pittsburgh Medical Center, M.D. Anderson Cancer Center,
Pittsburgh, PA, USA Houston, TX, USA
Vladimir Badmaev, MD Philippe G. Dartevelle, MD
Vice President, Scientific and Medical Affairs Professor of Thoracic and Cardiovascular Surgery
Sabinsa Pharmaceutical, Inc., at Paris Sud University
New Jersey, NJ, USA Head of the Department of Thoracic
and Vascular Surgery and Heart Lung Tansplantation
Joan E. Bailey-Wilson, PhD ˆ
Hopital Marie Lannelongue Le Plessis
Senior Investigator and Co-Branch Chief, Robinson France
National Human Genome Research Institute,
National Institutes of Health, Burton Dickey, MD
Baltimore, MD, USA Professor and Chair,
Department of Pulmonary Medicine
Benjamin Besse, MD The University of Texas
Assistant Professor, M. D. Anderson Cancer Center
Department of Medicine, Houston, TX, USA
Institut Gustave Roussy,
Villejuif, France Steven M. Dubinett, MD
Professor and Chief
Nishin 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, USA
Professor of Medicine and Cancer Biology,
Vanderbilt-Ingram Cancer Center, Kentya H. Ford, PhD
Nashville, 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, MD
The University of Texas M. D. Anderson Cancer Center, Medical Director, Thoracic Oncology
Houston, TX, USA Multidisciplinary Care Center;
Professor, Department of Thoracic/Head
Thierry Le Chevalier, MD and Neck Medical Oncology
Department of Medicine, The University of Texas,
Institut Gustave Roussy, M.D. Anderson Cancer Center
Villejuif, France Houston, TX , USA
vii

8. viii Contributors
Wilbur A. Franklin, MD Michael Kent, MD
Professor, Department of Pathology, Surgical Resident, Department of
University of Colorado Health Sciences Center, Thoracic Surgery,
Aurora, CO, USA Beth Israel Deaconess Medical Center,
Boston, MA, USA
Adi F. Gazdar, MD
Professor of Pathology and Deputy Director, Fadlo R. Khuri, MD
Hamon 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, USA
Ji-Youn Han, MD, PhD
Chief Scientist, Lung Cancer Branch, Ritsuko Komaki, MD
National Cancer Center Professor, Department of Radiation
Goyang, Gyeonggi, Korea Oncology,
Gloria Lupton Tennison Distinguished
Emer O. Hanrahan, MB, BCh, MRCPI Professorship for Lung Cancer Resarch
Medical Oncology Fellow, The University of Texas,
Department of Thoracic/Head and M. D. Anderson Cancer Center,
Neck Medical Oncology, Houston, TX, USA
The University of Texas M.D. Anderson
Cancer Center,
Jonathan Kurie, MD
Houston, TX, USA
Professor, Department of Thoracic/Head
and Neck Medical Oncology
John Heymach, MD, PhD
The University of Texas,
Assistant Professor,
M.D. Anderson Cancer Center
Department of Thoracic/Head and Neck Medical Oncology
Houston, TX, USA
and Cancer Biology
The 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, Canada
Department of Pharmacy Practice,
Purdue University School of Pharmacy &
Pharmaceutical Sciences, Primo N. Lara Jr, MD
West, Lafavette, Professor of Medicine,
IN, USA University of California Davis
Cancer Center, Sacramento, CA, USA
Minh Huynh, MD
Staff Oncologist Dae Ho Lee, MD
Kaiser 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 Medical
Vanderbilt University School of Medicine Center,
Vanderbilt University Cancer Center, Seoul, Korea
Nashville, TN, USA
Jay M. Lee, MD
Brian D. Kavanagh, MD, MPH Surgical Director, Thoracic Oncology Program
Professor and Vice Chairman, Assistant Professor of Surgery
Department of Radiation Oncology, Division of Cardiothoracic Surgery
University of Colorado Comprehensive Cancer Center, David Geffen School of Medicine at UCLA
Aurora, CO, USA Los Angeles, CA, USA

9. Contributors ix
Jin Soo Lee, MD Sacha Mussot, MD
Director, Thoracic and Vascular Surgeon and Staff Member
Research Institute, Department of Thoracic and Vascular Surgery
National Cancer Center, and Heart Lung Transplantation
Goyang, Gyeonggi, Korea ˆ
Hopital Marie Lannelongue – Le Plessis Robinson – France
Zhongxing Liao, MD Monique B. Nilsson, PhD
Associate 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, USA
Jie Lin, PhD Katherine M.W. Pisters, MD
Instructor, Department of Epidemiology, Professor of Medicine,
The University of Texas M.D. Anderson Cancer Center, Department of Thoracic/Head & Neck Medical
Houston, TX, USA Oncology,
Division of Cancer Medicine,
James D. Luketich, MD
The University of Texas M.D. Anderson Cancer
Sampson Endowed Professor of Surgery;
Center,
and Chief, Heart,
Houston, TX, USA
Lung and Esophageal Surgery Institute,
University of Pittsburgh
Alexander V. Prokhorov, MD, PhD
Medical Center,
Professor, Department of Behavioral Science,
Pittsburgh, PA, USA
The University of Texas M.D. Anderson Cancer
Center,
Thomas J. Lynch
Houston, TX, USA
Chief of Hematology–Oncology,
Massachusetts General Hospital,
Carolyn E. Reed, MD
Boston, 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, USA
University of British Columbia;
and Respiratory Physician, Kenneth E. Rosenzweig, MD
Department of Cancer Imaging, Associate Attending,
BC Cancer Research Centre, Department of Radiation Oncology,
Vancouver, BC, Canada Memorial Sloan–Kettering Cancer Center,
New York, NY, USA
John D. Minna, MD
Professor 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 Surgery
The University of Texas Southwestern Medical Center, Professor of Molecular and Cellular Oncology
Dallas, TX, USA Director, W.M. Keck Center for Innovative Cancer
Therapies
Seyed Javad Moghaddam, MD Chief, Section of Thoracic Molecular Oncology
Instructor, Department of Pulmonary Medicine The University of Texas,
The University of Texas, M.D. Anderson Cancer Center
M.D. Anderson Cancer Center, Houston, TX, USA
Houston, TX, USA
Mitsuo Sato, MD, PhD
James 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

10. x Contributors
Lecia Sequist, MD, MPH Robert D. Timmerman, MD
Instructor in Medicine, Professor and Vice Chairman,
Harvard Medical School, Effie Marie Cain Distinguished Chair
MGH Cancer Center, in Cancer Therapy Research,
Boston, MA, USA Department of Radiation Oncology,
University of Texas
David S. Shames, PhD Southwestern Medical Center,
Postdoctoral Fellow Dallas, TX, USA
Hamon Center for Therapeutic Oncology Research
The University of Texas Southwestern Medical Center, Anne S. Tsao, MD
Dallas, TX, USA Assistant Professor,
Department of Thoracic/Head and
Amir 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, USA
Houston, TX, USA
Suryakanta Velamuri, MD
Sherven 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, USA
UCLA Lung Cancer Research Program,
David Geffen School of Medicine at UCLA, Ignacio I. Wistuba, MD
West Los Angeles VA, Associate Professor of Pathology
Los Angeles, CA, USA and Thoracic/Head & Neck Medical
Oncology,
Alfred R. Smith, PhD The University of Texas
Professor, The University of Texas M.D. Anderson Cancer Center,
M.D. Anderson Proton Therapy Center, Houston, TX, USA
Houston, TX, USA
Xifeng Wu, MD, PhD
Margaret R. Spitz, MD, MPH Professor, Department of Epidemiology,
Professor and Chair, The University of Texas
Department of Epidemiology, M.D. Anderson Cancer Center,
The University of Texas Houston, TX, USA
M.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

11. Preface
When the first edition of Lung Cancer was pub- high risk for developing lung cancer. This will be
lished 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 for
would 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 techniques
the biology, prevention, diagnosis, and treatment have been developed which will make local tumor
of lung cancer convinced us that a third edition control more effective and less invasive. Combined
was warranted. This book is not intended as a com- modality therapy and new chemotherapeutic agents
prehensive 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 final
ment 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 are
oncogenic pathways in the lung cancer cell and possible because of the work of those dedicated
can mediate tumor regression with fewer adverse to translational research and rigorously conducted
events. Several chapters are devoted to summariz- clinical trials. We are optimistic that progress will
ing the most recent work in this field. Much research continue at a rapid pace and that deaths from lung
is attempting to identify biomarkers to predict a cancer will continue to decrease.
Jack A. Roth
James D. Cox
Waun Ki Hong
xi

12. CHAPTER 1
Smoking Cessation
Alexander V. Prokhorov, Kentya H. Ford, and Karen Suchanek Hudmon
Overview resulting in nearly 440,000 deaths each year [3].
The economic implications are enormous: more
Tobacco use is a public health issue of enormous than $75 billion in medical expenses and over $81
importance, 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 year
knowledge has been gained with respect to biobe- [4–8]. While the public often associates tobacco use
havioral 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 Surgeon
sation provides extensive health benefits for every- General’s Report on the health consequences of
one. 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 (Table
aids for cessation. The US Public Health Service Clin- 1.1). In 2000, 8.6 million persons in the United
ical 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 cumulative
encouraged 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 cancer
More than two decades ago, the former US Surgeon
General C. Everett Koop stated that cigarette smok- In the United States, approximately 85% of all
ing is the “chief, single, avoidable cause of death in lung cancers are in people who smoke or who
our society and the most important public health have smoked [3]. Lung cancer is fatal for most
issue of our time” [1]. This statement remains true patients. The estimated number of deaths of lung
today. In the United States, cigarette smoking is the cancer will exceed 1.3 million annually early in the
primary known cause of preventable deaths [2], third millennium [12]. Lung cancer is the leading
cause of cancer-related deaths among Americans
Lung Cancer, 3rd edition. Edited by Jack A. Roth, James D. Cox,
of both genders, with 174,470 estimated newly
and Waun Ki Hong. c 2008 Blackwell Publishing, diagnosed cases and 162,460 deaths [13,14]. The
ISBN: 978-1-4051-5112-2. number of deaths due to lung cancer exceeds the
1

13. 2 Chapter 1
Table 1.1 Health consequences of smoking. annual number of deaths from breast, colon, and
prostate cancer combined [15]. Recent advances in
Cancer 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, premetastasis
Cardiovascular Abdominal aortic aneurysm
stage treatment [17]. Prevention of lung cancer
diseases 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 established
Pulmonary Acute respiratory illnesses in longitudinal studies, one of which lasted as long
diseases 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 development
effects 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 of
Other 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 the
Source: Reference [9].

14. Smoking Cessation 3
same amount as men experience twice the risk of Smoking among lung
developing lung cancer [28,29]. cancer patients
Tobacco use among patients with cancer is a se-
Second-hand smoke and rious health problem with significant implications
lung cancer for morbidity and mortality [36–39]. Evidence in-
dicates that continued smoking after a diagnosis
While 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], risk
hand smoke contains the same carcinogens that are of second primary malignancy [42], and increases
inhaled 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, and
hand 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 one
quarter of the US population is exposed to second- third of cancer patients who smoked prior to their
hand 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 nonsmall
States [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 resumed
ing to Glantz and colleagues, for every eight smok- regular smoking after surgical treatment of lung
ers 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 positive
smoke exposure [35]. smoking history at and after diagnosis is high.
Since 1986, numerous additional studies have Patients who are diagnosed with lung cancer may
been conducted and summarized in the 2006 US face tremendous challenges and motivation to quit
Surgeon General’s report on “The Health Conse- after a cancer diagnosis can be influenced by a range
quences of Involuntary Exposure of Tobacco Smoke.” The of psychological variables. Schnoll and colleagues
report’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 relatives
lung 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. Lung
20 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 that
nonsmokers, 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 special
sure 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 of
other 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

15. 4 Chapter 1
Table 1.2 Percentage of current cigarette smokersa aged ≥18 years, by selected characteristics—National Health
Interview 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 13.3
Educationd 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 7.1
Age 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 8.6
Poverty levelf At or above 23.7 17.6 20.6
Below 34.3 26.9 29.9
Unknown 21.2 16.1 18.4
Total 23.9 18.1 20.9
a
Persons who reported having smoked at least 100 cigarettes during their lifetime and at the time of the interview reported
smoking 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 Americans
clear 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 smoking
Forms of tobacco varies considerably across populations (Table 1.2),
with a greater proportion of men (23.9%) than
Smoked 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 exhibit
clining 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 across
ing former smokers [3]. However, a considerable the United States, ranging from 11.5% in Utah to

16. Smoking Cessation 5
28.7% in Kentucky [51]. Twenty-three percent of less tobacco than standard cigarettes, bidis expose
high school students report current smoking, and their smokers to considerable amounts of hazardous
among 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 amount
These figures are of particular concern, because of carbon monoxide and nicotine and almost five
nearly 90% of smokers begin smoking before the times the amount of tar found in conventional
age of 18 years [53]. cigarettes [63].
Other common forms of burned tobacco in the
United States include cigars, pipe tobacco, and bidis. Smokeless tobacco
Cigars represent a roll of tobacco wrapped in leaf to- Smokeless tobacco products, also commonly called
bacco 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. Spit
past 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 in
cents’ experimentation with cigars [56]. In 1998, the cheek or lower lip. Snuff, commonly available as
approximately 5% of adults had smoked at least one loose particles or sachets (resembling tea bags), has
cigar in the past month [57]. The nicotine content a much finer consistency and is generally held in
of cigars sold in the United States ranged from 5.9 the mouth and not chewed. Most snuff products
to 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 snuff
and 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 typically
entire pack of cigarettes is able to deliver enough sniffed or inhaled through the nostrils; it is used less
nicotine 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 past
past 50 years [60]. It is a form of tobacco use seen month. Men used it at higher rates (5.8%) than
among less than 1% of Americans [60]. Bidi smok- women (0.3%) [60]. The prevalence of spit tobacco
ing 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, Alaska
ported 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 by
the 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 where
ticularly attractive to younger smokers. A survey smoking is banned.
of nearly 64,000 people in 15 states in the United
States revealed that young people (18–24 years of
age) reported higher rates of ever (16.5%) and Factors explaining tobacco use
current (1.4%) use of bidis then among older adults
(ages 25 plus years). With respect to sociodemo- Smoking initiation
graphic characteristics, the use of bidis is most com- In the United States, smoking initiation typically
mon among males, African Americans, and con- occurs during adolescence. About 90% of adult
comitant cigarette smokers [62]. Although featuring smokers have tried their first cigarette by 18 years

17. 6 Chapter 1
of 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. Nicotine
preventions 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 pleasure
month 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 tension
venting initiation of tobacco use and assisting young (β-endorphin and GABA) [78]. Upon entering the
smokers 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 the
personal, and environmental factors have been ex- brain that elicits feelings of pleasure and stimulates
amined as potential predictors of tobacco exper- the release of dopamine.
imentation and initiation of regular tobacco use Although withdrawal symptoms are not the only
among 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 many
Other 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 nicotine
ative affect, outcome expectations associated with [53]. This rapid dose-response, along with the short
smoking, resistance skills (self-efficacy), engaging in half-life of nicotine (t 1/2 = 2 h), underlies tobacco
other risk-taking behaviors, exposure to smoking in users’ frequent, repeated administration, thereby
movies, 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 nicotine
in identifying predictors of smoking initiation, few levels throughout the day to avoid withdrawal
studies have identified successful methods for pro- symptoms, to maintain pleasure and arousal, and
moting cessation among youth, despite the finding to modulate mood. Withdrawal symptoms include
that 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 heart
addictive 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 per
tive substance. Judging by the current diagnostic cri- day for many years [83,84]. Chippers do not tend
teria, tobacco dependence appears to be quite preva- to differ from other smokers in their absorption and
lent among cigarette smokers; more than 90% of metabolism of nicotine, causing some investigators
smokers meet the DSM-IV (Diagnostic and Statisti- to suggest that this level of consumption may be too
cal Manual of Mental Disorders) criteria for nicotine low to cause nicotine dependence. However, these
dependence [76]. Research has shown that nico- atypical smokers are usually eliminated from most

18. Smoking Cessation 7
studies, which are routinely limited to smokers of smoked, number of cigarettes smoked per day) will
at 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 not
ported 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 their
dependence [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 parents
nicotine 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 correlation
dence 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 consumed
use tobacco regularly, tend to exhibit high craving [90]. In recent years, it has become more difficult
for cigarettes and substantial levels of withdrawal to conduct adoption studies, because of the reduced
symptoms [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 and
dependence might lead to an overestimation of genetic effects
if early environmental influences are attributed to
As early as 1958, Fisher hypothesized that the link genetic influences [92].
between smoking and lung cancer could be ex- In twin studies, identical (monozygotic) twins
plained 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% of
More 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 to
toward 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 tobacco
result from an interplay of many factors (includ- use, one would expect to see a greater proportion
ing 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 is
to 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 the
it 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 largely
fluences 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 identical
demiologists 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 variance
if a genetic link for tobacco use exists, then tobacco in smoking appears to be attributable to genetic
use behaviors (e.g., smoking status, number of years factors.

19. 8 Chapter 1
Recent advances in the mapping of the human metabolism via the cytochrome P450 liver enzymes
genome have enabled researchers to search for (specifically, CYP2A6 and CYP2D6).
genes associated with specific disorders, including In summary, each of these types of study designs
tobacco use. Using a statistical technique called link- supports the hypothesis that genetics influence the
age 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, level
prior 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 given
disorder is coinherited with markers found in spec- that there are many predictors of tobacco use and
ified chromosomal regions. Typically, these types dependence, of which genetic predisposition is just
of 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 for
tance of the trait or disorder. This method works early identification of individuals who are at risk
well 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 for
multiple genes have an impact, such as with to- improving our treatment for dependence [91]. If
bacco use. In linkage studies of smoking, it is com- genetic research leads to new knowledge regarding
mon for investigators to identify families, ideally the mechanisms underlying the development and
with 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 we
other 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 best
sign 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 health
undergoes genotyping to obtain information about outcome with pharmacologic treatments, with a
the study participant’s unique genetic code. If a goal of determining which genetic profiles respond
gene in a specific region of a chromosome is as- most favorably to specific pharmaceutical aids for
sociated 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 increased
odds 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 the
provide insight into which genes might be promis- health consequences of smoking, released in 1990
ing “candidates” as contributors to tobacco use and and 2004, summarize abundant and significant
dependence. Currently, there are two general lines health benefits associated with giving up tobacco
of 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 improvements
dynamics (the way that nicotine affects the body) in pulmonary function and circulation. Within
and the other examines genes that affect nicotine 1–9 months of quitting, the ciliary function of
pharmacokinetics (the way that the body affects the lung epithelium is restored. Initially, patients
nicotine). A long list of candidate genes are being might experience increased coughing as the lungs
examined—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 results
those related to dopamine synthesis, receptor acti- in measurable improvements of lung function. Over
vation, reuptake, and metabolism) and (b) nicotine time, patients experience decreased coughing, sinus

20. Smoking Cessation 9
congestion, fatigue, shortness of breath, and risk for positive influence on survival rates. Although many
pulmonary 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 indicate
half that of continuing smokers. After 5–15 years, that there can be substantial medical benefits for
the 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 of
dying of lung cancer is approximately half that of Smoking cessation interventions
continuing 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 risk
15 years after quitting, a risk for coronary heart dis- of smoking-related disease [110]. Recognizing the
ease is reduced to a rate similar of that of people who complexity of tobacco use is a necessary first step
have never smoked. Smoking cessation can also lead in developing effective interventions and trials for
to a significant reduction in the cumulative risk for cessation and prevention. The biobehavioral model
death 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 tobacco
to those who continue to smoke [105]. Ossip-Klein use and addiction (Figure 1.1). These factors in turn
et al. [106] recently named tobacco use a “geriatric mediate dependence, cessation, and relapse in most
health issue.” Indeed, a considerable proportion of individuals, and treatment has been developed to
tobacco 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 the
tobacco health hazards. Elderly smokers frequently The health care provider’s role
claim that the “damage is done,” and it is “too late and responsibility
to quit;” however, a considerable body of evidence Health care providers are uniquely positioned to
refutes these statements. Even individuals who assist patients with quitting, having both access to
postpone quitting until age 65 can incur up to four quitting aids and commanding a level of respect that
additional 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, physicians
smokers 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 cessation
remember that it is never too late to advise their treatment. Although less attention has been paid to
elderly 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 serve
tinued smoking after a diagnosis of cancer has the public and situated to initiate behavior change
substantial adverse effects. For example, these among patients or complement the efforts of other
studies indicate that smoking reduces the over- providers [64,111].
all effectiveness of treatment, while causing com- Fiore and associates conducted a meta-analysis
plications with healing as well as exacerbating of 29 investigations in which they estimated that
treatment 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 receive
all survival rates [36–38,107–109]. On the other a tobacco cessation intervention from a physician
hand, the medical, health, and psychosocial bene- clinician or a nonphysician clinician are 2.2 and
fits of smoking cessation among cancer patients are 1.7 times as likely to quit smoking at 5 or more
promising. Gritz et al. [37] indicated that stopping months postcessation, respectively [112]. Although
smoking prior to diagnosis and treatment can have a brief advice from a clinician has been shown to

21. 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
• Nutrition
Figure 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 social
should 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 care
in 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 to
line 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-up
view 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-up
sist health care providers in delivering smoking (Table 1.3). Due to the possibility of relapse, health
cessation treatment. The Guideline emphasizes the care providers should also provide patients with
importance 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, reviews
brief 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’s
cotherapy, 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 refer
smoking cessation treatment, either alone or in con- these patients to other resources for quitting, such
junction with pharmacotherapy. These interven- as a toll-free tobacco cessation quitline (1-800-QUIT
tions, which include a variety of methods ranging NOW, in the US).

22. Smoking Cessation 11
Table 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
date
5 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 setting
Adapted 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 therapy
apy agents for cessation except in the presence of In clinical trials, patients who use NRT products are
special circumstances. These recommendations are 1.77 times as likely to quit smoking than are those
supported by the results of more than 100 controlled who receive placebo [7]. The main mechanism of
trials 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 tegmental
main abstinent long-term (greater than 5 mo) when area of the brain, which results in dopamine release
compared 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, so
of 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 abstaining
of success for any given quit attempt, particularly nicotine. Key advantages of NRT are that patients
when 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 the
mulations (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

23. 12
Table 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