Progress

Review

Groups

Report of the Lung Cancer 

Progress Review Group 

August 2001
Report of the Lung Cancer 

Progress Review Group

August 2001 
From the Leadership 

We are pleased to present this Report of the Lung Cancer Progress Review Group (PRG). The 

PRG enthusiastically accepted its charge to identify scientific priorities and needs and create a 

national agenda for research on lung cancer, and we believe that this report provides a 

compelling strategy for progress against this disease. 

Rather than propose a long list of recommendations, the PRG has identified five areas of 

research that will transform the prevention, diagnosis, and treatment of individuals with lung 

cancer. We believe that these areas truly represent the highest priorities in the field. In addition, 

we encourage the continued support and refinement of ongoing initiatives that affect lung cancer 

research and quality of life. 

Despite advances in our understanding of the causes, prevention, and treatment of cancer, 

progress against lung cancer has been slow. We appreciate the NCI’s decision to institute a PRG 

to address this challenging disease, and we look forward to assisting the NCI in implementing 

the PRG’s recommendations and to following their progress. 

John C. Ruckdeschel, M.D. Margaret R. Spitz, M.D., M.P.H. Scott Saxman, M.D. 

Co-Chair Co-Chair Executive Director 

Lung Cancer Lung Cancer Lung Cancer 

Progress Review Group Progress Review Group Progress Review Group 
We the undersigned members of the Lung Cancer Progress Review Group concur with the 

enclosed report. 

Margaret R. Spitz, M.D., M.P.H. John C. Ruckdeschel, M.D.

Co-Chair Co-Chair

The University of Texas H. Lee Moffitt Cancer Center and Research

M.D. Anderson Cancer Center Institute, University of South Florida

Scott Saxman, M.D. 

Executive Director

National Cancer Institute

Alex Adjei, M.D., Ph.D. Carolyn Aldige 

Mayo Clinic Cancer Research Foundation of America

Dileep Bal, M.D., M.S., M.P.H. Stephen Baylin, M.D. 

California Department of Health Services Johns Hopkins School of Medicine

Paul Bunn, Jr., M.D. Neil Caporaso, M.D. 

University of Colorado Cancer Center National Cancer Institute

Neil Clendeninn, M.D., Ph.D. Walter J. Curran, Jr., M.D. 

Agouron Pharmaceuticals, Inc. 

Virginia L. Ernster, Ph.D. 

Bodine Center for Cancer Treatment, Philadelphia 

William Evans, M.D. 

University of California, San Francisco Cancer Care Ontario

School of Medicine

Dorothy Hatsukami, Ph.D. Stephen S. Hecht, Ph.D. 

University of Minnesota Medical School University of Minnesota Cancer Center 
We the undersigned members of the Lung Cancer Progress Review Group concur with the 

enclosed report. 

Waun Ki Hong, M.D. 

The University of Texas 

M.D. Anderson Cancer Center 

David H. Johnson, M.D. 

Vanderbilt University Medical Center 

John D. Minna, M.D.

The University of Texas Southwestern

Medical Center

Edward F. Patz, Jr., M.D.

Duke University Medical Center 

Franklyn G. Prendergast, M.D., Ph.D. 

Mayo Clinic 

Joan Schiller, M.D. 

University of Wisconsin Medical School 

Sudhir Srivastava, Ph.D., M.P.H. 

National Cancer Institute 

David F. Yankelevitz, M.D. 

Cornell University 

James Jett, M.D. 

Mayo Clinic 

Elizabeth Layne, D.D.S., M.S.D. 

Alliance for Lung Cancer Advocacy, Support, 

and Education (ALCASE) 

Cherie Nichols, M.B.A. 

National Cancer Institute 

Jennifer Pietenpol, Ph.D. 

Vanderbilt University School of Medicine 

Valerie W. Rusch, M.D. 

Memorial Sloan-Kettering Cancer Center 

Peter G. Shields, M.D. 

Georgetown University Medical Center 

Melvyn Tockman, M.D., Ph.D. 

H. Lee Moffitt Cancer Center and Research 

Institute, University of South Florida 
Acknowledgments

The Report of the Lung Cancer Progress Review Group (PRG) is the product of 10 months of 

intense work that drew upon the combined skills and efforts of many. The PRG leadership 

extends special thanks to the following people: 

• The researchers, clinicians, and members of the advocacy community who participated in the 

Lung Cancer Roundtable Meeting in April 2001. The recommendations of the PRG are 

drawn from their insight and expertise. 

• Gerold Bepler, Ethan Dmitrovsky, Craig Earle, Wilbur Franklin, Tom Glynn, Paul 

Gumerlock, Curtis Harris, Fred Kadlubar, and Thomas Smith, who served as co-chairs for 

breakout sessions at the Roundtable meeting. Working alongside the PRG members, these 

individuals were instrumental in planning the breakout sessions and formulating the breakout 

session reports. We are greatly indebted to them for their tireless efforts. 

• Staff at the NCI Office of Science Planning and Assessment, particularly Kate Nagy, Terri 

Hallquist, Jim Corrigan, and Annabelle Uy, who provided strong guidance, technical support, 

and adept handling of diverse interests throughout the PRG process. 

• Lead writer Barbara Shapiro, who worked closely with us for months to draft and edit this 

unified report, and the team of expert science writers who worked diligently with us at the 

Roundtable to produce the early drafts of the report. 

• Josette Johnson, Syreeta Tate, Rob Wald, and their colleagues at Palladian Partners, who 

provided exceptionally efficient logistical support to the PRG. 

• Dr. Harold Moses, for his inspiring words to the Roundtable participants. 

Finally, we offer our sincerest thanks to the members of the Lung Cancer PRG. This report is a 

testament to their expertise, insight, and dedication. 
Table of Contents

Executive Summary ...........................................................1

Report of the Lung Cancer Progress Review Group ................................3

Overall State of the Science ..........................................3

Structure and Process of the Lung Cancer PRG ..........................5

Top-Priority Recommendations .......................................6

Other Key Recommendations ........................................9

Conclusion ......................................................10

Appendices 

Appendix A: About the National Cancer Institute’s Progress Review Groups . . 13

Appendix B: Breakout Reports

Biology ...................................................15

Chemoprevention ...........................................19

Early Detection and Diagnosis ................................23

Etiology ..................................................26

Prognosis and Staging .......................................31

Quality of Care .............................................34

Therapy ..................................................39

Tobacco Control ...........................................45

Appendix C: Lung Cancer Progress Review Group Roster ................51

Appendix D: Lung Cancer PRG Roundtable Participants .................53
Executive Summary
Executive Summary 

Lung cancer is the leading cause of cancer groups that transcend their individual 

death for both men and women in the United agendas. Those recommendations are: 

States, killing more people than breast, 

prostate, colon, and pancreas cancers • Foster the creation of scientifically 

combined: Fully 85 percent of patients who integrated, multi-disciplinary, multidevelop lung cancer die from it. We are still institutional research consortia (Lung 

largely ignorant of the molecular events Cancer Consortia; LCC) organized 

underlying the development of lung cancer around the problem of lung cancer rather 

and the mechanisms of resistance to drug than around specific research disciplines. 

and radiation therapy; no agent has been The support and development of 

found useful in the prevention of lung dedicated academic investigators who 

cancer; and the benefits of lung cancer speak a common language across basic 

screening and early detection are mired in science, translational science, and 

controversy. With half of all lung cancers in clinical and population-based studies are 

the United States now diagnosed in former key to the success of this initiative. The 

smokers, it is a sobering reality that tobacco need for such organizations was 

control will ameliorate but not, in the articulated by most of the breakout 

foreseeable future, eliminate the problem of groups, and they are the highest priority 

lung cancer. Yet we have funded lung of the Lung Cancer PRG. 

cancer research far below the levels that 

characterize other common malignancies • Develop and expand new approaches to 

and far out of proportion to its massive the biology and treatment of nicotine 

public health impact. addiction and mount studies to explore 

the differential toxicity of various 

In October 2000, the National Cancer tobacco products, including so-called 

Institute (NCI) convened the Lung Cancer “safer” or low-tar cigarettes. 

Progress Review Group (PRG) to identify 

high-priority areas of research that have the • Facilitate and hasten the evaluation of 

potential to reduce the great toll of this spiral computed tomography scanning as 

disease through advances in prevention, an effective means of detecting lung 

diagnosis, and treatment. The PRG’s 30 cancer early, reversing the current stage 

members—expert clinicians, scientists, distribution at presentation, and reducing 

industry representatives, and consumer mortality from lung cancer. 

advocates—met in January 2001 to select 

topics for a Roundtable PRG meeting in • Elucidate the contributions of injury, 

April 2001. Eight topics were explored in inflammation, and infection to the 

detail in breakout group sessions. The genesis of lung cancer. 

breakout groups produced detailed reports 

on all eight topics, which are appended to • Design, implement, and study “best 

the main PRG report. practices” in lung cancer management. 

The main report of the Lung Cancer PRG • Facilitate and encourage training 

highlights the overarching priorities programs that emphasize multiidentified by the eight Roundtable breakout disciplinary scientific investigation and 

state-of-the-art clinical care. 

Executive Summary 1 
The Lung Cancer PRG also made a number 

of recommendations that could be addressed 

effectively by ongoing initiatives at NCI, 

through strengthening of their lung cancer 

focus. Accordingly, the PRG strongly 

supports the continuation or, where 

necessary, the enhancement of programs 

related to bioinformatics, animal models, 

molecular profiling, study of special 

populations, tissue and data repositories, 

drug development and clinical trials 

infrastructures, and Centers of Excellence in 

Communications. 

2 Report of the Lung Cancer Progress Review Group 
Report of the Lung Cancer 

Progress Review Group
Report of the Lung Cancer Progress Review Group

OVERALL STATE OF THE SCIENCE 

Lung cancer presents a series of unique 

problems related to the virulence of the 

cancer itself and the response of the 

medical, scientific, and lay communities to 

its devastating impact on society. The lung 

defines our ability to breathe, and the loss of 

this capacity is one of the most frightening 

of all medical symptoms. Because it is a 

disease primarily of older patients who have 

smoked, lung cancer's negative impact on 

breathing compounds the concurrent effects 

of chronic smoking-related obstructive 

pulmonary disease and coronary artery 

disease. 

Since peaking in 1984, the U.S. age-adjusted 

lung cancer incidence has decreased by 

more than 19 percent in men of all ages 

combined, with decreases since 1970 

exceeding 40 percent among men less than 

age 55 years. Among women, rates 

continued to increase until recently and are 

now showing signs of leveling off. These 

trends largely reflect changes in smoking 

prevalence, which began to decline first 

among men and only later among women. 

Because 85 to 90 percent of lung cancer is 

attributable to smoking, lung cancer rates 

will continue to decline only if smoking 

prevalence declines further. 

The scope of the problem, however, remains 

enormous: 

1. Lung cancer is the leading cause of 

cancer death for both men and women 

and kills more patients than the next five 

most common cancers combined. Fully 

85 percent of patients who develop lung 

cancer die from it. 

2. In 2001, an estimated 169,500 

Americans will be diagnosed with lung 

cancer. Lung cancer represents 13 

percent of all incident cancers annually 

in the United States and 29 percent of all 

cancer deaths. 

3. Although lung cancer mortality rates 

began to decline in 1990 for men (about 

1.7 percent per year) and the 1-year 

relative survival rate for lung cancer 

overall has increased from 34 percent in 

1975 to 41 percent in 1996, mortality 

rates for women continued to increase at 

least until 1998. 

4. Since the 1980s, more women have died 

from lung cancer than from breast 

cancer—previously the major cause of 

cancer deaths in women. 

5. Even patients with the earliest surgical 

stage (T1N0) have disseminated disease 

between 15 and 30 percent of the time. 

6. Although the link to tobacco is the 

clearest etiologic relationship for a 

human cancer, the development of lung 

cancer in persons who have never 

smoked and in former smokers and the 

failure of the majority of heavy smokers 

to develop the disease are poorly 

understood. The complex interrelationships among genetic, molecular, 

and other biologic processes in 

modulating the carcinogenic response to 

tobacco smoke need to be further 

explored. 

7. Chemotherapy, surgery, and radiation 

therapy have had a modest effect on 

patient outcomes, but these are more 

often expressed as improvements in 

“time to progression” or short-term 

survival than as overall survival. The 

mechanisms of resistance to drug and 

radiation therapy are poorly understood. 

Report of the Lung Cancer Progress Review Group 3 
8. Despite significant progress, the 

molecular events underlying the 

development of lung cancer are largely 

unknown. 

9. No chemopreventive agent has been 

shown to be effective in the prevention 

of lung cancer, and there is often brisk 

debate about whether there are any 

proven means of diagnosing lung cancer 

early. 

If the disease itself were not malignant 

enough, we as scientists, clinicians, patients, 

and lay people have made the problem 

worse: 

1. We have allowed a “blame the victim” 

mentality to permeate our dealings with 

those who contract the illness through 

their smoking behaviors, denying them, 

in the process, much of the social 

support we routinely provide for patients 

with other cancer diagnoses. This has 

hindered the development of effective, 

broadly based advocacy efforts. 

2. We have allowed a pervasive sense of 

“therapeutic nihilism” to dominate the 

public and scientific discussion of lung 

cancer. The small (2 to 4 percent) 

changes in time to progression and 

survival that we frequently celebrate for 

patients with other cancers tend to be 

dismissed as irrelevant when we observe 

them in lung cancer trials. 

3. Our health care system is poorly 

organized to deal with lung cancer, 

leaving surgeons, radiotherapists, 

medical oncologists, pulmonologists, 

diagnostic radiologists, and pathologists 

working in completely separate clinical 

settings. This has resulted in suboptimal 

patterns of referral and staging in most 

communities and many academic 

centers. 

This “Balkanization” of the health care 

delivery system for patients with lung 

cancer results, in large measure, from 

the nature and content of the disciplinebased training programs. For example, 

the emphasis on cardiac surgery in most 

cardiothoracic training programs over 

the past two decades has left us with 

only a few hundred “general” thoracic 

surgeons who are skilled in, and 

committed to, the unique issues 

surrounding surgery for lung cancer. 

The concepts of multi-disciplinary care 

and interdisciplinary respect are given 

insufficient attention in many, if not 

most, training programs. 

4. We have funded lung cancer research far 

below the levels that characterize other 

common malignancies and far out of 

proportion to its massive public health 

impact. Support for lung cancer 

research has been insufficient, given that 

lung cancer is the leading cause of 

cancer mortality. There are few nonNCI sources of funding, whether Federal 

or non-Federal, to buttress NCI spending 

on lung cancer. 

5. There is no question that smoking has 

had an enormous negative impact on the 

health of the nation and that reducing 

tobacco use is one of our highest public 

health priorities. It is imperative that we 

enhance our understanding of smoking 

prevention and treatment, the effects of 

exposure to tobacco smoke, and 

tobacco-related carcinogenesis. On the 

other hand, even if we were to be 

successful in eradicating smoking today, 

we would still have decades of lung 

cancer to treat among former smokers. 

Therefore, it is also imperative that we 

continue to explore new treatment 

strategies and approaches to improve 

survival in patients who develop lung 

cancer. We must also continue to 

4 Report of the Lung Cancer Progress Review Group 
enhance our understanding of the 

biology of lung cancer so that these 

findings can be brought to bear on 

improving our diagnostic, preventive, 

and therapeutic approaches to lung 

cancer. 

STRUCTURE AND PROCESS OF THE 

LUNG CANCER PRG 

With these compelling issues in mind, the 

National Cancer Institute (NCI) convened 

the Lung Cancer Progress Review Group 

(PRG) in October 2000 to identify highpriority areas of research that could advance 

progress against lung cancer in the next 5 to 

10 years. The PRG was composed of 30 

expert clinicians, scientists, industry 

representatives, and consumer advocates. 

At a Planning Meeting held in January 2001, 

the Lung Cancer PRG organized a 

Roundtable to consider progress and identify 

research needs. The group selected the key 

topics to be explored in detail in breakout 

sessions and identified potential Roundtable 

participants whose expertise spanned the 

continuum of research. PRG members also 

served as co-chairs for the Roundtable 

breakout sessions. 

The Lung Cancer PRG Roundtable met 

April 16–18, 2001, in Chantilly, Virginia, 

with approximately 110 participants. The 

following eight topics were covered in the 

breakout sessions: 

• Biology 

• Chemoprevention 

• Detection and Diagnosis 

• Etiology 

• Prognosis and Staging 

• Quality of Care 

• Therapy 

• Tobacco Control 

Participants in the Roundtable were selected 

on the basis of their expertise in the field of 

lung cancer. Because of the limited number 

of basic and clinical research programs 

focused on lung cancer, scientists with 

molecular biology and signal transduction 

expertise who were not specifically working 

in the area of lung cancer were recruited to 

ensure the broadest possible perspective. 

To facilitate in-depth discussion at the 

Roundtable, participants spent most of the 

meeting in a single breakout session. 

However, to focus the starting point for each 

breakout group, an initial session was held 

in which clusters of the groups met together 

to review the science common to their areas 

and to begin the process of coalescing areas 

of discussion. The three clusters were: 

• Biology, Etiology, Chemoprevention 

• Prognosis and Staging, Quality of Care, 

Therapy 

• Detection and Diagnosis, 

Tobacco Control 

In addition, a shorter afternoon breakout 

session was scheduled with the same 

breakout topic areas and co-chairs, to allow 

participants to choose another area of 

interest. This session was designed to 

enable cross-fertilization of creative ideas 

across the group and to assist in identifying 

cross-cutting themes. 

In support of the priority-setting process, 

NCI provided the Roundtable participants 

with analyses of its lung cancer research 

portfolio and extensive information about 

ongoing NCI initiatives and activities that 

might address some of the needs of the field. 

This report is the result of the PRG’s 10-

month effort. The main report highlights the 

overarching themes from the Roundtable 

breakout groups that transcend individual 

breakout group agendas and cut across 

disciplines. Notably, the group made 

several recommendations related to research 

Report of the Lung Cancer Progress Review Group 5 
or resource needs that are unique to lung 

cancer; these are the highest priority 

recommendations put forward by the PRG. 

The group also made a number of 

recommendations that other PRGs have 

made or that may be addressed by existing 

NCI initiatives. We strongly support the 

continuation of these initiatives and the 

extension of their focus, where necessary, to 

include lung cancer. 

TOP-PRIORITY 

RECOMMENDATIONS 

It is important to note that the following 

recommendations are all considered major 

priorities of the Lung Cancer PRG. The 

order in which they are presented does not 

represent a priority ranking. 

Cross-Disciplinary Lung Cancer Consortia 

Recommendation: Foster the creation of 

scientifically integrated, multi-disciplinary, 

multi-institutional research consortia 

organized around the problem of lung 

cancer rather than around specific research 

disciplines. The support and development of 

dedicated academic investigators who speak 

a common language across basic science, 

translational science, and clinical and 

population-based studies are key to the 

success of this initiative. The need for such 

organizations was articulated by most of the 

Roundtable breakout groups, and the 

formation of these groups is one of the 

highest priorities of the Lung Cancer PRG. 

The Roundtable breakout groups all 

recognized the growing inability of lung 

cancer clinicians to participate meaningfully 

in translational and clinical research, given 

the fiscal constraints at most major medical 

centers. Furthermore, each area of research 

focus at NCI and the American Cancer 

Society currently has its own study group to 

advance knowledge within a discipline or to 

translate it to the clinical setting. The result 

is that lung cancer clinicians and researchers 

work in relative isolation and are dissipated 

across multiple research groups; no “critical 

mass” of scientific experts working together 

exists to conduct the large-scale research 

studies and clinical trials that are currently 

needed. 

The PRG envisions the creation of formal, 

funded Lung Cancer Consortia (LCC) using 

the existing Lung Cancer SPORES as core 

or affiliate members. The membership of 

the LCC could also include other interested 

collaborators from NCI initiatives, such as 

the Director’s Challenge, Early Detection 

Research Network, and Mouse Models of 

Human Cancer Consortium, as well as other 

institutions at which the study, treatment, 

and prevention of lung cancer are a priority. 

The Lung Cancer SPORES currently 

collaborate with one another on a variety of 

basic and translational research initiatives; 

the LCC would extend this focus to clinical, 

behavioral, and population-based research. 

In organization and activity, the LCC would 

closely resemble the former NCI-sponsored 

Lung Cancer Study Group (LCSG), which 

was active from 1977 to 1988 and brought 

together thoracic surgeons, radiation and 

medical oncologists, pathologists, 

radiologists, pulmonologists, and basic 

scientists, all of whom contributed their 

expertise to the problem of lung cancer. 

Strong and active LCC would offer a 

number of advantages: 

• They would provide a ready-made 

infrastructure through which large-scale 

clinical trials, including 

chemoprevention and screening trials, 

could be rapidly and efficiently 

conducted. 

• They would facilitate the conduct of 

interdisciplinary studies, such as those 

built around the 

biology/behavior/exposure continuum. 

6 Report of the Lung Cancer Progress Review Group 
• They would allow ongoing initiatives to 

be carried out in a more focused and 

relevant way. 

• They would foster collaboration among 

diverse lung cancer experts, particularly 

those involved in lung cancer etiology, 

prevention, and treatment, as well as 

researchers with an interest in end of life 

care. 

• They would greatly facilitate clinician 

participation in lung cancer research 

activities. 

• They would promote faster study of 

preventive and therapeutic approaches 

unique to lung cancer. 

• They would facilitate large-scale 

epidemiologic investigations and 

population-based studies of smoking 

intervention and nicotine addiction. 

These kinds of studies are not currently 

in the portfolio of the traditional 

Cooperative Groups. The current 

Cooperative Group mechanism separates 

the relatively small number of lung 

cancer clinicians and researchers by 

institution rather than by specific focus 

on lung cancer. 

This concept, as well as interactions among 

the SPORES, LCC, and NCI, could be 

further enhanced by organizing meetings, 

workshops, and consensus conferences that 

specifically address multi-disciplinary lung 

cancer research themes. 

Tobacco Control 

Recommendation: Develop and expand 

new approaches to the biology and treatment 

of nicotine addiction and mount studies to 

explore the differential toxicity of various 

tobacco and nicotine products, including 

cigarettes that purport to reduce tobacco 

toxin exposure (so-called "safe" or low-tar 

cigarettes). 

Recommendation: Continue and 

systematically evaluate population-based 

tobacco control efforts currently in progress 

or planned. Expanding the use of existing 

guidelines and developing new approaches 

to both smoking cessation and relapse 

prevention are of the highest priority. The 

PRG also encourages the adoption and 

implementation of these guidelines in lung 

cancer prevention, screening, and treatment 

trials. 

Consider the following facts: 

• 30 percent of all cancer mortality is 

attributable to tobacco use. 

• Cigarette smoking causes chronic lung 

disease and heart disease. Overall, 

cigarettes kill more than 430,000 

Americans every year. 

• When fully implemented, the U.S. 

Public Health Service guidelines for 

smoking cessation are effective only 25 

percent of the time, with quitting rates 

increasing with the number of cessation 

attempts. However, implementation of 

these guidelines has been limited, and 

methods for treatment can be improved. 

• Smoking prevalence has dropped 

markedly since the 1964 Surgeon 

General’s report, which is the primary 

reason that lung cancer mortality rates 

have begun to decline in the United 

States. However, an estimated one in 

four adults in the United States still 

smoke. Thus, the target group for 

prevention and detection of smokingrelated lung cancer in the United States 

is 91 million people (44 million former 

smokers and 47 million current 

smokers). 

Report of the Lung Cancer Progress Review Group 7 
• Because of the structural determinants of 

poverty, smoking and poorer health 

outcomes are more prevalent in certain 

racial and ethnic populations. AfricanAmerican men have the highest 

incidence and mortality rates from lung 

cancer. 

• Marketing of tobacco products has 

clearly targeted not only youth but other 

vulnerable populations. The most 

effective way to influence the problem 

of health disparities in the United States 

is to use population-based tobacco 

control strategies and protocols to 

reduce smoking. 

The Lung Cancer PRG recognized the scope 

of the problem and noted several key areas, 

listed below, in which immediate and 

intensive research and support is required. 

• Harm Reduction. “Harm reduction” is 

an old concept that is re-emerging with 

the development and marketing of socalled “safe” cigarettes. Three decades 

ago, the introduction of "low yield" 

cigarettes only increased the already 

significant public health burden due to 

tobacco use because it permitted 

smokers to believe they were reducing 

their risk of illness when no such data 

existed. Rapid and thorough analysis of 

the differential toxicity of these products 

is required, along with research that will 

examine if “harm reduction” is a viable 

public health strategy and that will 

provide a scientific basis for eventual 

policy decisions. 

• Genetics. There is growing research 

interest in identifying genes and their 

common variants that may predispose to 

nicotine addiction. Such biobehavioral 

research has the potential to target 

therapies more accurately according to 

the smoker’s genotype and in the context 

of the social and cultural milieu, and 

thus to enhance the success rates of 

cessation interventions. 

• Population-Based Programs. Because 

the tobacco industry’s marketing and 

promotion arm alone outspends the 

public health efforts of the various states 

and the Federal Government by an order 

of magnitude, it is vital to continually 

review and understand data generated 

from the large, population-based tobacco 

control programs currently in progress or 

planned. Surveillance and evaluation 

research of population-based tobacco 

control efforts, such as tobacco price 

increases, secondhand smoke policies, 

mass media efforts, and 

“denormalization” of tobacco use by 

adults and young people, are critical to 

offset the ongoing activities of the 

tobacco industry and create a substantive 

public health benefit at the population 

level. 

Early Detection 

Recommendation: Facilitate and hasten 

the evaluation of spiral computed 

tomography (CT) scanning to detect lung 

cancer at an early stage, reverse the current 

stage distribution at presentation, and reduce 

mortality from lung cancer. This will 

necessitate creation of a comprehensive lung 

cancer infrastructure that includes sharing of 

specimens and clinical and epidemiologic 

data to further our understanding of the 

pathobiology of the small or early lesions 

detected by this technology. 

Currently, the vast majority of patients 

present with locally advanced or metastatic 

disease. Any significant change in the stage 

distribution at presentation has the 

possibility of making a profound impact on 

cancer death rates, given the prevalence of 

lung cancer. Unfortunately, this area of 

research has become mired in wellintentioned but ultimately counterproductive 

8 Report of the Lung Cancer Progress Review Group 
arguments about the merits of the necessity 

for randomized, controlled trials with 

overall mortality as the sole endpoint. 

Several meetings co-sponsored by NCI and 

the American Cancer Society have 

determined that a number of study designs 

in addition to a mortality endpointrandomized trial (the gold-standard 

approach) are important and valid. NCI 

must continue to take a strong leadership 

role in facilitating the initiation and 

completion of a number of trials evaluating 

spiral CT as a means of detecting lung 

cancer early and reducing mortality. 

Understanding of Lung Carcinogenesis 

Recommendation: Elucidate the 

contributions of injury, inflammation, and 

infection to the genesis of lung cancer. 

Investigators of different disciplines need to 

work together to outline the specific cellular 

steps that underlie epithelial development in 

the airways during embryogenesis and 

during cell renewal in the normal adult lung. 

There is a need to study molecular mediators 

that drive the chronic pulmonary injury 

process and to develop the best model 

systems to study these interactions. NCI 

should bring together investigators from 

other institutes at NIH to address these 

emerging issues. 

Outcomes 

Recommendation: Design, implement, and 

study “best practices” in lung cancer 

management. 

The extent to which “best practices” (e.g., 

lobectomy as opposed to pneumonectomy; 

chemotherapy plus radiation for locally 

advanced disease) are employed is unclear. 

The extent to which existing guidelines 

(e.g., National Comprehensive Cancer 

Network) are in practice in the community 

at large is unknown. Expansion of the 

CanCORS program would allow a common 

data set on which to validate new measures 

of quality care and to evaluate novel 

programs of service delivery. 

In the absence of an understanding of 

whether disparities in lung cancer diagnosis, 

prevention, and treatment are grounded in 

physician behaviors, population differences, 

or health system functioning, it will not be 

possible to design and implement strategies 

to correct them. 

Training Programs 

Recommendation: Facilitate and 

encourage training programs that emphasize 

multi-disciplinary science and clinical care. 

As noted earlier, discipline-based training 

programs rarely address true multidisciplinary science and clinical care. Given 

the exigencies of discipline-based 

compensation, it is unlikely that the current 

training paradigms will change unless 

funding is specifically directed to address 

this problem. 

Early and mid-career programs for training 

in lung cancer care and research need to be 

expanded and innovative designs 

encouraged through grant and contract 

mechanisms. As techniques for early 

detection and prevention are developed, it 

will be critical to educate primary care 

physicians, lung-oriented specialists, and 

other health care professionals. 

OTHER KEY RECOMMENDATIONS 

The Lung Cancer PRG also made a number 

of recommendations that could be addressed 

effectively through ongoing or expanded 

initiatives at NCI. Accordingly, the PRG 

strongly supported the continuation or, 

where necessary, the enhancement of 

programs related to: 

Report of the Lung Cancer Progress Review Group 9 
• Bioinformatics, including the Center for 

Bioinformatics and the National 

Programs of Excellence in Biomedical 

Computing. 

• Animal Models. There is a need to 

exploit ongoing initiatives in the 

development of mouse models to have 

them mimic the human disease 

paradigm. 

• Molecular Profiling of Tumors, 

including NCI’s Director’s Challenge. 

Existing efforts could be further 

extended to focus more specifically on 

lung cancer and to include the study of 

preneoplastic tissues. 

• Special Populations and Population 

Disparities. We need innovative 

approaches to study the problem of lung 

cancer in specific subgroups of the 

population defined by age, gender, 

ethnicity, and smoking status, as well as 

families with multiple affected members 

and individuals with lung cancer as a 

second primary cancer. 

• Tissue and Data Repositories. 

Investigators need easy access to highquality tissue from the normal lung, 

precursor lesions, and invasive tumors, 

as well as serum and DNA, that are 

linked to comprehensive epidemiologic, 

clinical, and follow-up data. Access to 

specimens has consistently been 

identified as a barrier in all PRG reports. 

These specimens need to be stored 

according to optimal standard protocols. 

Collection of biospecimens from cohort 

as well as screening, chemoprevention, 

and therapeutic trials has the potential 

for garnering considerable new 

information at marginal incremental 

cost. 

• Drug Development and Clinical Trials 

Infrastructures. There is an urgent need 

to develop and test new targeted drugs 

for both the treatment and the prevention 

of lung cancer. Programs for 

development and testing of new drugs 

through NCI’s Cancer Therapy 

Evaluation Program and Division of 

Cancer Prevention should continue to be 

supported. 

• Centers of Excellence in 

Communications. These centers could 

be expanded to include a specific lung 

cancer focus. 

• Tobacco PRG. Although tobacco use is 

an integral part of the etiology, course, 

and treatment of lung cancer, the 

numerous and important issues raised by 

tobacco use and control transcend the 

problem of lung cancer and affect many 

other types of cancer. Therefore, the 

Lung PRG recommends that NCI 

convene a separate Tobacco PRG. 

CONCLUSION 

NCI has had the foresight to create a 

remarkable scientific infrastructure that 

offers the promise of true advances against 

the common epithelial cancers of adults, 

particularly lung cancer. The Lung PRG 

salutes and recognizes this progress but 

strongly cautions NCI that the current 

dissipation of lung cancer investigators 

across numerous clinical and researchfocused teams is not the optimal approach to 

attacking this problem. In the same way that 

the difficulties in translational and clinical 

science led to the formation of the NABTT 

(New Approaches to Brain Tumor 

Treatment) consortium (an NCI-supported 

group dedicated to study and treatment of 

central nervous system malignancies), so, 

too, must the efforts in lung cancer research 

be realigned. 

Ultimately, progress against lung cancer will 

depend on a concerted, multi-disciplinary 

10 Report of the Lung Cancer Progress Review Group 
effort. The priorities outlined here provide a 

framework for such an effort. It is hoped 

that, by fully addressing these priorities, we 

will effect a marked improvement in the 

understanding, prevention, detection, and 

treatment of lung cancer. 

Report of the Lung Cancer Progress Review Group 11 

Appendix A: About the National Cancer

Institute’s Progress Review Groups
Appendix A: About the National Cancer Institute's Progress Review 

Groups 

The National Cancer Institute (NCI) 

supports basic, clinical, and 

population-based research to elucidate the 

biology, etiology, early detection, 

prevention, and treatment of cancers of 

various organ sites. These research efforts 

have produced a substantial base of 

knowledge that, while providing a wealth of 

new scientific opportunities that can further 

advance our knowledge and progress against 

these diseases, also requires that the Institute 

determine the best uses for its resources. 

To help ensure the wise use of resources, 

NCI has established Progress Review 

Groups (PRGs) to assist in assessing the 

state of knowledge, reviewing the Institute's 

research portfolio, and identifying scientific 

priorities and needs for its large, 

site-specific research programs. 

CHARGE TO THE PRGs 

Each PRG is charged to: 

• Identify and prioritize scientific research 

opportunities and needs to advance 

medical progress against the cancer(s) 

under review. 

• Define the scientific resources needed to 

address these opportunities and needs. 

• Compare and contrast these priorities 

with the current NCI research portfolio. 

• Prepare a written report that describes 

findings and recommendations. 

• Discuss a plan of action with NCI 

leaders to ensure that the priority areas 

are addressed. 

The following section details the process 

used to execute these charges. 

THE PRG PROCESS 

PRG members are selected from among 

prominent members of the scientific, 

medical, and advocacy communities and 

from industry to represent the full spectrum 

of scientific expertise required to make 

comprehensive recommendations for the 

NCI's cancer research agenda. The 

membership is also selected for its ability to 

take a broad view in identifying and 

prioritizing scientific needs and 

opportunities that are critical to advancing 

the field of cancer research. 

The leadership of each PRG finalizes an 

agenda and process for a PRG Planning 

Meeting. At the Planning Meeting, 

participants are identified to take part in a 

subsequent Roundtable meeting. Topics are 

identified for Roundtable breakout sessions 

to which participants will be assigned and 

for which the PRG members will serve as 

co-chairs. 

A PRG Roundtable brings together in an 

open forum approximately 100–180 leading 

members of the relevant cancer research, 

medical, industry, and advocacy 

communities to formulate key scientific 

questions and priorities for the next 5–10 

years of research on specific cancers. As 

part of the process, the NCI provides the 

PRG Roundtable with an analysis of its 

portfolio of cancer research in the relevant 

organ site. This analysis is intended to 

enable the Roundtable to compare and 

contrast identified scientific priorities with 

the research currently being done under the 

Institute's auspices. Input from the 

Report of the Lung Cancer Progress Review Group 13 
Roundtable is used by the PRG in 

delineating and prioritizing 

recommendations for research, related 

scientific questions, and resource and 

infrastructure needs. At its discretion, the 

PRG may solicit additional input from the 

research and advocacy communities through 

workshops, ad hoc groups, or by other 

means. The PRG also may consider the 

deliberations of previously convened expert 

groups that have provided relevant cancer 

research information. 

THE PRG REPORT 

After the Roundtable, the PRG's 

recommendations are documented in a draft 

report, multiple iterations of which are 

reviewed by the PRG leadership and PRG 

members. The final draft report is then 

submitted for deliberation and acceptance by 

the NCI Advisory Committee to the 

Director. After the report is accepted, the 

PRG meets with the NCI Director to discuss 

the Institute's response to the report, which 

is widely disseminated and integrated into 

the Institute's planning activities. At this 

meeting, the PRG and the NCI identify the 

research priorities that ongoing NCI 

initiatives and projects do not address. Then 

the PRG and NCI discuss a plan for 

implementing the highest research priorities 

of the PRG. This plan becomes a blueprint 

for tracking and hastening progress against 

the relevant cancer. 

PRG reports on breast cancer, prostate 

cancer, colorectal cancer, brain tumors, 

pancreatic cancer, and leukemia, lymphoma, 

and myeloma, in addition to this PRG report 

on lung cancer, are available online at 

http://planning.cancer.gov. Other PRG 

reports currently in development or planned 

include reports on gynecologic cancers, 

kidney and bladder cancer, and stomach and 

esophageal cancer. 

14 Report of the Lung Cancer Progress Review Group 
Appendix B: Breakout Reports
Biology

Co-chairs: Dr. Stephen Baylin, 

Dr. Jennifer Pietenpol, 

Dr. Curtis Harris 

Writer: Dr. Frances McFarland 

INTRODUCTION 

There is a dire need to make a clinical 

impact on lung cancer through new 

strategies for treatment of established 

disease, earlier treatment intervention, and 

prevention. Accomplishing these goals is 

complicated by the fact that there are four 

major histological types of lung 

cancer—small cell, squamous cell, large 

cell, and adenocarcinomas—that may each 

have unique molecular aspects for precursor 

lesions and steps in progression. The 

translational research that will be essential 

to accomplish the goals for treatment and 

prevention is, in turn, driven by basic 

biological research aimed at understanding 

the cellular and molecular biology attendant 

to each of the major forms of lung cancer. 

Although many chromosomal changes have 

been outlined for progression steps in lung 

cancer, many of the genes in these regions 

that uniquely contribute to the origins of 

each cancer are not known, as they are for 

tumors such as colon cancer (examples of 

known genes are p53, p16, and K-ras). This 

may be largely because, unlike for colon 

cancer, distinct familial forms of lung cancer 

are not available to identify germline 

mutations that provide key information 

about the origins of the somatic forms of the 

tumors. Thus, new biological insights must 

be derived to outline the cellular and 

molecular pathways for development of lung 

cancer that will provide the needed markers 

for risk assessment and early diagnosis and 

will facilitate the development and 

evaluation of novel targets for treatment and 

prevention strategies. Thus, the 

recommendations from the Biology Working 

Group of the PRG focus on promoting ways 

to obtain this critically needed new biological 

information. 

The overall theme of the recommendations is 

that investigators of different disciplines need 

to work together to outline the specific 

cellular steps underlying epithelial 

development in the airways during 

embryogenesis and during cell renewal in 

normal adult lung and chronically injured 

lung exposed to tobacco. The stem cells 

involved in these processes need to be 

clarified and the signal transduction events 

that program these cells, including signaling 

to and from non-epithelial components of 

normal and adult lung, need to be explored 

and related to steps in lung carcinogenesis. 

Information on these processes may depend 

heavily on the study of lower organisms such 

as Drosophila and on derivation of mouse 

models. In turn, the mouse models can prove 

to be the key models for the study of lung 

cancers and testing of new agents to prevent 

and treat them. The use of genomics and 

proteomics will be critical for all of this 

research, as will constant extrapolation of all 

information to the clinical arena and back to 

the bench. The recommendations that follow 

are focused on advancing mechanisms to 

foster the integrated type of basic research 

that is clearly necessary to meet the research 

goals outlined above. 

RESEARCH PRIORITIES 

General Recommendations 

The context for recommendations from this 

PRG should emphasize opportunities to 

engage in and foster a highly integrated 

approach to basic studies of lung cancer. 

Such integration should involve harnessing 

the joint expertise of developmental 

Biology 15 
C.

biologists, cellular and molecular biologists, 

pulmonologists, clinical scientists, and 

experts in genomics and proteomics to the 

lung cancer problem. Intervening steps to 

prepare for such integrated research projects 

should include an NCI-supported series of 

interdisciplinary meetings to foster the 

concepts and especially the creative use of: 

• Animal models: how best to use them in 

the context of lung cancer, and how to 

facilitate involvement of the lung cancer 

research community in making an 

impact in etiology, prevention, 

molecular pharmacology, in vivo 

imaging, etc. This might involve 

expansion and participation of the lung 

cancer research community with the 

current mouse model consortium for the 

specific needs of lung cancer research. 

• Genomics and proteomics: how to use 

these tools in studies of developmental 

biology, early progression, etc. 

The overall goal of the following priorities 

is to have a significant impact on 

understanding of the genesis of the four 

major histological types of lung cancer and 

development of new markers for risk 

assessment, early detection, and targets for 

prevention and treatment. 

1. Define the molecular switches (genetic 

and epigenetic) of human lung cancer. 

A. Identify stem cells involved in the 

generation of the bronchial 

epithelium, in renewal of adult 

normal and neoplastic epithelium, 

and specific relationships of these 

cells to the genesis of each of the 

major types of lung cancer. 

B. Determine, at a molecular level, 

stromal-epithelial cell interactions 

that guide stem cell programming 

events and cell fate decision. This 

work must include efforts to evolve 

the model systems most useful for 

these studies. 

C. Clarify existing knowledge and 

develop new knowledge of pathways 

underlying the development of 

normal and neoplastic bronchial 

epithelium. This should include an 

emphasis on the study of Drosophila, 

Caenorhabditis elegans, and other 

model organisms for elucidating 

determinants of cell fate decisions. 

The work must also emphasize the 

use of in vitro models using human 

lung epithelial cells and animal 

models to outline and validate 

molecular pathways involved and 

their participation in the genesis of 

lung cancer. 

D. Creatively use genomics and 

proteomics for each of the study areas 

outlined above. 

Rationale 

In general, lung tumors are not responsive to 

current therapies, and this fact is complicated 

by the existence of four major types of cancer 

arising from a single epithelial cell system. 

Also, a major translational goal is to develop 

prevention strategies based on individual risk 

assessment. The specific molecular steps 

involved in the genesis of lung cancer, in 

general and with each of the specific 

histologies, are not well understood and 

represent barriers to these translational goals. 

2. Elucidate the contributions of injury, 

inflammation, and infection to the 

genesis of lung cancer. 

A. Develop the best model systems to 

study these interactions. 

B. Identify cells (including epithelial and 

non-epithelial cells) and molecular 

16 Report of the Lung Cancer Progress Review Group 
mediators (cytokines, oxygen 

radicals, products of lipid 

peroxidation, infectious agents such 

as viruses, etc.) that drive the chronic 

pulmonary injury process. This must 

be a collaboration between scientists 

and clinicians working in the areas 

of pulmonary biology and cancer 

biology. 

C. Identify the precise epithelial cell 

renewal events that are participating 

in the chronic injury response. 

D. Determine the contribution of all the 

above events to the genomic (genetic 

and epigenetic) changes in the 

bronchial epithelial cells throughout 

the stages of development of each of 

the major forms of lung cancer. 

Rationale 

Chronic injury, inflammation, and infection 

may contribute to lung cancer risk and result 

from cigarette smoking, in addition to the 

carcinogen exposure inherent to tobacco 

use. However, relatively little study has 

focused on the interplay between these 

parameters in the development of lung 

cancer. 

3. Clarify the biology of gender and 

ethnic differences in susceptibility to 

development of lung cancer. 

Use genomics and proteomics to study 

established tumors and early lesions 

collected from special populations (men and 

women and different ethnic groups). 

Inherent to these studies must be a 

collaborative effort to obtain the appropriate 

tissue samples required for study. 

Investigate potential hormonal determinants 

of lung cancer susceptibility between men 

and women. 

Determine what model systems may be 

generated to study these questions. 

Particularly, for the issue of gender, how 

does the hormonal milieu influence use of the 

current animal models to study the genesis of 

lung cancer and development of new ones? 

Rationale 

To date, little information has been generated 

on the differences in susceptibility for lung 

cancer development between men and 

women and among different ethnic groups. 

For example, the occurrence of lung cancer 

among non-smokers is much higher for 

Chinese women than Caucasian women. 

Much might be learned about the biology of 

lung cancer from studying these different 

populations from a basic science standpoint. 

RESOURCES NEEDED 

• The existing NCI initiatives in areas such 

as the mouse model consortium, the 

Director’s Challenge, tissue banking, and 

genomics and proteomics must be 

expanded to meet the specific needs of 

the research priorities outlined above. 

• Support will be required for the suggested 

meetings to establish concepts underlying 

the multi-disciplinary research in the 

suggested priorities. 

• The type of research most emphasized in 

the suggested priorities must be carried 

out in the setting of grant mechanisms 

such as interactive R01s and P01s. 

Consideration should be given to 

mobilizing a pool of funds to adequately 

support this research effort. Funding of 

IDEA awards (high risk, high impact) 

should be considered for each of the 

priorities. To foster the required 

interaction between pulmonologists and 

cancer biologists, joint funding 

mechanisms between the National Heart, 

Biology 17 
Lung, and Blood Institute and NCI 

should be developed. 

BARRIERS 

• The biggest barrier to progress toward 

these research goals would be the failure 

to perform the investigations in the 

highly integrated, multi-disciplinary 

manner articulated in the general 

recommendations. For example, in 

terms of technology development, there 

is a need to juxtapose relevant scientific 

questions with the new technology. 

18 Report of the Lung Cancer Progress Review Group 
Chemoprevention

Co-chairs: Dr. Waun Ki Hong, 

Dr. Ethan Dmitrovsky, 

Dr. Stephen Hecht 

Writer: Nancy Volkers 

BACKGROUND 

There is a pressing need for effective lung 

cancer chemoprevention strategies. This 

section of the PRG report summarizes three 

research priorities to advance the national 

lung cancer chemoprevention strategy. 

Lung cancer prevention is an attractive 

approach because the major etiologic 

agent—tobacco carcinogens—is known. 

Yet, even if all the national anti-smoking 

goals are achieved, lung cancer will remain 

a major clinical problem for decades to 

come. Previous work has shown that 

prevention of aerodigestive tract tumors is a 

promising approach based on the seminal 

work of Hong and colleagues, 

demonstrating that 13-cis-retinoic acid can 

treat oral leukoplakia. This work, conducted 

in the 1980s, was extended by showing that 

retinoids can prevent second aerodigestive 

tract tumors in patients with resected head 

and neck cancers. Similar work by 

Pastorino and colleagues demonstrated that 

retinyl palmitate can reduce incidence of 

second aerodigestive tract cancers in 

patients with resected stage I non-small cell 

lung cancer. Yet, independent, randomized 

placebo-controlled trials using beta-carotene 

or 13-cis-retinoic acid have failed to show 

clinical preventive benefit in current 

smokers. Treatment with 13-cis-retinoic 

acid did, however, show a potential benefit 

in persons who had never smoked. 

This work, conducted in large, multi-center 

clinical trials, underscores the need for 

identification of subjects who are at high 

risk for developing lung cancer and are 

favorable candidates for lung cancer 

chemoprevention trials. The value of 

epidemiological observations is therefore 

obvious, as is the need for more effective 

chemopreventive (natural or synthetic) agents 

and appropriate surrogate endpoints that 

might replace clinical outcome as a measure 

of efficacy. 

At this stage in the field of lung cancer 

chemoprevention, we do not yet have an 

example of a successful proof-of-principle 

trial that identifies effective chemopreventive 

agents, appropriate target populations, or 

validated surrogate endpoints. There is a 

consensus that an extraordinary opportunity 

exists for targeting lung cancer 

chemoprevention in the years ahead through 

the support of the National Cancer Institute. 

This opportunity derives from the presence of 

new therapeutic agents that target 

mechanistic pathways important in 

chemoprevention. Also, innovative 

diagnostic imaging approaches such as spiral 

computed tomography and autofluorescence 

bronchoscopy, will permit identification of 

early preneoplastic or neoplastic lesions. 

Conceivably, these imaging approaches will 

also highlight new subjects for participation 

in chemoprevention trials. 

However, these prospects exist in tandem 

with a therapeutic nihilism on the part of 

physicians and patients. Overcoming this 

nihilism will require an educational effort. 

To exploit the considerable opportunity for 

advances in lung cancer chemoprevention, 

three priorities are emphasized for their 

ability to enhance the national lung cancer 

chemoprevention effort. 

Chemoprevention 19 
RESEARCH PRIORITIES 

1. Develop new lung cancer 

chemoprevention agents. 

Rationale 

In addition to earlier encouraging work with 

retinoids as a paradigmatic approach to 

prevent lung cancer, newer agents appear 

quite promising for lung cancer 

chemoprevention. A comprehensive listing 

of all candidate lung cancer 

chemopreventive or therapeutic agents is 

beyond the scope of this report; however, 

clearly more candidate chemopreventive 

agents are available for clinical testing than 

have previously existed. For this reason, a 

new paradigm is needed for testing efficacy 

of new agents in chemoprevention trials. 

To date, it is not yet known which pathways 

are required for the maintenance or 

progression of preneoplastic lesions. Thus, 

additional candidate chemoprevention 

agents that target these carcinogenic 

pathways are needed. An agent must meet 

certain criteria, including: 

• A relevant mechanism of action. 

• Preclinical efficacy in in vitro and 

animal models. 

• A favorable toxicity profile. 

• Optimal pharmacokinetics. 

To develop new agents, closer 

collaborations are needed between basic and 

clinical scientists from academic and 

pharmaceutical settings. These 

collaborations should exploit relevant 

preclinical models and animal models 

(transgenic, knock-in, and chemical 

carcinogenesis). Interactions between 

tobacco carcinogens and candidate 

chemopreventive agents must be considered, 

especially because study subjects may 

continue to smoke; previous studies have 

demonstrated a negative interaction between 

certain chemopreventive agents and 

continuing exposure to tobacco carcinogens. 

This fact highlights the need to target specific 

agents to subjects carefully characterized by 

smoking status (current smokers, former 

smokers, and recent quitters), by genetic 

changes evident in the affected epithelium, 

and by phenotyping. 

CHALLENGES AND BARRIERS 

Development of chemopreventive agents 

presents distinct challenges: 

• Clinical trials of chemopreventive agents 

are expensive because of their long 

timeline and large, disseminated study 

populations. As a result, 

chemopreventive agents generally take 

longer to move from discovery to Food 

and Drug Administration (FDA) approval 

than agents under study for treatment. 

• There is only modest industry interest and 

participation in such trials, as well as in 

development of chemopreventive agents. 

Concerns relate to patent protection 

issues, safety in chemoprevention trials 

for at-risk subjects, and dose-limiting 

clinical toxicity. 

• The existing national infrastructure for 

such clinical trials is limited. 

To expedite the development and validation 

of new chemopreventive agents, closer 

collaborations are needed among academia, 

industry, and community researchers to 

identify and develop new chemoprevention 

agents. Surrogate endpoints for 

chemoprevention clinical trials should be 

redefined and evaluated by the FDA. 

Currently, the FDA has been reluctant to 

adopt surrogate endpoints in place of clinical 

outcome for chemoprevention trials. The use 

20 Report of the Lung Cancer Progress Review Group 
of such surrogate endpoints could shorten 

the time frame for clinical chemoprevention 

trials, making them less expensive and 

moving more agents toward approval at a 

faster rate. 

2. Establish a methodology to identify 

high-risk individuals. 

Rationale 

Although smoking is an established risk for 

lung cancer, only a minority of even heavy 

smokers will develop the disease. If reliable 

models for individuals at high risk for lung 

cancer can be developed, validated, and 

applied, clinical trials can be targeted to 

those cohorts in which the incidence of lung 

cancer will be high, limiting the size, scope, 

and cost of chemoprevention trials. 

High-risk profiles exist for heavy smokers, 

such as a more than 70 pack-year smoking 

history, older age (more than 50 years old), 

asbestos exposure, and chronic obstructive 

pulmonary disease. However, no model that 

incorporates any biomarkers of risk has yet 

been developed and validated, and we are 

still unable to identify those individuals at 

highest risk for tobacco-induced lung 

cancer. 

Resources exist to develop such 

methodology, for example: 

• Families at high risk for lung cancer, 

who likely harbor a genetic 

predisposition, can be studied to identify 

key genes involved in lung 

carcinogenesis. Genetic alterations 

discovered through studying high-risk 

families can be evaluated in appropriate 

animal models and validated as causes 

of lung cancer. These models in turn can 

be used to assess efficacy of 

chemopreventive agents. 

• Case-control and nested studies within 

cohorts can be performed to identify hosttobacco-carcinogen interactions and 

establish surrogate endpoints for lung 

cancer risk. When interactions have been 

established, animal models can be used to 

validate the discovery. 

• Imaging technologies can identify 

preneoplastic and fully transformed lung 

lesions, which can be used as surrogate 

endpoints in lung cancer 

chemoprevention trials. 

• Microarray profiles of normal, 

premalignant and neoplastic pulmonary 

tissue can be used to establish risk. 

• Clues from epidemiologic data (such as 

exposures to non-steroidal antiinflammatory drugs and dietary factors) 

can be exploited. 

3. Pursue streamlined, mechanism-based 

clinical chemoprevention trials. 

Rationale 

Previous chemoprevention trials have been 

designed with an empiric approach that is not 

based on a clear understanding of the biology 

of lung carcinogenesis and the mechanisms 

of drug action. It is necessary to develop 

ways to move agents more rapidly from 

preclinical settings to phase I and II trials, 

then validate their safety and efficacy to 

warrant advancement to phase III 

confirmatory chemoprevention trials. 

Both new and known single agents, as well 

as combinations, should be studied. It is 

appreciated that effective chemoprevention 

trials may require optimal combinations of 

agents. An advantage of targeted 

chemoprevention therapy is that a specific 

carcinogenic pathway is antagonized, 

limiting toxicity associated with nonselective therapies. Another advantage of 

Chemoprevention 21 
combination therapy is that conceivably, 

each agent could be administered at low 

doses, resulting in favorable toxicity 

profiles. 

Proof-of-principle trials (using single agents 

or combination regimens) afford an 

opportunity to assess not only whether a 

biologically plausible pathway is affected by 

the chemopreventive agent but whether the 

agent exerts the desired clinical effect. This 

can be accomplished by monitoring changes 

in affected epithelium in biopsies obtained 

before and after administration of the 

chemopreventive agent. 

Such trials should exploit available 

technologies, including newer ones like 

microarrays, proteomics, spiral computed 

tomography, and autofluorescence 

bronchoscopy. The use of combination 

regimens and novel delivery approaches, 

such as aerosolization, should be 

emphasized. 

In addition, the population available for 

clinical trials should be maximized; patients 

or subjects who do not meet the criteria for 

one chemoprevention trial may be eligible 

for a different one. Less than 5 percent of 

adult cancer patients enroll in clinical trials. 

Because chemoprevention trials can involve 

individuals who have not been diagnosed 

with cancer, enrollment may be even more 

difficult. Public education for current, 

former, and never smokers, perhaps through 

advocacy organizations and funding of 

educational announcements appearing in 

various media, is necessary to make patients 

and potential trial subjects aware of the 

purpose, design, and benefit of 

chemopreventive clinical trials. 

Education of physicians is also crucial to 

reduce the air of therapeutic nihilism and the 

idea of “blaming the victim.” This will not 

only increase trial accrual but help shift the 

cultural view of lung cancer as a disease that 

is somehow “deserved” by smokers who are 

diagnosed with it. 

RESOURCES NEEDED 

• A broader national infrastructure is 

necessary for lung cancer 

chemoprevention trials. The 

infrastructure should include multiple 

centers, greater partnership between 

academic and industry, and a central 

repository for biological specimens, 

epidemiological data, and clinical 

information. 

• Education and training are needed for 

patients, subjects, and physicians. 

Funding opportunities could be made 

available to advocacy groups, which are 

already important educational resources 

for affected individuals and their families 

but often must find funding from 

industry. 

• Increased funding is also needed for 

mechanism-driven chemoprevention 

trials, with increased participation by 

chemoprevention experts in the peer 

review process. 

• There is an extraordinary opportunity in 

lung cancer chemoprevention. Through 

focused research priorities and targeted 

investments, therapeutic nihilism can be 

overcome and the public health burden of 

lung cancer can be reduced. 

22 Report of the Lung Cancer Progress Review Group 
Early Detection and Diagnosis

Co-chairs: Dr. Edward Patz, 

Dr. Wilbur A. Franklin 

Writer: Bob Petersen 

INTRODUCTION 

The potential of new imaging and molecular 

techniques to significantly improve the 

detection of localized lung cancer provides 

an unprecedented opportunity to understand 

the biology, improve diagnosis, enhance 

treatment, and reduce mortality. These 

strategies have just begun to explore the 

utility of spiral computed tomography (CT), 

fluorescence bronchoscopy, PET imaging, 

and proteomic and genomic analysis of 

tumors and other specimens. These 

approaches (and in particular the application 

of spiral CT) have the potential to identify 

small and early lesions that have not been 

readily accessible in clinical practice through 

more conventional detection methods. 

Molecular profiling may assist in identifying 

high-risk populations, but spiral CT 

screening offers a unique opportunity to 

study early carcinogenesis, and potentially to 

reduce lung cancer mortality. 

However, the clinical and biological 

significance of these small and early lesions 

is not well understood. Determining the 

natural history of small pulmonary nodules 

and the morphological classification of 

premalignant sputum and bronchial cells 

(recognized by proteomic, genomic, and 

morphologic abnormalities) is essential if 

these novel strategies are to be effectively 

used.Although several clinical trials are in 

progress to evaluate new technologies and 

study early and small lesions, it is important 

to create the infrastructure necessary to 

standardize and share imaging features, 

clinical and epidemiologic information 

including smoking and family history, and 

specimen collection. In addition, as novel 

functional and molecular imaging 

technologies evolve, a mechanism for rapid 

evaluation of these advances in future early 

detection and screening studies is essential 

so their usefulness can be fully evaluated. 

We accordingly make the following 

recommendations. 

RESEARCH PRIORITIES 

1. Provide immediate support for 

clinical research initiatives covering 

the natural history, management, and 

follow-up of early or small lesions to 

evaluate their impact on lung cancer 

mortality and to develop optimal 

diagnostic work-up and treatment 

options. 

Rationale 

Although many of these small and early 

lesions are now being detected, their true 

clinical significance remains uncertain. This 

priority would suggest funding to pursue an 

improved understanding of this spectrum of 

lesions by many different disciplines. 

2. Develop a lung cancer infrastructure 

that includes sharing of specimens and 

data collected during the screening, 

evaluation, and follow-up of all 

individuals with early and/or small 

lesions. This process should be initiated 

by national and international workshops 

to develop optimal protocols for 

coordination, communication, and 

specimen collection and preservation, 

storage, shipping, and labeling of all 

such specimens. In addition, common 

data elements and uniform standards for 

use in a shared data repository should be 

developed and implemented in both 

randomized and cohort studies: 

Early Detection and Diagnosis 23 
A. Coordinate lung cancer screening 

activities to link expert groups, 

including but not limited to biology, 

imaging, pulmonology, medical and 

surgical oncology, epidemiology, 

biostatistics, and pathology as exist 

within the lung cancer SPORES, the 

EDRN (Early Detection Research 

Network), and the cohort and 

randomized controlled trials, such as 

the Framingham Heart Study, the 

Prostate, Lung, Colorectal, and 

Ovarian (PLCO) Cancer Screening 

Trial, the Lung Screening study 

(LSS), EPIC (Empowered Patients In 

Control), ELCAP (Early Lung 

Cancer Action Project), I-ELCAP, 

NY-ELCAP, and the Mayo, Moffitt, 

Munster, and Japanese studies. 

B. Create a decentralized infrastructure 

for collecting, preserving, storing, 

shipping, labeling, and sharing of 

these biologic specimens and clinical 

data. 

Rationale 

A top priority is development of a 

comprehensive infrastructure for (a) 

communication among experts in multiple 

disciplines and (b) collection of specimens 

from cohort and randomized controlled trials 

in which state-of-the-art technologies are 

applied and clinical data are obtained. The 

coordination of ideas and the expertise to 

integrate all specialties in a cohesive manner 

do not exist. Abnormalities that will be of 

particular interest include the small or early 

lesions that are being detected by these 

technologies. This infrastructure should 

facilitate rapid dissemination of data and 

ideas among all specialists interested in lung 

cancer. 

3. Foster and evaluate promising 

technologies and tools for lung cancer 

screening and early detection: 

computer-assisted diagnosis (CAD), 

volumetric computed tomography 

(VCT), small animal imaging, virtual 

bronchoscopy, and tissue sampling. 

Molecular imaging, and functional 

imaging (e.g., PET and optical imaging) 

should be evaluated in the clinical 

assessment of early and small lesions, 

and the targets, corresponding probes, 

and contrast agents of interest for lung 

cancer should be identified. Phase 3 

funding beyond the R21 and R33 

mechanisms is recommended for these 

technologies. In addition to cohort and 

case-series, randomized controlled trials 

with lung cancer mortality endpoints 

should be considered and supported 

when the usefulness of screening 

modalities is assessed. 

Rationale 

Imaging and molecular technologies are 

developing rapidly but are not necessarily 

focused on detection of early lung cancer. 

Expanded funding for new imaging 

technologies is recommended to ensure that 

lung cancer research takes maximum 

advantage of these technologies and to focus 

development of new technology on the 

problem of lung cancer. As lung cancer 

screening by high-throughput chest imaging 

becomes practical, CAD assistance to the 

radiologist will be essential for rapid 

evaluation of large numbers of highresolution images generated by modern 

multi-slice CT scanners. In addition, 

integration of these evolving technologies 

into current and future studies within the 

created infrastructure will be important. 

Although current mechanisms (R21 and 

R33) may provide short-term developmental 

support, they are of insufficient duration to 

bridge the gap between initial development 

and clinical implementation. 

24 Report of the Lung Cancer Progress Review Group 
4. Examine premalignant lung lesions 

with new technological approaches, 

including but not limited to 

proteomics and genomics. 

Rationale 

Lung carcinomas are typically late stage and 

biologically aggressive, which accounts for 

their poor prognosis. They are believed to 

represent the endpoint of a series of genetic 

and phenotypic changes that may precede an 

invasive tumor by many years. It may be 

appropriate to target these premalignant 

changes for early detection and intervention 

by fully characterizing their molecular 

characteristics, including evaluation of 

response to specifically targeted 

intervention. High-throughput technologies 

such as genomics and proteomics are 

becoming widely available, and it will be 

crucial to apply these technologies to the 

detection of early lung carcinogenesis and 

outcome assessment. 

5. Conduct long-term follow-up of 

individuals diagnosed with malignant 

and premalignant lesions after 

screening, to understand the 

modulation of natural history by 

targeted therapy. 

Rationale 

It will be important to continue funding for 

participants involved in current screening 

trials who had a tissue biopsy. The natural 

history of many of these lesions is not yet 

well understood; follow-up is essential to 

optimize future patient management and 

improved understanding of these small and 

early lesions. 

6. Conduct long-term follow-up of 

screened cohorts for clinical outcomes, 

including but not limited to smoking 

behavior and cost-effectiveness of 

screening. 

Rationale 

Current screening programs, projects, and 

activities have identified a spectrum of 

abnormalities (including genetic profiles for 

cigarette addiction) with unknown clinical 

and biologic significance. Long-term 

follow-up of trial participants will help 

determine the true clinical significance of 

abnormalities detected by screening and the 

ability of emerging technologies to reduce 

lung cancer mortality. 

RESOURCES NEEDED 

• Workshops to develop commons 

standards for interpretation of detection 

technologies, and the collection and 

sharing of data and specimens. 

• Bioinformatics for database building, 

web-based data mining, and 

communication. 

• Request for Applications for study of 

early lesions. 

• Funding mechanism to supplement R21 

and R33 for technology development. 

• Database and funding support of longterm follow-up, including data on lung 

cancer mortality, of individuals 

diagnosed with malignant and 

premalignant lesions after screening. 

BARRIERS 

• Funding. 

• Pre-existing uncoordinated specimen 

and clinical data collection practices. 

• Lack of infrastructure. 

Early Detection and Diagnosis 25 
Etiology

Co-chairs: Dr. Neil Caporaso, 

Dr. Peter Shields, 

Dr. Fred Kadlubar 

Writer: Cheryl Pellerin 

BACKGROUND 

Tobacco is the established central etiologic 

agent in lung cancer and is the major cause 

of cancer mortality in the United States. 

Although more than 85 percent of all lung 

cancers are attributed to cigarette smoking, 

only a fraction of long-term smokers 

(hypothesized to be genetically susceptible) 

will, in fact, develop lung cancer. The 

complexity of tobacco smoke and the 

contributions of non-tobacco modifiers of 

lung cancer risk lead to challenges for 

etiological studies and for risk assessment. 

There is a pressing need to explore factors 

that contribute to the elevated risk retained 

by former smokers, even after prolonged 

smoking cessation. Finally, tobacco use is 

an addiction that is not easily controllable, 

and better understanding of the biologic 

basis of nicotine dependence is a scientific 

and public health priority. 

Currently, we do not have validated-risk 

assessment models for lung cancer that 

incorporate biomarkers of susceptibility. 

The following recommendations are 

provided to develop such models that will 

enable us to characterize risk for both 

smokers and former smokers and will 

benefit screening and chemoprevention 

trials, as well as the evaluation of newly 

developing harm-reduction methods. More 

broadly, better understanding of etiology on 

both the molecular and population levels 

may be key to providing mechanistic 

insights that can enhance prevention and 

therapy efforts. 

RESEARCH PRIORITIES 

1. Explore etiologic factors for lung 

cancer in special populations. 

Rationale 

Tobacco research is central to our 

understanding of lung carcinogenesis and 

cancer risk. Although knowledge about 

tobacco carcinogenicity has been obtained 

from diverse lines of evidence, 

epidemiological studies in special 

populations are key to unraveling the 

interplay of extrinsic exposures and genetic 

and host factors that result in lung cancer. 

The study of special populations can address 

specific questions relating to tobacco risk 

and modifiers of tobacco risk (e.g., 

occupational exposures, nutrition, immune 

deficiencies, diet and nutrition, 

environmental factors, radiation, prior 

infection or infectious agents) that can be 

answered in the context of hypothesis-driven 

research. Thus, priority should be given to 

studying those populations, in some 

instances understudied in the past, that 

provide special opportunities to better 

elucidate etiological factors and further our 

understanding of- tobacco carcinogenesis. 

Further, the value of these studies is greatly 

enhanced by collection of biospecimens 

with the added opportunity to address 

mechanistic questions. The following 

groups were identified as providing study 

opportunities, but the list should not be 

limited to these: 

Former smokers: There are 44 million 

former smokers in the United States at 

substantial risk of lung cancer in spite of 

freeing themselves from nicotine 

dependence. It is a priority to improve 

understanding of factors that determine risk 

in this group. Efforts to better understand 

26 Report of the Lung Cancer Progress Review Group 
the molecular basis for elevated risk in this 

group through focused biomarker and 

genetic studies are needed to design 

effective interventions. 

Minorities: There are behavioral and 

biological factors that can be elucidated by 

studying different racial and ethnic groups. 

For example, African Americans are an 

understudied ethnic group, with a high risk 

of lung cancer, and specific socio-cultural 

factors such as mentholated cigarette use. 

Individuals with early lesions: Newer 

lung cancer screening studies, such as spiral 

computed tomography, provide an 

exceptional opportunity to identify 

individuals with early lesions and to 

identify biomarkers associated with benign, 

premalignant and early malignant outcomes. 

Nonsmokers: Study of nonsmokers offers 

the opportunity to improve understanding of 

carcinogenesis associated with low-level 

tobacco exposure through environmental 

tobacco smoke and to identify new etiologic 

agents and cofactors, such as postulated 

infectious causes. It is important to better 

understand the etiologic basis for lung 

cancer in those apparently free of exposure 

to tobacco. exposure. 

Gender-related risk factors: There are 

controversies regarding reported differences 

in smoking-associated lung cancer risk for 

women and men. There may be behavioral 

and biological factors that contribute to 

these differences, but additional studies are 

needed to determine if such factors exist. 

Comorbid conditions, such as depression, 

also should be considered. 

Lung cancer subgroups: Accumulating 

sufficient numbers of patients with unusual 

histologies (bronchioloalveolar carcinoma), 

young cases or nonsmokers is difficult for 

any individual study to accomplish. Efforts 

should therefore be undertaken to enhance 

cooperation across cohort or case-control 

studies of lung cancer subgroups, in order to 

achieve sufficient statistical power to study 

these and other key groups. 

Methodological (and sometimes political 

issues) may prove to be barriers; however, 

providing incentives through targeted grant 

supplements, encouraging adoption of 

common data elements and compatible 

biospecimen handling protocols should be 

encouraged. Although such cooperative 

efforts are challenging, they are a priority 

that merits continued efforts and incentives. 

Occupational cohorts: Occupational 

cohorts provide key opportunities to 

understand diverse exposure mechanisms as 

well as issues critical to workplace safety 

such as dose-response and threshold issues, 

to understand how such exposures interact 

with tobacco, and to evaluate new and 

evolving environmental hazards. Tumor 

phenotype studies in these groups provide a 

key resource in answering mechanistic 

questions such as whether mutational 

spectra may serve as valid molecular 

dosimeters of exposure. 

Groups that use harm-reduction 

strategies: Evaluation of populations that 

use methods for harm reduction (i.e., 

cigarette-like devices that reportedly reduce 

exposures or nicotine replacement therapies 

as an aid to reduce but not stop smoking) 

will be critical to understand how the 

changing nature of cigarettes alters risk. 

For example, low tar and nicotine cigarettes 

may result in reduced risk of squamous cell 

cancer but increased risk of 

adenocarcinoma. Biomarkers will be 

important to assess these issues since the 

public health impact will require time to 

manifest. 

2. Understand the role of genetic 

susceptibility in lung cancer. We 

support both linkage studies in families 

to accelerate the identification of highEtiology 27 
penetrance genes and population-based 

studies of appropriate size and design to 

study candidate genes. 

Rationale 

Focused studies on both high- and lowpenetrance susceptibility genes are needed. 

Segregation analysis, family studies, and 

mechanistic work all support a role for 

hereditary factors in lung cancer. But in 

common with other complex diseases, and 

despite a decade of study, the specific genes 

accounting for excess risk are incompletely 

understood. There is a consensus that both 

family and population-based studies are 

needed to achieve this understanding. 

Priority should be given to supporting 

studies in lung cancer families that have the 

potential to identify high-penetrance genes. 

Although it is challenging to identify, 

characterize, and collect lung cancer 

families, the potential payoff is great. 

Resources to support this effort should be a 

priority, because identifying a highpenetrance gene in lung cancer would be a 

landmark finding. 

Molecular epidemiology investigation of 

low penetrance genes should be 

mechanistically focused and should include 

evaluation of pathways other than 

carcinogen metabolism, such as those 

involving DNA repair, cell-cycle control, 

and apoptosis. To contribute meaningfully 

to the characterization of such lowpenetrance genes, population-based studies 

must be large (generally enrolling more than 

1,000 subjects), take into account ethnicity, 

include careful exposure assessment, and 

incorporate appropriate design features and 

biospecimens. These studies are costly 

because the scale of the effort implies a 

substantial infrastructure to support field 

and laboratory efforts. The scientific payoff 

is correspondingly great, however, and grant 

mechanisms to support larger integrated 

studies should be encouraged. Lung cancer 

is the paradigm for gene-environment 

interaction, and unraveling how genes and 

environment act in concert to promote lung 

carcinogenesis will have applicability for 

other cancer sites. 

Hypothesis-testing of single and small 

groups of candidate genes remains 

important, particularly when mechanistic 

studies are supportive, but studies that 

investigate multiple genes relating to 

specific biological pathways (e.g., the study 

of DNA repair genes) should be encouraged. 

Newer methodologies that take advantage of 

the emerging genetic database will require 

validation, and the development of new 

biostatistical methods should be 

aggressively pursued, since heretofore 

unknown genes or pathways may be 

identified. DNA microarrays that 

incorporate many single nucleotide 

polymorphisms (SNPs) of unknown function 

are seen as increasingly relevant. Although 

they have not yet found application in large 

population studies, they are likely to be 

implemented in the near future. 

Even with less costly high-throughput 

genotyping, the study size (thousands) 

and number of SNP markers (tens of 

thousands or more) available for the next 

generation of population studies will require 

the development of methods to optimize the 

quantitation and pooling of DNA samples. 

To conduct these studies that will apply the 

emerging information from the Human 

Genome Project, close cooperation among 

epidemiologists, bioinformatics, and 

geneticists will be needed. 

Where possible, tumor (target) tissue studies 

should be incorporated into epidemiological 

studies to investigate the relationship of 

tumor molecular phenotype to exposure (to 

address the mutational spectrum of 

particular exposures), to host genotype 

(study possible “second hits”), and to 

clinical variables (specific tumor mutations 

28 Report of the Lung Cancer Progress Review Group 
that predict histology, prognosis, and 

response to therapy). Such an integrated 

study setting, described in the next section, 

will offer the best opportunities to further 

validate and apply surrogate markers, such 

as, for example, DNA repair assays in 

lymphocytes, that are key to understanding 

and assessing the impact of exposures and 

susceptibility on carcinogenic risk. 

3. Study biomarkers in an integrated 

context. We place a strong emphasis on 

development, validation, and application 

of biomarkers to obtain answers to 

etiologic questions in the context of 

comprehensive studies that gather 

exposure information, clinical data, and 

tissue. Therefore, we propose the 

creation of innovative support 

mechanisms that encourage studies 

integrated centers that span the 

continuum of lung cancer and 

incorporate biomarkers linking behavior 

and exposure on one side to neoplastic 

outcomes on the other and that carefully 

consider the role of genetic 

susceptibilities at each successive phase 

of the continuum. 

Rationale 

There are no well-validated intermediate or 

susceptibility biomarkers that reliably 

predict lung cancer. Some may reflect 

exposure or susceptibility, whereas others 

may reflect the presence of cancer, but none 

can sufficiently link the two ends of the 

spectrum. This is a key requirement for 

improving risk assessment models. Such 

models will need to incorporate 

epidemiological data (including smoking, 

diet, family history, and other exposures) 

and multiple biomarkers along pathways 

that reflect different stages of 

carcinogenesis. 

Recent reports and technology advances 

suggest progress in many categories of 

biomarkers including cytogenetic markers 

(FISH), carcinogen-DNA adducts, tumor 

mutations (CGH, loss of heterozygosity), 

proteomics, expression (arrays and specific 

genes), cytology, and epigenetic markers. 

Investigations conducted in this type of 

setting can provide an exceptional 

opportunity to advance mechanistic 

understanding, identify subgroups at altered 

risk, understand the relative contributions of 

tobacco exposure and host factors to disease, 

and advance chemoprevention and early 

detection efforts. 

Studies or centers should receive special 

consideration for funding if they propose 

such a multidisciplinary approach to 

development, validation, and use of 

biomarkers. The Etiology Breakout Group 

proposed the concept of the BEGIN model, 

which would incorporate the entities of 

Behavior, Exposure, Genetics (Germline), 

Intermediate Biomarkers, and Neoplastic 

molecular markers (i.e., tumor tissue). (Need 

to highlight the first letter of each) Such 

integrated approaches should allow for the 

most efficient characterization and 

development of new biomarkers that are 

needed for risk assessment and 

chemoprevention approaches. This, in turn, 

would ensure that biomarker studies are 

conducted in a setting that promotes 

multidisciplinary participation, a rich array 

of study questions that can be addressed, the 

opportunity to include behavioral issues in 

studies (e.g., smoking cessation, smoking 

topography, psychological factors that 

contribute to smoking persistence), and a 

highly efficient and cost-effective approach. 

Questions that are critical to both behavioral 

and cancer scientists, such as, “What are the 

genes that contribute to smoking 

dependency?” may also be efficiently 

addressed in such study settings. 

Etiology 29 
RESOURCES NEEDED 

• NCI’s Extraordinary Opportunity in 

tobacco should be maintained as a 

means of supporting broad and vigorous 

scientific and public health efforts 

focused on the major etiologic factor in 

lung cancer. 

• An ability to combine data across studies 

is needed. A web site should be created 

that encourages the use of common data 

elements relevant to lung cancer and 

provides technical information on 

standardization, best practices, and 

protocols involved in biospecimen 

collection, processing, and information 

management. 

• Training in genomic, post-genomics 

(expression and proteomics), and 

informatics is needed for investigators at 

all levels to take advantage of 

interdisciplinary opportunities. 

Although recently created 

Transdisciplinary Tobacco Centers have 

training programs, most are weak in the 

area of tobacco carcinogenesis. 

• Standardized validated questionnaires 

that assess tobacco exposure accurately 

at diverse levels should be made 

available through web-based resources. 

BARRIERS 

• Previous studies of genetic susceptibility 

factors have been too small to achieve 

adequate statistical power. Clinicallybased studies that include molecular 

markers sometimes fail to gather critical 

exposure data. 

• Bioinformatics, biorepository, and data 

management support are generally 

needed to support large-scale integrated 

studies and to promote pooling across 

studies, sharing of specimens, improved 

quality control, and other scientific 

priorities. 

• Insufficient data are available to evaluate 

the ability of purported harm-reduction 

strategies or products to reduce lung 

cancer risk. 

• Animal models for complex exposures 

are inadequate for exploration of tobacco 

carcinogenesis, dose-response 

relationships, and dose adjustments that 

mimic harm-reduction strategies. 

• Epidemiologic study designs have not 

fostered the comprehensive evaluation 

of biomarkers specifically correlating 

the relationship of surrogate 

susceptibility markers both with 

etiologic factors and with tumor 

phenotype. 

30 Report of the Lung Cancer Progress Review Group 
Prognosis and Staging

Co-chairs: Dr. Valerie W. Rusch, 

Dr. Paul H. Gumerlock 

Writer: Alice Lium 

INTRODUCTION 

There are generally recognized deficiencies 

in the staging of both non-small cell lung 

cancer (NSCLC) and small cell lung cancer 

(SCLC). Improvements in the staging of 

lung cancer will form the cornerstone of 

studies of the biology of the disease, which 

in turn will allow hypothesis-driven clinical 

trials and lead to critical advances in 

therapy. The issues related to staging and 

prognosis can be broadly considered under 

the categories of clinical staging and 

biological/molecular staging. 

RESEARCH PRIORITIES 

1. Revise and refine the current clinical 

staging systems for NSCLC and 

SCLC—an improvement that will also 

facilitate evaluation of imaging 

modalities for lung cancer. This 

priority requires the development of a 

linked clinical and pathological 

database. 

2. Investigate molecular markers of 

detection, staging, prognosis, and 

response to therapy. This priority 

requires creation of a biospecimen 

repository linked to the 

clinical/pathological database and is 

best achieved through a diseasespecific, multi-center, and multidisciplinary lung cancer group. 

Develop statistical approaches (e.g., 

algorithms) and present data in a standard 

format that will make it possible to integrate 

clinical information and molecular profiling. 

This priority requires development and 

support of bioinformatics, statistics, and 

clinical epidemiologic expertise, as well as 

relevant infrastructure. 

STANDARD CLINICAL AND 

PATHOLOGICAL STAGING 

Rationale 

The current staging systems for both 

NSCLC and SCLC have notable 

deficiencies because they fail to discriminate 

several prognostic groups accurately. For 

NSCLC, the current TNM system, based on 

primary tumor, regional nodes, and 

metastasis, may not precisely describe very 

early (less than 2 cm) tumors, and 

conversely, may not accurately stratify the 

more advanced tumor subsets. For SCLC, a 

significant discrepancy exists between what 

is usual clinical practice and the American 

Joint Committee on Cancer (AJCC) 

recommendations for staging. Most 

oncologists use a “limited versus extensive” 

stage classification, whereas the AJCC 

staging manual indicates that the same 

TNM-based system used for NSCLC should 

be applied to SCLC. 

Clinical staging is also hampered by 

variations and inadequacies in pretreatment 

imaging studies. Few standards exist, and 

the algorithms for follow-up remain 

undefined. Investigation in this area is 

needed. 

RESOURCES NEEDED 

• Revision of the staging system will 

require large, multi-center clinical 

databases with well-characterized 

patients, long-term clinical follow-up, 

and careful clinical-pathological 

correlation. Such databases do not exist. 

An effort under way by the International 

Prognosis and Staging 31 
Association for the Study of Lung 

Cancer (IASLC) is hindered by large 

international variations in the types and 

contents of data sets, as well as a lack of 

funding; therefore, this issue, as well as 

studies of imaging modalities, would 

best be addressed by a funded, diseasespecific, lung cancer group effort to 

generate and maintain a clinical database 

that incorporates standardized 

nomenclature. 

BIOLOGICAL AND MOLECULAR 

STAGING 

Rationale 

Improvements in the TNM-based clinical 

and pathological staging will be unable to 

describe fully the biology of individual 

tumors. A staging system that includes 

molecular profiling of abnormalities will be 

pivotal to defining prognosis and selecting 

therapy. Despite much investigation into 

individual genetic abnormalities in lung 

cancer during the past decade, 

comprehensive analysis of genetic 

abnormalities in relation to clinical and 

pathological features is still lacking. 

Molecular profiling is a major objective for 

which significant resources will be required. 

This effort may require an intensive study of 

very well defined, relatively small patient 

cohorts (100–200 patients), followed by 

validation across larger cohorts. Genetic 

studies should include non-smokes as well 

as smokers. 

Beyond contributing to prognosis, important 

applications of molecular profiling of both 

smokers and non-smokers include predicting 

response to therapeutic interventions 

(chemotherapy, radiation, targeted 

therapies), detection of occult metastases, 

and risk stratification for recurrence or the 

development of second primary tumors. 

Emerging information suggests that serum 

markers, including shed tumor DNA and 

proteins, may be useful in detection, staging, 

and evaluation of response to therapy. This 

is an area of novel investigation with great 

clinical potential. 

The wealth of new molecular information 

and the complexity of the analyses needed to 

integrate molecular and clinical data, 

particularly array data, require statistical and 

bioinformatics research and development of 

algorithms. Recruitment and training of 

relevant personnel with multi-disciplinary 

expertise in these areas (e.g., pathology and 

bioinformatics) is of paramount importance. 

The professionals required for this effort 

should be regarded as participating faculty, 

not merely as service personnel. 

RESOURCES NEEDED 

• Critical to this effort will be the 

previously described prospective clinical 

database, paired with a biospecimen 

repository. Such a repository should 

include snap-frozen tumor and related 

benign tissues suitable for array 

analyses; fixed, paraffin-embedded 

specimens for tissue arrays; 

serum/plasma, sputum, buccal mucosal 

cells, urine, and bone marrow. The 

collection and characterization of such a 

resource require a close, funded 

collaboration among pulmonary 

medicine physicians, thoracic surgeons, 

pathologists, oncologists, 

epidemiologists, and molecular 

biologists. Components of such a 

resource now exist in various cancer 

centers and cooperative groups, but a 

comprehensive and integrated highquality resource tied to a clinical 

database does not. A biospecimen 

repository that can rapidly yield clinical 

correlation is best developed in a 

national setting by a multi-disciplinary, 

lung cancer-specific, multi-center group. 

32 Report of the Lung Cancer Progress Review Group 
Additionally, bioinformatics and 

statistical resources are needed in the 

forms of hardware, software 

development, and algorithm 

development. These resources should be 

developed in both cancer centers and 

cooperative groups. This effort will also 

require the establishment of common 

data elements for clinical, pathological, 

and molecular data sets. 

EDUCATIONAL NEEDS 

• The support and development of 

dedicated academic investigators who 

speak a common language across all 

relevant disciplines is key to the success 

of this effort. At present, the large 

challenge presented by lung cancer is 

studied by very small numbers of 

clinical and laboratory investigators. 

Formal opportunities for crossdisciplinary education are needed and 

could be the subject of regular NCIsponsored training conferences. These 

should be aimed not only at established 

investigators and trainees but at the 

primary physicians who initially care for 

patients with lung cancer. Of equal 

importance is the dissemination of new 

information about prognosis and 

methods of staging to patients and their 

caregivers. One way this might be 

accomplished is through the support of 

advocacy groups. 

BARRIERS 

• A significant barrier to creating the 

biospecimen repository is the increasing 

regulatory burden on investigators. In 

recognition of the importance of patient 

confidentiality and anonymity, this 

burden could be diminished through a 

concerted NCI-sponsored effort to 

standardize and facilitate informed 

consents and Institutional Review Board 

review. 

• With respect to lung cancer studies, 

consideration could be given to the fact 

that most of the molecular alterations 

under study are somatic rather than 

germline. Further, in lung cancer—a 

disease whose biology is poorly 

understood—exploratory analyses of asyet uncharacterized or unknown genes 

should be emphasized. Genetic studies 

that involve both smokers and nonsmokers may reveal genetic 

predispositions to the disease. 

Discovery of new genes is critical for 

advances in lung cancer staging and 

therapy. Undue regulatory barriers may 

inhibit this very important approach to 

the study and treatment of lung cancer. 

Prognosis and Staging 33 
Quality of Care 

Co-chairs: Dr. William Evans, 

Dr. Thomas Smith, 

Dr. Craig Earle 

Writer: Kit Johnston 

BACKGROUND 

Quality of care has been defined by the 

Institute of Medicine as “the degree to 

which health services...are consistent with 

current professional knowledge.” In 

addition, quality care is “...care that 

incorporates respect for patients’ values and 

preferences” (National Cancer Policy 

Board). 

The quality of care for lung cancer patients 

was considered in the context of these 

definitions using the quality triad of 

structure, process, and outcome. Using this 

approach, it was possible to identify 

research opportunities that would address 

gaps in our current knowledge of the quality 

of care of lung cancer patients and build on 

existing research initiatives. 

The Quality of Care Working Group 

considered the structural issues for the 

quality of lung cancer patient care to be 

those elements or components of the health 

system that are required for delivery of 

services from screening to diagnosis, 

treatment, supportive care, and palliative 

care. Although discussion focused on the 

specific needs of patients receiving 

treatment and related care, because of the 

magnitude of the perceived problems, it was 

also noted that significant structural issues 

exist in relation to the provision of 

screening and prevention services and 

programs. 

Health system organizational structures that 

could affect the quality of care for lung 

cancer patients include: (a) the type of 

health care facility (e.g., tertiary care vs. 

community oncology clinic); (b) the 

organization of service delivery (e.g., 

multidisciplinary clinics and tumor boards 

vs. private solo practice); (c) the availability 

of human resources and degree of 

specialization; (d) access to new 

technologies and equipment; and (e) the 

availability of, and access to, home health 

and hospice care. Knowledge of the optimal 

components and organization of service 

provision would not only facilitate the 

spread of current best practices but serve as 

a platform for the conduct of clinical 

research and the rapid dissemination of 

research findings. 

The Quality of Care Working Group agreed 

that it would be extremely useful to know 

the extent to which best practices for the 

management of lung cancer are currently 

adopted and appropriately applied in various 

settings across the United States. There is 

research evidence, for example, that curative 

lobectomy is not used to the optimal extent 

for minority groups, and there is substantial 

anecdotal information on the non-uniform 

use of combined-modality treatment for 

stage III non-small cell lung cancer 

(NSCLC) and of systemic chemotherapy in 

advanced disease. This knowledge base 

needs to be greatly expanded if current and 

future treatments are to be disseminated to 

the benefit of all patients. Studies are 

required to determine the use of these best 

practices, including such potentially curative 

interventions as lobectomy for stages I and 

II NSCLC and combined-modality chemoradiotherapy for limited small cell lung 

cancer (SCLC) and stage III NSCLC. 

Similarly, information on the use of 

prophylactic cranial irradiation (PCI) in 

SCLC and chemotherapy in stage IV 

34 Report of the Lung Cancer Progress Review Group 
NSCLC would be invaluable in directing 

efforts to ensure that lung cancer patients are 

offered the best therapy currently available. 

In addition, information on the prevalence of 

inappropriate use of practices, such as the 

administration of adjuvant chemotherapy or 

radiotherapy after completely resected 

NSCLC would be important to shape 

educational initiatives in order to ensure 

conservation of scarce resources and the 

delivery of optimal care. 

Additional questions of concern for 

processes of care include (a) the extent of 

surveillance for new primary tumors in 

patients with curatively treated stage I and II 

NSCLC, (b) the extent to which patients 

with stage III NSCLC are appropriately 

assessed (staged) for combined-modality 

therapy, and (c) whether patients with stage 

IV NSCLC share in the decision-making for 

care, receive psychosocial care and 

informational support appropriate to need, 

and are offered participation in a clinical 

trial. For end-of-life care, it would be 

important to examine the processes of care 

to ensure optimal control of pain and 

symptoms, the appropriate use of advanced 

directives and the involvement of patients 

and their families in the decision-making for 

the most appropriate location of dying (e.g. 

home, hospice, hospital). 

The principal outcomes examined in lung 

cancer clinical trials have been response and 

survival; patient-related outcomes have been 

examined much less often. Outcomes of 

importance to patients include quality of 

life, complications of therapy, quality of 

death, economic burden, and satisfaction 

with care, and these outcomes need to be 

formally adopted into future clinical 

research endeavors. 

RESEARCH PRIORITIES 

1. Develop, implement, and evaluate 

models of care delivery to optimize the 

delivery of best-known clinical 

practice and to determine the effects 

of these models on the processes and 

outcomes of care and on accrual of 

patients to clinical trials. For 

example, assess the effect of 

specialized or multidisciplinary 

management settings, telemedicine 

initiatives, informatics support, and 

integrated supportive and palliative 

services. 

Rationale 

Several studies have found that medical 

interventions for which good evidence of 

survival benefit exists are not uniformly 

adopted (e.g., lobectomy for early-stage 

NSCLC, prophylactic cranial irradiation for 

SCLC, and concurrent combined-modality 

therapy for limited SCLC and stage III 

NSCLC). There is also evidence of a strong 

relationship between volume of activity and 

patient outcomes. Although current 

initiatives such as CanCORS may start to 

document the extent of the problem in lung 

cancer care, further work will be needed to 

determine why such disparities exist and to 

develop strategies to correct them. In doing 

so, it will be important to identify valid 

measures of the quality of lung cancer care 

and to evaluate novel programs of service 

delivery, including approaches such as 

regional diagnostic assessment units and 

multidisciplinary consultation, access to 

allied health professionals for supportive 

care, access to peer support, and access to 

hospice care. Research proposals may range 

from innovative pilot studies to optimize the 

delivery of such services to a consortium 

performing cluster randomization to 

evaluate specific interventions. It will be 

essential to engage community practices in 

Quality of Care 35 
these efforts and to evaluate outcomes in 

relation to patient volumes. 

1. Build on existing NCI programs, to 

address the special needs of lung 

cancer patients: 

A. Earmark funds within the Centers of 

Excellence in Cancer 

Communication and related 

initiatives to study ways to (a) 

improve communication between 

doctors and lung cancer patients and 

their family members; (b) enhance 

patient and provider knowledge of 

prevention, screening, and care 

options; (c) increase shared decisionmaking around lung cancer therapies 

and complementary and alternative 

medicine; and (d) increase 

participation in clinical trials. 

B. Extend CISNET activities to (a) 

include the development of a model 

of lung cancer management to 

support the evaluation of new 

technologies and (b) assist design of 

clinical trials and inform policy 

decisions. 

Rationale 

Lung cancer is unique within oncology in 

many ways: 

• It is the most common cause of cancerrelated death; for this reason, new 

screening and treatment technologies 

can have enormous public health 

implications. 

• The population it affects tends to be 

older and of lower socioeconomic and 

educational levels than other 

malignancies. 

• Treatments, particularly for advanced 

disease, have significant side effects and 

are often of only modest benefit. 

• The stigma that lung cancer is a selfinflicted disease, coupled with a 

pervasive sense of therapeutic nihilism, 

conspire to create a medical environment 

in which many patients with advanced 

lung cancer are not even offered 

treatment. 

Consequently, it is important to overcome 

the atmosphere of therapeutic nihilism, to 

educate care providers and patients, and to 

identify strategies that facilitate the 

communication of treatment options that 

take into account patient preferences for 

care. It is also important to explore the use 

of complementary and alternative medicines 

among lung cancer patients and 

communication strategies that can heighten 

awareness of, and participation in, clinical 

trials. 

Because of the great need to make 

therapeutic progress against this disease, 

participation of patients in clinical trials 

must be greatly enhanced. Experience with 

other diseases provides evidence that 

patients in clinical trials receive high-quality 

care. Furthermore, patients with cancer feel 

that it is an important element of quality of 

care to have access to trials. It is crucial that 

patients participating in such trials have 

adequate decision-making support. For 

example, decision aids could be developed 

and assessed in terms of their ability to help 

patients make decisions with a clear 

understanding of the goals of the trial and 

their influence on patient satisfaction with 

the decision-making process. 

Several expensive new technologies are 

being introduced into lung cancer 

management, including spiral computed 

tomography (SCT) for screening and PET 

scans for staging and assessment of response 

36 Report of the Lung Cancer Progress Review Group 
to treatment. Because lung cancer is so 

common, such developments have important 

economic, public health, human resource, 

and policy implications. Computerized 

disease models should be used to evaluate 

these issues. Moreover, models can be used 

to optimize the selection of target 

populations in the design of large 

prospective trials. 

3. Extend the work currently under way 

at the NCI Outcomes Branch to 

develop standard tools for measuring 

patient-reported outcomes of 

particular relevance to lung cancer 

patients, to be incorporated into NCIsponsored clinical trials: 

A. Convene a consensus meeting that 

includes patients to define the 

specific data elements, their 

definitions, and methodological 

approaches necessary to capture 

these patient-related measures of 

quality of care: quality of life; 

assessment of symptoms; physical 

and psychosocial effects of 

treatment; patient satisfaction; and 

economic burden for patients and 

caregivers. 

B. Convene a separate consensus 

meeting to define the data on 

resource use that should be captured 

alongside clinical trials and define 

which trials are the best candidates 

for such economic evaluations. This 

information can improve 

understanding of the relative costeffectiveness of new interventions 

and assess the economic impacts of 

their adoption on the health care 

system. 

Rationale 

Clinical trials have traditionally focused on 

response and survival outcomes. 

Unfortunately, only modest progress has 

been made in the treatment of lung cancer; 

consequently, patient-reported outcomes, 

such as quality of life, cancer-related 

symptoms, and complications of care, 

should assume greater importance. For 

some of these measures, a plethora of 

instruments already exist; for others, these 

measurement tools will need to be 

developed. NCI’s Outcomes Branch has 

convened the Cancer Outcomes 

Measurement Working Group (COMWG) to 

evaluate outcome measures for cancer in 

general. The Quality of Care Working 

Group proposes that this work be extended 

to identify a standard set of core measures 

for inclusion in appropriate lung cancer 

trials. For some measures, such as quality 

of life, this will involve choosing the best 

instruments among many, whereas areas 

such as patient satisfaction are in need of 

methodological research, including both 

quantitative and qualitative techniques and 

the evaluation of the clinical significance of 

changes in scores. NCI should provide 

additional support to clinical trials 

specifically for the study of these outcomes. 

RESOURCES NEEDED 

Funds are needed for investigator-initiated 

pilot studies or randomized trials through 

existing cooperative groups, NCI’s 

Community Clinical Oncology Program, 

health maintenance organizations, or new 

consortia to address issues related to the 

organization of service delivery to achieve 

optimal quality of care and maximize 

clinical research capability: 

1. Building on existing NCI programs: 

A. Earmark funds in the Cancer 

Excellence in Cancer 

Communication program for 

evaluation of communication issues 

for lung cancer patients. 

Quality of Care 37 
B. Provide new funds to CISNET to 

develop a model of lung cancer 

disease management. 

2. Support the development of standard 

tools for measuring patient-reported 

outcomes and economic burden: 

A. Fund a consensus meeting of 

representatives of the lung cancer 

clinical trials community; the 

pharmaceutical industry and patients, 

family members, and survivors to 

develop data elements and their 

definitions for inclusion in NCIsponsored clinical trials. 

B. Fund a consensus meeting to 

determine the resource use data that 

should be captured alongside clinical 

trials and the criteria to define the 

most appropriate trials requiring 

economic evaluation. 

C. Commit NCI funds to apply these 

tools to measure the patient-related 

outcomes in future lung cancer 

clinical trials. 

38 Report of the Lung Cancer Progress Review Group 
Therapy

Co-chairs: Dr. Paul Bunn, Jr., 

Dr. Walter Curran, Jr., 

Dr. Gerold Bepler 

Writer: Donna Savage 

INTRODUCTION 

Lung cancer is the leading cause of cancerrelated mortality in the United States and in 

the world. In the United States, the 5-year 

survival rate remains less than 15 percent. 

However, major advances in the treatment 

of lung cancer have occurred in the past 

decade. For example, a 50–70 percent 

improvement in the median survival times of 

patients with locally advanced small cell 

lung cancer and non-small cell lung cancer 

has been achieved. Such improvement 

emphasizes the success of multi-disciplinary 

lung cancer research. 

Advances in lung cancer have not been as 

well recognized or as widely implemented 

as would be anticipated, given the common 

nature and severity of the illness. At the 

same time, lung cancer offers many great 

research opportunities: 

• This disease has a high incidence and 

known etiology. 

• People at risk are easily identified. 

• Tissue is fairly accessible. 

• The biotechnology and pharmaceutical 

industries are interested in studying new 

agents in this disease. 

• The public is acutely aware of the 

devastating nature of the lung cancer. 

Despite these significant opportunities for 

research, lung cancer receives 

disproportionately less funding than other 

cancers. Funding lung cancer research at 

appropriate levels is especially important 

when one considers its prevalence and 

economic impact. 

There are several barriers to progress in 

therapeutic research for lung cancer. These 

include: 

• A lack of funding mechanisms for 

multi-disciplinary collaborations. 

• A lack of lung cancer-specific tumor 

banks with associated clinical 

information and ongoing support for 

tissue acquisition for pathologists and 

surgeons to collect and process tissue 

samples. 

• Insufficient training and educational 

opportunities. 

• A lack of salary support and 

academic recognition for clinical 

investigators. 

• Regulatory burdens. 

• Limited public understanding of the 

advances achieved through multispecialty research and care. 

• Lack of adequate support for 

participation in cooperative group 

clinical trials. 

The rapid rate of discovery of candidate 

molecular targets for lung cancer therapy 

and candidate agents has increased the 

opportunity for benefit from enhanced 

research support. This progress has created 

the need for new paradigms of clinical trial 

design. Additionally, improvements in 

functional imaging and planning and 

Therapy 39 
delivery of radiation oncology treatment 

provide an unprecedented opportunity to 

enhance tumor control while decreasing 

treatment-related morbidity. Such 

developments further emphasize the need 

for coordinated research among many 

disciplines. 

Progress in lung cancer research is 

evidenced by the activity of the centers with 

SPORE grants, the success of clinical trial 

groups that study stages III and IV disease, 

and the emergence of an active advocacy 

group, Alliance for Lung Cancer Advocacy, 

Support, and Education (ALCASE). 

Progress has been limited, however, in 

identifying and testing new therapeutic 

approaches for patients with stages I and II 

lung cancer, in verifying the clinical utility 

of molecular predictors of either prognosis 

or response to treatment, and in being able 

to rapidly perform phase I and II studies of 

new targeted therapies with biologic 

endpoints. Progress will also continue to be 

limited in the future by the paucity of 

clinical investigators staying in or entering 

academic medical oncology in general, and 

lung cancer research specifically. 

A coalition of lung cancer-specific clinical 

centers of excellence working together, 

modeled on SPORE lung cancer-specific 

translational research centers of excellence, 

would enable clinical opportunities to be 

addressed. A strong intramural lung cancer 

center of excellence would synergize with 

this extramural effort. 

RESEARCH PRIORITIES 

1. Select, test, and validate new targets 

in therapeutic clinical trials. 

Rationale 

The advances in understanding of lung 

cancer pathogenesis have identified multiple 

new targets for therapeutic intervention. 

The number of potential targets and 

interventions based on these targets exceeds 

the capacity of clinical trials to accrue the 

patients needed to address all potential 

agents. Therefore, a method of selecting 

and setting priorities for the best targets is 

necessary. One way to assist this prioritysetting process is to identify the most 

frequent abnormalities in specific lung 

cancers compared with normal tissues, 

which requires access to well-characterized 

specimens from patients with lung cancer of 

various histologies and stages. These wellcharacterized specimens with clinical 

correlations are not available. In addition, 

there are inadequate ways of funding the 

acquisition and processing of such biologic 

specimen repositories, and regulatory 

burdens inhibit establishment of such 

repositories. 

To use biologic information from tissue 

samples in clinical trial and clinical 

management decisions, assays must provide 

rapid and reproducible results. Because 

clinical circumstances often allow for only 

small biopsies of tumor specimens, these 

assays must be able to be conducted with 

small amounts of tissue. In addition, clinical 

trials must test the ability of functional 

imaging techniques to provide relevant 

information about antitumor response and 

targeting success, without the need for 

invasive procedures. 

Adequate attention to all of these issues 

would require support of thoracic surgeons 

to obtain the proper specimens, support of 

pathologists to access and process the 

specimens appropriately, uniform clinical 

and pathologic staging, therapy, and followup of the patients from whom the tissue was 

obtained. 

40 Report of the Lung Cancer Progress Review Group 
2. Optimize design, conduct, and 

support of clinical trials: 

A. Establish a consortium of centers 

with multi-disciplinary excellence in 

lung cancer clinical trials. 

B. Develop lung cancer-specific 

Requests for Applications (RFAs) 

and Requests for Proposals (RFPs) 

for study of selected novel therapies 

in lung cancer. 

Rationale 

Advances in lung cancer care during the last 

10 years have resulted from landmark 

observations in randomized trials of patients 

with stage III and stage IV disease. 

However, advances in biology and 

technology require new clinical trial 

paradigms with an emphasis on design and 

accrual to novel Phase I and II trials, as well 

as studies of early-stage disease in which the 

therapies will have the greatest impact on 

mortality. These novel early-phase and 

early-stage trials, by definition, will require 

coordination among centers, each of which 

must have excellence in multi-disciplinary 

interactions. Most of these trials will 

require tissue correlations, functional 

surrogate endpoints, or both, as discussed in 

the first recommendation. We recognize 

that many cancers (e.g., breast, prostate, and 

ovarian) have multiple specific funding 

mechanisms, from NIH as well as other 

Federal and non-Federal organizations. 

Because few such opportunities are 

available in lung cancer, the 

recommendations for RFAs and RFPs are 

particularly important. 

The number of patients accrued to trials in 

stage I and stage II lung cancer is 

inadequate. In addition, the number of 

Phase I and II trials is not sufficient to 

assess all the new targeted therapies and 

combinations. This creates the need for new 

funding mechanisms to support these types 

of trials. Barriers to clinical trial accrual are 

listed in the third recommendation. 

Solutions to the burdens and costs 

associated with regulations include the 

development of standardized informed 

consent forms, the protocol-specific 

definitions of standard care and research 

care, and centralization of Institutional 

Review Board processes. Uniform and 

simple ways of complying with regulations 

in the most cost-effective manner need to be 

developed centrally. 

3. Support and expand multidisciplinary interactions in clinical 

research: 

A. Support a consortium of centers of 

excellence that would be able to 

rapidly design and conduct earlystage and early-phase trials. 

B. Support individual centers that have 

unique clinical trial concepts and 

targets. 

C. Compensate principal investigators 

on all peer-reviewed clinical trials. 

Rationale 

Early-stage and early-phase trials will 

require consistent collaborations among 

specialists with particular expertise in 

thoracic oncology, including surgeons, 

radiologists, pulmonologists, medical 

oncologists, radiation oncologists, 

pathologists, and laboratory-based scientists. 

No current funding mechanisms support this 

type of multi-specialty interaction. We 

believe that new funding mechanisms 

should be developed. The first would 

support a consortium of centers of 

excellence that could rapidly design and 

conduct early-stage, early-phase trials. This 

approach requires a modest infrastructure, 

Therapy 41 
including a competitively designated 

statistical and informatics center. This 

consortium could also address other issues, 

such as a clinical database linked to a 

specimen biorepository. The second would 

support individual centers with unique 

clinical trial concepts and targets through 

lung cancer-specific RFAs and RFPs. 

Only small numbers of academic clinical 

oncologists are dedicated to lung cancer 

studies. The reasons include lack of salary 

support and academic recognition for 

clinical investigators, lack of multidisciplinary funding mechanisms, and 

mounting regulatory burdens and associated 

costs. Thus, we recommend that the 

principal investigators on all peer-reviewed 

clinical trials be compensated for their time 

and effort by well-defined support that can 

come from existing center grants or from the 

new coalition. 

The burdens mentioned are coupled with a 

history of clinical and therapeutic nihilism 

toward lung cancer in the medical and 

academic communities. Thus, we 

recommend RFAs and RFPs for education 

and communication specific to lung cancer. 

RESOURCES NEEDED 

Resources that could support current and 

future efforts in lung cancer include: 

1. International database for staging 

classification and modifications 

thereof. The current lung cancer staging 

classification was based on data 

collected through the Lung Cancer Study 

Group and the M.D. Anderson Cancer 

Center through the efforts of Dr. Clifton 

Mountain. This database no longer 

exists and was flawed by a number of 

factors, including the fact that patients 

with stage IIIB or IV disease were not 

included and old staging and treatment 

protocols were used. A recent meeting 

including representatives from 

International Association for the Study 

of Lung Cancer, the World Health 

Organization, the International Union 

Against Cancer, European Union for 

Research and Treatment of Cancer, 

American Joint Commission on Cancer, 

and others was recently held in London, 

and all agreed to participate in a new 

international database. Funding for such 

a database, however, is problematic. It 

was agreed that the United States was a 

logical “home” for such a database, and 

a competitive funding mechanism was 

reviewed as highly desirable and 

efficient. 

2. Support for surgeons and pathologists 

to collect, prepare, and preserve wellcharacterized specimens with 

adequate clinical staging and followup for multivariate prognostic studies 

and for predictive therapy studies. 

Adequate collection, processing, 

distribution, and study of wellcharacterized specimens was viewed as a 

critical problem that could be solved by 

specific funding of data managers to 

assist surgeons and pathologists in tissue 

collection and processing and to assist 

treating oncologists in collecting the 

clinical information and in follow-up. 

Funding could flow through groups 

conducting lung cancer trials, including 

studies through any or all of the 

following: cooperative groups, a new 

Lung Cancer Study Group, and cancer 

centers. The tissue collection would 

include paraffin blocks, fresh tissues, 

and biopsy specimens. 

3. A research consortium for early phase 

I-II trials and for trials in stages I and 

II lung cancer, including lesions less 

than 1 cm. It was obvious to all 

participants that a suboptimal number of 

patients have been enrolled in earlystage trials since the closure of the Lung 

42 Report of the Lung Cancer Progress Review Group 
Cancer Study Group. It was also clear 

that input from thoracic surgeons is 

essential for early-stage trials. The cost 

of the infrastructure for such a group 

need not be large, because the statistical 

portion could, as well as new groups of 

patients (e.g., with tumors less than 1 

cm), available for study. Finally, these 

trials require multi-specialty excellence 

in pulmonology, biology, imaging, 

pathology, thoracic surgery, radiation 

oncology, and medical oncology. 

Thereafter, one or two groups consisting 

of a consortium of centers with multispecialty experts in early-stage and 

early-phase trials was thought to be 

critical. 

4. Support for academic lung cancer 

physicians-scientists through Cancer 

Center Support Grant (CCSG) and 

group mechanisms. Lung cancer is not 

seen as an attractive field of research 

because of the nihilist view of various 

specialists, the multi-specialty 

requirements for successful research, the 

poor outcome of patients, and the stigma 

of tobacco. Existing political pressures 

led to creation of multiple avenues for 

support of investigators in other cancers, 

including the Department of Defense, 

private foundations, and NCI. Lung 

cancer investigators do not have access 

to these funding mechanisms and receive 

little encouragement from department 

chairs. Principal investigators on all 

peer-reviewed clinical trials need to be 

compensated for their time and effort in 

order to have credibility within the 

academic environment and protected 

time for their research. Specific support 

mechanisms are needed. These can be 

directed through existing CCSG and 

cooperative group mechanisms. 

5. A strong intramural NCI program in 

lung cancer. The previous excellence 

of the NCI intramural program in lung 

cancer was viewed as an example of the 

ways in which intramural and extramural 

scientists can advance the state of the 

art. It was noted that the emphasis and 

excellence of the intramural program 

had dissipated. The group recommended 

re-establishing an intramural center of 

excellence in lung cancer research. 

6. Adequate support for participation in 

clinical trials. The regulatory burden on 

the clinician has increased dramatically 

over the past five years. The current cooperative group mechanism does not 

adequately compensate investigators for 

their regulatory and data management 

costs of putting an patient on trial. This 

is a strong dis-incentive for participating 

in clinical research. 

7. Adequate support for junior 

investigators. A young investigator 

interested in clinical lung cancer 

research has a formidable uphill task 

finding protected time to do so, given 

the clinical and fiscal pressures on most 

academic departments of medicine. 

There will be few academic clinical 

researchers in lung cancer in five to ten 

years unless resources are found to 

support them in their early career 

development. The K24 is an excellent 

approach to this problem, but requires 

that investigators already have peerreviewed support. 

BARRIERS 

1. Education and training. Lung cancerspecific education and training of 

physicians and other caregivers, the 

public, and patients and families is 

needed. There should be RFAs and 

RFPs for education and training. 

2. Investigator support and recognition. 

Clinical lung cancer-specific salary 

support and academic recognition for 

Therapy 43 
principal investigators is not equivalent 

to peer-reviewed funding. This could be 

rectified through the cancer centers, 

cooperative groups, and a consortium 

mechanism. 

3. Regulatory issues. Centralized, 

simplified processes (including the 

definition of standard care and research 

care and a standardized Institutional 

Review Board) should be endorsed, a 

standardized consent form should be 

developed and used, and the costs 

associated with regulatory burdens 

should be reimbursed. 

44 Report of the Lung Cancer Progress Review Group 
Tobacco Control

Co-chairs: Dr. Dileep Bal, 

Dr. Dorothy Hatsukami, 

Dr. Thomas Glynn 

Writer: Cheryl Ulmer 

BACKGROUND 

Nicotine addiction is the single most 

important challenge facing efforts to reduce 

lung cancer incidence and mortality in the 

United States; 30 percent of all cancer 

mortality is attributable to tobacco use. No 

other cluster of risk factors, including 

genetic and biological factors, lifestyle 

factors, and environmental factors, has as 

high an association with lung cancer as 

smoking. Because smoking accounts for 

almost 90% of all lung cancer cases, and 

because quitting smoking can reduce (but 

not eliminate) the elevated relative risk of 

lung cancer, the greatest impact on deaths 

from lung cancer in the United States will 

result from efforts to prevent smoking and 

from helping smokers to quit. Thus, 

significant attention and resources should be 

allocated to interventions to reduce tobacco 

use and to the evaluation of the effects of 

those interventions. 

Eliminating tobacco use as a risk factor for 

lung cancer is especially challenging 

because of tobacco’s addictive nature. 

Although smoking prevalence has dropped 

40 percent since the 1964 Surgeon General’s 

report, one in four adults still smokes. 

Another one in four is a former smoker, who 

retains an elevated risk for cancer. 

Furthermore, this is one area where health 

disparities are most apparent and lethal. The 

highest prevalence and greatest burden of 

disease today, and in the future, is borne by 

those with the least income and education. 

For example, women with only 9–11 years 

of education are three times more likely to 

be current smokers (32.9 percent) than are 

women with 16 or more years of education 

(11.2 percent). Furthermore, marketing of 

tobacco products has clearly targeted not 

only youth but other vulnerable populations 

as well. The most effective way to influence 

the problem of health disparities in the 

United States is to use targeted populationbased tobacco control strategies and 

protocols to reduce smoking. 

Overall, cigarettes kill more than 430,000 

Americans each year. We must increase the 

societal investment and commitment to 

research that can identify effective tobacco 

control measures, and ensure the broadest 

implementation of those measures. At 

present, the health community is at a distinct 

fiscal disadvantage. The tobacco industry 

spends more than $8.2 billion per year 

promoting its products in the United States 

alone, 10 times more than all 50 states 

combined are spending on tobacco 

prevention and cessation. 

Secondhand smoke is the third leading cause 

of preventable death in the United States, 

killing an estimated 53,000 non-smokers 

each year, approximately 3,000 of them 

from lung cancer. Reviews published in the 

1986 Report of the Surgeon General, by the 

National Research Council in 1986, and by 

the U.S. Environmental Protection Agency 

(EPA) in 1992 concluded that exposure to 

secondhand smoke causes lung cancer. 

Several large U.S. population-based and 

smaller hospital-based case-control studies 

have been published since the EPA review 

was completed, as has a large multi-center 

European case-control study. Most of these 

studies have corroborated the association 

between at least high levels of exposure to 

secondhand smoke and lung cancer, 

although results from single studies have not 

always been statistically significant. 

Tobacco Control 45 
RESEARCH PRIORITIES 

1. Support research initiatives to 

understand the biology of and to 

improve the treatment of nicotine 

addiction and to examine tobacco 

harm reduction targeted to those who 

are unwilling or unable to quit. 

Rationale 

The U.S. Public Health Service guideline on 

smoking cessation provides clear, concise, 

and evidence-based clinical guidance for 

clinicians and the general public on what 

treatment approaches work best. Although 

significant progress has been made in the 

success rates from these therapies, there is 

considerable need for more research on 

smoking cessation, because the long-term 

quitting rates at present seldom exceed 25 

percent and because real world effectiveness 

of treatments remains unclear. This 

challenge highlights the need to develop a 

greater understanding of the biobehavioral 

and social processes that are responsible for 

the trajectories from tobacco 

experimentation to dependence in order to 

inform, target, and improve on 

interventions. 

Research on harm-reduction products and 

approaches should also be given attention. 

According to the Institute of Medicine 

report Clearing the Smoke: Assessing the 

Science Base for Tobacco Harm Reduction, 

“a product is harm reducing if it lowers total 

tobacco-related mortality and morbidity 

even though use of that product may involve 

continued exposure to tobacco-related 

toxicants.” Given the existing harmreduction products and the potential for new 

tobacco and cigarette-like products that are 

being developed by the tobacco industry, 

alleged to be “safer” than conventional 

cigarettes, the development of methods and 

standards to identify and define the 

differential toxicity of these products is 

necessary to protect the public health. 

Furthermore, the relationship between 

intermediate biomarkers for exposure to 

tobacco toxins and disease, and the doseresponse relationship between tobacco 

exposure and these biomarkers, needs to be 

explored. Of equal importance is the need 

to address the public health implications of 

tobacco harm-reduction products and how to 

communicate to the public the implications 

of using these products. Three decades ago, 

the introduction of "low tar" cigarettes only 

increased the already significant public 

health burden due to tobacco use because it 

permitted smokers to believe they were 

reducing their risk of illness when no such 

data existed. As new "low-yield products" 

are introduced by the tobacco industry, an 

acceleration of research in this area is 

imperative if we are to avoid further adverse 

public health consequences. 

Examples of necessary research directions 

follow. 

• Improve understanding of the nicotine 

addiction continuum—from initiation to 

dependence to cessation to relapse—and 

the multiple factors and causal pathways 

that may contribute to the development 

of nicotine addiction. These factors can 

range from a greater understanding of 

the genetic basis of addiction, evaluation 

of specific receptor targets of nicotine, to 

changes in the brain resulting from 

chronic exposure to tobacco. In addition, 

a greatly expanded effort is needed to 

explore gene-environment interactions 

and to better characterize and measure 

the influence of environmental and 

genetic factors on the addictive process. 

• Improve current pharmacological 

treatments (e.g., combination medication 

therapies, non-nicotine products, 

products that target specific receptor 

sites, and antagonist therapies); develop 

novel behavioral treatments that 

46 Report of the Lung Cancer Progress Review Group 
augment pharmacological treatments or 

stand alone; and explore patienttreatment matching, which may include 

a pharmacogenetics approach, and 

pursue this approach with appropriate 

attention to privacy and confidentiality 

issues. 

• Develop animal models for 

understanding the effects of nicotine 

from the cellular to the behavioral level, 

including models to test novel 

medications. Results from animal 

models should be used to inform human 

models, and results from human models 

should be used to drive research with 

animals. 

• Assess harm-reduction approaches, that 

is, reduced smoking with and without 

the aid of pharmacological agents and 

potential reduced-exposure tobacco or 

cigarette-like products. The 

recommended areas of research include 

those specified by the Institute of 

Medicine report Clearing the Smoke: 

Assessing the Science Base for Tobacco 

Harm Reduction: (a) “description of 

dose-response relationship between 

smoke and/or constituent exposure and 

health outcomes in the context of 

exposure reduction; (b) identification 

and development of surrogates for 

disease (e.g. biomarkers that reflect 

mechanisms of disease and that serve as 

intermediate indicators of disease and 

disease risk) (c) the development of 

appropriate animal models and in vitro 

assays of the pathogenesis of tobaccoattributable diseases (e.g., cell culture, 

animal studies, and molecular studies to 

document specific tobacco toxicants as 

the most likely causative agents for 

disease, to better define pathogenic 

effects of tobacco smoke exposure, to 

better explain the relationship of disease 

risk regression and exposure regression, 

and to validate biomarkers of exposure 

and biological effect) (d) short-term 

clinical and epidemiological studies; and 

(e) long-term epidemiological studies 

and surveillance.” In addition, research 

on risk perception and risk 

communication and marketing issues 

related to these harm-reduction 

approaches should be pursued to 

minimize their negative impact on public 

health. 

• Assess the safety of nicotine (e.g., longterm use, use in pregnant women). 

2. Encourage and fund integration of 

tobacco research into existing and 

proposed lung cancer prevention, 

screening and treatment trials. In 

addition, smoking cessation advice 

should be a routine part of any clinical 

trial involving smokers. 

Rationale 

Numerous untapped opportunities exist 

among ongoing intervention trials (e.g., lung 

cancer screening and chemoprevention) for 

tobacco-related research to be conducted, 

integrated, or supplemented. These 

opportunities—which could range from 

cessation research to collection of moderator 

variables to establishment of a longitudinal 

cohort—can be cost effective, unique, and 

opportunistic and provide data leading to 

future NCI studies and initiatives that may 

help in reducing the burden on society from 

lung cancer. 

Advantages of integrating tobacco-related 

research, as a formal grant or contract 

supplement or as an ad hoc initiative, 

include: 

• The opportunity to conduct valuable 

tobacco research at substantial savings 

in cost and resources, because much of 

the initial research cost (e.g., accrual, 

Tobacco Control 47 
staffing) will be borne by the parent 

grant or contract. 

• The opportunity, when integrating with 

lung cancer genetic studies, to obtain 

data on tobacco-related geneenvironment interaction. 

• The opportunity, when integrating with 

lung screening trials, to conduct studies 

that can help elucidate the effect of socalled “reduced risk” cigarettes. 

• The opportunity to collect and analyze 

data on the natural history of individual 

smoking patterns and their role in 

promoting, delaying, or accelerating 

lung carcinogenesis. 

• The opportunity, when integrating with 

long-term follow-up trials, to obtain 

longitudinal tobacco-related data at a 

fraction of the cost such longitudinal 

data collection would ordinarily incur, 

and the opportunity to examine how 

changes in smoking behavior might 

modify the effects of treatment and early 

detection trials. 

• The opportunity, when integrating with 

lung screening or chemoprevention 

trials, for “teachable moments” and 

study of the effectiveness of nicotine 

dependence treatment among 

participants who smoke. 

• The opportunity to “customize” tobaccospecific supplements (e.g., questionnaire 

items, serum collection) to ongoing 

trials. 

• The opportunity to recruit additional, or 

“oversample,” underrepresented 

populations. 

3. Expand the capacity and resources for 

NCI population-based tobacco control 

research, evaluation and surveillance 

initiatives, including domestic and 

international data on tobacco control 

efforts at the societal level, tobacco 

industry marketing activities, and 

smoking prevalence trends. 

Rationale 

Extensive information can be mined and 

may otherwise be lost—from both ongoing 

natural experiments with tobacco control 

programs in the states (e.g., Massachusetts, 

California, Florida, Oregon, and Arizona) 

and from future efforts—that can provide 

invaluable guidance for tobacco control 

program design, implementation, removal of 

barriers to implementation, and evaluation 

of efficacy and effectiveness. Better 

understanding of these large, populationbased tobacco control programs is 

important, because they have the potential to 

create a substantive public health benefit at 

the population level. Population-based 

approaches, such as tobacco price increases, 

secondhand smoke policies (e.g., clean 

indoor air legislation), and further altering 

norms to decrease the social acceptability of 

smoking among adults and young people, 

reach large numbers of smokers compared 

with efforts that focus solely on individual 

smokers. 

Further, valuable data can be obtained from 

other activities (e.g., scientifically rigorous 

assessments of tobacco industry marketing, 

legal actions, tobacco control program 

dissemination and adoption) that are not 

systematically monitored and evaluated by 

others. These resources would allow for 

rapid assessments of important research 

questions and quick-turnaround data 

collection on an as-needed basis and provide 

a foundation for future NCI research 

initiatives. 

This is an especially important activity for 

NCI to undertake, because data collection 

and analysis proposed here are not 

48 Report of the Lung Cancer Progress Review Group 
sufficiently supported within NCI or any 

other organization. If these data do not 

become available or evaluations of existing 

or upcoming natural experiments are not 

conducted, future tobacco control programs 

will be based on an insufficient database and 

inadequate data analysis and interpretation. 

Providing NCI with the ability to collect, 

analyze, and evaluate these data will go a 

long way toward making future tobacco 

control programs as science- and data-based 

as possible. 

Key elements of a population-based 

evaluation and (community-based) 

surveillance strategy could include: 

• Establishing NCI as a clearinghouse in 

collaboration with other organizations 

and agencies—for multiple tobaccorelated datasets. 

• Building more robust etiological models 

of such issues as the initiation and 

maintenance of tobacco use and building 

the knowledge base about how to deliver 

more effective treatment methods across 

a variety of population groups. 

• Developing epidemiological field 

stations capable of the early detection of 

community, state, and regional trends in 

tobacco use and tobacco control 

interventions and evaluating those trends 

in a timely manner. 

• Evaluating natural experiments—either 

independently or collaboratively—that 

are likely to become more prevalent as 

states begin to spend their Master 

Settlement Agreement (MSA) funds 

from the tobacco industry. 

• Studying the role that key moderator 

variables (e.g., sex, race, age, genetics, 

socioeconomic status) may play in 

tobacco addiction, treatment, and relapse 

prevention. 

• Considering how population disparities 

and the tobacco industry targeting of 

vulnerable populations, particularly with 

regard to socioeconomic status, may 

drive future tobacco control needs and 

initiatives. 

• Enabling NCI to analyze international 

datasets specific to lung cancer and 

generally relevant to tobacco issues 

(e.g., effect of advertising bans, 

effectiveness of warning labels, tobacco 

industry marketing techniques). 

• Providing the opportunity to conduct 

studies of lung cancer and tobaccorelated risk assessment and awareness in 

a variety of settings and with a variety of 

populations. 

• Conducting cost-effectiveness studies, 

for example, of treatment delivery, 

specific tobacco control activities, and 

the effects of dissemination and adoption 

of initiatives that are scientifically sound 

and have been proven effective. 

RESOURCES NEEDED 

Resources that could support current and 

future efforts in tobacco control include: 

• Education and training of a new cadre of 

tobacco researchers. 

• Coordination mechanisms and 

collaborations and linkages with other 

NIH institutes, other governmental 

agencies (e.g., Centers for Disease 

Control and Prevention, Food and Drug 

Administration), non-profit 

organizations (e.g., Robert Wood 

Johnson Foundation, American Legacy 

Foundation), and the pharmaceutical 

industry. 

Tobacco Control 49 
• An increase in the NCI budget devoted 

to tobacco that more closely reflects the 

cancer burden caused by tobacco use. 

• Expansion of initiatives similar to 

TTURC (Transdisciplinary Tobacco Use 

Research Centers, funded by NCI and 

the National Institute on Drug Abuse) or 

NCI’s SPORE (Specialized Programs of 

Research Excellence). A 

transdisciplinary approach involves 

research that crosses and integrates 

theories and methods from different 

disciplines. 

• Use of existing expertise and current and 

future surveillance units to develop 

standards and standardized measures for 

surveys and surveillance. 

• A Tobacco PRG or second iteration of 

the Tobacco Research Implementation 

Group report. 

BARRIERS 

• Insufficient funds for tobacco control, in 

proportion to tobacco’s contribution to 

the problem of lung cancer. According 

to the Tobacco Research Implementation 

Plan, tobacco-related research projects 

currently represent around 3.1 percent of 

the NCI budget. 

• Insufficient transdisciplinary 

communication and collaboration. 

• Lack of centers with critical mass of 

collaborating researchers across 

disciplines. 

• Limited resources to facilitate the 

development of evaluation standards and 

standardized measures for tobacco use 

(including initiation and cessation) and 

variables such as risk factors, policies, 

regulations and programs that affect 

tobacco use. 

50 Report of the Lung Cancer Progress Review Group 
Appendix C: Lung Cancer 

Progress Review Group Roster
Lung Cancer Progress Review Group Roster

Margaret R. Spitz, M.D., M.P.H.

Co-Chair

The University of Texas

M.D. Anderson Cancer Center

John C. Ruckdeschel, M.D.

Co-Chair

H. Lee Moffitt Cancer Center and

Research Institute, 

University of South Florida

Scott Saxman, M.D.

Executive Director

National Cancer Institute

Alex Adjei, M.D., Ph.D.

Mayo Clinic

Carolyn Aldige

Cancer Research Foundation of America

Dileep Bal, M.D., M.S., M.P.H.

California Department of Health Services

Stephen Baylin, M.D.

Johns Hopkins School of Medicine

Paul Bunn, Jr., M.D.

University of Colorado Cancer Center

Neil Caporaso, M.D.

National Cancer Institute

Neil Clendeninn, M.D., Ph.D.

Agouron Pharmaceuticals, Inc.

Walter J. Curran, Jr., M.D.

Bodine Center for Cancer Treatment, 

Philadelphia

Virginia L. Ernster, Ph.D.

University of California, San Francisco

School of Medicine

William Evans, M.D.

Cancer Care Ontario

Dorothy Hatsukami, Ph.D.

University of Minnesota Medical School

Stephen S. Hecht, Ph.D.

University of Minnesota Cancer Center

Waun Ki Hong, M.D.

The University of Texas

M.D. Anderson Cancer Center

James Jett, M.D.

Mayo Clinic

David H. Johnson, M.D.

Vanderbilt University Medical Center

Elizabeth Layne, D.D.S., M.S.D.

Alliance for Lung Cancer Advocacy,

Support, and Education (ALCASE)

John D. Minna, M.D.

The University of Texas Southwestern

Medical Center

Cherie Nichols, M.B.A.

National Cancer Institute

Edward F. Patz, Jr., M.D.

Duke University Medical Center

Jennifer Pietenpol, Ph.D.

Vanderbilt University School of Medicine

Franklyn G. Prendergast, M.D., Ph.D.

Mayo Clinic

Valerie W. Rusch, M.D.

Memorial Sloan-Kettering Cancer Center

Joan Schiller, M.D.

University of Wisconsin Medical School

Lung Cancer Progress Review Group Roster 51 
Peter G. Shields, M.D.

Georgetown University Medical Center

Sudhir Srivastava, Ph.D., M.P.H.

National Cancer Institute

Melvyn Tockman, M.D., Ph.D.

H. Lee Moffitt Cancer Center and Research

Institute, University of South Florida

David F. Yankelevitz, M.D.

Cornell University

52 Report of the Lung Cancer Progress Review Group 
Appendix D: Lung Cancer Progress Review

Group Roundtable Participants
Lung Cancer PRG Roundtable Participants

Alex Adjei, M.D., Ph.D.

Mayo Clinic

Michael Alavanja, Ph.D.

National Cancer Institute

Carolyn Aldige

Cancer Research Foundation of America

Chris Amos, Ph.D.

The University of Texas 

M.D. Anderson Cancer Center

David Atkins, M.D.

Agency for Healthcare Research and Quality

Noreen Aziz, M.D., Ph.D.

National Cancer Institute

Peter Bach, M.D.

Memorial Sloan-Kettering Cancer Center

Dileep G. Bal, M.D., M.S., M.P.H.

California Department of Health Services

Douglas Ball, M.D.

Johns Hopkins School of Medicine

Stephen Baylin, M.D.

Johns Hopkins School of Medicine

Steven Belinksy, Ph.D.

Lovelace Respiratory Research Institute

Gerold Bepler, M.D., Ph.D.

Roswell Park Cancer Institute

William Blot, Ph.D.

International Epidemiology Institute

Paul Bunn, Jr., M.D.

University of Colorado Cancer Center

David Burns, M.D.

University of California, San Diego

Tim Byers, M.D., M.P.H.

University of Colorado School of Medicine

Neil Caporaso, M.D.

National Cancer Institute

David P. Carbone, M.D., Ph.D.

Vanderbilt - Ingram Cancer Center

David Christiani, M.D.

Harvard University

Fung-Lung Chung, Ph.D.

American Health Foundation

Richard Clayton, Ph.D.

University of Kentucky, Lexington

Neil Clendeninn, M.D., Ph.D.

Agouron Pharmaceuticals, Inc.

C. Norman Coleman, M.D. 

National Cancer Institute 

James Corrigan, Ph.D.

National Cancer Institute

Walter J. Curran, Jr., M.D.

Bodine Center for Cancer Treatment,

Philadelphia

Janet Dancey, M.D.

National Cancer Institute

Peter V. Danenberg, Ph.D.

University of Southern California

Channing Der, Ph.D.

University of North Carolina

Ethan Dmitrovsky, M.D.

Dartmouth Medical School

Lung Cancer PRG Roundtable Participants 53 
Deborah Duran, Ph.D.

National Cancer Institute

Craig Earle, M.D.

Harvard Medical School

Mary Edgerton, M.D., Ph.D.

Vanderbilt University

Virginia L. Ernster, Ph.D.

University of California, San Francisco

School of Medicine

William Evans, M.D.

Cancer Care Ontario

Margaret Fitch, Ph.D.

Toronto-Sunnybrook Regional Cancer Centre

(Cancer Care Ontario)

Wilbur Franklin, M.D.

University of Colorado Health Sciences

Center

Matthew Freedman, M.D., M.B.A.

Georgetown University Medical Center

Thomas Glynn, Ph.D.

American Cancer Society

Richard Gralla, M.D.

Columbia University

Ellen Gritz, Ph.D.

The University of Texas

M.D. Anderson Cancer Center

Paul H. Gumerlock, Ph.D.

University of California

Davis Cancer Center

Curtis Harris, M.D.

National Cancer Institute

Dorothy Hatsukami, Ph.D.

University of Minnesota Medical School

Cheryl Healton, Dr.P.H.

American Legacy Foundation

Stephen S. Hecht, Ph.D.

University of Minnesota Cancer Center

Claudia Henschke, M.D., Ph.D.

Weill Medical College of Cornell University

James Herman, M.D.

The Johns Hopkins University

Walter Hittelman, Ph.D.

The University of Texas 

M.D. Anderson Cancer Center

Michael Hogan, Ph.D.

Baylor University

Waun Ki Hong, M.D.

The University of Texas 

M.D. Anderson Cancer Center

Kay Huebner, Ph.D.

Kimmel Cancer Center

Jin Jen, M.D., Ph.D.

National Cancer Institute

James Jett, M.D.

Mayo Clinic

David H. Johnson, M.D.

Vanderbilt University Medical Center

Anita Johnston

Lung Cancer Advocate

Fred Kadlubar, Ph.D.

National Center for Toxicological Research

Karen Kelly, M.D.

University of Colorado Health 

Sciences Center

Jeffrey Kern, M.D.

Case Western Reserve University

54 Report of the Lung Cancer Progress Review Group 
Richard D. Klausner, M.D.

National Cancer Institute

Jonathan Kurie, M.D.

The University of Texas 

M.D. Anderson Cancer Center

Stephen Lam, M.D.

University of British Columbia

Elizabeth Layne, D.D.S., M.S.D.

Alliance for Lung Cancer Advocacy, Support,

and Education

Emmanuel Lazaridis, Ph.D.

H. Lee Moffitt Cancer Center and Research

Institute, University of South Florida

Scott Leischow, Ph.D.

National Cancer Institute

Stephanie London, M.D., Ph.D.

National Institute of Environmental

Health Sciences

David Longfellow, Ph.D.

National Cancer Institute

Reuben Lotan, Ph.D.

The University of Texas 

M.D. Anderson Cancer Center

Al Malkinson, Ph.D.

University of Colorado Health Sciences

Center

Pamela Marcus, Ph.D.

National Cancer Institute

Peggy McCarthy, M.B.A.

Alliance for Lung Cancer Advocacy, Support,

and Education (ALCASE)

John D. Minna, M.D.

The University of Texas Southwestern 

Medical Center at Dallas

Harold Moses, M.D.

Vanderbilt-Ingram Comprehensive 

Cancer Center

James Mulshine, M.D.

National Cancer Institute

Kate Nagy, M.A.

National Cancer Institute

Cherie Nichols, M.B.A.

National Cancer Institute

Karen Parles

Lung Cancer Online

Edward F. Patz, Jr., M.D.

Duke University Medical Center

Terry G. Pechacek, Ph.D.

Centers for Disease Control

Frederica P. Perera, Dr.P.H.

Columbia University

Raymond Petryshyn, Ph.D.

National Cancer Institute

Steven Piantadosi, M.D., Ph.D.

Johns Hopkins University School of Medicine

Jennifer Pietenpol, Ph.D.

Vanderbilt University School of Medicine

Armin Pfoh, Ph.D.

GE Corporate Research and Development

Franklyn G. Prendergast, M.D., Ph.D.

Mayo Clinic

Scott Rivers

Alliance for Lung Cancer Advocacy, Support,

and Education (ALCASE)

Patrick Roche, Ph.D.

Mayo Clinic

Lung Cancer PRG Roundtable Participants 55 
April Roeseler 

California Department of Health Services

Selma Rosen 

The Lung Cancer Society of Long Island

Kenneth Rosenzweig, M.D.

Memorial Sloan-Kettering Cancer Center

Jack Roth, M.D.

The University of Texas 

M.D. Anderson Cancer Center

John C. Ruckdeschel, M.D.

H. Lee Moffitt Cancer Center and Research

Institute, University of South Florida 

Valerie W. Rusch, M.D.

Memorial Sloan-Kettering Cancer Center

Scott Saxman, M.D. 

National Cancer Institute

Joan Schiller, M.D.

University of Wisconsin Medical School

Charles Scott, Ph.D.

American College of Radiology

Peter G. Shields, M.D.

Georgetown University Medical Center

Jill Siegfried, Ph.D.

University of Pittsburgh

Jeff Sloan, Ph.D.

Mayo Clinic

Robert Smith, Ph.D.

American Cancer Society

Thomas J. Smith, M.D.

Virginia Commonwealth University

Margaret R. Spitz, M.D.

The University of Texas 

M.D. Anderson Cancer Center

Sudhir Srivastava, Ph.D., M.P.H.

National Cancer Institute

Vernon Steele, Ph.D.

National Cancer Institute

Daniel Sullivan, M.D.

National Cancer Institute

Eva Szabo, M.D.

National Cancer Institute

Eric Moon-shong Tang, Ph.D.

New York University School of Medicine

Melvyn Tockman, M.D., Ph.D.

H. Lee Moffitt Cancer Center and Research

Institute, University of South Florida 

William Travis, M.D.

Armed Forces Institute of Pathology

Annabelle Uy, M.S.

National Cancer Institute

Sholom Wacholder, Ph.D.

National Cancer Institute

John Wang, Ph.D.

Michigan State University

Lee W. Wattenberg, M.D.

University of Minnesota School of Medicine

Scott Wong, M.D.

Alliance for Lung Cancer Advocacy, Support,

and Education (ALCASE)

Jim Wright, M.D.

Hamilton Regional Cancer Clinic, CCO

David F. Yankelevitz, M.D.

Cornell University

56 Report of the Lung Cancer Progress Review Group 
NIH Pu

blication Number 01–5025


August 2001 

T897