ABSTRACT: Despite improvements in drug therapy, late-stage lung cancer remains routinely incurable. The field of screening for early lung cancer is a challenging, fast-moving, cross-disciplinary area, not without controversy. The ideal situation is one in which we approach screening proactively to allow it to mature as a public health strategy. Spiral CT screening for lung cancer is a new and promising approach to thoracic imaging; it allows for a much more rapid and comprehensive evaluation of a structure than the original CT scan. In this review we will discuss issues inherent to the lung cancer screening process, including the value of smoking cessation strategies, the challenge with the rapid pace of developments in the field, cost concerns, consideration of biases in trial design (overdiagnosis, for example), overtreatment, and radiation risk. We discuss recommendations from several organizations, such as the US Preventive Services Task Force and the American Cancer Society.
Lung cancer has killed over 1 million victims in this country over the past 5 years and will kill at least that many over the next 5 years as well.[1-3] The overwhelming majority of these victims die due to a late diagnosis. Chest x-ray is a poor tool for finding early curable disease. Despite improvements in drug therapy, late-stage lung cancer is routinely incurable. There have been a number of detailed reviews on the subject of lung cancer screening recently published in highly visible journals. As recently reviewed by the United States Preventive Services Task Force (USPSTF), lung cancer screening is a dynamic area where recent publications have led to a change in their recommendation from discouraging lung cancer screening to an I classification:
"The USPSTF makes no recommendation (either for or against) the use of computed tomography (CT) in persons who have no symptoms of lung cancer. If screening is being considered, physicians are advised to discuss with the patient the pros and cons, with an emphasis on the lack of studies showing that screening helps people live longer and on reports that false positive test results are common and can lead to unnecessary worry, testing, and surgery."
This indeterminate designation, which is the same classification as for prostate cancer screening with prostate-specific antigen, is based on a lack of definitive data for or against screening.
In the course of this review, issues inherent to the lung cancer screening process will be discussed, considering how each step could be optimized to enhance prospects for eventual screening benefit. This is a challenging, fast-moving, and cross-disciplinary area. It is important that oncologists have in-depth exposure to the spectrum of such issues to inform their clinical actions and discussions with patients in this area.
Spiral CT screening for lung cancer is a new and promising approach to thoracic imaging. Spiral CT differs from the original CT scan related to the design of the scanner; it allows much more rapid and comprehensive evaluation of a structure. Even spiral CT imaging has undergone considerable improvement even since the first positive pilot articles on lung cancer screening with spiral CT in 1999, when Henschke and coworkers first reported their promising results with this tool. In addition, there have been improvements in software tools and many other related aspects of lung cancer screening.[5,7]
As we and several others have recently discussed, there are still many significant challenges in learning how to most efficiently, effectively, and economically provide this service. The dominant public health response to the high rate of lung cancer mortality has been to use tobacco control strategies to address the problem of lung cancer. In both the Mayo Clinic and Cornell CT screening studies, smoking cessation counseling in the setting of lung cancer screening was associated with more favorable quit rates.[8,9]
While smoking cessation strategies are of fundamental importance in rapidly improving outcomes in cardiovascular disease, the risk of developing lung cancer remains elevated after smoking cessation. Lung cancers are being diagnosed at least as frequently in the over 45 million former smokers as in current smokers; smoking cessation strategies are of no further utility in that growing cohort of former smokers.
As progress in cardiovascular disease has not been matched in lung cancer outcomes, the result is that lung cancer has recently emerged as the dominant cause of death in tobacco-exposed individuals. Tobacco-related diseases are the leading cause of premature death and account for half of health-care costs in our society, so better approaches to lung cancer management beyond smoking cessation are critical at least for the one in four adults in our society who are currently former smokers. Recently, thoughtful publications have called for a full-scale reconsideration of our efforts to significantly impact unfavorable cancer outcomes.[ 14] Implementing a much more comprehensive and carefully organized program of early lung cancer detection and management research is the most promising way to improve outcomes in this broad segment of our society.
Where Are We Now With Lung Cancer Outcomes?
With over 160,000 deaths projected for this year, lung cancer accounts for 30% of cancer deaths in the United States. Regional or distant metastatic spread is evident in at least three-quarters of lung cancer cases at time of diagnosis, so the 5-year survival rate for lung cancer is about 15%. For localized cancer, the 5-year survival rates are often better than 60%. As a point of reference, localized breast and prostate cancer are detected at rates of 63% and 82%, with 5-year survival rates of 87% and 98%, respectively.
Promising reports with highresolution CT detection have renewed interest in early lung cancer screening but no major lung cancer screening trial has been completed in the United States since the early 1980s. There is growing appreciation of the methodologic limitations of the previous chest x-ray screening trials and their inadequacy as a basis for current health-care policy. However, concern about the cost and other healthcare consequences of CT-based lung cancer detection has led to considerable controversy about the merits of this direction. Against this charged backdrop, it is timely to review the status of early lung cancer detection.
All single-arm, spiral CT screening studies have reported considerably higher stage I frequency than the national experience of 17%, with some studies reporting stage I detection frequency in excess of 80%.[7,16] From a large Japanese experience from 1975 to 1993, 26,338 screening chest xrays detected 42% of cases as stage I lung cancer with an average primary size of 3 cm; 33% were stage III/ IV. During 1993, this group began using CT; by 2002, 15,342 scans were performed. With CT screening, 78% of the detected cases were stage I with a mean diameter of 1.5 cm and the rate of detection for stage III/VI disease had decreased to 14%. With this transition, the overall 5-year survival improved from 49% with chest x-ray-detected cases to 84% with CTdetected cases. This result is not definitive, as the observational study design cannot account for all sources of potential bias in the study subject. Yet it still constitutes a remarkable improvement in outcomes compared to historical standards. Other Japanese groups have reported similar positive experiences.
The International Early Lung Cancer Action Project (I-ELCAP) screening experience with current and former smokers was recently presented with prevalence evaluation of over 26,000 subjects and follow-up incidence data from 19,700 subjects.[19,20]. In this multinational experience with over 350 lung cancers detected, the frequency of stage I was 82%. With follow-up on some cases as far out as 100 months, the lung cancer-related survival rate was over 95%.
The notable factor associated with this remarkable experience is that the I-ELCAP study sites adhere to a standardized multidisciplinary algorithm for case workup and therapeutic intervention. From their long experience with lung cancer screening at the Weill Medical College of Cornell University, they have evolved to a defined best practice for all aspects of the lung cancer screening process.[ 18,19] In the process they have redefined the clinical management of early lung cancer. They have approached this challenge as a public health issue, looking at factors such as optimizing cost. To accomplish this, they have pioneered the development of image processing tools to use the dynamic information extractable from serial high-resolution spiral CT as a reflection of biological aggressiveness to segregate clinically significant lung cancer nodules.[21-23] They have evolved a much more disciplined and minimally invasive approach to case workup. They have defined a new lexicon of terms to define a phase of early lung cancer that was clinically inapparent prior to the advent of highresolution spiral CT.
The rapid pace and scope of this work has been disruptive in the field, stirring controversy. The literature in the field has been confusing to many, as issues such as cost efficiency have been so widely divergent.[ 20,26] This dynamic tension is heightened by the amount and intensity of public interest in this area, leaving the practicing oncologist attempting to respond to inquiries from patients in a quandary. A major concern about widespread CT screening relates to its cost, especially in light of one study that projected enormous costs from models assembled using assumptions based on early screening reports.  In contrast, more extensive use of noninvasive imaging techniques in the workup of screen-detect lesions may explain why the cost features of other screening management approaches are less expensive. With the ELCAP approach only 13% of the screened cases require further follow-up, with most of those cases evaluated by serial CT imaging for nodule growth rate.[23-25] Further potential for cost savings and morbidity reductions can be achieved by carefully defining the risk features of the screened cohort, by reducing the screening intensity in following up screen-negative populations, as well as by furthering innovation with the imaging technology.