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Lung Cancer

Lung Cancer Screening

^a Division of Hematology-Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA; ^b Rush University Medical School, Chicago, Illinois, USA

Key Words. Computerized tomographic scans • Spiral CT screening • Lung cancer

Correspondence: Apar Kishor Ganti, M.D., Division of Hematology-Oncology, Department of Internal Medicine, University of Nebraska Medical Center, 987680 Nebraska Medical Center, Omaha, Nebraska 68198-7680, USA. Telephone: 402-559-6210 Fax: 402-559-6520; e-mail: aganti{at}unmc.edu

Received December 16, 2005; accepted for publication March 16, 2006.

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Chest Radiographs and Sputum... Computerized Tomography for... Questions Raised by Studies... Role of Advances in... Nonimaging Modalities of... Conclusions Disclosure of Potential... References

 
After completing this course, the reader will be able to:

1. Identify the role of screening in the diagnosis of lung cancer.
   
2. Discuss the advantages and disadvantages of screening for lung cancer using CT scans.
   
3. Describe the impact of advances in technology on screening for lung cancer.
   
4. Name the nonimaging modalities that may play a role in lung cancer screening in the future.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Chest Radiographs and Sputum... Computerized Tomography for... Questions Raised by Studies... Role of Advances in... Nonimaging Modalities of... Conclusions Disclosure of Potential... References

 
Advances in imaging technology have ushered in a new era for lung cancer screening in high-risk individuals using computed tomographic (CT) scans. Although most published studies are nonrandomized observational cohorts of volunteers, the ability of CT scans to detect early stage lung cancer is undisputable. What is unresolved is the ability of spiral CT screening to affect lung cancer-related mortality. A large randomized trial sponsored by the National Cancer Institute to address this question is currently under way. Genomic and proteomic approaches promise to complement the ability of spiral CT to detect early lung cancer in the next few years. Currently, the decision to screen for lung cancer should involve a careful discussion with the individuals involved about the potential advantages, costs, and drawbacks of the approach.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Chest Radiographs and Sputum... Computerized Tomography for... Questions Raised by Studies... Role of Advances in... Nonimaging Modalities of... Conclusions Disclosure of Potential... References

 
Lung cancer is the leading cause of cancer-related mortality in the world, with almost one million deaths annually [1]. It was estimated that in 2005, in the U.S. alone, there would be more than 170,000 new cases of lung cancer, with approximately 163,000 related deaths [2]. Given these dismal statistics, it is natural to try to find a means to decrease the mortality from this disease.

The vast majority of patients with lung cancer have a current or previous history of cigarette smoking [3, 4]. As a result, it would be attractive to target lifestyle changes and decrease the incidence of smoking to decrease the incidence of and consequently the mortality from lung cancer. A major limitation of this approach is that almost half of the patients with lung cancer are former smokers, and close to 90,000 deaths occur annually in former smokers and never smokers who would not benefit from stop-smoking strategies alone [5, 6].

The reason lung cancer is so frequently lethal is that most of the patients are diagnosed in later stages of the disease, when their malignancy is incurable. In contrast, outcomes are significantly better in patients diagnosed at earlier, resectable stages, with the 5-year survival rate for stage I disease approaching 70% [7–12]. Thus, if the disease could be detected at an earlier stage, curative resections could be possible, and thereby the mortality rates from lung cancer would decrease.

	CHEST RADIOGRAPHS AND SPUTUM CYTOLOGY FOR LUNG CANCER SCREENING

Top Learning Objectives Abstract Introduction Chest Radiographs and Sputum... Computerized Tomography for... Questions Raised by Studies... Role of Advances in... Nonimaging Modalities of... Conclusions Disclosure of Potential... References

 
Lung cancer satisfies most of the conditions put forth by Wilson and Jungner [13] that would make it amenable for screening. It is a major public health problem, and if detected early, there is a possibility that a curative resection could be performed. The major problem with lung cancer has been the absence of an effective method to screen for early stage disease among the high-risk population.

In the 1960s and 1970s, there were large randomized trials conducted both in the U.S. and Europe that randomized volunteers to either periodic chest radiography or a control arm following a baseline examination [14, 15]. Although these studies both found a higher incidence of resectable disease in the screened population, none of these experiences showed a lung cancer mortality reduction with screening. There were a number of serious methodological flaws in the design of these studies that makes their interpretation difficult [16]. Studies were also performed to evaluate the utility of sputum cytology in addition to chest radiography as a tool for lung cancer screening [15, 17–19]. Again, though these studies found higher 5-year survival rates in the screened groups, an equal number of patients in both groups eventually died from their disease. One interesting observation, especially in the Johns Hopkins study [19], was the high incidence (~50%) of interval cases, that is, cases that were detected between the screening studies. Also, more than half of the cancers detected in these screening studies were advanced stage at diagnosis, again demonstrating the insensitivity of chest radiography in the diagnosis of early lung cancer.

	COMPUTERIZED TOMOGRAPHY FOR SCREENING

Top Learning Objectives Abstract Introduction Chest Radiographs and Sputum... Computerized Tomography for... Questions Raised by Studies... Role of Advances in... Nonimaging Modalities of... Conclusions Disclosure of Potential... References

 
The rapid advances in radiographic technology, especially that of computed tomographic (CT) scans and the demonstrated ability of these scans to detect early-stage lung cancer in pilot studies, have rekindled an interest in screening for lung cancer [20]. Refinements in CT design, including improvements in microprocessor-based image acquisition and analyses, have resulted in significant improvements in the quality of the images, and with the current technology, a low-resolution image of the entire thorax can be obtained with low radiation exposure and within a single breathhold using low-dose CT (120 kVp, 25 mAs) [21].

Preliminary studies from Japan demonstrated that low-dose CT scans were very effective in detecting early-stage lung cancer [22, 23]. Kaneko et al. [22] compared the efficacy of CT scans with that of chest radiographs in over 1,300 high-risk patients. Of the 15 cases of lung cancer detected by spiral CT, the chest X-ray was normal in 11.

At the same time, the Early Lung Cancer Action Project (ELCAP) was started at Cornell Medical Center in 1993. In the first published report from that study, Henschke et al. [24] presented the findings from 1,000 high-risk individuals in 1999 following screening with low-dose CT scans. They were able to detect 27 cases of lung cancer, of which 23 were stage I. They concluded that low-dose CT can improved the likelihood of detecting lung cancer at an earlier and potentially more curable stage [24]. The estimated 5-year survival rate in this group of patients was 60%–80% [25]. The study was then extended to other centers, and at a recent update of the International ELCAP (I-ELCAP), screening CT scans had been performed on more than 25,000 high-risk individuals, and 382 malignancies were detected, a vast majority of which were stage I. The 8-year case fatality rate in that study was 4% [26]. This accomplishment may not represent a sufficient level of evidence to be convincing about the benefits of lung cancer screening, but it is undisputable that this is the best outcome ever reported with a large cohort.

The results of these and most other similar studies conducted in North America, Europe, and Japan [27–29] have demonstrated that the vast majority of lung cancers detected by screening, both baseline and annual, are stage I at diagnosis [30]. Because stage I lung cancer is the most curable form of the disease, the proponents of this approach have argued that an increase in the detection of stage I disease will ultimately result in a decrease in lung cancer-related mortality. Although there are no mature randomized clinical trials that have addressed this specific issue, observational studies from Japan have demonstrated a decrease in 5-year mortality with screening using CT scans, as opposed to chest radiographs [30]. The significant experience in Japan with lung cancer screening has been of considerable importance in moving the field, as recently recognized by the U.S. Preventive Services Task Force in modifying the screening recommendations from discouraging screening to making no recommendation (either for or against) the use of CT scans [31].

However, not all reported trials with spiral CT scans have the same favorable results. In a recent pilot study evaluating the feasibility of a randomized controlled trial comparing low-dose CT scans with chest radiographs for lung cancer screening found only a 48% rate of detection of stage I lung cancer at initial screening and 25% for annual follow-up scanning [32]. Because this was a pilot study to establish the feasibility of conducting such a trial, these results may not present a true picture of the ability of CT scans to detect early-stage lung cancer because of the small number of subjects.

Worried by the fact that, despite being nonreimbursed, widespread ad hoc screening would become prevalent, the National Cancer Institute (NCI) expedited the launch of the National Lung Cancer Screening Trial to evaluate if CT screening leads to a significant improvement in lung cancer-related mortality compared with chest radiography. That trial has already completed full accrual and uses multi-detector-row scanners (mostly four rows) for the 25,000 volunteers on the CT arm of that trial [30].

	QUESTIONS RAISED BY STUDIES USING CT SCANS FOR SCREENING

Top Learning Objectives Abstract Introduction Chest Radiographs and Sputum... Computerized Tomography for... Questions Raised by Studies... Role of Advances in... Nonimaging Modalities of... Conclusions Disclosure of Potential... References

 
Proponents of the routine use of CT scans for lung cancer screening argue that the data from the I-ELCAP and similar studies conducted in Japan, North America, and Italy are so impressive that screening for lung cancer with low-dose CT scans will lead to an improvement in lung cancer-related mortality. The limitation of all these studies is that they were all observational, using volunteer cohorts. As a result, the reported outcomes may reflect the confounding influence of bias rather than a true effect.

The traditional end point of a randomized trial for success of a screening modality is significantly lower lung cancer-related mortality in the screened versus the control population. A growing challenge in lung cancer screening research is the inability of randomized controlled clinical trial design to keep pace with the unprecedented progress that is being made in imaging technology and interpretation. Investigators at Cornell have long argued for a strategy to overcome this methodological challenge by conducting large, well-designed, population-based observational studies and to account for potential biases by attempting to study their magnitude of influence. Prior experience has shown that the results of well-conducted observational studies are similar to those obtained in randomized controlled trials [33, 34].

Another argument put forth by the critics of this approach is the possibility of overdiagnosis of lung cancer. Although more than 80% of the screen-detected tumors were stage I disease, they argue that there was no stage shift [35]. A true stage shift is defined as an increase in early stage disease, associated with a corresponding decrease in late-stage disease. Also, there seems to be no difference in the incidence of advanced-stage disease between the low-dose CT studies and the chest radiographic trials (~3/1,000 patients). An obvious limitation of these kinds of analyses, however, is that the two populations chosen at different time periods in different studies may not be comparable. Also, mature mortality data using low-dose CT scans for lung cancer screening are lacking [36–38]. However, autopsy studies suggest that overdiagnosis may not be a significant problem in lung cancer, with lung cancer diagnosed for the first time in only 0.8% of all autopsies [39]. Bianchi et al. [40] compared the gene-expression profile of screen-detected lung carcinomas with those of a matched case-control population of patients presenting with symptomatic lung cancer and found that all the tumors detected by screening had biochemical gene-expression patterns indistinguishable from those of symptomatic lung carcinomas.

A major concern for the use of CT scans is the false-positive rates. In the study conducted at the Mayo Clinic, almost 70% of the volunteers had noncalcified pulmonary nodules. Only a fraction of these required further invasive follow-up, including resection of benign lesions in eight patients [41]. The false-positive rates in that study ranged from 92.9% for nodules >4 mm in diameter to 96% for all nodules [35]. In contrast, in the I-ELCAP, only 23% of the volunteers had noncalcified nodules at baseline screening that needed further evaluation [24]. The reasons for these differences appear to be twofold. The Mayo Clinic trial, which started later than the ELCAP, used a four-slice CT scanner that is more sensitive than the single-slice scanner used in the ELCAP. Also, there may be a higher incidence of pulmonary nodules in the midwestern U.S. because of endemic fungal infections [42]. However, as more data on the behavior of these nodules become available, it is possible that the smaller nodules, especially those <5.0 mm, could be evaluated during annual follow-up scans [43]. Although the perioperative mortality in the Mayo Clinic experience was only 1.7% [44], there is a real concern that, if screening is made widely available to the population, smaller centers with lesser expertise may not be able to duplicate the low complication rates achieved at the Mayo Clinic. Currently there is a 3.8% incidence of mortality with wedge resection of pulmonary nodules in community hospitals in the U.S. [45]. In order to try to minimize the number of invasive procedures required to confirm (or exclude) malignancy and the inherent risk for complications therein, Libby et al. [46] created an algorithm based on the ELCAP data and the medical literature from 1993–2003 for nodules discovered incidentally on CT. They based this upon the size of the nodule, number of nodules, density of the nodule(s), and patient characteristics such as age, gender, smoking history, occupational history, and any antecedent granulomatous disease. An additional advantage of this approach is that it can be used for a wider population than those typically enrolled in CT screening programs.

Critics have raised the issue of cost-effectiveness of screening for lung cancer with CT scans. Mahadevia et al. [47] used a computer-simulated model based on the Mayo Clinic findings to estimate the cost of screening to be $116,300 per quality-adjusted life-year (QALY) under favorable assumptions for current smokers. This estimate was $558,600 and $2,322,700 per QALY gained for quitting and former smokers, respectively. This would suggest that CT screening is prohibitively expensive to be of any clinical relevance. However, other analyses based on the ELCAP and the Italian studies have come to much different conclusions. Wisnivesky and associates estimated the same amount to be U.S.$2,500 per year of life saved under favorable conditions based on the ELCAP data [48]. In addition, they found that the cost-effectiveness ratio exceeded $50,000 per year of life saved only if the chance of overdiagnosis was >50%. Similarly, based on the findings of the Milan study, Pastorino et al. [28] suggested that the findings of Mahadevia et al. were too pessimistic. In an analysis in the Australian setting, Manser et al. [49] found that, for male smokers aged 60–64 years, the incremental cost-effectiveness ratio was $57,325 per life-year saved and $105,090 per QALY saved. For women aged 60–64 years, the cost-effectiveness ratio was $51,001 per life-year saved and $88,583 per QALY saved. They concluded that, in order for lung cancer screening to be cost-effective, only individuals at the highest risk should be targeted for screening. Caution should be exercised while interpreting the results of such studies because, as a result of the variable methodologies employed, the conclusions may mirror the biases of the individual investigators rather than the ground truth [30].

Another potential source for contention is the risk for radiation exposure with low-dose CT scans used for screening. A recent report on radiation risk reported the potential frequency of eventual carcinogenesis associated with low-dose spiral CT based on highly conservative extrapolations using our existing but limited human radiation exposure information [50]. In this analysis, Brenner suggested that, if half of the high-risk population in the U.S. was screened with low-dose CT scans annually for 20–25 years, there would be an estimated 36,000 new lung cancers solely as a result of radiation exposure over that 20-year period, an increase of 1.8%. The International Commission on Radiological Protection predicts that the CT scanning techniques used in 2001 would induce five cancers per 100,000 examinations [51]. However, Lenzen et al. [52] suggested that, with helical CT, it was possible to reduce the equivalent dose of radiation close to that of a conventional chest X-ray in two projections, thereby decreasing the risk for malignancy further. This lower exposure not with standing, the risk for lung cancer is significantly higher in the tobacco-exposed, older individual than the theoretical risk of radiation-induced lung cancer. Although every effort must be taken to minimize exposure to radiation, the lethal effects of tobacco are substantial. Also, the lethality of lung cancer in individuals being followed with annual spiral CT scans is likely to be considerably less lethal than diagnosis in the absence of screening, so this is a dynamic issue that must be considered in perspective.

	ROLE OF ADVANCES IN IMAGING TECHNOLOGY

Top Learning Objectives Abstract Introduction Chest Radiographs and Sputum... Computerized Tomography for... Questions Raised by Studies... Role of Advances in... Nonimaging Modalities of... Conclusions Disclosure of Potential... References

 
One of the major issues with any screening trial is the rapid advances in imaging technology. In this age of rapidly advancing technology, it is unlikely that a randomized study sufficiently powered to address the issue of decreased mortality with lung cancer screening can be completed before advances in the quality of imaging render it obsolete. The substantial improvements in the speed and quality of CT imaging have allowed for a much more realistic three-dimensional representation of actual respiratory anatomy. As the speed, resolution, and cost of CT scanners continue to improve, computer techniques for the measurement and analysis of nodules will also achieve corresponding improvements in accuracy and diagnostic utility. Future knowledge-based CT computer-aided diagnosis (CAD) systems will provide detailed analysis of not only malignant lesions but also related conditions, such as emphysema [53, 54]. With the latest 64-detector-row scanners being able to image the entire thorax within a single breath, the amount of data generated in this process is daunting. Higher resolution imaging may result in greater sensitivity and hence there will be a need to accurately identify suspicious lesions in order to decrease the evaluation process. In order to reliably establish clinically relevant features, such as boundaries of small lesions abutting normal adjacent structures, the amount of imaging information required by a CAD system may far exceed the amount of information that a radiologist would be able to review in a reasonable amount of time. In order to accelerate the maturation of image-processing tools for CAD, the NCI has developed the Lung Image Database Consortium. This image database will allow comparison and optimization of CAD algorithms and serve as an important resource for the development of CAD methods [55].

	NONIMAGING MODALITIES OF SCREENING

Top Learning Objectives Abstract Introduction Chest Radiographs and Sputum... Computerized Tomography for... Questions Raised by Studies... Role of Advances in... Nonimaging Modalities of... Conclusions Disclosure of Potential... References

 
The emerging fields of genomic and proteomic techniques promise to have a major impact on the early detection of lung cancer. Although there are no concrete data establishing the efficacy of these approaches in detecting lung cancer at an early, preclinical stage, enough exciting observations have been made to make these approaches worth investigation.

Studies have demonstrated that genomic instability can be identified in the bronchoalveolar lavage fluid of patients with lung cancer [56]. Similarly, the serum of patients with lung cancer has shown the presence of DNA markers such as mutations, microsatellite alterations, or methylation of promoter regions of specific cancer-related genes [57–60]. Sozzi et al. [61] compared the amount of plasma DNA determined through the use of real-time quantitative polymerase chain reaction amplification of the human telomerase reverse transcriptase gene in 100 non-small cell lung cancer patients and 100 age-, sex-, and smoking-matched controls. They found that the median concentration of circulating plasma DNA in patients was almost eight times higher than in controls. This ability to detect DNA changes in the serum holds great potential for the development of serum markers for the early detection of lung cancer.

Proteomic approaches rely on the detection of antibodies directed at known proteins considered important in lung carcinogenesis. Tockman et al. [62] demonstrated that a monoclonal antibody, HNRNP A2/B1, was 90% accurate in predicting patients who would develop lung cancer over the next few years. The development of matrix-assisted laser desorption ionization mass spectroscopy has provided a new, powerful technique for the study of cancer proteomics [63]. This technique allows the generation of a protein "profile" based on the molecular weights and relative abundance of all proteins in a sample. The proteins that are differentially expressed can then be identified and tested as potential biomarkers [64]. In addition, these markers may allow for more rapid and reliable development of drugs to manage early lung cancer.

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Chest Radiographs and Sputum... Computerized Tomography for... Questions Raised by Studies... Role of Advances in... Nonimaging Modalities of... Conclusions Disclosure of Potential... References

 
Screening for lung cancer is currently undergoing a lot of flux, with new data emerging. This has led to a change in the recommendations by the U.S. Preventative Service Task Force [31]. However, any decision to screen for lung cancer should be preceded by a discussion with the individual about the various aspects of lung cancer screening, including smoking cessation, the potential morbidity, mortality, and associated medical costs, the incidence of "false positives" and "false negatives," the absence of data suggesting that screening will improve lung cancer-related mortality, and the expertise of the individual center in evaluating any abnormality that may be detected on the screening scan [30].

Lung cancer, as the most lethal cancer in the world, presents an enormous health care challenge. However, the key to reversing the situation may be in embracing a public health sensibility in harnessing the power of CT imaging in a carefully validated approach to the early management of lung cancer.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Learning Objectives Abstract Introduction Chest Radiographs and Sputum... Computerized Tomography for... Questions Raised by Studies... Role of Advances in... Nonimaging Modalities of... Conclusions Disclosure of Potential... References

 
The authors indicate no potential conflicts of interest.

	REFERENCES

Top Learning Objectives Abstract Introduction Chest Radiographs and Sputum... Computerized Tomography for... Questions Raised by Studies... Role of Advances in... Nonimaging Modalities of... Conclusions Disclosure of Potential... References

 

1. Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin 1999;49:33–64, 31.[Abstract/Free Full Text]
2. Jemal A, Murray T, Ward E et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10–30.[Abstract/Free Full Text]
3. Wingo PA, Ries LA, Giovino GA et al. Annual report to the nation on the status of cancer, 1973–1996, with a special section on lung cancer and tobacco smoking. J Natl Cancer Inst 1999;91:675–690.[Abstract/Free Full Text]
4. Capewell S, Sankaran R, Lamb D et al. Lung cancer in lifelong non-smokers. Edinburgh Lung Cancer Group. Thorax 1991;46:565–568.[Abstract/Free Full Text]
5. Tong L, Spitz MR, Fueger JJ et al. Lung carcinoma in former smokers. Cancer 1996;78:1004–1010.[CrossRef][Medline]
6. Fellows JL, Trosclair A. Annual smoking-attributable mortality, years of potential life lost and economic cost—United States 1005–1999. Morb Mortal Wkly Rep 2002;51:300–303.[Medline]
7. Mountain CF. A new international staging system for lung cancer. Chest 1986;89:225S–233S.[Free Full Text]
8. Shimizu J, Watanabe Y, Oda M et al. [Results of surgical treatment of stage I lung cancer]. Nippon Geka Gakkai Zasshi 1993;94:505–510. Japanese.[Medline]
9. Mountain CF, Lukeman JM, Hammar SP et al. Lung cancer classification: the relationship of disease extent and cell type to survival in a clinical trials population. J Surg Oncol 1987;35:147–156.[Medline]
10. Williams DE, Pairolero PC, Davis CS et al. Survival of patients surgically treated for stage I lung cancer. J Thorac Cardiovasc Surg 1981;82:70–76.[Abstract]
11. Martini N. Surgical treatment of lung cancer. Semin Oncol 1990;17 (suppl 7):9–10.[Medline]
12. Shah R, Sabanathan S, Richardson J et al. Results of surgical treatment of stage I and II lung cancer. J Cardiovasc Surg (Torino) 1996;37:169–172.[Medline]
13. Wilson JM, Jungner YG. [Principles and practice of mass screening for disease.] Bol Oficina Sanit Panam 1968;65:281–393. Spanish.[Medline]
14. Brett GZ. Earlier diagnosis and survival in lung cancer. Br Med J 1969;4:260–262.[Abstract/Free Full Text]
15. Fontana RS, Sanderson DR, Woolner LB et al. Lung cancer screening: the Mayo program. J Occup Med 1986;28:746–750.[Medline]
16. Fontana RS, Sanderson DR, Woolner LB et al. Screening for lung cancer. A critique of the Mayo Lung Project. Cancer 1991;67:1155–1164.[CrossRef][Medline]
17. Kubik A, Polak J. Lung cancer detection. Results of a randomized prospective study in Czechoslovakia. Cancer 1986;57:2427–2437.[CrossRef][Medline]
18. Melamed MR, Flehinger BJ, Zaman MB et al. Screening for early lung cancer. Results of the Memorial Sloan-Kettering study in New York. Chest 1984;86:44–53.[Abstract/Free Full Text]
19. Tockman M. Survival and mortality from lung cancer in a screened population: The John Hopkins study. Chest 1986;89:325S.[Free Full Text]
20. Ganti AK, Mulshine JL. Lung cancer screening: panacea or pipe dream? Ann Oncol 2005;16(suppl 2):ii215–ii219.[Free Full Text]
21. Bastarrika G, Pueyo JC, Mulshine JL. Radiologic screening for lung cancer. Expert Rev Anticancer Ther 2002;2:385–392.[CrossRef][Medline]
22. Kaneko M, Eguchi K, Ohmatsu H et al. Peripheral lung cancer: screening and detection with low-dose spiral CT versus radiography. Radiology 1996;201:798–802.[Abstract/Free Full Text]
23. Sone S, Takashima S, Li F et al. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998;351:1242–1245.[CrossRef][Medline]
24. Henschke CI, McCauley DI, Yankelevitz DF et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99–105.[CrossRef][Medline]
25. Henschke CI. Early Lung Cancer Action Project: overall design and findings from baseline screening. Cancer 2000;89:2474–2482.[CrossRef][Medline]
26. Henschke CI, Sone S, Markowitz S. International Early Lung Cancer Action Project (I-ELCAP): evaluation of low-dose CT screening. Proceedings of the Annual Meeting of the Radiological Society of North America, Chicago, Illinois, November 28–December 3, 2004.
27. Swensen SJ, Jett JR, Sloan JA et al. Screening for lung cancer with low-dose spiral computed tomography. Am J Respir Crit Care Med 2002;165:508–513.[Abstract/Free Full Text]
28. Pastorino U, Bellomi M, Landoni C et al. Early lung-cancer detection with spiral CT and positron emission tomography in heavy smokers: 2-year results. Lancet 2003;362:593–597.[CrossRef][Medline]
29. Sobue T, Moriyama N, Kaneko M et al. Screening for lung cancer with low-dose helical computed tomography: anti-lung cancer association project. J Clin Oncol 2002;20:911–920.[Abstract/Free Full Text]
30. Mulshine JL, Sullivan DC. Clinical practice. Lung cancer screening. N Engl J Med 2005;352:2714–2720.[Free Full Text]
31. Humphrey LL, Teutsch S, Johnson M. Lung cancer screening with sputum cytologic examination, chest radiography, and computed tomography: an update for the U.S. Preventive Services Task Force. Ann Intern Med 2004;140:740–753.[Abstract/Free Full Text]
32. Gohagan JK, Marcus PM, Fagerstrom RM et al. Final results of the Lung Screening Study, a randomized feasibility study of spiral CT versus chest X-ray screening for lung cancer. Lung Cancer 2005;47:9–15.[CrossRef][Medline]
33. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000;342:1887–1892.[Abstract/Free Full Text]
34. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000;342:1878–1886.[Abstract/Free Full Text]
35. Swensen SJ, Jett JR, Hartman TE et al. CT screening for lung cancer: five-year prospective experience. Radiology 2005;235:259–265.[Abstract/Free Full Text]
36. Patz EF Jr, Goodman PC. Low-dose spiral computed tomography screening for lung cancer: not ready for prime time. Am J Respir Crit Care Med 2001;163:813–814.[Free Full Text]
37. Grannis FW Jr. Lung cancer overdiagnosis bias: "the gyanousa am loose!" Chest 2001;119:322–323.[Free Full Text]
38. Heffner JE, Silvestri G. CT screening for lung cancer: is smaller better? Am J Respir Crit Care Med 2002;165:433–434.[Free Full Text]
39. McFarlane MJ, Feinstein AR, Wells CK. Clinical features of lung cancers discovered as a postmortem "surprise". Chest 1986;90:520–523.[Abstract/Free Full Text]
40. Bianchi F, Hu J, Pelosi G et al. Lung cancers detected by screening with spiral computed tomography have a malignant phenotype when analyzed by cDNA microarray. Clin Cancer Res 2004;10:6023–6028.[Abstract/Free Full Text]
41. Swensen SJ, Jett JR, Hartman TE et al. Lung cancer screening with CT: Mayo Clinic experience. Radiology 2003;226:756–761.[Abstract/Free Full Text]
42. Henschke CI, Yankelevitz DF, Libby D et al. CT screening for lung cancer: the first ten years. Cancer J 2002;8(suppl 1):S47–S54.
43. Henschke CI, Yankelevitz DF, Naidich DP et al. CT screening for lung cancer: suspiciousness of nodules according to size on baseline scans. Radiology 2004;231:164–168.[Abstract/Free Full Text]
44. Crestanello JA, Allen MS, Jett JR et al. Thoracic surgical operations in patients enrolled in a computed tomographic screening trial. J Thorac Cardiovasc Surg 2004;128:254–259.[Abstract/Free Full Text]
45. Romano PS, Mark DH. Patient and hospital characteristics related to inhospital mortality after lung cancer resection. Chest 1992;101:1332–1337.[Abstract/Free Full Text]
46. Libby DM, Smith JP, Altorki NK et al. Managing the small pulmonary nodule discovered by CT. Chest 2004;125:1522–1529.[Abstract/Free Full Text]
47. Mahadevia PJ, Fleisher LA, Frick KD et al. Lung cancer screening with helical computed tomography in older adult smokers: a decision and cost-effectiveness analysis. JAMA 2003;289:313–322.[Abstract/Free Full Text]
48. Wisnivesky JP, Mushlin AI, Sicherman N et al. The cost-effectiveness of low-dose CT screening for lung cancer: preliminary results of baseline screening. Chest 2003;124:614–621.[Abstract/Free Full Text]
49. Manser R, Dalton A, Carter R et al. Cost-effectiveness analysis of screening for lung cancer with low dose spiral CT (computed tomography) in the Australian setting. Lung Cancer 2005;48:171–185.[CrossRef][Medline]
50. Brenner DJ. Radiation risks potentially associated with low-dose CT screening of adult smokers for lung cancer. Radiology 2004;231: 440–445.[Abstract/Free Full Text]
51. Diederich S, Wormanns D, Heindel W. Low-dose CT: new tool for screening lung cancer? Eur Radiol 2001;11:1916–1924.[CrossRef][Medline]
52. Lenzen H, Roos N, Diederich S et al. [Radiation exposure in low dose computerized tomography of the thorax]. Radiologe 1996;36:483–488. German.[CrossRef][Medline]
53. Reeves AP, Kostis WJ. Computer-aided diagnosis for lung cancer. Radiol Clin North Am 2000;38:497–509.[CrossRef][Medline]
54. Wormanns D, Fiebich M, Saidi M et al. Automatic detection of pulmonary nodules at spiral CT: clinical application of a computer-aided diagnosis system. Eur Radiol 2002;12:1052–1057.[CrossRef][Medline]
55. Clarke LP, Croft BY, Staab E et al. National Cancer Institute initiative: lung image database resource for imaging research. Acad Radiol 2001;8:447–450.[CrossRef][Medline]
56. Liloglou T, Maloney P, Xinarianos G et al. Cancer-specific genomic instability in bronchial lavage: a molecular tool for lung cancer detection. Cancer Res 2001;61:1624–1628.[Abstract/Free Full Text]
57. Cuda G, Gallelli A, Nistico A et al. Detection of microsatellite instability and loss of heterozygosity in serum DNA of small and non-small cell lung cancer patients: a tool for early diagnosis? Lung Cancer 2000;30: 211–214.[CrossRef][Medline]
58. Esteller M, Sanchez-Cespedes M, Rosell R et al. Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients. Cancer Res 1999;59:67–70.[Abstract/Free Full Text]
59. Chen XQ, Stroun M, Magnenat JL et al. Microsatellite alterations in plasma DNA of small cell lung cancer patients. Nat Med 1996;2: 1033–1035.[CrossRef][Medline]
60. Sozzi G, Musso K, Ratcliffe C et al. Detection of microsatellite alterations in plasma DNA of non-small cell lung cancer patients: a prospect for early diagnosis. Clin Cancer Res 1999;5:2689–2692.[Abstract/Free Full Text]
61. Sozzi G, Conte D, Leon M et al. Quantification of free circulating DNA as a diagnostic marker in lung cancer. J Clin Oncol 2003;21:3902–3908.[Abstract/Free Full Text]
62. Tockman MS, Gupta PK, Myers JD et al. Sensitive and specific monoclonal antibody recognition of human lung cancer antigen on preserved sputum cells: a new approach to early lung cancer detection. J Clin Oncol 1988;6:1685–1693.[Abstract/Free Full Text]
63. Chaurand P, Stoeckli M, Caprioli RM. Direct profiling of proteins in biological tissue sections by MALDI mass spectrometry. Anal Chem 1999;71:5263–5270.[Medline]
64. Wardwell NR, Massion PP. Novel strategies for the early detection and prevention of lung cancer. Semin Oncol 2005;32:259–268.[CrossRef][Medline]

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