- Email: [email protected]
Lung cancer screening — where we are in 2004 (take home messages)
Lung Cancer 45 Suppl. 2 (2004) S39–S42
www.elsevier.com/locate/lungcan
Lung cancer screening – Where we are in 2004 (take home messages) Karl-Matthias Deppermann Ruppiner Kliniken, Klinik f¨ ur Pneumologie, D-16816 Neuruppin, Germany
KEYWORDS Lung cancer screening; Low-dose CT; Sputum analysis; Fluorescence bronchoscopy
Summary The best prognosis for lung cancer can be expected by diagnosis at an early stage of the disease. Long-term survival may be improved by increasing the number of early-stage diagnoses. At the present time, three different screening tools for lung cancer are available: Low-dose CT scanning, sputum analysis and fluorescence bronchoscopy. Each of these tools has a different screening target. Low-dose CT scanning focusses on small pulmonary nodules, sputum analysis has the potential of detecting lung cancer of the central airways, and fluorescence bronchoscopy can identify pre-malignancy, carcinoma in situ and minimally invasive squamous cell carcinoma. The best way forward appears to be a combination of all techniques. Sputum analysis can be used to define a better-characterised risk population, and subsequently this population can undergo low-dose CT and fluorescence bronchoscopy. © 2004 Elsevier Science Ltd.
1. Introduction The major goal in lung cancer research is the improvement of long-term survival. In spite of all efforts in conventional treatment of lung cancer by surgery, radiotherapy and chemotherapy in the last decades, survival of lung cancer has experienced only minor improvements over the last 30 years. In other tumour entities, like prostate, colorectal or breast cancer, substantial improvement in longterm survival has been made. Part of this success can be ascribed to screening programmes. Screening of lung cancer has, therefore, been a continuing issue over the last 30 years. Randomised controlled trials from the 1970s, using chest X-ray and sputum, could not show a reduction * Karl-Matthias Deppermann, MD. Tel.: +49-(3391)-39-31-12; fax: +49-(3391)-39-31-39. E-mail: [email protected]
in mortality [1–4]. The results of these studies have been leading to a nihilism concerning lung cancer screening over a long period of time [5]. But new developments in radiographic techniques and new molecular methods as well as bronchoscopic techniques have stimulated an increased interest in lung cancer screening. Lung cancer screening is attractive for several reasons: Still today, lung cancer continues to be the leading cause of cancer-related deaths in the world. In the USA, the number of deaths caused by lung cancer still exceeds the total number of deaths from breast, colon, prostate and cervical cancer. Prognosis of lung cancer is correlated to the stage of disease at the time of diagnosis. Whereas stage–IA patients have a survival rate of 67%, the survival rate declines from 40% to less than 5% for patients with stage-II through stage-IV disease at the time of diagnosis. Accordingly, curative treatment is only
0169-5002/$ – see front matter © 2004 Published by Elsevier Ireland Ltd. doi:10.1016/j.lungcan.2004.07.000
S40
K.-M. Deppermann
effective in early stages, but less than 20% of the patients present with asymptomatic stage I. At the present time three different lung cancer screening tools are being discussed.
2. Screening tools In spite of technical developments such as, e.g., sequential CT, the introduction of spiral CT in the late 1980s or the more recently introduced multidetector-row spiral CT which led to an increase in detection of small pulmonary nodules, the sensitivity of CT scanning regarding exclusively endobronchial lesions is low, due to partial volume artefacts. In this gap fits the analysis of sputum, which is particularly helpful in detecting squamous cell lung cancer, located in the central airways. New molecular biomarkers have expanded the spectrum of sputum examination and improved the former low sensitivity. Fluorescence bronchoscopy is an ideal complement to sputum analysis, because pre-malignancy, carcinoma in situ and minimally invasive squamous cell carcinoma can be localised, especially in occult tumours, which cannot be identified radiographically.
3. Low-dose CT In the last decade, seven one-armed feasibility studies were performed that used low-dose CT as a screening tool [6–15]. These studies include nearly 18,000 volunteers. The definitions of the risk population were different, with ages varying between 40 and 60 years and with an inclusion criterion of a tobacco burden of more than 20 pack-years in some studies, while smoking was no inclusion criterion in others. Prevalence-screen data from these trials confirm that CT is more sensitive in detecting lung nodules than conventional chest radiographs (Table 1). The rate of non-calcified pulmonary nodules was high and varied between 6 and 66%. The high rate of pulmonary nodules found in CT that requires Table 1 Feasibility studies
4. Sputum analysis Prevalence data
CT > chest radiograph 0.03–0.12% vs 0.43–2.7% NPN
subsequently invasive diagnostic procedures is a major point of criticism. Only a small number of these nodules have proved to be malignant lesions, in a range from 0.4% to 2.7%. Using a diagnostic algorithm, the rate of invasive procedures in benign lesions could be reduced to 20–30%. The algorithm qualified a tumour diameter of 10 mm or greater for biopsy. Only non-calcified, non-fatcontaining lesions increasing in size, underwent invasive diagnostic. Furthermore, those studies revealed a significant number of cases with asymptomatic non-smallcell lung cancer, which was more pronounced for prevalence than for incidence screening. The rate of stage–IA lung cancer and resectable cancer was much higher than in all populations, presenting with symptoms. At the present time, screening of lung cancer with low-dose CT is not recommended. Although the feasibility studies could identify a higher rate of lung cancer at an early stage of disease, this does not mean that the rate of advanced lung cancer is decreasing. A shift of stage from advanced to earlier stages could not be demonstrated. The data of the non-randomised trials are influenced by biases, such as the lead-time, length-time and over-diagnosis bias. The studies do not support the assumption that simply detecting smallersized tumours will be sufficient for achieving a meaningful reduction in lung-cancer mortality. As long as a significant reduction in mortality is not shown, we have to realise that repeated screening by low-dose CT carries a small but definitive risk in inducing malignancies. Moreover, morbidity will be increased by invasive procedures in benign lesions. The only possibility for answering all these questions is to perform randomised controlled trials with a screening arm and a control arm. But such trials will need thousands of volunteers and this will incur considerable costs. Randomised controlled trials were recently initiated in North America and in Europe. The biggest trial, in the USA, will include a total number of 50,000 subjects. Results will only be available in several years.
6–66%
Malignant lesions
0.4–2.7%
Diagnostic algorithm
Threshold 10 mm, noncalcified nodules, growth kinetic
Invasive procedures for benign lesions: 20–30%
Another screening tool is the analysis of sputum. Cytological examination of the sputum has been used since 1930. It is especially helpful in detecting central squamous cell and small-cell carcinomas. Sputum samples are easily obtained and cytological examination is inexpensive [16–18]. The material is specific for the airways and analysis has a high specificity. But there are also some disadvantages,
Lung cancer screening – Where we are in 2004 (take home messages) Table 2 Improvement of sputum analysis Cytology
DNA-Methylation
Nuclear image analysis
FISH analysis
Immunohistochemistry
K-ras mutations
DNA Analysis
p53 mutations
RNA Analysis
including low sensitivity in earlier trials and difficulties in obtaining proper material. There exists a wide range in reader variability, resulting in the problem of low reproducibility. Molecular methods have been developed only recently and were not available in earlier studies. Several approaches can improve the sensitivity of sputum analysis [19–22]. The risk population should be defined better in terms of age, pack-years and reduction in FEV1. Sputum induction should be improved and standardised. The main focus should be on the examination of the sputum samples (Table 2). Examination should comprise cytology nuclear image analysis, immunohistochemistry as well as DNA and RNA analysis. Most promising is the detection of malignancy-associated changes, detected by automated quantitative image cytometry and k–ras analysis.
5. Fluorescence bronchoscopy White-light bronchoscopy (WLB) is the most commonly used diagnostic tool for obtaining a definite histological diagnosis for lung cancer. However, it has limitations concerning detection of premalignant lesions. To circumvent these limitations, fluorescence bronchoscopy was developed. Earlier studies utilized fluorescent drugs which were preferentially retained in malignant tissue. This technique has several problems including high cost, photosensitisation of the skin, interference with tissue auto-fluorescence, and the need for preparation. Autofluorescence has substituted drug-induced fluorescence bronchoscopy. This technique uses the difference in autofluorescence between normal, pre-malignant, and tumour tissue. Several studies have compared the diagnostic specificity and sensitivity of LIFE (laser-induced fluorescence endoscopy) bronchoscopy versus WLB in diagnosing pre-invasive and early invasive lesions [23–25]. They report a higher sensitivity at the cost of lower specificity. The low diagnostic specificity might be attributable to the visualisation of more abnormal foci with the LIFE system with the consequence of a larger number of biopsies and more false-positive results. It is
S41
unknown whether LIFE bronchoscopy will lead to a reduction of lung-cancer mortality. Also, no data on cost/effectiveness and cost/benefit analyses are available at the present time.
6. Conclusion The Vancouver group of Stephan Lam has recently published a study combining sputum analysis with low-dose CT and fluorescence bronchoscopy [26]. They used automated quantitative image cytometry for identifying malignancy-associated changes in the sputum. 423 out of 561 had sputum abnormalities, and 259 non-calcified pulmonary nodules were detected (Figure 1). Lung cancer could be diagnosed in 14 subjects, 13 of whom had sputum atypia. 9 out of 13 were detected by CT and 4 out of 13 by fluorescence bronchoscopy. This is the first reported study combining sputum, low-dose-CT and fluorescence bronchoscopy. It shows that sputum analysis has the potential to identify a high-risk population. In this population, the detection rate of early lung cancer is increased and the number of unnecessary CT scans is reduced. The results of this pilot study have a potential impact on future screening trials. In such trials the risk population should be defined very carefully, with risk factors comprising age, smoking habit, and reduction in FEV1. The risk population can be defined, additionally, by methods like automated quantitative image cytometry of sputum samples or biomarkers from proteomic and genomic examination of sputum or blood. This highrisk group should subsequently undergo screening 50 years of age > 30 pack years
Sputum induction (AQC)
Sputum atypia
CT
normal sputum
LIFE
CT
CT+LIFE
• 423/561 with sputum atypia • Noncalcified pulmonary nodules 259/561 • 14/561 with lung cancer • 13/14 of the lung cancer patients with sputum atypia • 9/13 with lung cancer and sputum atypia detected by CT • 4/13 with lung cancer and sputum atypia detected by LIFE Fig. 1. Adapted from McWilliams et al. [26].
S42 procedures like low-dose CT scanning, fluorescence bronchoscopy and, perhaps, newer technologies, like optical coherence tomography. But all these tools and procedures have to be validated in randomised controlled trials with the endpoint “mortality reduction”.
References 1. Fontana RS, Sanderson DR, Taylor WF, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Mayo Clinic study. Am Rev Respir Dis 1984;130(4):561–5. 2. Frost JK, Ball Jr WC, Levin ML, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Johns Hopkins study. Am Rev Respir Dis 1984;130(4):549–54. 3. 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(1):44–53. 4. Kubik A, Polak J. Lung cancer detection. Results of a randomized prospective study in Czechoslovakia. Cancer 1986;57(12):2427–37. 5. Eddy DM. Screening for lung cancer. Ann Intern Med 1989; 111(3):232–7. 6. Diederich S, Lenzen H, Windmann R, et al. Pulmonary nodules: experimental and clinical studies at low-dose CT. Radiology 1999;213(1):289–98. 7. Kaneko M, Eguchi K, Ohmatsu H, et al. Peripheral lung cancer: screening and detection with low-dose spiral CT versus radiography. Radiology 1996;201(3):798–802. 8. Sobue T, Moriyama N, Kaneko M, et al. Screening for lung cancer with low-dose helical computed tomography: antilung cancer association project. J Clin Oncol 2002;20(4): 911–20. 9. Sone S, Takashima S, Li F, et al. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998;351(9111):1242–5. 10. Sone S, Li F, Yang ZG, et al. Results of three-year mass screening programme for lung cancer using mobile low-dose spiral computed tomography scanner. Br J Cancer 2001;84(1): 25–32. 11. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354(9173):99–105. 12. Henschke CI, Naidich DP, Yankelevitz DF, et al. Early lung cancer action project: initial findings on repeat screenings. Cancer 2001;92(1):153–9.
K.-M. Deppermann 13. 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(4):508–13. 14. Swensen SJ, Jett JR, Hartman TE, et al. Lung cancer screening with CT: Mayo Clinic experience. Radiology 2003;226(3):756–61. 15. Diederich S, Wormanns D, Semik M, et al. Screening for early lung cancer with low-dose spiral CT: prevalence in 817 asymptomatic smokers. Radiology 2002;222(3):773–81. 16. Prindiville SA, Byers T, Hirsch FR, et al. Sputum cytological atypia as a predictor of incident lung cancer in a cohort of heavy smokers with airflow obstruction. Cancer Epidemiol Biomarkers Prev 2003;12(10):987–93. 17. Payne PW, Sebo TJ, Doudkine A, et al. Sputum screening by quantitative microscopy: a reexamination of a portion of the National Cancer Institute Cooperative Early Lung Cancer Study. Mayo Clin Proc 1997;72(8):697–704. 18. Marek W, Kotschy-Lang N, Muti A, et al. Can semi-automated image cytometry on induced sputum become a screening tool for lung cancer? Evaluation of quantitative semi-automated sputum cytometry on radon- and uranium-exposed workers. Eur Respir J 2001;18(6):942–50. 19. Tockman MS, Mulshine JL, Piantadosi S, et al. Prospective detection of preclinical lung cancer: results from two studies of heterogeneous nuclear ribonucleoprotein A2/B1 overexpression. Clin Cancer Res 1997;3(12 Pt 1):2237–46. 20. Thunnissen FB. Sputum examination for early detection of lung cancer. J Clin Pathol 2003;56(11):805–10. 21. Belinsky SA, Nikula KJ, Palmisano WA, et al. Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci USA 1998;95(20):11891–6. 22. Hahn WC, Weinberg RA. Rules for making human tumor cells. N Engl J Med 2002;347(20):1593–603. 23. Hirsch FR, Prindiville SA, Miller YE, et al. Fluorescence versus white-light bronchoscopy for detection of preneoplastic lesions: a randomized study. J Natl Cancer Inst 2001;93(18):1385–91. 24. Haussinger K, Stanzel F, Markus A, et al. Early diagnosis of bronchial carcinoma. Technical endoscopic progress – a step toward new screening concepts? Pneumologie 1999;53(2): 77–82. 25. Bota S, Auliac JB, Paris C, et al. Follow-up of bronchial precancerous lesions and carcinoma in situ using fluorescence endoscopy. Am J Respir Crit Care Med 2001;164(9):1688–93. 26. McWilliams A, Mayo J, MacDonald S, et al. Lung cancer screening: a different paradigm. Am J Respir Crit Care Med 2003;168(10):1167–73.
www.elsevier.com/locate/lungcan
Lung cancer screening – Where we are in 2004 (take home messages) Karl-Matthias Deppermann Ruppiner Kliniken, Klinik f¨ ur Pneumologie, D-16816 Neuruppin, Germany
KEYWORDS Lung cancer screening; Low-dose CT; Sputum analysis; Fluorescence bronchoscopy
Summary The best prognosis for lung cancer can be expected by diagnosis at an early stage of the disease. Long-term survival may be improved by increasing the number of early-stage diagnoses. At the present time, three different screening tools for lung cancer are available: Low-dose CT scanning, sputum analysis and fluorescence bronchoscopy. Each of these tools has a different screening target. Low-dose CT scanning focusses on small pulmonary nodules, sputum analysis has the potential of detecting lung cancer of the central airways, and fluorescence bronchoscopy can identify pre-malignancy, carcinoma in situ and minimally invasive squamous cell carcinoma. The best way forward appears to be a combination of all techniques. Sputum analysis can be used to define a better-characterised risk population, and subsequently this population can undergo low-dose CT and fluorescence bronchoscopy. © 2004 Elsevier Science Ltd.
1. Introduction The major goal in lung cancer research is the improvement of long-term survival. In spite of all efforts in conventional treatment of lung cancer by surgery, radiotherapy and chemotherapy in the last decades, survival of lung cancer has experienced only minor improvements over the last 30 years. In other tumour entities, like prostate, colorectal or breast cancer, substantial improvement in longterm survival has been made. Part of this success can be ascribed to screening programmes. Screening of lung cancer has, therefore, been a continuing issue over the last 30 years. Randomised controlled trials from the 1970s, using chest X-ray and sputum, could not show a reduction * Karl-Matthias Deppermann, MD. Tel.: +49-(3391)-39-31-12; fax: +49-(3391)-39-31-39. E-mail: [email protected]
in mortality [1–4]. The results of these studies have been leading to a nihilism concerning lung cancer screening over a long period of time [5]. But new developments in radiographic techniques and new molecular methods as well as bronchoscopic techniques have stimulated an increased interest in lung cancer screening. Lung cancer screening is attractive for several reasons: Still today, lung cancer continues to be the leading cause of cancer-related deaths in the world. In the USA, the number of deaths caused by lung cancer still exceeds the total number of deaths from breast, colon, prostate and cervical cancer. Prognosis of lung cancer is correlated to the stage of disease at the time of diagnosis. Whereas stage–IA patients have a survival rate of 67%, the survival rate declines from 40% to less than 5% for patients with stage-II through stage-IV disease at the time of diagnosis. Accordingly, curative treatment is only
0169-5002/$ – see front matter © 2004 Published by Elsevier Ireland Ltd. doi:10.1016/j.lungcan.2004.07.000
S40
K.-M. Deppermann
effective in early stages, but less than 20% of the patients present with asymptomatic stage I. At the present time three different lung cancer screening tools are being discussed.
2. Screening tools In spite of technical developments such as, e.g., sequential CT, the introduction of spiral CT in the late 1980s or the more recently introduced multidetector-row spiral CT which led to an increase in detection of small pulmonary nodules, the sensitivity of CT scanning regarding exclusively endobronchial lesions is low, due to partial volume artefacts. In this gap fits the analysis of sputum, which is particularly helpful in detecting squamous cell lung cancer, located in the central airways. New molecular biomarkers have expanded the spectrum of sputum examination and improved the former low sensitivity. Fluorescence bronchoscopy is an ideal complement to sputum analysis, because pre-malignancy, carcinoma in situ and minimally invasive squamous cell carcinoma can be localised, especially in occult tumours, which cannot be identified radiographically.
3. Low-dose CT In the last decade, seven one-armed feasibility studies were performed that used low-dose CT as a screening tool [6–15]. These studies include nearly 18,000 volunteers. The definitions of the risk population were different, with ages varying between 40 and 60 years and with an inclusion criterion of a tobacco burden of more than 20 pack-years in some studies, while smoking was no inclusion criterion in others. Prevalence-screen data from these trials confirm that CT is more sensitive in detecting lung nodules than conventional chest radiographs (Table 1). The rate of non-calcified pulmonary nodules was high and varied between 6 and 66%. The high rate of pulmonary nodules found in CT that requires Table 1 Feasibility studies
4. Sputum analysis Prevalence data
CT > chest radiograph 0.03–0.12% vs 0.43–2.7% NPN
subsequently invasive diagnostic procedures is a major point of criticism. Only a small number of these nodules have proved to be malignant lesions, in a range from 0.4% to 2.7%. Using a diagnostic algorithm, the rate of invasive procedures in benign lesions could be reduced to 20–30%. The algorithm qualified a tumour diameter of 10 mm or greater for biopsy. Only non-calcified, non-fatcontaining lesions increasing in size, underwent invasive diagnostic. Furthermore, those studies revealed a significant number of cases with asymptomatic non-smallcell lung cancer, which was more pronounced for prevalence than for incidence screening. The rate of stage–IA lung cancer and resectable cancer was much higher than in all populations, presenting with symptoms. At the present time, screening of lung cancer with low-dose CT is not recommended. Although the feasibility studies could identify a higher rate of lung cancer at an early stage of disease, this does not mean that the rate of advanced lung cancer is decreasing. A shift of stage from advanced to earlier stages could not be demonstrated. The data of the non-randomised trials are influenced by biases, such as the lead-time, length-time and over-diagnosis bias. The studies do not support the assumption that simply detecting smallersized tumours will be sufficient for achieving a meaningful reduction in lung-cancer mortality. As long as a significant reduction in mortality is not shown, we have to realise that repeated screening by low-dose CT carries a small but definitive risk in inducing malignancies. Moreover, morbidity will be increased by invasive procedures in benign lesions. The only possibility for answering all these questions is to perform randomised controlled trials with a screening arm and a control arm. But such trials will need thousands of volunteers and this will incur considerable costs. Randomised controlled trials were recently initiated in North America and in Europe. The biggest trial, in the USA, will include a total number of 50,000 subjects. Results will only be available in several years.
6–66%
Malignant lesions
0.4–2.7%
Diagnostic algorithm
Threshold 10 mm, noncalcified nodules, growth kinetic
Invasive procedures for benign lesions: 20–30%
Another screening tool is the analysis of sputum. Cytological examination of the sputum has been used since 1930. It is especially helpful in detecting central squamous cell and small-cell carcinomas. Sputum samples are easily obtained and cytological examination is inexpensive [16–18]. The material is specific for the airways and analysis has a high specificity. But there are also some disadvantages,
Lung cancer screening – Where we are in 2004 (take home messages) Table 2 Improvement of sputum analysis Cytology
DNA-Methylation
Nuclear image analysis
FISH analysis
Immunohistochemistry
K-ras mutations
DNA Analysis
p53 mutations
RNA Analysis
including low sensitivity in earlier trials and difficulties in obtaining proper material. There exists a wide range in reader variability, resulting in the problem of low reproducibility. Molecular methods have been developed only recently and were not available in earlier studies. Several approaches can improve the sensitivity of sputum analysis [19–22]. The risk population should be defined better in terms of age, pack-years and reduction in FEV1. Sputum induction should be improved and standardised. The main focus should be on the examination of the sputum samples (Table 2). Examination should comprise cytology nuclear image analysis, immunohistochemistry as well as DNA and RNA analysis. Most promising is the detection of malignancy-associated changes, detected by automated quantitative image cytometry and k–ras analysis.
5. Fluorescence bronchoscopy White-light bronchoscopy (WLB) is the most commonly used diagnostic tool for obtaining a definite histological diagnosis for lung cancer. However, it has limitations concerning detection of premalignant lesions. To circumvent these limitations, fluorescence bronchoscopy was developed. Earlier studies utilized fluorescent drugs which were preferentially retained in malignant tissue. This technique has several problems including high cost, photosensitisation of the skin, interference with tissue auto-fluorescence, and the need for preparation. Autofluorescence has substituted drug-induced fluorescence bronchoscopy. This technique uses the difference in autofluorescence between normal, pre-malignant, and tumour tissue. Several studies have compared the diagnostic specificity and sensitivity of LIFE (laser-induced fluorescence endoscopy) bronchoscopy versus WLB in diagnosing pre-invasive and early invasive lesions [23–25]. They report a higher sensitivity at the cost of lower specificity. The low diagnostic specificity might be attributable to the visualisation of more abnormal foci with the LIFE system with the consequence of a larger number of biopsies and more false-positive results. It is
S41
unknown whether LIFE bronchoscopy will lead to a reduction of lung-cancer mortality. Also, no data on cost/effectiveness and cost/benefit analyses are available at the present time.
6. Conclusion The Vancouver group of Stephan Lam has recently published a study combining sputum analysis with low-dose CT and fluorescence bronchoscopy [26]. They used automated quantitative image cytometry for identifying malignancy-associated changes in the sputum. 423 out of 561 had sputum abnormalities, and 259 non-calcified pulmonary nodules were detected (Figure 1). Lung cancer could be diagnosed in 14 subjects, 13 of whom had sputum atypia. 9 out of 13 were detected by CT and 4 out of 13 by fluorescence bronchoscopy. This is the first reported study combining sputum, low-dose-CT and fluorescence bronchoscopy. It shows that sputum analysis has the potential to identify a high-risk population. In this population, the detection rate of early lung cancer is increased and the number of unnecessary CT scans is reduced. The results of this pilot study have a potential impact on future screening trials. In such trials the risk population should be defined very carefully, with risk factors comprising age, smoking habit, and reduction in FEV1. The risk population can be defined, additionally, by methods like automated quantitative image cytometry of sputum samples or biomarkers from proteomic and genomic examination of sputum or blood. This highrisk group should subsequently undergo screening 50 years of age > 30 pack years
Sputum induction (AQC)
Sputum atypia
CT
normal sputum
LIFE
CT
CT+LIFE
• 423/561 with sputum atypia • Noncalcified pulmonary nodules 259/561 • 14/561 with lung cancer • 13/14 of the lung cancer patients with sputum atypia • 9/13 with lung cancer and sputum atypia detected by CT • 4/13 with lung cancer and sputum atypia detected by LIFE Fig. 1. Adapted from McWilliams et al. [26].
S42 procedures like low-dose CT scanning, fluorescence bronchoscopy and, perhaps, newer technologies, like optical coherence tomography. But all these tools and procedures have to be validated in randomised controlled trials with the endpoint “mortality reduction”.
References 1. Fontana RS, Sanderson DR, Taylor WF, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Mayo Clinic study. Am Rev Respir Dis 1984;130(4):561–5. 2. Frost JK, Ball Jr WC, Levin ML, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Johns Hopkins study. Am Rev Respir Dis 1984;130(4):549–54. 3. 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(1):44–53. 4. Kubik A, Polak J. Lung cancer detection. Results of a randomized prospective study in Czechoslovakia. Cancer 1986;57(12):2427–37. 5. Eddy DM. Screening for lung cancer. Ann Intern Med 1989; 111(3):232–7. 6. Diederich S, Lenzen H, Windmann R, et al. Pulmonary nodules: experimental and clinical studies at low-dose CT. Radiology 1999;213(1):289–98. 7. Kaneko M, Eguchi K, Ohmatsu H, et al. Peripheral lung cancer: screening and detection with low-dose spiral CT versus radiography. Radiology 1996;201(3):798–802. 8. Sobue T, Moriyama N, Kaneko M, et al. Screening for lung cancer with low-dose helical computed tomography: antilung cancer association project. J Clin Oncol 2002;20(4): 911–20. 9. Sone S, Takashima S, Li F, et al. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998;351(9111):1242–5. 10. Sone S, Li F, Yang ZG, et al. Results of three-year mass screening programme for lung cancer using mobile low-dose spiral computed tomography scanner. Br J Cancer 2001;84(1): 25–32. 11. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354(9173):99–105. 12. Henschke CI, Naidich DP, Yankelevitz DF, et al. Early lung cancer action project: initial findings on repeat screenings. Cancer 2001;92(1):153–9.
K.-M. Deppermann 13. 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(4):508–13. 14. Swensen SJ, Jett JR, Hartman TE, et al. Lung cancer screening with CT: Mayo Clinic experience. Radiology 2003;226(3):756–61. 15. Diederich S, Wormanns D, Semik M, et al. Screening for early lung cancer with low-dose spiral CT: prevalence in 817 asymptomatic smokers. Radiology 2002;222(3):773–81. 16. Prindiville SA, Byers T, Hirsch FR, et al. Sputum cytological atypia as a predictor of incident lung cancer in a cohort of heavy smokers with airflow obstruction. Cancer Epidemiol Biomarkers Prev 2003;12(10):987–93. 17. Payne PW, Sebo TJ, Doudkine A, et al. Sputum screening by quantitative microscopy: a reexamination of a portion of the National Cancer Institute Cooperative Early Lung Cancer Study. Mayo Clin Proc 1997;72(8):697–704. 18. Marek W, Kotschy-Lang N, Muti A, et al. Can semi-automated image cytometry on induced sputum become a screening tool for lung cancer? Evaluation of quantitative semi-automated sputum cytometry on radon- and uranium-exposed workers. Eur Respir J 2001;18(6):942–50. 19. Tockman MS, Mulshine JL, Piantadosi S, et al. Prospective detection of preclinical lung cancer: results from two studies of heterogeneous nuclear ribonucleoprotein A2/B1 overexpression. Clin Cancer Res 1997;3(12 Pt 1):2237–46. 20. Thunnissen FB. Sputum examination for early detection of lung cancer. J Clin Pathol 2003;56(11):805–10. 21. Belinsky SA, Nikula KJ, Palmisano WA, et al. Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci USA 1998;95(20):11891–6. 22. Hahn WC, Weinberg RA. Rules for making human tumor cells. N Engl J Med 2002;347(20):1593–603. 23. Hirsch FR, Prindiville SA, Miller YE, et al. Fluorescence versus white-light bronchoscopy for detection of preneoplastic lesions: a randomized study. J Natl Cancer Inst 2001;93(18):1385–91. 24. Haussinger K, Stanzel F, Markus A, et al. Early diagnosis of bronchial carcinoma. Technical endoscopic progress – a step toward new screening concepts? Pneumologie 1999;53(2): 77–82. 25. Bota S, Auliac JB, Paris C, et al. Follow-up of bronchial precancerous lesions and carcinoma in situ using fluorescence endoscopy. Am J Respir Crit Care Med 2001;164(9):1688–93. 26. McWilliams A, Mayo J, MacDonald S, et al. Lung cancer screening: a different paradigm. Am J Respir Crit Care Med 2003;168(10):1167–73.