A Pause, Progress, and Reassessment in Lung Cancer Screening
http://www.100md.com
《新英格兰医药杂志》
We are all well acquainted with the frightfully high incidence of lung cancer and the short survival of patients after the diagnosis has been made. The extremely low survival rate is attributable in part to the advanced stage of the disease at the time of diagnosis. The 5-year survival rate among patients with stage I lung cancer is approximately 70%, and it declines to about 5% among patients with stage IV lung cancer. The serendipitous discovery of lung cancer in asymptomatic people is currently the principal way in which stage I lung cancer is detected.
Unfortunately, we have not left behind the idea that lung cancer is a punishment, not a disease.1 The legacy of the stigma that has been associated with lung cancer may have delayed the launching of vigorous research on early detection of the disease. The three widely cited studies from the 1970s that failed to show a benefit of the radiographic screening of cigarette smokers did not help matters.2
The clinically suitable and widespread use of screening methods to detect cancers of the breast, colon, cervix, and prostate at least in part accounts for the lower mortality among patients with these cancers than among patients with lung cancer. Nevertheless, in 1996, the U.S. Preventive Services Task Force made a recommendation against screening for lung cancer. The results of randomized, controlled studies — the gold standard — are unavailable, but recommendations based on other studies were formulated, and in 2004, the task force concluded that the evidence was insufficient to make a recommendation for or against the screening of asymptomatic persons for lung cancer.3
Screening is not a test but a process. This distinction matters. Findings on radiographic screening lead to a diagnostic workup. Once a diagnosis is made, the process dictates the choice of treatment. Each of the steps in a screening algorithm is a medical decision in which the physician, acting as the patient's advocate, weighs benefits and risks. Physicians caring for people who are susceptible to lung cancer face four conflicting factors: the demand from the public to act, the need to consider cost-effectiveness and social responsibility, the need for scientific knowledge, and the lack of definitive evidence. Multidisciplinary teamwork to address these factors will benefit patients and society.4
Advances in technology will permit the detection of smaller and smaller tumors and thus presumably detection at earlier stages of the disease. Tumors that are detected at earlier and later stages may be the same size, but they may not have the same biologic properties. Virulence and doubling time are particularly important. Tumor growth can be extrapolated from the rate of change in the size of the tumor on repeated radiographic studies performed at determined intervals. However, the evolution of the tumor as seen on radiographic images does not necessarily follow a predictable step-by-step pattern. Metastatic disease can occur even while the image of the primary tumor remains small. Computer-assisted diagnosis of radiographic images, which involves three-dimensional volumetric measurements, will permit shorter intervals between screening tests, which could provide valuable information about the growth rate of the tumor. These techniques will also increase the sensitivity and specificity of computed tomographic (CT) studies.5,6
In this issue of the Journal, Henschke et al., writing for the International Early Lung Cancer Action Program (I-ELCAP), contribute a substantial amount of new, important information regarding the management of clinical stage I lung cancer that is detected on CT screening.7 This multicenter, multispecialty study with a defined algorithm was conducted in both academic institutions and community hospitals, thereby demonstrating adaptability in various health care delivery systems. The rate of survival among patients with lesions detected on CT who then underwent an appropriate diagnostic procedure (usually fine-needle aspiration) and resection of stage I lung cancer was similar to the rate among patients with early-stage breast cancer that is detected by means of mammography and resected. In contrast to the survival rate of about 70% at 5 years among patients with clinical stage I lung cancer, Henschke et al. report a 10-year survival rate of 88%.
A troublesome problem in screening for lung cancer is the definition of a "high-risk" population — the population that could best benefit from lung cancer screening. The I-ELCAP study included more than 31,000 subjects who were at risk for lung cancer because they had a history of cigarette smoking or a history of occupational exposure (e.g., to asbestos, beryllium, uranium, or radon), or they had never smoked but had been exposed to secondhand smoke with or without a family history of lung cancer. The study was a systematic case–control observational study, not the gold-standard randomized trial. Nevertheless, before the I-ELCAP study, we lacked documentation of the results of a detection test combined with planned management and long-term follow-up. Previous information was based in large part on incidental rather than methodically collected findings in lung cancer.8 In the study reported by Henschke et al., each institution specified its own criteria for enrollment, possibly affecting the yield of the detection test but not other data. In many patients, the diagnostic procedure was triggered by evidence of tumor growth on serial CT scans, and in these patients, a pathological diagnosis of lung cancer led to surgical resection.
One of the inherent weaknesses of any single radiographic or biomarker test for lung cancer is the inability to provide unequivocal information about the biology of a tumor — that is, its growth pattern and how it will respond to therapy. A combination of new molecular and radiographic approaches can enrich the information on which physicians base their decisions.9,10,11
The I-ELCAP study has considerable merit, but important questions remain. It is possible that without consideration of tumor biology, biases such as lead time and overdiagnosis could have been introduced in the final analysis of mortality. In the short run, chest CT scans alone do not reveal the differences between tumors and growing granulomatous lesions. Moreover, centrally located tumors or tumors located in the airway are not readily detectable by means of CT scanning. The question of cost-effectiveness remains unanswered.
We are making solid progress in combining CT scanning with sputum analysis, fluorescence bronchoscopy, and analysis of pulmonary fluids, exhaled gases, and blood by genomic, proteomic, and immunologic methods. Routine clinical applications of these methods, however, are not available. These technological wonders require extensive validation and proof that markers alone or in combination are sufficiently specific for the detection and diagnosis of lung cancer.
After the long pause that followed the inconclusive studies of the 1970s, a seminal article by Henschke and colleagues in 1999 ignited a controversy about lung cancer screening by means of radiographic techniques.12 The National Institutes of Health responded to the debate promptly by investing in a very large, randomized screening study for lung cancer by means of CT scanning and chest radiography. Another randomized study of lung cancer screening is being conducted under the auspices of the Mayo Clinic.13 These projects have sparked similar studies in Europe and have served as a template for the incorporation of biomarker studies into radiographic screening.9 The study reported by Henschke et al. in this issue of the Journal is a provocative, welcome salvo in the long struggle to reduce the tremendous burden of lung cancer on society.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Pulmonary Cancer Detection and Prevention Program, Fox Chase Cancer Center, Philadelphia.
References
Chapple A, Ziebland S, McPherson A. Stigma, shame, and blame experienced by patients with lung cancer: qualitative study. BMJ 2004;328:1470-1470.
Early lung cancer detection: summary and conclusions. Am Rev Respir Dis 1984;130:565-570.
Preventive Services Task Force. Screening for lung cancer. (Accessed October 5, 2006, at http://www.ahrq.gov/clinic/uspstf/uspslung.htm.)
Mulshine JL, Sullivan DC. Lung cancer screening. N Engl J Med 2005;352:2714-2720.
Clarke LP, Croft BY, Staab E, Baker H, Sullivan DC. National Cancer Institute initiative: lung image database resource for imaging research. Acad Radiol 2001;8:447-450.
Goodman LR, Gulsun M, Washington L, Nagy PG, Piacsek KL. Inherent variability of CT lung nodule measurements in vivo using semiautomated volumetric measurements. AJR Am J Roentgenol 2006;186:989-994.
The International Early Lung Cancer Action Program Investigators. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006;355:1763-1771.
Patz EF Jr, Swensen SJ, Herndon JE II. Estimate of lung cancer mortality from low-dose spiral computed tomography screening trials: implications for current mass screening recommendations. J Clin Oncol 2004;22:2202-2206.
Zhong L, Coe SP, Stromberg AJ, Khattar NH, Jett JR, Hirschowitz EA. Profiling tumor-associated antibodies for early detection of non-small cell lung cancer. J Thorac Oncol 2006;1:513-9.
Potti A, Mukherjee S, Petersen R, et al. A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 2006;355:570-580.
Bastarrika G, Garcia-Velloso MJ, Lozano MD, et al. Early lung cancer detection using spiral computed tomography and positron emission tomography. Am J Respir Crit Care Med 2005;171:1378-1383.
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.
Swensen SJ, Jett JR, Hartman TE, et al. CT screening for lung cancer: five-year prospective experience. Radiology 2005;235:259-265.(Michael Unger, M.D.)
Unfortunately, we have not left behind the idea that lung cancer is a punishment, not a disease.1 The legacy of the stigma that has been associated with lung cancer may have delayed the launching of vigorous research on early detection of the disease. The three widely cited studies from the 1970s that failed to show a benefit of the radiographic screening of cigarette smokers did not help matters.2
The clinically suitable and widespread use of screening methods to detect cancers of the breast, colon, cervix, and prostate at least in part accounts for the lower mortality among patients with these cancers than among patients with lung cancer. Nevertheless, in 1996, the U.S. Preventive Services Task Force made a recommendation against screening for lung cancer. The results of randomized, controlled studies — the gold standard — are unavailable, but recommendations based on other studies were formulated, and in 2004, the task force concluded that the evidence was insufficient to make a recommendation for or against the screening of asymptomatic persons for lung cancer.3
Screening is not a test but a process. This distinction matters. Findings on radiographic screening lead to a diagnostic workup. Once a diagnosis is made, the process dictates the choice of treatment. Each of the steps in a screening algorithm is a medical decision in which the physician, acting as the patient's advocate, weighs benefits and risks. Physicians caring for people who are susceptible to lung cancer face four conflicting factors: the demand from the public to act, the need to consider cost-effectiveness and social responsibility, the need for scientific knowledge, and the lack of definitive evidence. Multidisciplinary teamwork to address these factors will benefit patients and society.4
Advances in technology will permit the detection of smaller and smaller tumors and thus presumably detection at earlier stages of the disease. Tumors that are detected at earlier and later stages may be the same size, but they may not have the same biologic properties. Virulence and doubling time are particularly important. Tumor growth can be extrapolated from the rate of change in the size of the tumor on repeated radiographic studies performed at determined intervals. However, the evolution of the tumor as seen on radiographic images does not necessarily follow a predictable step-by-step pattern. Metastatic disease can occur even while the image of the primary tumor remains small. Computer-assisted diagnosis of radiographic images, which involves three-dimensional volumetric measurements, will permit shorter intervals between screening tests, which could provide valuable information about the growth rate of the tumor. These techniques will also increase the sensitivity and specificity of computed tomographic (CT) studies.5,6
In this issue of the Journal, Henschke et al., writing for the International Early Lung Cancer Action Program (I-ELCAP), contribute a substantial amount of new, important information regarding the management of clinical stage I lung cancer that is detected on CT screening.7 This multicenter, multispecialty study with a defined algorithm was conducted in both academic institutions and community hospitals, thereby demonstrating adaptability in various health care delivery systems. The rate of survival among patients with lesions detected on CT who then underwent an appropriate diagnostic procedure (usually fine-needle aspiration) and resection of stage I lung cancer was similar to the rate among patients with early-stage breast cancer that is detected by means of mammography and resected. In contrast to the survival rate of about 70% at 5 years among patients with clinical stage I lung cancer, Henschke et al. report a 10-year survival rate of 88%.
A troublesome problem in screening for lung cancer is the definition of a "high-risk" population — the population that could best benefit from lung cancer screening. The I-ELCAP study included more than 31,000 subjects who were at risk for lung cancer because they had a history of cigarette smoking or a history of occupational exposure (e.g., to asbestos, beryllium, uranium, or radon), or they had never smoked but had been exposed to secondhand smoke with or without a family history of lung cancer. The study was a systematic case–control observational study, not the gold-standard randomized trial. Nevertheless, before the I-ELCAP study, we lacked documentation of the results of a detection test combined with planned management and long-term follow-up. Previous information was based in large part on incidental rather than methodically collected findings in lung cancer.8 In the study reported by Henschke et al., each institution specified its own criteria for enrollment, possibly affecting the yield of the detection test but not other data. In many patients, the diagnostic procedure was triggered by evidence of tumor growth on serial CT scans, and in these patients, a pathological diagnosis of lung cancer led to surgical resection.
One of the inherent weaknesses of any single radiographic or biomarker test for lung cancer is the inability to provide unequivocal information about the biology of a tumor — that is, its growth pattern and how it will respond to therapy. A combination of new molecular and radiographic approaches can enrich the information on which physicians base their decisions.9,10,11
The I-ELCAP study has considerable merit, but important questions remain. It is possible that without consideration of tumor biology, biases such as lead time and overdiagnosis could have been introduced in the final analysis of mortality. In the short run, chest CT scans alone do not reveal the differences between tumors and growing granulomatous lesions. Moreover, centrally located tumors or tumors located in the airway are not readily detectable by means of CT scanning. The question of cost-effectiveness remains unanswered.
We are making solid progress in combining CT scanning with sputum analysis, fluorescence bronchoscopy, and analysis of pulmonary fluids, exhaled gases, and blood by genomic, proteomic, and immunologic methods. Routine clinical applications of these methods, however, are not available. These technological wonders require extensive validation and proof that markers alone or in combination are sufficiently specific for the detection and diagnosis of lung cancer.
After the long pause that followed the inconclusive studies of the 1970s, a seminal article by Henschke and colleagues in 1999 ignited a controversy about lung cancer screening by means of radiographic techniques.12 The National Institutes of Health responded to the debate promptly by investing in a very large, randomized screening study for lung cancer by means of CT scanning and chest radiography. Another randomized study of lung cancer screening is being conducted under the auspices of the Mayo Clinic.13 These projects have sparked similar studies in Europe and have served as a template for the incorporation of biomarker studies into radiographic screening.9 The study reported by Henschke et al. in this issue of the Journal is a provocative, welcome salvo in the long struggle to reduce the tremendous burden of lung cancer on society.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Pulmonary Cancer Detection and Prevention Program, Fox Chase Cancer Center, Philadelphia.
References
Chapple A, Ziebland S, McPherson A. Stigma, shame, and blame experienced by patients with lung cancer: qualitative study. BMJ 2004;328:1470-1470.
Early lung cancer detection: summary and conclusions. Am Rev Respir Dis 1984;130:565-570.
Preventive Services Task Force. Screening for lung cancer. (Accessed October 5, 2006, at http://www.ahrq.gov/clinic/uspstf/uspslung.htm.)
Mulshine JL, Sullivan DC. Lung cancer screening. N Engl J Med 2005;352:2714-2720.
Clarke LP, Croft BY, Staab E, Baker H, Sullivan DC. National Cancer Institute initiative: lung image database resource for imaging research. Acad Radiol 2001;8:447-450.
Goodman LR, Gulsun M, Washington L, Nagy PG, Piacsek KL. Inherent variability of CT lung nodule measurements in vivo using semiautomated volumetric measurements. AJR Am J Roentgenol 2006;186:989-994.
The International Early Lung Cancer Action Program Investigators. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006;355:1763-1771.
Patz EF Jr, Swensen SJ, Herndon JE II. Estimate of lung cancer mortality from low-dose spiral computed tomography screening trials: implications for current mass screening recommendations. J Clin Oncol 2004;22:2202-2206.
Zhong L, Coe SP, Stromberg AJ, Khattar NH, Jett JR, Hirschowitz EA. Profiling tumor-associated antibodies for early detection of non-small cell lung cancer. J Thorac Oncol 2006;1:513-9.
Potti A, Mukherjee S, Petersen R, et al. A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 2006;355:570-580.
Bastarrika G, Garcia-Velloso MJ, Lozano MD, et al. Early lung cancer detection using spiral computed tomography and positron emission tomography. Am J Respir Crit Care Med 2005;171:1378-1383.
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.
Swensen SJ, Jett JR, Hartman TE, et al. CT screening for lung cancer: five-year prospective experience. Radiology 2005;235:259-265.(Michael Unger, M.D.)