To Screen or Not To Screen
2003; Elsevier BV; Volume: 123; Issue: 6 Linguagem: Inglês
10.1378/chest.123.6.1788
ISSN1931-3543
AutoresDavid E. Ost, Rakesh Shah, Daniel Fein, Alan M. Fein,
Tópico(s)Lung Cancer Diagnosis and Treatment
ResumoWhether at international medical forums, within the halls of local hospitals, in medical offices, or in the lay press, the debate over whether or not to screen for lung cancer continues, even though the public demands guidance and few problems frustrate physicians more than their inability to prevent deaths from the disease. Affecting close to 200,000 people annually in the United States, this devastating malignancy is the most common cause of cancer death worldwide. Previously considered an affliction of men, lung cancer is now the most common cause of death from cancer in women. Despite improvements in management, the mortality rate has continued to hover at > 85% at 5 years.1Jemal A Thomas A Murray T et al.Cancer statistics 2002.CA Cancer J Clin. 2002; 52: 23-47Crossref PubMed Scopus (2916) Google ScholarGiven the fact that the cause of lung cancer (cigarette smoking) is known and identifiable, the disease should be amenable to early intervention. Screening patients who are at risk prior to the development of clinical signs of illness would seem to be a logical first step in addressing this critical public health problem. Screening for other types of cancer has been a doctrine of almost biblical proportions in the medical community. Presumably, detecting lung cancer at an earlier stage would allow patients to undergo treatment, usually surgical resection, prior to the development of metastasis. In fact, several screening studies already have demonstrated that diagnosis at an earlier stage than is typically encountered with standard practice is possible. And yet, standard medical practice has focused largely on the recognition and diagnosis of the disorder once signs and symptoms have developed, rather than on screening.Many other common cancers have been approached through broad-based public health screening programs that now are ingrained in North American clinical practice. The American Cancer Society,2American Cancer Society Cancer prevention and early detection worksheet for men.Available at: www.cancer.orgGoogle Scholarfor example, recommends routine breast self-examination of asymptomatic women for breast cancer starting at age 20 years, yearly mammography after age 40 years, and screening for prostate cancer in men starting at age 50 years through prostate-specific antigen testing and digital examination. Screening for colon cancer involves regular endoscopic procedures that many consider invasive and potentially harmful. These practices are still in place despite numerous recent challenges to their validity and cost-effectiveness. In contrast, the support for lung cancer screening from organized medicine and public health organizations is virtually nonexistent. A recent “cancer-screening” day at our institution, for example, attracted thousands of visitors but did not have a single exhibit on how to prevent or detect lung cancer. No organizations recommend the routine screening of general populations even for those who are at an elevated risk. The rationale put forward for this position is the lack of evidence that current screening techniques reduce lung cancer-specific mortality.But controversy, and in some instances a similar lack of definitive evidence, has not curtailed screening for other types of cancer. Whether or not the inconsistent standard from one disease to another as to what constitutes “sufficient evidence” is warranted is a difficult question. In part, the answer depends on the underlying values of society. Undeniably, some people regard lung cancer as a self-inflicted problem resulting from excessive smoking, the type of behavior that was termed “willful and self destructive” 900 years ago by Maimonides. “Live sensibly, among a thousand people, one dies a natural death; the rest succumb to irrational modes of living,” he stated. An element of that philosophy persists today, specifically that smokers’ self-destructive behavior renders them undeserving of screening and early intervention. Societal values also shape any discussion of who should pay for screening and what cost-effectiveness standards justify its routine use.Underlying these issues is the fundamental one concerning the nature of the scientific evidence for and against lung-cancer screening, and the question of why current practice standards for lung cancer differ so much from those for other common, but less lethal, oncologic diseases. One can ask whether maintaining the status quo is warranted, given the information that has emerged recently from studies utilizing screening based on low-dose spiral CT scanning.3Sone S Takashima S Li F et al.Mass screening for lung cancer with mobile spiral computed tomography scanner.Lancet. 1998; 351: 1242-1245Abstract Full Text Full Text PDF PubMed Scopus (876) Google Scholar4Henschke CI McCauley DI Yankelvitz DF et al.Early Lung Cancer Action Project: overall design and findings from baseline screening.Lancet. 1999; 354: 99-105Abstract Full Text Full Text PDF PubMed Scopus (2151) Google ScholarHowever, many concerns have contributed to the current intellectual and clinical inertia, notably overdiagnosis, lead-time, and length-time bias.Overdiagnosis concerns center on the detection of relatively nonprogressive, indolent lesions, which can result in unnecessary and possibly harmful procedures in the course of evaluating and treating patients. Such lesions, however, represent preclinical disease that would not have become apparent clinically had it not been discovered by screening. Although opinion is divided, some estimates hold that up to one third of lung cancers that are detected early will not progress.5Reich JM Improved survival and higher mortality: the conundrum of lung cancer screening.Chest. 2002; 122: 329-337Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar6Black WC Overdiagnosis: an underrecognized cause of confusion and harm in cancer screening.J Natl Cancer Inst. 2000; 92: 1290-1292Crossref Scopus (199) Google ScholarLead-time is the period between the detection of the disease by screening and the point at which it becomes symptomatic. For unscreened patients, disease-specific survival is defined as the length of time from the clinical diagnosis of disease to death from the disease. For screened patients, it is the time from the detection of disease by the screening test to death from the disease. Lead-time bias refers to the fact that screening may create the impression that patients survive longer from the time of diagnosis simply because the screening test detected the disease before it became symptomatic. Even if the disease is totally untreatable, disease-specific survival can increase, but overall survival will remain the same with or without screening.Length-time bias is related to the biological heterogeneity of lung cancer. Some cancers metastasize relatively early, while others progress at a slower rate. The latter cancers, which exist longer than the former in a preclinical asymptomatic phase, are more likely to be detected during screening. Therefore, of all tumors detected by screening programs, a higher percentage would be slow-growing, less biologically aggressive tumors. Such overrepresentation of less aggressive tumors also would increase disease-specific survival among the screened cohort but would not necessarily increase overall survival.Because of these considerations, disease-specific mortality, rather than disease-specific survival, is thought to be the appropriate end point for evaluating the efficacy of screening programs. One reason why prior randomized clinical trials (evaluating > 35,000 patients over several decades) have failed to quench the debate is because of their inability to demonstrate any impact on disease-specific mortality through screening. Based on the principles of bias described above, it has been hypothesized that when a lung cancer is detected by screening at an earlier stage, the time of “recognized illness” is prolonged but survival is not improved. Four randomized controlled trials that were performed during the 1970s demonstrated that screening with chest radiography, both with and without sputum cytology, permits the recognition of disease at an earlier stage.7Flehinger BJ Melamed MR Zaman MG et al.Early lung cancer detection: results of the initial screen (prevalence) radiologic and cytologic screening in the Memorial Sloan-Kettering study.Am Rev Respir Dis. 1984; 130: 555-560PubMed Google Scholar8Frost JK Ball Jr, WC Levin ML et al.Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the John Hopkins study.Am Rev Respir Dis. 1984; 130: 549-554PubMed Google Scholar9Fontana 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: 561-565PubMed Google ScholarMortality in the Mayo Lung Project was 11% higher in the screened group compared to control subjects, a finding that was attributed in part to randomization imbalances and overdiagnosis bias. Even a 20-year follow-up of the original Mayo Lung Cancer screening project failed to demonstrate any difference in mortality rates between screened groups and control groups (4.4 vs 3.9 per 1,000 person-years, respectively).10Marcus PM Bergstralh EJ Faferstrom RM et al.Lung cancer mortality in the Mayo Lung Project: impact of extended follow-up.J Natl Cancer Inst. 2000; 20: 1308-1316Crossref Scopus (455) Google ScholarMore recently, studies3Sone S Takashima S Li F et al.Mass screening for lung cancer with mobile spiral computed tomography scanner.Lancet. 1998; 351: 1242-1245Abstract Full Text Full Text PDF PubMed Scopus (876) Google Scholar4Henschke CI McCauley DI Yankelvitz DF et al.Early Lung Cancer Action Project: overall design and findings from baseline screening.Lancet. 1999; 354: 99-105Abstract Full Text Full Text PDF PubMed Scopus (2151) Google Scholar11Nawa T Nakagawa T Kusano S et al.Lung cancer screening using low-dose spiral CT: results of baseline and 1-year follow-up studies.Chest. 2002; 122: 15-20Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholarof low-dose spiral CT scanning in both the United States and Japan have demonstrated the modality’s potential for detecting lung cancer in the preclinical stage, when surgical resection is possible. In the Early Lung Cancer Action Project study,12Henschke CI Yankelvitz DF CT screening for lung cancer.Radiol Clin North Am. 2000; 38: 487-495Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholarlow-dose spiral CT scanning detected six times more lung cancers than did chest radiography, and most of them < 1.0 cm in size. While these data are promising, there are no reports to date that have demonstrated a definitive reduction in all-cause mortality from any lung cancer-screening program.Given the raging debate and the continued fundamental differences in the interpretation of the evidence, where should we go from here? Screening, and utilizing standard chest radiology and sputum cytology cannot be advocated as the primary tool for an early lung cancer detection program. Low-dose spiral CT scanning has added incrementally to our early-detection capability, yet proof of efficacy and even safety remain controversial. What other technologies hold promise? Innovations in molecular biology and new technologies could enhance our ability to detect lesions and characterize the biological potential of nodules, thus enabling us to move beyond simply detecting tumors to distinguishing benign from malignant ones, and discriminating between indolent and aggressive ones. Such progress is critical if we are to address the concerns of length-time bias and lead-time bias. Several approaches have been suggested,13Kersting M Friedl C Kraus A et al.Differential frequencies of p16(INK4a) promoter hypermethylation, p53 mutation and K-ras mutation in exfoliative material mark the development of lung cancer in symptomatic chronic smokers.J Clin Oncol. 2000; 18: 3221-3229PubMed Google Scholar14Mulshine JL Scott F Molecular markers in lung cancer detection: new screening tools.Chest. 1995; 107: 280S-286SAbstract Full Text Full Text PDF PubMed Google Scholar15Payne PW Sebo TG 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: 697-704Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholarincluding more sophisticated sputum analyses utilizing molecular techniques, immunostaining, or automated cytometry. In addition, bronchoscopic examination of the airway has been enhanced to allow photodetection of tumors that are confined to the epithelium. While these approaches are promising, they remain unproven in large-scale population studies.16Prakash UBS Advances in bronchoscopic procedures.Chest. 1999; 116: 1403-1408Abstract Full Text Full Text PDF PubMed Scopus (69) Google ScholarIn this issue of CHEST (see page 2115), Phillips et al expand on previous work, examining the role of volatile organic compounds and monomethylated alkanes in human breath as biological markers of lung cancer.17Phillips M Gleeson K Hughes MB et al.Volatile organic compounds in breath as markers of lung cancer: a cross-sectional study.Lancet. 1999; 353: 1930-1933Abstract Full Text Full Text PDF PubMed Scopus (744) Google ScholarThose entities are produced by lipid peroxidation of polyunsaturated fatty acids in ubiquitous cell membranes, which are measured in the breath as ethanes, pentanes, or methylated alkanes. In this preliminary work, the authors present evidence suggesting that lung cancers are associated with a relatively unique chemical footprint, an observation that may be incorporated into lung cancer screening. In a group of 219 subjects, 178 of whom had undergone bronchoscopy for the evaluation of lung cancer, breath analysis detected lung cancer with a sensitivity of 90% and a specificity of 83%. The negative predictive value was a remarkable 99%, a finding that, if confirmed, could lead to the elimination of most benign false-positive results that are picked up on spiral CT screening, thus obviating the need for further workup and potentially unnecessary surgery. Unfortunately, separation by tumor type or smoking status was not associated with unique patterns on breath analysis. Disappointingly, there did not seem to be a correlation between cancer stage, and therefore tumor mass, and chemical footprint. In addition, the authors observed high rates of false-positive results in those subjects in whom cancer had not been confirmed by CT scanning or bronchoscopy. The authors suggest a role for breath analysis in screening, with CT scanning or bronchoscopy reserved only for those with positive results. If this technology were developed further, however, the optimal sequencing of CT scanning and breath analysis would need to be evaluated. It may be that spiral CT scanning would be the initial test, with breath analysis used subsequently.As a New Yorker might ask, “Is this approach ready for Broadway?” The answer is decidedly “not yet!” While no one could question the extraordinary individual, community, and financial consequences of the lung-cancer epidemic, public health criteria, such as the impact on disease-specific mortality and cost-effectiveness, must be considered before population-based disease-finding programs can be implemented. If public funds are to be spent on an avoidable disease, public debate on the issue of who is to pay for the screening must be part of the process as well. Given the finite amount of health-care resources that are available, the potential benefits of lung cancer screening must be weighed against the potential good that those same dollars could achieve by being spent on other programs, such as increasing vaccination rates or improving access to prenatal care. The important point is not whether or not lung-cancer screening should be initiated, but that open, scientifically rigorous, public debate should be part of the process. The medical community needs to have sufficient data to be able to advise policy makers on the costs and consequences of the various alternatives.Scientific questions and standards remain problematic. It is necessary to understand the natural history of lung cancer in order to intercept the disease course at an early stage, prior to the critical point when treatment is rendered largely ineffective. For lung cancer, that critical point is when the disease metastasizes. The question that still needs to be answered is whether various screening methods allow for early detection and resection prior to the critical point, or whether they merely detect predominantly slow-growing cancers that are not biologically aggressive and that might never have become clinically significant.Yet, the biological potential of individual lung cancers remains uncertain in light of epidemiologic observations that tell us that some detected cancers will, in fact, remain dormant and of no clinical import when discerned at an early stage. It is unclear whether exhaled breath analysis can provide insight into the biological risk profile of individual tumors or whether it simply identifies a tumor’s presence. If only the latter is true, an important issue becomes the threshold of tumor burden at which such analysis is effective (ie, whether it is before or after the critical point).Additionally, little is known about the practicality and cost of breath analysis. On the upside, the large number of false-positive results may represent the presence of cancer below the current state of the art for radiographic and bronchoscopic detection. Conversely, they may exemplify the results of testing with a technology that is subject to a multitude of confounding variables. Collection, storage, patient flow, and transport must be standardized. Reproducibility and quality assurance need to be examined. Patients in the study were, for the most part, fasting in preparation for bronchoscopy, making it important to assess the impact of dietary choices on test results. Costs need to be examined carefully, considering the potential of testing at least 50 million current and former smokers. Much human and technical engineering analysis must be performed to validate this technology. If the technology can be refined, we need to investigate whether or not other alternative markers, such as p53 genes, would be more sensitive and specific compared to volatile organic markers.The news provided in this report is exciting. The burden of lung cancer is heavy, and clinicians are painfully aware of the divergent interpretations and views that trials in lung cancer screening evoke. As a result, many physicians feel buffeted by the public demand to act, the scientific imperative to know, and the lack of definitive evidence. To screen or not to screen is no longer the question. The question is how! Whether at international medical forums, within the halls of local hospitals, in medical offices, or in the lay press, the debate over whether or not to screen for lung cancer continues, even though the public demands guidance and few problems frustrate physicians more than their inability to prevent deaths from the disease. Affecting close to 200,000 people annually in the United States, this devastating malignancy is the most common cause of cancer death worldwide. Previously considered an affliction of men, lung cancer is now the most common cause of death from cancer in women. Despite improvements in management, the mortality rate has continued to hover at > 85% at 5 years.1Jemal A Thomas A Murray T et al.Cancer statistics 2002.CA Cancer J Clin. 2002; 52: 23-47Crossref PubMed Scopus (2916) Google Scholar Given the fact that the cause of lung cancer (cigarette smoking) is known and identifiable, the disease should be amenable to early intervention. Screening patients who are at risk prior to the development of clinical signs of illness would seem to be a logical first step in addressing this critical public health problem. Screening for other types of cancer has been a doctrine of almost biblical proportions in the medical community. Presumably, detecting lung cancer at an earlier stage would allow patients to undergo treatment, usually surgical resection, prior to the development of metastasis. In fact, several screening studies already have demonstrated that diagnosis at an earlier stage than is typically encountered with standard practice is possible. And yet, standard medical practice has focused largely on the recognition and diagnosis of the disorder once signs and symptoms have developed, rather than on screening. Many other common cancers have been approached through broad-based public health screening programs that now are ingrained in North American clinical practice. The American Cancer Society,2American Cancer Society Cancer prevention and early detection worksheet for men.Available at: www.cancer.orgGoogle Scholarfor example, recommends routine breast self-examination of asymptomatic women for breast cancer starting at age 20 years, yearly mammography after age 40 years, and screening for prostate cancer in men starting at age 50 years through prostate-specific antigen testing and digital examination. Screening for colon cancer involves regular endoscopic procedures that many consider invasive and potentially harmful. These practices are still in place despite numerous recent challenges to their validity and cost-effectiveness. In contrast, the support for lung cancer screening from organized medicine and public health organizations is virtually nonexistent. A recent “cancer-screening” day at our institution, for example, attracted thousands of visitors but did not have a single exhibit on how to prevent or detect lung cancer. No organizations recommend the routine screening of general populations even for those who are at an elevated risk. The rationale put forward for this position is the lack of evidence that current screening techniques reduce lung cancer-specific mortality. But controversy, and in some instances a similar lack of definitive evidence, has not curtailed screening for other types of cancer. Whether or not the inconsistent standard from one disease to another as to what constitutes “sufficient evidence” is warranted is a difficult question. In part, the answer depends on the underlying values of society. Undeniably, some people regard lung cancer as a self-inflicted problem resulting from excessive smoking, the type of behavior that was termed “willful and self destructive” 900 years ago by Maimonides. “Live sensibly, among a thousand people, one dies a natural death; the rest succumb to irrational modes of living,” he stated. An element of that philosophy persists today, specifically that smokers’ self-destructive behavior renders them undeserving of screening and early intervention. Societal values also shape any discussion of who should pay for screening and what cost-effectiveness standards justify its routine use. Underlying these issues is the fundamental one concerning the nature of the scientific evidence for and against lung-cancer screening, and the question of why current practice standards for lung cancer differ so much from those for other common, but less lethal, oncologic diseases. One can ask whether maintaining the status quo is warranted, given the information that has emerged recently from studies utilizing screening based on low-dose spiral CT scanning.3Sone S Takashima S Li F et al.Mass screening for lung cancer with mobile spiral computed tomography scanner.Lancet. 1998; 351: 1242-1245Abstract Full Text Full Text PDF PubMed Scopus (876) Google Scholar4Henschke CI McCauley DI Yankelvitz DF et al.Early Lung Cancer Action Project: overall design and findings from baseline screening.Lancet. 1999; 354: 99-105Abstract Full Text Full Text PDF PubMed Scopus (2151) Google ScholarHowever, many concerns have contributed to the current intellectual and clinical inertia, notably overdiagnosis, lead-time, and length-time bias. Overdiagnosis concerns center on the detection of relatively nonprogressive, indolent lesions, which can result in unnecessary and possibly harmful procedures in the course of evaluating and treating patients. Such lesions, however, represent preclinical disease that would not have become apparent clinically had it not been discovered by screening. Although opinion is divided, some estimates hold that up to one third of lung cancers that are detected early will not progress.5Reich JM Improved survival and higher mortality: the conundrum of lung cancer screening.Chest. 2002; 122: 329-337Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar6Black WC Overdiagnosis: an underrecognized cause of confusion and harm in cancer screening.J Natl Cancer Inst. 2000; 92: 1290-1292Crossref Scopus (199) Google Scholar Lead-time is the period between the detection of the disease by screening and the point at which it becomes symptomatic. For unscreened patients, disease-specific survival is defined as the length of time from the clinical diagnosis of disease to death from the disease. For screened patients, it is the time from the detection of disease by the screening test to death from the disease. Lead-time bias refers to the fact that screening may create the impression that patients survive longer from the time of diagnosis simply because the screening test detected the disease before it became symptomatic. Even if the disease is totally untreatable, disease-specific survival can increase, but overall survival will remain the same with or without screening. Length-time bias is related to the biological heterogeneity of lung cancer. Some cancers metastasize relatively early, while others progress at a slower rate. The latter cancers, which exist longer than the former in a preclinical asymptomatic phase, are more likely to be detected during screening. Therefore, of all tumors detected by screening programs, a higher percentage would be slow-growing, less biologically aggressive tumors. Such overrepresentation of less aggressive tumors also would increase disease-specific survival among the screened cohort but would not necessarily increase overall survival. Because of these considerations, disease-specific mortality, rather than disease-specific survival, is thought to be the appropriate end point for evaluating the efficacy of screening programs. One reason why prior randomized clinical trials (evaluating > 35,000 patients over several decades) have failed to quench the debate is because of their inability to demonstrate any impact on disease-specific mortality through screening. Based on the principles of bias described above, it has been hypothesized that when a lung cancer is detected by screening at an earlier stage, the time of “recognized illness” is prolonged but survival is not improved. Four randomized controlled trials that were performed during the 1970s demonstrated that screening with chest radiography, both with and without sputum cytology, permits the recognition of disease at an earlier stage.7Flehinger BJ Melamed MR Zaman MG et al.Early lung cancer detection: results of the initial screen (prevalence) radiologic and cytologic screening in the Memorial Sloan-Kettering study.Am Rev Respir Dis. 1984; 130: 555-560PubMed Google Scholar8Frost JK Ball Jr, WC Levin ML et al.Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the John Hopkins study.Am Rev Respir Dis. 1984; 130: 549-554PubMed Google Scholar9Fontana 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: 561-565PubMed Google ScholarMortality in the Mayo Lung Project was 11% higher in the screened group compared to control subjects, a finding that was attributed in part to randomization imbalances and overdiagnosis bias. Even a 20-year follow-up of the original Mayo Lung Cancer screening project failed to demonstrate any difference in mortality rates between screened groups and control groups (4.4 vs 3.9 per 1,000 person-years, respectively).10Marcus PM Bergstralh EJ Faferstrom RM et al.Lung cancer mortality in the Mayo Lung Project: impact of extended follow-up.J Natl Cancer Inst. 2000; 20: 1308-1316Crossref Scopus (455) Google Scholar More recently, studies3Sone S Takashima S Li F et al.Mass screening for lung cancer with mobile spiral computed tomography scanner.Lancet. 1998; 351: 1242-1245Abstract Full Text Full Text PDF PubMed Scopus (876) Google Scholar4Henschke CI McCauley DI Yankelvitz DF et al.Early Lung Cancer Action Project: overall design and findings from baseline screening.Lancet. 1999; 354: 99-105Abstract Full Text Full Text PDF PubMed Scopus (2151) Google Scholar11Nawa T Nakagawa T Kusano S et al.Lung cancer screening using low-dose spiral CT: results of baseline and 1-year follow-up studies.Chest. 2002; 122: 15-20Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholarof low-dose spiral CT scanning in both the United States and Japan have demonstrated the modality’s potential for detecting lung cancer in the preclinical stage, when surgical resection is possible. In the Early Lung Cancer Action Project study,12Henschke CI Yankelvitz DF CT screening for lung cancer.Radiol Clin North Am. 2000; 38: 487-495Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholarlow-dose spiral CT scanning detected six times more lung cancers than did chest radiography, and most of them < 1.0 cm in size. While these data are promising, there are no reports to date that have demonstrated a definitive reduction in all-cause mortality from any lung cancer-screening program. Given the raging debate and the continued fundamental differences in the interpretation of the evidence, where should we go from here? Screening, and utilizing standard chest radiology and sputum cytology cannot be advocated as the primary tool for an early lung cancer detection program. Low-dose spiral CT scanning has added incrementally to our early-detection capability, yet proof of efficacy and even safety remain controversial. What other technologies hold promise? Innovations in molecular biology and new technologies could enhance our ability to detect lesions and characterize the biological potential of nodules, thus enabling us to move beyond simply detecting tumors to distinguishing benign from malignant ones, and discriminating between indolent and aggressive ones. Such progress is critical if we are to address the concerns of length-time bias and lead-time bias. Several approaches have been suggested,13Kersting M Friedl C Kraus A et al.Differential frequencies of p16(INK4a) promoter hypermethylation, p53 mutation and K-ras mutation in exfoliative material mark the development of lung cancer in symptomatic chronic smokers.J Clin Oncol. 2000; 18: 3221-3229PubMed Google Scholar14Mulshine JL Scott F Molecular markers in lung cancer detection: new screening tools.Chest. 1995; 107: 280S-286SAbstract Full Text Full Text PDF PubMed Google Scholar15Payne PW Sebo TG 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: 697-704Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholarincluding more sophisticated sputum analyses utilizing molecular techniques, immunostaining, or automated cytometry. In addition, bronchoscopic examination of the airway has been enhanced to allow photodetection of tumors that are confined to the epithelium. While these approaches are promising, they remain unproven in large-scale population studies.16Prakash UBS Advances in bronchoscopic procedures.Chest. 1999; 116: 1403-1408Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar In this issue of CHEST (see page 2115), Phillips et al expand on previous work, examining the role of volatile organic compounds and monomethylated alkanes in human breath as biological markers of lung cancer.17Phillips M Gleeson K Hughes MB et al.Volatile organic compounds in breath as markers of lung cancer: a cross-sectional study.Lancet. 1999; 353: 1930-1933Abstract Full Text Full Text PDF PubMed Scopus (744) Google ScholarThose entities are produced by lipid peroxidation of polyunsaturated fatty acids in ubiquitous cell membranes, which are measured in the breath as ethanes, pentanes, or methylated alkanes. In this preliminary work, the authors present evidence suggesting that lung cancers are associated with a relatively unique chemical footprint, an observation that may be incorporated into lung cancer screening. In a group of 219 subjects, 178 of whom had undergone bronchoscopy for the evaluation of lung cancer, breath analysis detected lung cancer with a sensitivity of 90% and a specificity of 83%. The negative predictive value was a remarkable 99%, a finding that, if confirmed, could lead to the elimination of most benign false-positive results that are picked up on spiral CT screening, thus obviating the need for further workup and potentially unnecessary surgery. Unfortunately, separation by tumor type or smoking status was not associated with unique patterns on breath analysis. Disappointingly, there did not seem to be a correlation between cancer stage, and therefore tumor mass, and chemical footprint. In addition, the authors observed high rates of false-positive results in those subjects in whom cancer had not been confirmed by CT scanning or bronchoscopy. The authors suggest a role for breath analysis in screening, with CT scanning or bronchoscopy reserved only for those with positive results. If this technology were developed further, however, the optimal sequencing of CT scanning and breath analysis would need to be evaluated. It may be that spiral CT scanning would be the initial test, with breath analysis used subsequently. As a New Yorker might ask, “Is this approach ready for Broadway?” The answer is decidedly “not yet!” While no one could question the extraordinary individual, community, and financial consequences of the lung-cancer epidemic, public health criteria, such as the impact on disease-specific mortality and cost-effectiveness, must be considered before population-based disease-finding programs can be implemented. If public funds are to be spent on an avoidable disease, public debate on the issue of who is to pay for the screening must be part of the process as well. Given the finite amount of health-care resources that are available, the potential benefits of lung cancer screening must be weighed against the potential good that those same dollars could achieve by being spent on other programs, such as increasing vaccination rates or improving access to prenatal care. The important point is not whether or not lung-cancer screening should be initiated, but that open, scientifically rigorous, public debate should be part of the process. The medical community needs to have sufficient data to be able to advise policy makers on the costs and consequences of the various alternatives. Scientific questions and standards remain problematic. It is necessary to understand the natural history of lung cancer in order to intercept the disease course at an early stage, prior to the critical point when treatment is rendered largely ineffective. For lung cancer, that critical point is when the disease metastasizes. The question that still needs to be answered is whether various screening methods allow for early detection and resection prior to the critical point, or whether they merely detect predominantly slow-growing cancers that are not biologically aggressive and that might never have become clinically significant. Yet, the biological potential of individual lung cancers remains uncertain in light of epidemiologic observations that tell us that some detected cancers will, in fact, remain dormant and of no clinical import when discerned at an early stage. It is unclear whether exhaled breath analysis can provide insight into the biological risk profile of individual tumors or whether it simply identifies a tumor’s presence. If only the latter is true, an important issue becomes the threshold of tumor burden at which such analysis is effective (ie, whether it is before or after the critical point). Additionally, little is known about the practicality and cost of breath analysis. On the upside, the large number of false-positive results may represent the presence of cancer below the current state of the art for radiographic and bronchoscopic detection. Conversely, they may exemplify the results of testing with a technology that is subject to a multitude of confounding variables. Collection, storage, patient flow, and transport must be standardized. Reproducibility and quality assurance need to be examined. Patients in the study were, for the most part, fasting in preparation for bronchoscopy, making it important to assess the impact of dietary choices on test results. Costs need to be examined carefully, considering the potential of testing at least 50 million current and former smokers. Much human and technical engineering analysis must be performed to validate this technology. If the technology can be refined, we need to investigate whether or not other alternative markers, such as p53 genes, would be more sensitive and specific compared to volatile organic markers. The news provided in this report is exciting. The burden of lung cancer is heavy, and clinicians are painfully aware of the divergent interpretations and views that trials in lung cancer screening evoke. As a result, many physicians feel buffeted by the public demand to act, the scientific imperative to know, and the lack of definitive evidence. To screen or not to screen is no longer the question. The question is how!
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