This Article Abstract Figures Only Full Text (PDF) Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ellis, J R C Articles by Gleeson, F V Search for Related Content PubMed PubMed Citation Articles by Ellis, J R C Articles by Gleeson, F V

Lung cancer screening

Department of Radiology, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK

Correspondence: Dr F V Gleeson

	Abstract

Top Abstract Introduction The concept of screening Evaluating the evidence Does screening overdiagnose lung... New horizons Implications and challenges of... Conclusions References

 
Prior attempts to screen for lung cancer using chest radiography and sputum cytology have proved unsuccessful. Recent reports have investigated the role of spiral CT in early lung cancer detection and have suggested that screening would be of value. Prior to the introduction of a national lung cancer screening programme, it would be essential to demonstrate that this would reduce mortality and would be cost effective.

	Introduction

Top Abstract Introduction The concept of screening Evaluating the evidence Does screening overdiagnose lung... New horizons Implications and challenges of... Conclusions References

 
The concept of screening for lung cancer is not new. A prospective trial aimed at demonstrating the efficacy of screening was commenced just 1 year after Sir Richard Doll reported the link between the disease and cigarette smoking [1, 2]. Lung cancer remains a prevalent and deadly disease on a worldwide scale, with an estimated one million deaths per annum at the millennium; over 80% of these cases will be cigarette smokers [3]. Modern enlightenment as to the risk of smoking may have contributed to cessation of the habit in many, but even in those who have quit smoking the risk of developing lung cancer remains elevated for many years, with decades of abstinence required before their risk falls to that of a life-long non-smoker [3]. Medicine remains unable to offer a cure, with only surgical resection of early stage disease raising hope for the patient.

The overall 5-year survival in lung cancer is just 7–13%. Cure rate is directly linked to disease stage, with 5-year survival of treated stage 1 disease being 70%. Unfortunately, only 20% of lung cancers are detected during their stage 1 phase [4]. It is therefore not surprising that schemes designed to offer intervention following detection of early stage lung cancer have been examined for almost 50 years. This article aims to define the concept and to document the history of lung cancer screening. It also discusses major criticisms of the main trials and the implications of implementing a screening programme.

	The concept of screening

Top Abstract Introduction The concept of screening Evaluating the evidence Does screening overdiagnose lung... New horizons Implications and challenges of... Conclusions References

 
In a screening programme, a test is performed on asymptomatic individuals who are at risk of developing a disease whose outcome can be improved by early detection and intervention. The original, and "classical", criteria for appraising whether to screen for a disease were established in 1968 by Wilson and Junger [5]. A summary of screening criteria are set out in Table 1. What happens when these criteria are applied to screening for lung cancer? Nobody doubts the immense burden of the disease. Furthermore, it is accepted that lung cancer can be detected by conventional and accepted means, that is by simple chest radiography, in its early stages and that therapy can be curative in this early stage. However, the sticking point is: can it be shown that screening produces an improved outcome in the population being screened compared with a similar population who are not screened?

View larger version (18K): [in this window] [in a new window]   Figure 1. Definitions of outcome measures.

Randomized controlled trials
Mayo Lung Project [8, 9]
10 933 male smokers over the age of 45 years underwent a prevalence screen for lung cancer consisting of chest radiography and sputum cytology. 9211 of these patients were then randomized, 4618 to the study group and 4593 to the control group. The screened group underwent 4-monthly chest radiographs and sputum cytology. The control group was advised to have an annual chest radiograph and sputum cytology. No reminders were sent to those patients in the control group. Patients in the screened group showed improved survival, improved fatality and improved staging and resectability compared with the control group. However, there was no reduction in mortality from lung cancer in the screened group. Indeed, mortality was slightly higher, although this did not reach statistical significance. This paradoxical but critical result was due to an apparent increased incidence of lung cancer in the screened group compared with the control group. Further explanation of this is provided later.

Memorial Sloan Kettering Lung Project/Johns Hopkins Lung Project [10–12]
These trials were close in design and effectively evaluated the role of sputum cytology in screening. No mortality reduction was detected between the randomized groups.

Czechoslovakian study [13, 14]
The fourth RCT commenced in 1975 and randomized 6346 male smokers between the ages of 40 years and 64 years to one of two groups following a prevalence screen. The study group underwent chest radiography and sputum cytology every 6 months for 3 years, whereas the control group underwent chest radiography and sputum cytology at 3 years. Following this, both groups underwent chest radiography at the end of the fourth, fifth and sixth years of study. Although survival was greater in the study group, there was a non-statistically significant increase in mortality in this group, similar to the Mayo trial.

Other trials
As well as the "big four" RCTs in lung cancer screening, there have been trials that would constitute "Level 2" evidence according to EBM. Unfortunately, their results are no more promising than those generated by their randomized controlled counterparts. There have been two non-randomized controlled studies. The North London Lung Cancer Study [15], which commenced in 1959, randomized over 55 000 male smokers over the age of 40 years to a study group receiving biannual chest radiographs for 3 years or to a control group who underwent chest radiography at the beginning and end of the study only. The Erfurt County Germany Study [16] was a case control study comparing a group who underwent biannual chest radiography with a control group that received a chest radiograph every 1–2 years. Both of these studies echoed the results of the Mayo project; there was improved survival, staging and resectability in the screened group, but no reduction in mortality could be demonstrated. Again, there was an increased incidence of lung cancer in the screened groups.

Finally, there have been four non-randomized uncontrolled trials of lung cancer screening. The Philadelphia Pulmonary Neoplasm Research Project [1] and the Veterans Administration trial [17] showed no benefit in screening. The South London Lung Cancer Study [18] and the Tokyo Metropolitan Government Study [19] showed survival benefits in the screened group.

As well as reviewing prospective trials, one should not forget that lung cancer screening is already carried out in some countries, with work published from investigators. In Japan, under the Health and Welfare Law for the Aged, physicians must screen for gastric, cervical, breast, colorectal and lung cancer. Chest radiography and sputum cytology constitute the screening test for lung cancer. A retrospective case control report of this screening, carried out since 1987, claims a 46% reduction in mortality since screening began [20]. A published cost effectiveness decision analysis [21] estimates an expenditure of US $93 000 per life saved. Hungary also screens for lung cancer using a mass miniature radiography campaign [22], with proponents supporting its continuation despite the trial evidence showing no reduction in mortality with screening.

	Evaluating the evidence

Top Abstract Introduction The concept of screening Evaluating the evidence Does screening overdiagnose lung... New horizons Implications and challenges of... Conclusions References

 
It is not unreasonable to presume, following 10 trials of lung cancer screening involving around one-third of a million patients, that there is a widespread and accepted answer to the question "does it actually work?" This is not the case.

What, therefore, did the trials actually show? If we take their data at face value, and attribute most weight to the RCTs, then we conclude that there is no statistically significant reduction in mortality in a population screened by chest radiography compared with a control group. In fact, mortality appeared to increase in some of the screened populations. However, there has been extensive criticism of the RCTs.

Confining ourselves to radiological means of detection, the Memorial Sloan Kettering Trial and the Johns Hopkins Lung Project may be omitted from consideration. Both of these studies effectively evaluated the efficacy of screening with sputum cytology alone, with both study and control groups receiving identical chest radiography provision. They were not designed to evaluate the use of the chest radiograph as a screening tool.

The Mayo Lung Project is considered to be the most definitive trial to date, comparing the "most intensive" with the "least intensive" groups in terms of screening intervention. The fact that no mortality benefit was shown is felt to be the best evidence to date that screening for lung cancer by chest radiography does not work. But there were problems with the Mayo study. The control group was contaminated in the sense that over 50% of patients in this group underwent chest radiography during the study. The rate of adherence to trial protocol was just 75% in the screened group and 50% in the control. Subsequent statistical analysis of the trial design has shown that the study was underpowered and could only detect a 50% reduction in mortality. The trial had just a 19% chance of detecting a 10% decrease in mortality [23]. What of the Czech study? After just 3 years, both control and study group underwent an identical chest radiography protocol. This again contaminates the control group of a study designed to elucidate the efficacy of screening by chest radiography.

As well as the technical criticisms of design and execution of the Mayo and Czech projects, some authors have questioned the fundamental concept underpinning their negative conclusions [24], i.e. is mortality the best outcome measure in such a study? It is traditionally held that mortality is the "gold standard" outcome, as other outcome parameters such as survival and fatality can be confounded by trial biases [6]. For example, the presence of lead time bias can lead to apparent improved survival and fatality, although mortality would be immune from such an effect (see Table 3).

Mortality is equal to the product of incidence and fatality. Therefore, although fatality, and therefore survival, was improved in the Mayo study, the increased incidence of lung cancer in the screened group meant that there was no mortality benefit from screening. Different explanations have been proposed to explain the increased incidence of lung cancer in the screened groups, and their proponents view on the efficacy of screening are diametrically opposed. Which should we believe?

	Does screening overdiagnose lung cancer?

Top Abstract Introduction The concept of screening Evaluating the evidence Does screening overdiagnose lung... New horizons Implications and challenges of... Conclusions References

 
Some argue that the increased incidence of lung cancer in the screened groups was a result of an imbalance of covariates of risk for lung cancer that was not controlled for in the randomization process [24]. The logical progression here is that the increased incidence of lung cancer in the screened group occurred by chance and, therefore, that the mortality calculation (incidence multiplied by fatality) was flawed. If this is the case, then fatality and survival would be more appropriate outcome measures and the case for screening gains support. It is not inconceivable that covariates of risk of lung cancer, e.g. genetic predisposition, were imbalanced in the study groups, despite what was thought to be adequate randomization. That this should occur in more than one randomized trial is intriguing.

Another explanation is that screening for lung cancer unearths biologically unimportant tumours as well as those that are significant. Proponents of this theory [25, 26] use autopsy data [27] and raw data re-analysis to argue that lung cancers exist that do not manifest during life and that do not cause the death of the patient. The co-morbidity of smoking-related disease in this population provides further intuitive evidence for this theory. The logical progression of this would be that screening would "discover" lung cancers that would otherwise lay dormant for the life of the patient. This "overdiagnosis" would explain the increased incidence of lung cancer in the screened group. To subscribe to this overdiagnosis theory, therefore, is to conclude that screening, at least by chest radiography, is not to be recommended, because any survival/fatality benefit of screening is outweighed by the increased incidence and therefore increased mortality brought about by overdiagnosis.

Despite the aggression of lung cancer, it is possible that tumours exist that do not become manifested during a life cut short by another smoking-related disease. Interestingly, indirect evidence of biologically "unimportant" lung cancer can be derived from data in lung volume reduction surgery studies and series documenting doubling times in the growth of lung cancer. In a recent paper comparing lung reduction to medical management in patients with severe emphysema, deaths occurred in the medical management control group at 72 days, 242 days and 475 days after the study commenced [28]. The deaths were due to respiratory failure. However, doubling times of lung cancers have been reported to vary between 42 days and 590 days [29], which infers that some patients who are at a high risk of having a lung cancer could die from respiratory failure before their cancers, which may have long doubling times, present clinically. Indeed, the detection of presumed lung cancers on chest radiography and CT in patients "not fit" for biopsy or surgery is a not infrequent clinical scenario.

	New horizons

Top Abstract Introduction The concept of screening Evaluating the evidence Does screening overdiagnose lung... New horizons Implications and challenges of... Conclusions References

 
Chest radiography and sputum cytology are not the only investigations that can detect lung cancer, although they are the only tests to have undergone prospective trial. Not surprisingly, the role of spiral CT has been studied. A recent study, the Early Lung Cancer Action Project (ELCAP), has produced data on the ability of CT to detect small non-calcified nodules in a cohort of 1000 smokers with a 10-pack-year history over the age of 60 years [30]. The study was of a single cohort non-comparative design and aimed to establish curability rate based on the size of the nodules detected. ELCAP is not a prospective trial of CT in lung cancer screening. However, the results were quite clear. CT detected non-calcified nodules in 233 patients compared with 68 patients by chest radiography. The study protocol then recommended performing high resolution CT (HRCT) in patients with 1–6 non-calcified nodules less than 5 mm in size and repeating this protocol every 3, 6, 12 and 24 months, or proceding to biopsy for nodules more than 6 mm in size. By following this protocol, CT detected more malignant nodules than chest radiography (2.7% vs 0.7%) and, critically, detected more stage 1 disease than chest radiography (2.3% vs 0.4%). In ELCAP, just 28 out of the 1000 patients screened underwent a biopsy and as many as 27 of 28 of these nodules proved to be malignant; only one biopsy was performed on a benign nodule. 26 of the 27 malignant nodules were resectable. No patient underwent thoracotomy for benign disease.

A similar study from Japan reported that spiral CT detected lung cancer in 0.48% of a patient cohort whereas conventional screening with chest radiography, and sputum cytology performed in the same area previously detected a lung cancer rate of just 0.03–0.05% [31].

CT can detect smaller nodules than chest radiography, but would small nodule detection actually reduce mortality? A recent study of over 500 patients detected no correlation between the size of T1N0M0 tumours and survival with 3 cm cancers leading to the same outcome as 1 cm cancers. The authors comment that improved small nodule detection with screening CT may not significantly improve lung cancer mortality and they recommend that a trial be carried out [32]. The presence of occult metastatic disease could reduce the impact of small nodule detection and resection on mortality from lung cancer. Worrying data exist to show that patients with small tumours can still harbour malignant cells in normal sized nodes and that malignant cells can be detected in the peripheral blood/bone marrow in patients with tumours of all sizes and stages [33–36].

A prospective RCT of spiral CT in lung cancer screening is awaited. Of particular interest would be whether or not a CT screened group would show an increased incidence of lung cancer compared with a control group, as in the Mayo Study. If biologically "unimportant" lung cancer does exist, however unlikely this may seem, then CT may well just detect more of it.

New and novel non-radiological means of lung cancer detection may also play a future role. Exhalation of certain volatile organic compounds can be detected in some patients with lung cancer [37]. Preliminary analysis of data has predicted a diagnosis of lung cancer in 72% of patients with proven disease. 67% of patients clear from lung cancer tested negative. It is proposed that breath tests may help stratify patient risk in future detection programmes.

Molecular medicine also gives hope. Examination of sputum for overexpression of antigen hn RNP A2/B1 using a monoclonal antibody may have a future use [38]. Finally, with the human genome on the threshold of being unravelled there are as yet no genetic markers of predisposition that are specific enough to be useful in patient selection [39]. Lung cancer does not have a BRCA1/2 equivalent, at least not yet.

	Implications and challenges of screening

Top Abstract Introduction The concept of screening Evaluating the evidence Does screening overdiagnose lung... New horizons Implications and challenges of... Conclusions References

 
Despite the lack of evidence from RCTs of the value of screening for lung cancer using chest radiography±sputum cytology, screening in some form cannot be dismissed as a future health strategy. Spiral CT will undoubtedly be further scrutinized as either a primary or secondary modality in screening. However, screening would have challenges for the radiologist and the patient.

Challenges for the radiologist
There is a proven error rate in interpretation of chest radiographs of between 20% and 50%, even amongst experienced radiologists [40]. Digital radiography and multislice spiral CT fall by the wayside as dismal second best when the power of the "retrospectoscope" is focused on a series of chest radiographs. 75% of perihilar and 90% of peripheral cancers detected in the Mayo lung project were visible in retrospect, some up to 53months previously [41]. CT also misses lung cancer [42]; the nodules missed were usually small, around 2–2.5 mm, but were still clearly seen in retrospect. Clearly these error rates would be inconsequential if a carefully designed prospective controlled trial showed outcome improvement in any case. To put it another way, screening may still be of overall benefit to the population even though nodules are missed.

Undoubtedly there would be medicolegal implications to misses in lung cancer screening. In the USA, litigators have previously called for a failure to detect any lung cancer under any circumstances to constitute negligence [43]. Therefore, using the Mayo data, up to 90% of patients in whom screening detected lung cancer could sue the radiologists who identified the cancers for their earlier misses. Thankfully, this system does not yet operate anywhere.

Finally, it is prudent to comment on the increased workload that screening with spiral CT would cause. The ELCAP screened 1000 smokers, aged 60 years or older with at least a 10-pack-year history of smoking. The report does not state the total number of CT examinations performed, but it is in excess of 1300. In the UK, there are approximately 11 819 000 people over the age of 60 years, of whom about 16%, or 1 891 040 individuals, smoke [44]. We have found no data to suggest how many of these have a 10-year-pack history, but it is perhaps a substantial proportion. Using the ELCAP data, approximately 2 458 000 CT examinations would be required to screen the over 60s smoking population once. This figure does not include biopsies. If a CT costs between £20 and £100, then the cost to the nation of the first round of screening the over 60s population would be between £49 200 000 and £246 000 000. Additional cost would be generated by the CT guided biopsies and thoracotomies. This figure is much larger than the cost of the current breast screening programme, which costs £37 000 000 to screen 1 250 000 women per annum [45].

Challenges for the patient
The radiologist's problem of misreading the film translates to a problem to the patient of false negative and false positive reports. The implications of false negatives are clear, but one should not forget the impact on patients of an incorrect "positive call". Some reassurance is provided by the ELCAP study that, although not designed to trial screening, reported only one biopsy of a benign nodule [30]. As mentioned earlier, close regular follow-up with HRCT was the key that prevented biopsy of benign lesions.

X-ray dose to the population would also have to be considered. Whereas many would dismiss the dose received from a chest radiograph, the dose from CT, which would undoubtedly form the next layer of the investigation strategy, would have to be assessed in any screening programme. Again, the ELCAP group report that their initial CT examinations were of low dose, exposing the patient to just a small amount of radiation greater than a chest radiograph [30].

An interesting question relates to how, if at all, screening would impact on smoking habits. Would screening, for example, encourage complacency amongst smokers? Could screening be regarded as a safety net, to catch and cure those unlucky enough to develop lung cancer as a consequence of their smoking? An interesting piece of data emerged from the ELCAP study: patients who were shown their own CT images, even when they were negative, became more likely to quit smoking than otherwise [30].

Challenges for society
Who, exactly, would be eligible for screening in the UK? The original chest radiography RCTs in America and Czechoslovakia focused on male smokers over the age of 40 years. ELCAP examined over 60s only. Clearly, if the under 60s were also screened according to the ELCAP criteria then the time and resources needed would be even greater than that estimated above. It would be a difficult decision to decide the age range of patients eligible, as well as the volume of cigarette consumption required. Ex-smokers and passive smokers, for example, may wish to be screened. These factors would be intrinsically linked to the bill to the National Health Service (NHS) that a programme would generate. Any estimate of total cost to the NHS is very speculative and once again is critically dependent upon how many patients are eligible. Presumably society would demand value for money. Cost per life saved would no doubt be a vital statistic in any UK lung cancer screening programme.

	Conclusions

Top Abstract Introduction The concept of screening Evaluating the evidence Does screening overdiagnose lung... New horizons Implications and challenges of... Conclusions References

 
If one accepts the original RCT data, then there is evidence that screening for lung cancer with chest radiography±sputum cytology has no beneficial effect on mortality. If, as many do, one rejects the data on the grounds of inadequate study power and imperfect methodology, then there is still no evidence that screening in such a fashion reduces mortality, although absence of evidence of effect does not equate to evidence of absence of effect.

The tide of opinion seems to be moving against the negative attitude towards screening that has prevailed since the apparently negative RCTs. Whether or not to screen with spiral CT is now being debated. The ELCAP results highlight the numbers of resectable and curable stage 1 cancers that spiral CT could detect. ELCAP also sets a high standard of follow-up scanning methodology, which avoids unnecessary intervention in patients with benign disease. Whether or not other centres can reproduce these results is awaited.

Perhaps the way forward is a further trial, although in a society where government resourcing of health is carefully scrutinized, any programme must be shown to be cost effective.

Received for publication November 20, 2000. Revision received February 13, 2001. Accepted for publication April 4, 2001.

	References

Top Abstract Introduction The concept of screening Evaluating the evidence Does screening overdiagnose lung... New horizons Implications and challenges of... Conclusions References

 

1. Weiss W, Boucot KR, Cooper DA. The Philadelphia pulmonary neoplasm research project: survival factors in bronchogenic carcinoma. JAMA 1971;216:2119–23.[Abstract/Free Full Text]
2. Doll R, Hill AB. Smoking and carcinoma of the lung: preliminary report. BMJ 1950;2:739–48.
3. Strauss GM. Screening for lung cancer. Surg Oncol Clin N Am 1999;8:747–74.[Medline]
4. Porter JC, Spiro SG. Detection of early lung cancer. Thorax 2000; 55 (Suppl. 1):S56–S62.[Medline]
5. Gray JAM. In: Evidence-based health care: how to make health policy and management decisions. New York, NY: Churchill Livingstone, 1997.
6. Morrison AS. Screening in chronic disease. In: Monographs in epidemiology and biostatistics (2nd edn). New York, NY: Oxford University Press, 1992.
7. Berlin NI, Buncher CR, Fontana RS, Frost JK, Melamed MR. The National Cancer Institute cooperative early lung cancer detection program. Am Rev Respir Dis 1984;130:545–9.[Medline]
8. Fontana RS, Sanderson DR, Taylor WF, Woolner LB, Miller WE, Muhm JR, 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;130:561–5.[Medline]
9. Fontana RS, Sanderson DR, Woolner LB, Taylor WF, Miller WE, Muhm JR. Lung cancer screening: the Mayo program. J Occup Med 1986;28:746–50.[Medline]
10. Melamed MR, Flehinger BJ, Zaman MB, Heelan RT, Perchick WA, Martini N. Screening for early lung cancer: results of the Memorial-Sloan Kettering study in New York. Chest 1984;86:44–53.[Abstract/Free Full Text]
11. Tockman MS. Survival and mortality from lung cancer in a screened population: the Johns Hopkins Study. Chest 1986;89:324S–325S.[Medline]
12. Frost JK, Ball WC, Levin ML, Tockman MS, Baker RR, Carter D, 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;130:549–54.[Medline]
13. Kubik A, Polak J. Lung cancer detection: results of a randomised prospective study in Czechoslovakia. Cancer 1986;57:2427–37.[Medline]
14. Kubik A, Parkin DM, Khlat M, Erban J, Polak J, Adamec M. Lack of benefit from semi-annual screening for cancer of the lung: follow-up report of a randomised controlled trial on population of high risk males in Czechoslovakia. Int J Cancer 1990;45:26–33.[Medline]
15. Brett GZ. The value of lung cancer detection by six-monthly chest radiographs. Thorax 1968;23:414–20.[Abstract/Free Full Text]
16. Wilde J. A 10 year follow up of semi annual screening for early detection of lung cancer in the Erfurt County, GDR. Eur Respir J 1989;2:656–62.[Abstract]
17. Lilienfield A, Archer PG, Burnett CH, Chamberlain EW, Chazin BJ, Davies D, et al. An evaluation of radiologic and cytologic screening for the early detection of lung cancer: a cooperative pilot study of the American Cancer Society and the Veterans Administration. Cancer Res 1966;26:2083–121.[Abstract/Free Full Text]
18. Nash FA, Morgan JM, Tomkins JG. South London Lung Cancer Study. BMJ 1968;2:715–21.
19. HayataY, Funatsu H, Kato H. Results of lung cancer screening programs in Japan: early detection and localisation of lung tumours in high risk groups. In: Band PR, editor. Early detection and localization of lung tumors in high risk groups. Recent results of cancer research series, Vol. 82. Heidelberg: Springer Verlag, 1982;179–86.
20. Okamoto N, Suzuki T, Hesegawa H, Gotoh T, Hagiwara S, Sekimoto M, et al. Evaluation of a clinic based screening program for lung cancer with a case control design in Kanagawa, Japan. Lung Cancer 1999;25:77–85.[Medline]
21. Baka Y, Takahashi M, Tominguchi S, Kiyota S. Cost effectiveness decision analysis of mass screening for lung cancer. Acad Radiol 1998; 5(Suppl. 12):5344–6.
22. Ajkay Z. Early Lung Cancer Action Project. Lancet 1999;354:1206.
23. Fontana RS, Sanderson DR, Woolner LB, Taylor WF, Miller WE, Muhan JR, et al. Screening for lung cancer, a critique of the Mayo Lung Project. Cancer 1991;67:1155–64.[Medline]
24. Strauss GM, Gleason RE, Sugarbaker DJ. Screening for lung cancer. Another look; a different view. Chest 1997;111:754–68.[Abstract/Free Full Text]
25. Eddy D. Screening for lung cancer. Ann Intern Med 1989;111:232–7.
26. Reich JM. Lung cancer screening does not favourably affect outcome. Chest 1998;113:557.[Free Full Text]
27. McFarlane MJ, Feinstein AR, Wells CK, Chan CK. The ‘epidemiologic necropsy’: unexpected detections, demographic selections, and changing rates of lung cancer. J Am Med Assoc 1987;258:331–8.[Abstract/Free Full Text]
28. Geedales D, Davies M, Koyanna H, Hansell D, Pastorino U, Pepper J, et al. Effect of lung volume reduction surgery in patients with severe emphysema. N Engl J Med 2000;343:239–45.[Abstract/Free Full Text]
29. Meyer J. Growth rate versus prognosis in resected primary bronchogenic carcinomas. Cancer 1973;31:1468–72.[Medline]
30. Henschke CI, McCauley DI, Yankelevitz DF, Naidich DP, McGuinness G, Miettinen OS, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99–105.[Medline]
31. Sone S, Takashima S, Li F, Yang Z, Honda T, Maryama Y, et al. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998;351:1242–5.[Medline]
32. Patz EF, Rossi S, Harpole DH, Herndon JE, Goodman PC. Correlation of tumor size and survival in patients with Stage 1A non-small cell lung cancer. Chest 2000;117:1568–71.[Abstract/Free Full Text]
33. Peck K, Sher YP, Shih JY, Roffler SR, Wu CW, Yang PC. Detection and quantitation of circulating cancer cells in the peripheral blood of lung cancer patients. Cancer Res 1998;58:2761–5.[Abstract/Free Full Text]
34. Chen ZL, Perez S, Holmes EC, Wang HJ, Coulson WF, Wen DR, et al. Frequency and distribution of occult micrometastases in lymph nodes of patients with non-small cell lung cancer. J Nat Cancer Inst 1993;85:493–8.[Abstract/Free Full Text]
35. Passlick BP, Izbicki JR, Kubuschok B, Thetter O, Pantel K. Detection of disseminated lung cancer cells in lymph nodes: impact on staging and prognosis. Ann Thorac Surg 1996;61:177–83.[Abstract/Free Full Text]
36. Pantel K, Izbicki J, Passlick B, Angstwurm M, Haussinger K, Thetter O, et al. Frequency and prognostic significance of isolated tumour cells in bone marrow of patients with non-small cell lung cancer without overt metastases. Lancet 1996;347:649–53.[Medline]
37. Phillips M, Gleeson K, Hughes JMB, Greenberg J, Cataneo RN, Baker L. Volatile organic compounds in breath as markers of lung cancer: a cross sectional study. Lancet 1999;353:1930–3.[Medline]
38. Zhou J, Mulshine JL, Unsworth EJ, Scott FM, Avis IM, Vos MD, et al. Identification of a heterogenous ribonucleoprotein (hn RNP) as an early lung cancer detection marker. J Biol Chem 1996;271:10760–6.[Abstract/Free Full Text]
39. Bepler G. Lung cancer epidemiology and genetics. J Thorac Imaging 1999;14:228–34.[Medline]
40. Woodring JH. Pitfalls in the radiologic diagnosis of lung cancer. AJR 1990;154:1165–75.[Free Full Text]
41. Muhm JR, Miller WE, Fontana RS, Sanderson DR, Uhlenhopp MA. Lung cancer detected during a screening program using four month chest radiographs. Radiology 1983;148:609–15.[Abstract/Free Full Text]
42. Gurney JW. Missed lung cancer at CT: imaging findings in nine patients. Radiology 1996;199:117–22.[Abstract/Free Full Text]
43. Potchen EJ, Bisesi MA. When is it malpractice to miss lung cancer on chest radiographs? Radiology 1990;175:29–32.[Free Full Text]
44. Personal communication, General Household Survey Office, London.
45. www.cancerscreening.nhs.uk.

This article has been cited by other articles:

				O. Topaloglu, M. O. Hoque, Y. Tokumaru, J. Lee, E. Ratovitski, D. Sidransky, and C.-s. Moon Detection of Promoter Hypermethylation of Multiple Genes in the Tumor and Bronchoalveolar Lavage of Patients with Lung Cancer Clin. Cancer Res., April 1, 2004; 10(7): 2284 - 2288. [Abstract] [Full Text] [PDF]

				U. Mattsson, M. Jontell, and P. Holmstrup ORAL LICHEN PLANUS AND MALIGNANT TRANSFORMATION: IS A RECALL OF PATIENTS JUSTIFIED? Critical Reviews in Oral Biology & Medicine, September 1, 2002; 13(5): 390 - 396. [Abstract] [Full Text] [PDF]

				R. M. Friedenberg The 21st Century: The Age of Screening Radiology, April 1, 2002; 223(1): 1 - 4. [Full Text] [PDF]

				J. E. Heffner and G. Silvestri CT Screening for Lung Cancer . Is Smaller Better? Am. J. Respir. Crit. Care Med., February 15, 2002; 165(4): 433 - 434. [Full Text] [PDF]

This Article Abstract Figures Only Full Text (PDF) Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ellis, J R C Articles by Gleeson, F V Search for Related Content PubMed PubMed Citation Articles by Ellis, J R C Articles by Gleeson, F V