martes, 18 de junio de 2019

Lung Cancer Screening (PDQ®)—Health Professional Version - National Cancer Institute

Lung Cancer Screening (PDQ®)—Health Professional Version - National Cancer Institute



National Cancer Institute

Lung Cancer Screening (PDQ®)–Health Professional Version

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Overview

Separate PDQ summaries on Lung Cancer Prevention, Small Cell Lung Cancer Treatment,Non-Small Cell Lung Cancer Treatment, and Levels of Evidence for Cancer Screening and Prevention Studies are also available.

Evidence of Benefit Associated With Screening

Screening by low-dose helical computed tomography: benefit

One large randomized trial reported that screening persons aged 55 to 74 years who have cigarette smoking histories of 30 or more pack-years and who, if they are former smokers, have quit within the last 15 years reduces lung cancer mortality by 20% (95% confidence interval [CI], 6.8–26.7; P = .004) and all-cause mortality by 6.7% (95% CI, 1.2–13.6; P = .02).[1] An updated analysis showed that the estimated reduction in lung cancer mortality was 16% (95% CI, 5–25).[2]
Magnitude of Effect: 16% relative reduction in lung cancer–specific mortality.
  • Study Design: Evidence obtained from a randomized controlled trial (RCT).
  • Internal Validity: Good.
  • Consistency: Not applicable (N/A)—one randomized trial to date.
  • External Validity: Fair.

Screening by low-dose helical computed tomography: harms

Based on solid evidence, approximately 96% of all positive, low-dose helical computed tomography screening exams do not result in a lung cancer diagnosis.[1] False-positive exams may result in unnecessary invasive diagnostic procedures.
Magnitude of Effect: Based on the findings from a large randomized trial, the average false-positive rate per screening round was 23.3%. A total of 0.06% of all false-positive screening results led to a major complication after an invasive procedure performed as diagnostic follow-up to the positive screening result. Over three screening rounds, 1.8% of participants who did not have lung cancer had an invasive procedure following a positive screening result.
  • Study Design: Evidence obtained from an RCT.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Fair.
Overdiagnosis
Based on fair evidence, some lung cancers detected by low-dose helical computed tomography screening appear to represent overdiagnosed cancer. The magnitude of overdiagnosis was 18% in one randomized trial and 67% in another randomized trial. These cancers result in unnecessary diagnostic procedures and also lead to unnecessary treatment. Harms of diagnostic procedures and treatment occur most frequently among long-term and/or heavy smokers because of smoking-associated comorbidities that increase risk propagation.
Magnitude of Effect: 18% to 67%, depending on characteristics of screened population and screening regimen.
  • Study Design: RCTs.
  • Internal Validity: Good.
  • Consistency: Fair.
  • External Validity: Fair.

Evidence of No Benefit Associated With Screening

Screening by chest x-ray and/or sputum cytology: benefits

Based on solid evidence, screening with chest x-ray and/or sputum cytology does not reduce mortality from lung cancer in the general population or in ever-smokers.
Magnitude of Effect: N/A.
  • Study Design: RCTs.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Screening by chest x-ray and/or sputum cytology: harms

False-positive exams
Based on solid evidence, at least 95% of all positive chest x-ray screening exams do not result in a lung cancer diagnosis. False-positive exams result in unnecessary invasive diagnostic procedures.
  • Study Design: RCTs.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.
Overdiagnosis
Based on solid evidence, a modest but non-negligible percentage of lung cancers detected by screening chest x-ray and/or sputum cytology appear to represent overdiagnosed cancer; the magnitude of overdiagnosis appears to be between 5% and 25%. These cancers result in unnecessary diagnostic procedures and also lead to unnecessary treatment. Harms of diagnostic procedures and treatment occur most frequently among long-term and/or heavy smokers because of smoking-associated comorbidities that increase risk propagation.
Magnitude of Effect: Between 5% and 25%, depending on characteristics of screened population and screening regimen.
  • Study Design: RCTs.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.
References
  1. Aberle DR, Adams AM, Berg CD, et al.: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365 (5): 395-409, 2011. [PUBMED Abstract]
  2. Pinsky PF, Church TR, Izmirlian G, et al.: The National Lung Screening Trial: results stratified by demographics, smoking history, and lung cancer histology. Cancer 119 (22): 3976-83, 2013. [PUBMED Abstract]

Description of the Evidence

Incidence and Mortality

Lung cancer is the third most common form of noncutaneous cancer in the United States and is the leading cause of cancer death in men and in women. In 2019 alone, it is estimated that 116,440 men and 111,710 women will be diagnosed with lung cancer, and 76,650 men and 66,020 women will die of this disease. The lung cancer death rate rose rapidly over several decades in both sexes, with a persistent decline for men commencing in 1991. From 2011 to 2015, death rates decreased by about 3% per year in men and by 1.5% per year in women.[1]

Risk Factors

The most important risk factor for lung cancer (as for many other cancers) is tobacco use.[2,3] Cigarette smoking has been definitively established by epidemiologic and preclinical animal experimental data as the primary cause of lung cancer. This causative link has been widely recognized since the 1960s, when national reports in Great Britain and the United States brought the cancer risk of smoking prominently to the public’s attention.[3] The percentages of lung cancers estimated to be caused by tobacco smoking in males and females are 90% and 78%, respectively.
For a complete description of factors associated with an increased or decreased risk of lung cancer, refer to the PDQ summary on Lung Cancer Prevention for more information.

Evidence of Benefit Associated With Screening

Screening by low-dose helical computed tomography

There have been intensive efforts to improve lung cancer screening with newer technologies, including low-dose helical computed tomography (LDCT).[4,5] LDCT was shown to be more sensitive than chest radiography. In the Early Lung Cancer Action Project (ELCAP),[5] LDCT detected almost six times as many stage I lung cancers as chest radiography, and most of these tumors were no larger than 1 cm in diameter.
A systematic analysis [6] summarized 13 observational studies of LDCT undertaken between 1993 and 2004 and that included 60 to 5,201 participants. Some Japanese studies included nonsmokers, but the others were limited to current and former smokers. Variability in detection of nodules—between 3% and 51%—may be attributed to several factors:
  • The definition of nodules (some studies required a size threshold).
  • The CT technology (thin slice detects more and smaller nodules).
  • Geographic variation in endemic granulomatous disease.
Overall, lung cancer was diagnosed in 1.1% to 4.7% of screened participants; most of these diagnoses were early-stage disease.[6]
With completion of the National Lung Screening Trial (NLST), there is now evidence that screening with LDCT can reduce lung cancer mortality risk in ever-smokers who have smoked 30 pack-years or more and in former smokers who have quit within the past 15 years. The NLST included 33 centers across the United States. Eligible participants were between the ages of 55 years and 74 years at randomization, had a history of at least 30 pack-years of cigarette smoking, and, if former smokers, had quit within the past 15 years. A total of 53,454 persons were enrolled; 26,722 persons were randomly assigned to receive screening with LDCT, and 26,732 persons were randomly assigned to receive screening with chest x-ray. Any noncalcified nodule found on LDCT that measured at least 4 mm in any diameter and any noncalcified nodule or mass identified on x-ray images were classified as positive. Radiologists, however, had the option of calling a final screen negative if a noncalcified nodule had been stable on the three screening exams. The LDCT group had a substantially higher rate of positive screening tests than did the radiography group (round 1, 27.3% vs. 9.2%; round 2, 27.9% vs. 6.2%; and round 3, 16.8% vs. 5.0%). Overall, 39.1% of participants in the LDCT group and 16.0% in the radiography group had at least one positive screening result. Of those who screened positive, the false-positive rate was 96.4% in the LDCT group and 94.5% in the chest radiography group. This was consistent across all three rounds.[7] A review of two surrogate markers of benefit from the LDCT for lung cancer screening determined that there is no discernible relationship between the proportion of stage I lung cancers or lung cancer-specific survival for stage I disease and lung cancer mortality benefit at 4 years.[8]
In the LDCT group, 649 cancers were diagnosed after a positive screening test, 44 after a negative screening test, and 367 among participants who either missed the screening or received the diagnosis after the completion of the screening phase. In the radiography group, 279 cancers were diagnosed after a positive screening test, 137 after a negative screening test, and 525 among participants who either missed the screening or received the diagnosis after the completion of the screening phase. Three hundred fifty-six deaths from lung cancer occurred in the LDCT group, and 443 deaths from lung cancer occurred in the chest x-ray group, with a relative reduction in the rate of death from lung cancer of 20% (95% confidence interval [CI], 6.8%–26.7%) with LDCT screening.[7] An updated analysis showed that the estimated reduction in lung cancer mortality was 16% (95% CI, 5%–25%).[9] Overall, mortality was reduced by 6.7% (95% CI, 1.2%–13.6%). The number needed to screen with LDCT to prevent one death from lung cancer was 320.[7]
Since the publication of the results of the NLST, more has been learned about who may benefit the most from screening for lung cancer using LDCT.[10-12] One group of investigators developed an individual risk model to assess who might benefit from screening. The model used additional factors not used as inclusion criteria in the NLST, such as a history of chronic obstructive pulmonary disease, personal or family history of lung cancer and a more detailed smoking history. More persons would have been eligible to be screened using the trial's criteria as opposed to the inclusion criteria of the NLST without missing patients with cancer.[11] A second group performed a reanalysis of the NLST data and calculated each patient’s risk of developing lung cancer and estimated each patient's lung cancer mortality.[12] The investigators then divided the NLST participants into five groups on the basis of risk. The number needed to screen to avoid a lung cancer death in the low-risk group was 5,276; 161 screens were needed in the high-risk group to avoid a lung cancer death. Further, the number of false-positive screens decreased from 1,648 in the lowest quintile of risk to 65 in the highest risk group. The three highest quintiles of risk accounted for 88% of the mortality reduction from screening, whereas the lowest quintile accounted for only a 1% reduction in mortality. These studies illustrate possible improvements for determining the population of patients who may benefit the most from screening, potentially reducing the number of false positives, and reducing the potential harm related to the adverse events associated with their evaluation. One other benefit of calculating individual risk is the ability to incorporate the findings into a shared decision-making process so that patients can decide whether to undergo screening.[12] However, a recent comparison of ten models used for predicting lung cancer or lung cancer mortality risk found that four of the models were well calibrated with reasonable discrimination, but none of these models were considered superior to the others for the use of identifying lung cancer risk among individuals who had ever smoked. Additional work is needed to address modeling weaknesses.[13]
Other randomized clinical trials (RCTs) of LDCT are under way or are already completed in a number of countries.[14] The largest is the Dutch-Belgian Randomized Lung Cancer Screening Trial (or NELSON trial).[15] This study differs from the NLST in that the control group does not have chest radiographic screening. Other smaller trials in Europe also compare a nonscreening arm with LDCT.[16-20] These smaller trials are largely not powered to assess mortality as an endpoint, but there is an effort under way to combine the findings from these studies with the NELSON data, once the data are fully mature. These studies may also be able to assess consistency with the NLST findings. In addition to the data gleaned from ongoing trials, the NLST data are being analyzed to examine other important issues in lung cancer screening, including cost-effectiveness, quality of life, and whether screening would benefit individuals younger than those enrolled in the NLST and those with fewer than 30 pack-years of smoking exposure. Data from the U.S. Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial suggest that, in the absence of screening, the risk of lung cancer death for current smokers who have a smoking history of 20 to 29 pack-years is no different than that of former smokers who have quit within 15 years and have a smoking history of more than 30 pack-years (hazard ratio, 1.07; CI, 0.75–1.5). Although the risk for the former-smokers group is no different than that of the current-smokers group (for whom LDCT screening is recommended by the U.S. Preventive Services Task Force), the efficacy of screening is unknown in the former-smokers group.[21]
[Note: A Guide has been developed to help patients and physicians assess the benefits and harms of LDCT screening for lung cancer.[22]]

Screening and smoking cessation

The target population for lung cancer screening has a high prevalence of current smokers compared with the general population. A lung cancer screening program could potentially impact the likelihood of smoking cessation, theoretically promoting cessation among those screened who have lung abnormalities detected on their screen. Conversely, screening could also be a deterrent to cessation among those with no evidence of lung abnormalities on their screen. The Danish Lung Cancer Screening Trial is a randomized trial that compared LDCT with no intervention among participants aged 50 to 70 years who had at least a 20 pack-year smoking history.[23] The proportion of participants who had quit smoking was monitored every year for 5 years of follow-up and remained virtually identical in the two groups from baseline (CT group and control group each had 23% ex-smokers) until the 5-year follow-up (43% ex-smokers in both groups). The comparison of these two randomized groups indicates that the CT screening program had zero net effect on the likelihood of smoking cessation.
Another report used data from the NLST to address the question of whether the screening result influenced the likelihood of smoking cessation.[24] The NLST compared CT with chest x-ray, and data from both arms were pooled to examine the impact of abnormal findings on the likelihood of smoking cessation. Compared with those who did not have abnormal findings, current smokers who had a screening examination that was suspicious for lung cancer (but was not lung cancer) were significantly more likely to have stopped smoking 1 year later. The associations with quitting smoking among those who had a major lung abnormality, which was not suspicious for lung cancer, or a minor abnormality were weaker and not uniformly statistically significant.
A third study from the U.K. Lung Cancer Screening pilot trial of a LDCT scan found that screening was associated with a statistically significant increase in short- and long-term cessation, and this effect was greatest among those whose initial screening test was positive, warranting additional clinical investigation.[25]
The results of these studies suggest that the net impact of a CT program on smoking cessation varied,[23] but there appears to be a higher likelihood of smoking cessation among current smokers who have findings suspicious for lung cancer.[24] This is an important research area that needs to be clarified.

Evidence of No Benefit Associated With Screening

Screening by chest x-ray and/or sputum cytology

The question of lung cancer screening dates back to the 1950s, when rising lung cancer incidence and mortality rates indicated a need for intervention. In response to the emerging lung cancer problem, five studies of chest imaging, two of which were controlled, were undertaken during the 1950s and 1960s.[26-33] Two studies also included sputum cytology.[26-30] The results of these studies suggested no overall benefit of screening, although design limitations prevented the studies from providing definitive evidence.
In the early 1970s, the National Cancer Institute funded the Cooperative Early Lung Cancer Detection Program,[34] which was designed to assess the ability of screening with radiologic chest imaging and sputum cytology to reduce lung cancer mortality in male smokers. The program comprised three separate RCTs, each enrolling about 10,000 male participants aged 45 years and older who smoked at least one pack of cigarettes a day in the previous year. One study was conducted at the Mayo Clinic,[35-37] one at Johns Hopkins University,[38-40] and one at Memorial Sloan-Kettering Cancer Center.[40-43] The Hopkins and Sloan-Kettering studies employed the same design: persons randomly assigned to the intervention arm received sputum cytology every 4 months and annual chest imaging, while persons randomly assigned to the control arm received annual chest imaging. Neither study observed a reduction in lung cancer mortality with screening.[40] The two studies were interpreted as showing no benefit of frequent sputum cytology when added to an annual regimen of chest x-ray.
The design of the Mayo Clinic study (known as the Mayo Lung Project, or MLP), was different. All potential participants were screened with chest imaging and sputum cytology, and those known or suspected to have lung cancer, as well as those in poor health, were excluded. Remaining persons were randomly assigned to either an intervention arm that received chest imaging and sputum cytology every 4 months for 6 years, or to a control arm that received a one-time recommendation at trial entry to receive the same tests on an annual basis. No reduction in lung cancer mortality was observed. The MLP was interpreted in the 1970s as showing no benefit of an intense screening regimen with chest x-ray and sputum cytology.
One RCT of lung cancer screening with chest imaging was conducted in Europe in the 1970s. The Czechoslovakian study began with a prevalence screen (chest imaging and sputum cytology) of 6,364 males aged 40 to 64 years who were current smokers with a lifetime consumption of at least 150,000 cigarettes.[44,45] All participants except the 18 diagnosed with lung cancer as a result of the prevalence screen were randomly assigned to one of two arms: an intervention arm, which received semi-annual screening for 3 years, or a control arm, which received screening during the third year only. The investigators reported 19 lung cancer deaths in the intervention arm and 13 in the control arm, and concluded that frequent screening was not necessary.
By 1990, the medical community was still unsure about the relationship between screening with chest imaging (using traditional chest x-ray) and lung cancer mortality. Although previous studies showed no benefit, findings were not definitive because of a lack of statistical power. A multiphasic trial with ample statistical power, the PLCO Cancer Screening Trial,[46] began in 1992. PLCO enrolled 154,901 participants aged 55 to 74 years, including women (50%) and never smokers (45%). Half were randomly assigned to screening, and the other half were advised to receive their usual medical care. PLCO had 90% power to detect a 20% reduction in lung cancer mortality.
The lung component of PLCO addressed the question of whether annual single-view (posterior-anterior) chest x-ray was capable of reducing lung cancer mortality as compared with usual medical care. When the study began, all participants randomly assigned to screening were invited to receive a baseline and three annual chest x-ray screens, although the protocol ultimately was changed to screen never-smokers only three times. At 13 years of follow-up, 1,213 lung cancer deaths were observed in the intervention group, compared with 1,230 lung cancer deaths in the usual-care group (mortality relative risk, 0.99; 95% CI, 0.87–1.22). Sub-analyses suggested no differential effect by sex or smoking status.[46]
Given the abundance and consistency of evidence, as well as the lack of benefit observed in the PLCO trial, it is appropriate to conclude that lung cancer screening with chest x-ray and/or sputum cytology, regardless of sex or smoking status, does not reduce lung cancer mortality.
References
  1. American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available online. Last accessed June 7, 2019.
  2. The Health Consequences of Smoking: A Report of the Surgeon General. Atlanta, Ga: U.S. Department of Health and Human Services, CDC, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2004. Also available online. Last accessed March 6, 2019.
  3. Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Service. Washington, DC: US Department of Health, Education, and Welfare, 1965. PHS Publ No 1103.
  4. Ahrendt SA, Chow JT, Xu LH, et al.: Molecular detection of tumor cells in bronchoalveolar lavage fluid from patients with early stage lung cancer. J Natl Cancer Inst 91 (4): 332-9, 1999. [PUBMED Abstract]
  5. Henschke CI, McCauley DI, Yankelevitz DF, et al.: Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 354 (9173): 99-105, 1999. [PUBMED Abstract]
  6. Bach PB, Mirkin JN, Oliver TK, et al.: Benefits and harms of CT screening for lung cancer: a systematic review. JAMA 307 (22): 2418-29, 2012. [PUBMED Abstract]
  7. Aberle DR, Adams AM, Berg CD, et al.: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365 (5): 395-409, 2011. [PUBMED Abstract]
  8. Woo KM, Gönen M, Schnorr G, et al.: Surrogate Markers and the Association of Low-Dose CT Lung Cancer Screening With Mortality. JAMA Oncol 4 (7): 1006-1008, 2018. [PUBMED Abstract]
  9. Pinsky PF, Church TR, Izmirlian G, et al.: The National Lung Screening Trial: results stratified by demographics, smoking history, and lung cancer histology. Cancer 119 (22): 3976-83, 2013. [PUBMED Abstract]
  10. Moyer VA; U.S. Preventive Services Task Force: Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 160 (5): 330-8, 2014. [PUBMED Abstract]
  11. Tammemägi MC, Katki HA, Hocking WG, et al.: Selection criteria for lung-cancer screening. N Engl J Med 368 (8): 728-36, 2013. [PUBMED Abstract]
  12. Kovalchik SA, Tammemagi M, Berg CD, et al.: Targeting of low-dose CT screening according to the risk of lung-cancer death. N Engl J Med 369 (3): 245-54, 2013. [PUBMED Abstract]
  13. Katki HA, Kovalchik SA, Petito LC, et al.: Implications of Nine Risk Prediction Models for Selecting Ever-Smokers for Computed Tomography Lung Cancer Screening. Ann Intern Med 169 (1): 10-19, 2018. [PUBMED Abstract]
  14. Doria-Rose VP, Szabo E: Screening and prevention of lung cancer. In: Kernstine KH, Reckamp KL, eds.: Lung Cancer: A Multidisciplinary Approach to Diagnosis and Management. New York, NY: Demos Medical, 2011, pp 53-72.
  15. Horeweg N, van der Aalst CM, Vliegenthart R, et al.: Volumetric computed tomography screening for lung cancer: three rounds of the NELSON trial. Eur Respir J 42 (6): 1659-67, 2013. [PUBMED Abstract]
  16. Paci E, Puliti D, Lopes Pegna A, et al.: Mortality, survival and incidence rates in the ITALUNG randomised lung cancer screening trial. Thorax 72 (9): 825-831, 2017. [PUBMED Abstract]
  17. Wille MM, Dirksen A, Ashraf H, et al.: Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-Risk Profiling. Am J Respir Crit Care Med 193 (5): 542-51, 2016. [PUBMED Abstract]
  18. Infante M, Cavuto S, Lutman FR, et al.: Long-Term Follow-up Results of the DANTE Trial, a Randomized Study of Lung Cancer Screening with Spiral Computed Tomography. Am J Respir Crit Care Med 191 (10): 1166-75, 2015. [PUBMED Abstract]
  19. Pastorino U, Rossi M, Rosato V, et al.: Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev 21 (3): 308-15, 2012. [PUBMED Abstract]
  20. Pastorino U, Silva M, Sestini S, et al.: Prolonged Lung Cancer Screening Reduced 10-year Mortality in the MILD Trial. Ann Oncol : , 2019. [PUBMED Abstract]
  21. Pinsky PF, Kramer BS: Lung Cancer Risk and Demographic Characteristics of Current 20-29 Pack-year Smokers: Implications for Screening. J Natl Cancer Inst 107 (11): , 2015. [PUBMED Abstract]
  22. Woloshin S, Schwartz LM, Black WC, et al.: Cancer screening campaigns--getting past uninformative persuasion. N Engl J Med 367 (18): 1677-9, 2012. [PUBMED Abstract]
  23. Ashraf H, Saghir Z, Dirksen A, et al.: Smoking habits in the randomised Danish Lung Cancer Screening Trial with low-dose CT: final results after a 5-year screening programme. Thorax 69 (6): 574-9, 2014. [PUBMED Abstract]
  24. Tammemägi MC, Berg CD, Riley TL, et al.: Impact of lung cancer screening results on smoking cessation. J Natl Cancer Inst 106 (6): dju084, 2014. [PUBMED Abstract]
  25. Brain K, Carter B, Lifford KJ, et al.: Impact of low-dose CT screening on smoking cessation among high-risk participants in the UK Lung Cancer Screening Trial. Thorax 72 (10): 912-918, 2017. [PUBMED Abstract]
  26. 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 26 (10): 2083-121, 1966. [PUBMED Abstract]
  27. Boucot KR, Weiss W: Is curable lung cancer detected by semiannual screening? JAMA 224 (10): 1361-5, 1973. [PUBMED Abstract]
  28. Brett GZ: The value of lung cancer detection by six-monthly chest radiographs. Thorax 23 (4): 414-20, 1968. [PUBMED Abstract]
  29. Brett GZ: Earlier diagnosis and survival in lung cancer. Br Med J 4 (678): 260-2, 1969. [PUBMED Abstract]
  30. Dales LG, Friedman GD, Collen MF: Evaluating periodic multiphasic health checkups: a controlled trial. J Chronic Dis 32 (5): 385-404, 1979. [PUBMED Abstract]
  31. Nash FA, Morgan JM, Tomkins JG: South London Lung Cancer Study. Br Med J 2 (607): 715-21, 1968. [PUBMED Abstract]
  32. Weiss W, Boucot KR, Cooper DA: The Philadelphia pulmonary neoplasm research project. Survival factors in bronchogenic carcinoma. JAMA 216 (13): 2119-23, 1971. [PUBMED Abstract]
  33. Weiss W, Boucot KR: The Philadelphia Pulmonary Neoplasm Research Project. Early roentgenographic appearance of bronchogenic carcinoma. Arch Intern Med 134 (2): 306-11, 1974. [PUBMED Abstract]
  34. Berlin NI: Overview of the NCI Cooperative Early Lung Cancer Detection Program. Cancer 89 (11 Suppl): 2349-51, 2000. [PUBMED Abstract]
  35. Fontana RS, Sanderson DR, Taylor WF, et al.: Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Mayo Clinic study. Am Rev Respir Dis 130 (4): 561-5, 1984. [PUBMED Abstract]
  36. Fontana RS, Sanderson DR, Woolner LB, et al.: Lung cancer screening: the Mayo program. J Occup Med 28 (8): 746-50, 1986. [PUBMED Abstract]
  37. Fontana RS, Sanderson DR, Woolner LB, et al.: Screening for lung cancer. A critique of the Mayo Lung Project. Cancer 67 (4 Suppl): 1155-64, 1991. [PUBMED Abstract]
  38. Frost JK, Ball WC Jr, Levin ML, et al.: Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Johns Hopkins study. Am Rev Respir Dis 130 (4): 549-54, 1984. [PUBMED Abstract]
  39. Levin ML, Tockman MS, Frost JK, et al.: Lung cancer mortality in males screened by chest X-ray and cytologic sputum examination: a preliminary report. Recent Results Cancer Res 82: 138-46, 1982. [PUBMED Abstract]
  40. Doria-Rose VP, Marcus PM, Szabo E, et al.: Randomized controlled trials of the efficacy of lung cancer screening by sputum cytology revisited: a combined mortality analysis from the Johns Hopkins Lung Project and the Memorial Sloan-Kettering Lung Study. Cancer 115 (21): 5007-17, 2009. [PUBMED Abstract]
  41. Flehinger BJ, Kimmel M, Polyak T, et al.: Screening for lung cancer. The Mayo Lung Project revisited. Cancer 72 (5): 1573-80, 1993. [PUBMED Abstract]
  42. Melamed M, Flehinger B, Miller D, et al.: Preliminary report of the lung cancer detection program in New York. Cancer 39 (2): 369-82, 1977. [PUBMED Abstract]
  43. Melamed MR, Flehinger BJ, Zaman MB, et al.: Screening for early lung cancer. Results of the Memorial Sloan-Kettering study in New York. Chest 86 (1): 44-53, 1984. [PUBMED Abstract]
  44. Kubík A, Polák J: Lung cancer detection. Results of a randomized prospective study in Czechoslovakia. Cancer 57 (12): 2427-37, 1986. [PUBMED Abstract]
  45. Kubik A, Parkin DM, Khlat M, et al.: Lack of benefit from semi-annual screening for cancer of the lung: follow-up report of a randomized controlled trial on a population of high-risk males in Czechoslovakia. Int J Cancer 45 (1): 26-33, 1990. [PUBMED Abstract]
  46. Oken MM, Hocking WG, Kvale PA, et al.: Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial. JAMA 306 (17): 1865-73, 2011. [PUBMED Abstract]

Harms of Screening

Screening by Low-Dose Helical Computed Tomography

False-positive exams

False-positive exams are particularly problematic in the context of lung cancer screening. Persons most likely to be screened for lung cancer, i.e., heavy smokers, have comorbidities (such as chronic obstructive pulmonary disease and heart disease) that make them poor candidates for certain diagnostic procedures.
False-positive test results must be considered when lung cancer screening with low-dose helical computed tomography (LDCT) is being evaluated. A false-positive test may lead to anxiety and invasive diagnostic procedures, such as percutaneous needle biopsy or thoracotomy. The percentage of false-positive findings varies substantially among studies and is primarily attributable to differences in how a positive scan is defined (the size criteria), the thickness of the slice used between cuts (smaller slice thicknesses lead to detection of more nodules) and whether the subject resides in a geographic location where granulomatous disease is highly prevalent. A systematic review of the benefits and harms of computed tomography (CT) screening for lung cancer reported that the follow-up of a screen-detected nodule most often included further imaging, which varied among 21 screening trials between 1% and nearly 45%. Positron emission tomography scanning was performed in 2.5% to 5% of patients.[1] The frequency of nonsurgical biopsies or procedures in screening trials ranges from 0.7% to 4.4%. Of those biopsied, there was marked variation in the finding of a benign result (6%–79%). The rate of surgical resection for screen detected nodules in screening trials is between 0.9% and 5.6%. Of patients who underwent surgery, between 6% and 45% had a benign nodule discovered during surgery,[2] a potential harm of lung cancer screening. In the National Lung Screening Trial (NLST), most major complications related to invasive procedures and surgeries occurred in patients diagnosed with lung cancer, with a major complication rate of 14%. Additionally, a complication rate of 4.1 deaths and 4.5 complications per 10,000 diagnostic events can be expected in patients determined to have a benign nodule. The rates of complications from the NLST may not be generalizable to a community setting; participants in the NLST were younger, better educated, and less likely to be current smokers (therefore healthier) than the population of smokers and former smokers in the general U.S. population who would be eligible for screening. Of note, 82% of the participants were enrolled at large academic medical centers, and 76% of the enrollees were seen at National Cancer Institute–designated cancer centers. This may account for the extremely low complication rate and surgical mortality (1%) found in the NLST that led the multisociety position paper to strongly recommend that screening be carried out at centers with the same patient-management resources as those in the NLST.[1]
The rates of potential screening harms can vary as lung cancer screening is implemented in a real-world setting. In one study, the authors examined the effects of introducing a LDCT lung cancer screening program into selected Veterans Health Administration (VA) hospitals across the United States.[3] In another study, 93,000 patients were assessed for eligibility to receive one round of LDCT screening: 4,246 patients met the criteria (as per the 2013 U.S. Preventive Service Task Force recommendations);[4] of those eligible, 58% of patients agreed to be screened, and 50% of patients (n = 2,106) actually underwent screening. Sixty percent of patients had a false-positive test, 56% of patients had a suspicious nodule that required ongoing monitoring, and 3.5% of patients underwent diagnostic evaluation for a positive screen. The high rate of false-positive tests (compared with 27.3% of patients in the NLST for a first screen) may be attributed to the VA program’s definition of a positive screen, which used Fleischer Society guidelines for management of CT-detected nodules,[5] whereas the NLST had an absolute cut-off value of 4 mm to define a positive nodule.[2] Most nodules detected in the VA pilot program were 4 mm or less (55%). However, there is currently no uniformly accepted protocol for nodule management in LDCT lung cancer screening, so wide rates of variability in false-positive results could be likely with broad implementation. Additionally, 41% of participants in the VA program had incidental findings of unclear significance that were reported by the reading radiologist to likely require follow-up or further evaluation.[3]

Overdiagnosis

A less familiar harm is overdiagnosis, which means the diagnosis of a condition that would not have become clinically significant had it not been detected by screening.[6] Had the patient not been diagnosed with cancer, the patient would have died of other competing comorbidities. In the case of screening with LDCT, overdiagnosis could lead to unnecessary diagnosis of lung cancer requiring some combination of therapy (e.g., lobectomy, chemotherapy, and radiation therapy). Autopsy studies suggest that a significant number of individuals die with lung cancer rather than from it. In one study, about one-sixth of all lung cancers found at autopsy had not been clinically recognized before death.[7] This may be an underestimate; depending on the extent of the autopsy, many small lung cancers that are detectable by CT may go unrecorded in an autopsy record.[8] Studies in Japan provide additional evidence that screening with LDCT could lead to a substantial amount of overdiagnosis.[9] Studies are needed to establish the level of overdiagnosis that might be associated with CT screening for lung cancer. However, in one study, the volume-doubling times of 61 lung cancers were estimated using an exponential model and successive CT images. Lesions were classified into three of the following types:
  • Type G (ground glass opacity).
  • Type GS (focal glass opacity with a solid central component).
  • Type S (solid nodule).
The mean-doubling times were 813 days, 457 days, and 149 days for types G, GS, and S, respectively. In this study, annual CT screening identified a large number of slowly growing adenocarcinomas that were not visible on chest x-ray, suggesting overdiagnosis.[10]
In a screening trial with more than 5,000 participants, the proportion of cancers that would be considered overdiagnoses was evaluated. Volume-doubling time was used as a surrogate for overdiagnosis. Patients with a calculated volume-doubling time of more than 400 days before surgical resection were considered to have an overdiagnosed cancer.[11] The investigators discovered that 25% of those ultimately diagnosed with lung cancer met the criteria of an indolent screen-detected nodule, suggesting that one in four cancers in that trial were overdiagnosed.[11] Similar rates of overdiagnosis have been documented in breast cancer. This rate is consistent with previous chest radiograph screening studies and for other solid tumors. Data from the NLST showed a persistent gap of about 120 excess lung cancer cases in the LDCT group compared with the chest radiograph group. This suggests that 18% of screen-detected lung cancers were overdiagnosed, although long-term follow-up is needed.[12] Additional evidence of overdiagnosis with LDCT screening was observed in the randomized Danish Lung Cancer Screening Trial. At 10 years of follow-up (5 years after the last screening exam), almost twice as many lung cancers had been diagnosed in the screening group than in the control group (5.1 vs. 2.7 cases per 1,000 person-years or 100 vs. 53 lung cancer cases in 4,104 total participants, respectively); most of the lung cancers were early stage adenocarcinomas, with no statistically significant difference in the number of stage III and IV cancers between the two groups.[13] Overdiagnosis was estimated at 67%.[14]
About 20 years of follow-up of the Mayo Lung Project (MLP) cohort indicates that 17% of lung cancers diagnosed as the result of an intense regimen of chest x-ray and sputum cytology are overdiagnosed;[15] 585 lung cancers had been diagnosed in the intervention arm as compared with 500 in the usual-care arm. After 13 years of follow-up of the Prostate, Lung, Colorectal and Ovarian (PLCO) cohort, 1,696 lung cancers had been diagnosed in the intervention arm as compared with 1,620 lung cancers in the usual-care arm.[16] This suggests that about 25% of the 307 cancers diagnosed as the result of annual chest x-ray were overdiagnosed.

Complications of diagnostic evaluation

In the PLCO,[16] 0.4% of participants with at least one positive screen who had a diagnostic evaluation had a complication associated with a diagnostic procedure. The most common of the 69 complications were pneumothorax (29%), atelectasis (15%), and infection (10%).
A retrospective cohort study of community practices indirectly estimated the complication rates and downstream medical costs of invasive diagnostic procedures performed for lung abnormalities that were identified through lung cancer screening. The complications rates of 23% (aged 55–64 years) and 23.8% (aged 65–77 years) were more than twice that reported in the NLST (8.5%–9.8%). The mean costs ranged from $6,320 to $56,845, suggesting that the NLST, which was conducted in the context of a controlled clinical trial, may have underestimated the potential for adverse events and high downstream costs in the community setting. Despite study limitations, including the lack of information about patient eligibility for lung cancer screening and the extent to which complications were affected by poorer patient health and lower quality of care, these results reinforce the need for discussion of risks, benefits, and shared decision making.[17]

Increase in lung cancer mortality

Findings from the MLP hinted at the possibility of an increase in lung cancer mortality for persons screened with an intense regimen of chest x-ray and sputum cytology.[18] At the end of 20 years of follow-up, the lung cancer mortality rate was 4.4 cases per 1,000 deaths in the intervention arm and 3.9 cases per 1,000 deaths in the usual-care arm. The two rates were not statistically different from one another (P = .09). No increase in risk was seen in the intervention arms of the John Hopkins University and Memorial Sloan-Kettering studies (relative risk [RR], 0.88; 95% confidence interval [CI], 0.74–1.05), and the PLCO (RR, 0.99; 95% CI, 0.87–1.22).

Radiation exposure

Another potential risk from screening with LDCT is radiation exposure. The average exposure is very low for an LDCT at 1.5 mSv. It is estimated that over a 3-year period of screening, NLST participants have been exposed to an average of 8 mSv of radiation (which accounts for radiation from screens and additional imaging for screen-detected nodules). Modeling from previous work on radiation exposure and the development of cancer suggests that there could be one death per 2,500 screens in those participating in a screening program such as the NLST, although the benefit of screening (1 death avoided per 320 screens) far outweighs the risk. Younger persons and those without a significant risk of lung cancer may be more likely to suffer a radiation-induced lung cancer from screening than to be spared a lung cancer death.[1]

Screening by Chest X-ray and/or Sputum Cytology

Unless reported above, data on harms associated with sputum cytology or a combined regimen of sputum cytology and chest x-ray have not been published.
In the PLCO Cancer Screening Trial, the percentage of false positive screens (among all positive lung cancer screens) was 98%.[19] When smoking status was considered, the percentage of false-positive screens (among all positive screens) was highest in never-smokers (>99%) and lowest in current smokers (95%). After adjustment for smoking, the percentage of false-positive screens did not differ by sex.
References
  1. Bach PB, Mirkin JN, Oliver TK, et al.: Benefits and harms of CT screening for lung cancer: a systematic review. JAMA 307 (22): 2418-29, 2012. [PUBMED Abstract]
  2. Aberle DR, Adams AM, Berg CD, et al.: Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365 (5): 395-409, 2011. [PUBMED Abstract]
  3. Kinsinger LS, Anderson C, Kim J, et al.: Implementation of Lung Cancer Screening in the Veterans Health Administration. JAMA Intern Med 177 (3): 399-406, 2017. [PUBMED Abstract]
  4. Moyer VA; U.S. Preventive Services Task Force: Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 160 (5): 330-8, 2014. [PUBMED Abstract]
  5. MacMahon H, Austin JH, Gamsu G, et al.: Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology 237 (2): 395-400, 2005. [PUBMED Abstract]
  6. Black WC: Overdiagnosis: An underrecognized cause of confusion and harm in cancer screening. J Natl Cancer Inst 92 (16): 1280-2, 2000. [PUBMED Abstract]
  7. Chan CK, Wells CK, McFarlane MJ, et al.: More lung cancer but better survival. Implications of secular trends in "necropsy surprise" rates. Chest 96 (2): 291-6, 1989. [PUBMED Abstract]
  8. Dammas S, Patz EF Jr, Goodman PC: Identification of small lung nodules at autopsy: implications for lung cancer screening and overdiagnosis bias. Lung Cancer 33 (1): 11-6, 2001. [PUBMED Abstract]
  9. Marcus PM, Fagerstrom RM, Prorok PC, et al.: Screening for lung cancer with helical CT scanning. Clinical Pulmonary Medicine 9 (6): 323-9, 2002.
  10. Hasegawa M, Sone S, Takashima S, et al.: Growth rate of small lung cancers detected on mass CT screening. Br J Radiol 73 (876): 1252-9, 2000. [PUBMED Abstract]
  11. Veronesi G, Maisonneuve P, Bellomi M, et al.: Estimating overdiagnosis in low-dose computed tomography screening for lung cancer: a cohort study. Ann Intern Med 157 (11): 776-84, 2012. [PUBMED Abstract]
  12. Patz EF Jr, Pinsky P, Gatsonis C, et al.: Overdiagnosis in low-dose computed tomography screening for lung cancer. JAMA Intern Med 174 (2): 269-74, 2014. [PUBMED Abstract]
  13. Wille MM, Dirksen A, Ashraf H, et al.: Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-Risk Profiling. Am J Respir Crit Care Med 193 (5): 542-51, 2016. [PUBMED Abstract]
  14. Heleno B, Siersma V, Brodersen J: Estimation of Overdiagnosis of Lung Cancer in Low-Dose Computed Tomography Screening. JAMA Intern Med : , 2018. [PUBMED Abstract]
  15. Marcus PM, Bergstralh EJ, Zweig MH, et al.: Extended lung cancer incidence follow-up in the Mayo Lung Project and overdiagnosis. J Natl Cancer Inst 98 (11): 748-56, 2006. [PUBMED Abstract]
  16. Oken MM, Hocking WG, Kvale PA, et al.: Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial. JAMA 306 (17): 1865-73, 2011. [PUBMED Abstract]
  17. Huo J, Xu Y, Sheu T, et al.: Complication Rates and Downstream Medical Costs Associated With Invasive Diagnostic Procedures for Lung Abnormalities in the Community Setting. JAMA Intern Med : , 2019. [PUBMED Abstract]
  18. Marcus PM, Bergstralh EJ, Fagerstrom RM, et al.: Lung cancer mortality in the Mayo Lung Project: impact of extended follow-up. J Natl Cancer Inst 92 (16): 1308-16, 2000. [PUBMED Abstract]
  19. Hocking WG, Hu P, Oken MM, et al.: Lung cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. J Natl Cancer Inst 102 (10): 722-31, 2010. [PUBMED Abstract]

Informed Medical Decision Making

Informed medical decision making is increasingly recommended for individuals who are considering cancer screening. Many different types and formats of decision aids have been studied. (Refer to the PDQ summary on Cancer Screening Overview for more information.)

Changes to This Summary (06/11/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Description of the Evidence
Added text to state that a review of two surrogate markers of benefit from the low-dose helical computed tomography for lung cancer screening determined that there is no discernible relationship between the proportion of stage I lung cancers or lung cancer-specific survival for stage I disease and lung cancer mortality benefit at 4 years (cited Woo et al. as reference 8).
Added text to state that a recent comparison of ten models used for predicting lung cancer or lung cancer mortality risk found that four of the models were well calibrated with reasonable discrimination, but none of these models were considered superior to the others for the use of identifying lung cancer risk among individuals who had ever smoked; additional work is needed to address modeling weaknesses (cited Katki et al. as reference 13).
Added Pastorino et al. as reference 20.
Harms of Screening
Added text about a retrospective cohort study of community practices, which indirectly estimated the complication rates and downstream medical costs of invasive diagnostic procedures performed for lung abnormalities that were identified through lung cancer screening; despite study limitations, including the lack of information about patient eligibility for lung cancer screening and the extent to which complications were affected by poorer patient health and lower quality of care, these results reinforce the need for discussion of risks, benefits, and shared decision making (cited Huo et al. as reference 17).
This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about lung cancer screening. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Screening and Prevention Editorial Board. PDQ Lung Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lung/hp/lung-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389268]
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  • Updated: June 11, 2019
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