Linda L. Humphrey, MD, MPH; Mark Deffebach, MD; Miranda Pappas, MA; Christina Baumann, MD, MPH; Kathryn Artis, MD, MPH; Jennifer Priest Mitchell, BA; Bernadette Zakher, MBBS; Rongwei Fu, PhD; Christopher G. Slatore, MD, MS
Disclaimer: The findings and conclusions in this review are those of the authors, who are responsible for its content, and do not necessarily represent the views of the AHRQ, the U.S. Department of Veterans Affairs, or the U.S government. No statement in this review should be construed as an official position of the AHRQ or the U.S. Department of Health and Human Services. The Department of Veterans Affairs did not have a role in the conduct of the study; the collection, management, analysis, or interpretation of data; or the preparation of the manuscript.
Acknowledgment: The authors thank Andrew Hamilton, MLS, MS, who conducted literature searches and Amanda Brunton, BS, who assisted with preparing the manuscript.
Grant Support: By AHRQ under contract HHSA-290-2007-10057-I-EPC3, task order 13, and the Portland Veterans Affairs Medical Center. Drs. Humphrey, Deffebach, and Slatore are supported by resources from the Portland Veterans Affairs Medical Center. Dr. Slatore is sponsored by a Veterans Affairs Health Services Research and Development Career Development Award.
Potential Conflicts of Interest: Dr. Humphrey: Employment: Department of Veterans Affairs; Other: UpToDate. Dr. Deffebach: Payment for writing or reviewing the manuscript (money to institution): USPSTF; Other: UpToDate. Ms. Pappas and Drs. Artis and Zakher: Other: AHRQ. Dr. Baumann: Support for travel to meetings for the study or other purposes (money to institution): AHRQ. Dr. Slatore: Grants/grants pending: Department of Veterans Affairs, American Lung Association, Chest/LUNGevity Foundation; Personal fees: National Lung Cancer Partnership; Other: American College of Chest Physicians. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1080.
Requests for Single Reprints: Linda L. Humphrey, MD, MPH, Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, Mailcode BICC, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Humphrey, Deffebach, Baumann, Artis, Zakher, Fu, and Slatore; Ms. Pappas; and Ms. Mitchell: Oregon Health & Science University, Mailcode BICC, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098.
Author Contributions: Conception and design: L.L. Humphrey, M. Pappas, C. Baumann, K. Artis, C.G. Slatore.
Analysis and interpretation of the data: L.L. Humphrey, M. Deffebach, M. Pappas, C. Baumann, K. Artis, B. Zakher, R. Fu, C.G. Slatore.
Drafting of the article: L.L. Humphrey, M. Deffebach, M. Pappas, C. Baumann, B. Zakher, C.G. Slatore.
Critical revision of the article for important intellectual content: L.L. Humphrey, M. Deffebach, M. Pappas, C. Baumann, K. Artis, R. Fu, C.G. Slatore.
Final approval of the article: L.L. Humphrey, M. Deffebach, M. Pappas, B. Zakher, R. Fu, C.G. Slatore.
Statistical expertise: R. Fu, C.G. Slatore.
Administrative, technical, or logistic support: M. Deffebach, M. Pappas, J.P. Mitchell.
Collection and assembly of data: L.L. Humphrey, M. Deffebach, M. Pappas, C. Baumann, K. Artis, J.P. Mitchell, B. Zakher, R. Fu, C.G. Slatore.
Lung cancer is the leading cause of cancer-related death in the United States. Because early-stage lung cancer is associated with lower mortality than late-stage disease, early detection and treatment may be beneficial.
To update the 2004 review of screening for lung cancer for the U.S. Preventive Services Task Force, focusing on screening with low-dose computed tomography (LDCT).
MEDLINE (2000 to 31 May 2013), the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth quarter of 2012), Scopus, and reference lists.
English-language randomized, controlled trials or cohort studies that evaluated LDCT screening for lung cancer.
One reviewer extracted study data about participants, design, analysis, follow-up, and results, and a second reviewer checked extractions. Two reviewers rated study quality using established criteria.
Four trials reported results of LDCT screening among patients with smoking exposure. One large good-quality trial reported that screening was associated with significant reductions in lung cancer (20%) and all-cause (6.7%) mortality. Three small European trials showed no benefit of screening. Harms included radiation exposure, overdiagnosis, and a high rate of false-positive findings that typically were resolved with further imaging. Smoking cessation was not affected. Incidental findings were common.
Three trials were underpowered and of insufficient duration to evaluate screening effectiveness. Overdiagnosis, an important harm of screening, is of uncertain magnitude. No studies reported results in women or minority populations.
Strong evidence shows that LDCT screening can reduce lung cancer and all-cause mortality. The harms associated with screening must be balanced with the benefits.
Agency for Healthcare Research and Quality.
Summary of evidence search and selection.
COSMOS = Continuing Observation of Smoking Subjects; DANTE = Detection and Screening of Early Lung Cancer by Novel Imaging Technology and Molecular Essays; DLCST = Danish Lung Cancer Screening Trial; I-ELCAP = International Early Lung Cancer Action Program; LSS = Lung Screening Study; LUSI = Lung Cancer Screening Intervention; MILD = Multicentric Italian Lung Detection; NELSON = Dutch–Belgian Randomised Controlled Trial for Lung Cancer Screening in High-Risk Subjects; NLST = National Lung Screening Trial; PALCAD = ProActive Lung Cancer Detection; PLCO = Prostate, Lung, Colorectal, and Ovarian; PLuSS = Pittsburgh Lung Screening Study; RCT = randomized, controlled trial.
* Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews.
† Identified from reference lists or hand searching and suggested by experts.
‡ Studies that provided data and contributed to the body of evidence were considered included.
§ In the final report (24); not reported in this review.
Appendix Table 1. Evidence Table for Included Randomized Trials
Table. Summary of Included Randomized, Controlled Trials
Trial results for lung cancer mortality.
DANTE = Detection and Screening of Early Lung Cancer by Novel Imaging Technology and Molecular Essays; DLCST = Danish Lung Cancer Screening Trial; MILD = Multicentric Italian Lung Detection; NLST = National Lung Screening Trial.
* Annual screening group compared only with control group; biennial screening group not shown.
Trial results for all-cause mortality.
Appendix Table 2. Included Cohort Studies
Appendix Table 3. Summary of Evidence
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John Brodersen, Jakob Fraes Rasmussen and Bruno Heleno
Research Unit and Section of General Practice, Department of Public Health, University of Copenhagen, Denmark
August 19, 2013
Recommendation about low-dose computed tomography screening is premature
The U.S. Preventive Services Task Force (USPSTF) has published a systematic review on screening for lung cancer with low-dose computed tomography (LDCT).(1) Seven randomized controlled trials (RCTs) on LDCT (one from the U.S., six from Europe) were identified but only four were included in the review because the other three have not reported results in the intervention and control groups yet. A reduction in lung-cancer specific mortality and a trend for reduced overall mortality was seen in the U.S. trial (which compared LDCT with chest X-ray, and had far more participants and years of follow-up than other trials), but not in any of the three European trials (which compared LDCT with no screening, have less participants, and have not reported final results). In addition, the USPSTF noted that the main harms were: radiation exposure, overdiagnosis, a high rate of false-positives and common incidental findings. In this comment we argue that the available evidence on screening harms is still too scarce to make definitive recommendations about low-dose computed tomography screening. We disagree with two arguments presented by the USPSTF: 1) that no studies formally reported overdiagnosis, and 2) that screening did not affect overall health-related quality of life or long-term anxiety. 1) Overdiagnosis The European trials, which compared LDCT with no screening, have not had enough follow-up time to report overdiagnosis. However, they all found more early-stage lung cancer, but not fewer cases of advanced lung cancer in the LDCT groups. (1) This is indirect evidence for overdiagnosis. In the NLST, which compared LDCT with chest X-ray, 119 more cases of lung cancer in the LDCT group were found (approximately 4 more lung cancers per 1000 participants).(2) Furthermore, overdiagnosis has previously been reported in chest X-ray screening.(3) Our interpretation is that LDCT-screening results in some degree of overdiagnosis, but the exact degree of overdiagnosis cannot be estimated before the European trials (which compared LDCT with no screening) have had sufficient follow-up time.(4) There was no evidence of overdiagnosis at 6 years of follow-up in the Prostate, Lung, Colorectal, and Ovarian (PLCO) study within the subgroup of participants that met the eligibility criteria of the NLST.(5) Nevertheless, in the Mayo Lung Project (MLP), lung cancer screening with chest X-ray was associated with approximately 10 overdiagnosed cancers per 1000 participants.(6) Thus, the reduction 3 lung-cancer deaths per 1000 participants found in the NLST(7) needs to be balanced against the plausible estimates of overdiagnosis: from 4/1000 participants (NLST + PLCO estimate) to 14/1000 participants (NLST + MLP estimate). 2) Psychosocial consequences, If psychosocial consequences of cancer screening are to be measured there is a need for questionnaires with high content validity and adequate psychometric properties.(8) In a qualitative study none of the interviewees reported pathological levels on anxiety and depression that needed therapeutic and/or pharmaceutical treatment.(9) The use of anxiolytic or antidepressant medication might therefore be an insufficient surrogate outcome for psychosocial consequences of LDCT-screening.(10) So far, RCTs on LDCT-screening have not provided evidence that the questionnaires used in their surveys have adequate measurement qualities and properties. Therefore, the results of these surveys are questionable. In the DLCST an instrument has been developed using qualitative group interviews and item response theory modeling: the Consequences of Screening in Lung Cancer (COS-LC) questionnaire.(9) The COS-LC has been used trough out the DLCST.(11) In the DLCST we have found that participation in lung cancer screening has negative psychosocial consequences for the apparently healthy participants one year after randomization.(12) In another study we have revealed substantial socio-demographic and psychosocial participation bias in DLCST(13) that most likely has underestimated the negative psychosocial consequences in the first study.(12) Before it can be assessed if a medical screening modality results in more good than harm – or vice versa – high quality evidence about the potential intended beneficial effects and the potential unintended harmful effects is needed. The USPSTF has 30 July on its website (http://www.uspreventiveservicestaskforce.org/draftrec.htm) published a draft of their recommendation for LDCT-screening based on their review that be commented until 26 August. The USPSTF recommends annual screening for lung cancer with low-dose computed tomography (LDCT) in persons at high risk for lung cancer based on age and smoking history. We do not think there is high quality evidence to support this recommendation because of the lack of high quality evidence about overdiagnosis and psychosocial consequences of LDCT-screening. Without such information we cannot understand how there is either “high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial”.The European RCTs will hopefully be able to raise sufficient evidence about the degree of overdiagnosis of LDCT-screening of which the true effect can only be determined in comparison to a non-screening control group.(4) Furthermore, in the DLCST we are working on our data on costs and psychosocial consequences and hope to report our main results soon. In addition, cost-effectiveness analysis can only be conducted if evidence about all relevant benefits and harms exists. Without high quality evidence about overdiagnosis, psychosocial consequences and cost effectiveness we find that any recommendation about LDCT-screening is premature.
(1) Humphrey LL, Deffebach M, Pappas M, Baumann C, Artis K, Mitchell JP, et al. Screening for Lung Cancer With Low-Dose Computed Tomography: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation. Ann Intern Med 2013 Jul 30;N/A(N/A):N/A.
(2) Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011 Aug 4;365(5):395-409.
(3) Manser R, Lethaby A, Irving LB, Stone C, Byrnes G, Abramson MJ, et al. Screening for lung cancer. Cochrane Database Syst Rev 2013;6:CD001991.
(4) Field JK, van Klaveren R, Pedersen JH, Pastorino U, Paci E, Becker N, et al. European randomized lung cancer screening trials: Post NLST. J Surg Oncol 2013 Jul 1;n/a.
(5) Oken MM, Hocking WG, Kvale PA, Andriole GL, Buys SS, Church TR, et al. Screening by Chest Radiograph and Lung Cancer Mortality: The Prostate, Lung, Colorectal, and Ovarian (PLCO) Randomized Trial. JAMA 2011 Oct 26.
(6) Marcus PM, Bergstralh EJ, Fagerstrom RM, Williams DE, Fontana R, Taylor WF, et al. Lung cancer mortality in the Mayo Lung Project: impact of extended follow-up. J Natl Cancer Inst 2000 Aug 16;92(16):1308-16.
(7) Heleno B, Rasmussen JF, Brodersen J. Reduced Lung-Cancer Mortality with CT Screening. N Engl J Med 2011 Nov 24;365(21):2035-8.
(8) Brodersen J, McKenna SP, Doward LC, Thorsen H. Measuring the psychosocial consequences of screening. Health Qual Life Outcomes 2007 Jan 8;5(1):3.
(9) Brodersen J, Thorsen H, Kreiner S. Consequences Of Screening in Lung Cancer: Development and Dimensionality of a Questionnaire. Value in Health 2010 Aug 18;13(5):601-12.
(10) Kaerlev L, Iachina M, Pedersen JH, Green A, Norgard BM. CT-Screening for lung cancer does not increase the use of anxiolytic or antidepressant medication. BMC Cancer 2012;12:188.
(11) Pedersen JH, Ashraf H, Dirksen A, Bach K, Hansen H, Tønnesen P, et al. The Danish Randomized Lung Cancer CT Screening Trial – Overall Design and Results of the Prevalence Round. Journal of Thoracic Oncology 2009 May;4(5):608-14.
(12) Aggestrup LM, Hestbech MS, Siersma V, Pedersen JH, Brodersen J. Psychosocial Consequences of Allocation to Lung Cancer Screening – a Randomised Controlled Trial. BMJ Open 2012;10.1136/bmjopen-2011-000663.
(13) Hestbech MS, Siersma V, Dirksen A, Pedersen JH, Brodersen J. Participation bias in a randomised trial of screening for lung cancer. Lung Cancer 2011 Sep;73(3):325-31.
John Brodersen 1, Asger Dirksen 2, Jesper Holst Pedersen 3
1 Research Unit and Section of General Practice, Department of Public Health, University of Copenhagen, 2 Department of Respiratory medicine, Gentofte University Hospital, and 3 Department of Thoracic
Clarifying information about the Danish Lung Cancer Screening Trial
The U.S. Preventive Services Task Force (USPSTF) has published a systematic review on screening for lung cancer with low-dose computed tomography (LDCT). In the review the USPSTF stated 1) that there were insufficient and unequal follow-up in three European randomized controlled trials to evaluate the degree of overdiagnosis and 2) that the allocation in the Danish Lung Cancer Screening Trial (DLCST) was unclear. In this comment we (as representatives of the Danish Lung Cancer Screening Trial (DLCST)) present clarifying information about the DLCST. 1) Insufficient and unequal follow-up. We agree with the USPSTF that the follow-up of the DLCST (and the two other European trials) is insufficient to assess the impact on mortality and the level of overdiagnosis. However, for mortality and cancer incidence the follow-up in the screening and control group was equal as stated in our status-paper after five annual screening rounds: “…the latest follow-up for both groups was set as end of screening, 31 March 2010.” 2) Unclear allocation in the DLCST Allocation in the DLCST was described for the first time in our paper reporting on the prevalence round: "Participants were randomized by a computer program (random permuted blocks of 10 participants) to either annual screening by low-dose CT (the screening group) or the control group who were not offered CT screening." Later, in our paper including all five screening rounds we wrote: "After inclusion, the participants were randomized to the screening group (n=2052) or the control group (n=2052). The screening group received five annual low-dose chest CT scans (one baseline scan and four subsequent incidence scans)."We would have been happy to clarify any matter about allocation concealment if any of the authors of the USPSTF had contacted us. The participants in the DLCST were randomised by a centrally-held, computer-generated list (random permuted blocks of 10 participants). Allocation concealment was ensured, as the computer application did not release the randomization code until the participant had been recruited into the trial, which took place after eligibility was checked and informed consent was provided. During the entire recruitment period (October 2004 to March 2006), the researchers involved in participant recruitment were unaware that the randomised list contained random permuted blocks, and thus could not guess the next allocation in the sequence.
 Humphrey LL, Deffebach M, Pappas M, Baumann C, Artis K, Mitchell JP et al. Screening for Lung Cancer With Low-Dose Computed Tomography: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation. Ann Intern Med 2013; N/A(N/A):N/A.
 Saghir Z, Dirksen A, Ashraf H, Bach KS, Brodersen J, Clementsen PF et al. CT screening for lung cancer brings forward early disease. The randomised Danish Lung Cancer Screening Trial: status after five annual screening rounds with low-dose CT. Thorax 2012; 67(4):296-301.
 Pedersen JH, Ashraf H, Dirksen A, Bach K, Hansen H, Tønnesen P et al. The Danish Randomized Lung Cancer CT Screening Trial – Overall Design and Results of the Prevalence Round. Journal of Thoracic Oncology 2009; 4(5):608-614.
Linda Humphrey, MD, MPH, Mark Deffebach, MD, Miranda Pappas, MA, Bernadette Zakher, MBBS, Christopher Slatore, MD, MS
Portland VA Medical Center
November 25, 2013
Dear Dr. Broderson:
Thank you for your letters regarding our recent systematic review of low-dose CT screening for lung cancer. We appreciate your interest and respond below:
1. Over-diagnosis--- as we note in our paper and the associated systematic review, over-diagnosis is a risk of lung cancer screening and of uncertain magnitude. We do not believe that a valid estimate of over-diagnosis comes from the Mayo Lung Project for many reasons, most outlined in our report [Humphrey, 2013 #16875] and the prior review [Humphrey, 2004 #61]). More research in this important area is needed.
2. We rated the quality of the DLCST as moderate. Limitations we identified included a lack of description of allocation concealment as you note. The paper states that patients were randomized at their first visit. Allocation concealment was not described, only that patients were randomized in block permutation form. [Pedersen, 2009 #3703] In general, we rely on information in publications to evaluate trial quality. In addition, on page 5 of the 2012 paper, unequal follow-up is noted. Specifically, the paper states that, “Information on lung cancer in the control group is not as up to date as in the screening group.”[Saghir, 2012 #8634]
3. As we note in our paper, we strongly agree that more research in the area of psychosocial outcomes will be very important to aid individual decision making for people considering low-dose CT screening for lung cancer.
Please note also that we do not make recommendations about screening. These are made by the Task Force based on the systematic review we prepare. We very much look forward to more data from current trials to better inform decision making in lung cancer screening. Thank you again for your interest.
Linda Humphrey, MD, MPH
Mark Deffebach, MD
Miranda Pappas, MA
Bernadette Zakher, MBBS
Christopher Slatore, MD, MS
Humphrey LL, Deffebach M, Pappas M, et al. Screening for Lung Cancer With Low-Dose Computed Tomography: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation. Ann Intern Med. 2013;159:411–420. doi: 10.7326/0003-4819-159-6-201309170-00690
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Published: Ann Intern Med. 2013;159(6):411-420.
Cancer Screening/Prevention, Hematology/Oncology, High Value Care, Lung Cancer, Prevention/Screening.
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