Letters
Annals of Internal Medicine COMMENTS
AND
RESPONSES
Screening for Lung Cancer With Low-Dose Computed Tomography TO THE EDITOR: Humphrey and colleagues (1) recommend 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. Given the lack of evidence about overdiagnosis, psychosocial consequences, and cost-effectiveness of this screening, we cannot understand how there is “high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial” (2). There is considerable uncertainty about the extent of overdiagnosis with LDCT screening. We think that plausible estimates can be obtained from the NLST (National Lung Screening Trial), which is a trial of LDCT versus chest radiography, and from 2 trials of screening with chest radiography. The LDCT group of the NLST had an excess of 119 cases of lung cancer compared with the chest radiography group (approximately 4 more cases of lung cancer per 1000 participants) (3). No evidence of overdiagnosis was available at 6-year follow-up in the PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial within the subgroup of participants who met the eligibility criteria of the NLST (4). Nevertheless, in the Mayo Lung Project, lung cancer screening with chest radiography was associated with approximately 10 overdiagnosed cases of cancer per 1000 participants (5). Thus, the reduction of 3 deaths from lung cancer per 1000 participants found in the NLST needs to be balanced against the plausible estimates of overdiagnosis, which range from 4 per 1000 participants (the NLST and PLCO Cancer Screening Trial estimate) to 14 per 1000 participants (the NLST and Mayo Lung Project estimate). If psychosocial consequences of cancer screening are to be measured, questionnaires with high content validity and adequate psychometric properties are needed. In a qualitative study, none of the interviewees reported pathologic levels of anxiety and depression that needed therapeutic or pharmaceutical treatment (6). The use of anxiolytic or antidepressant medication might therefore be an insufficient surrogate outcome for psychosocial consequences of LDCT screening. So far, randomized, controlled trials on LDCT screening have not provided adequate evidence about the measurement qualities and properties of the questionnaires that were used. Therefore, the results of these surveys are questionable. In the DLCST (Danish Lung Cancer Screening Trial), an instrument has been developed using qualitative group interviews and item-response theory modelling: the Consequences of Screening in Lung Cancer questionnaire (6). This tool has been used throughout the DLCST. In this trial, we found that participation in lung cancer screening had negative psychosocial consequences for the apparently healthy participants 1 year after randomization. In another study (7), we revealed substantial sociodemographic and psychosocial participation bias in the DLCST that has probably underestimated the negative psychosocial consequences in Hestbech and colleagues’ study (8). We hope that the European randomized, controlled trials will be able to directly estimate the degree of overdiagnosis of LDCT
screening. Furthermore, in the DLCST, we are working on data on costs and psychosocial consequences and hope to report our main results soon. In addition, cost-effectiveness can be analyzed only if evidence about all relevant benefits and harms exists. Without highquality evidence about overdiagnosis, psychosocial consequences, and cost-effectiveness, we believe that any recommendation about LDCT screening is premature. John Brodersen, MD, GP, PhD Jakob Fraes Rasmussen, MD Bruno Heleno, MD, GP University of Copenhagen Copenhagen, Denmark Potential Conflicts of Interest: None disclosed. Forms can be viewed at
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽L13-1112. References 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;159:411-20. [PMID: 23897166] 2. Moyer VA; U.S. Preventive Services Task Force. Screening for Lung Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2013. [PMID: 24378917] [Epub ahead of print] 3. Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, et al; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409. [PMID: 21714641] 4. Oken MM, Hocking WG, Kvale PA, Andriole GL, Buys SS, Church TR, et al; PLCO Project Team. Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial. JAMA. 2011;306: 1865-73. [PMID: 22031728] 5. 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;92:1308-16. [PMID: 10944552] 6. Brodersen J, Thorsen H, Kreiner S. Consequences of screening in lung cancer: development and dimensionality of a questionnaire. Value Health. 2010;13:601-12. [PMID: 20345552] 7. 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;2:e000663. [PMID: 22382119] 8. Hestbech MS, Siersma V, Dirksen A, Pedersen JH, Brodersen J. Participation bias in a randomised trial of screening for lung cancer. Lung Cancer. 2011;73:325-31. [PMID: 21324544]
TO THE EDITOR: In their review, Humphrey and colleagues (1) stated that follow-up was insufficient and unequal to evaluate the degree of overdiagnosis in 3 European randomized, controlled trials and that the allocation in the DLCST was unclear. As representatives of that study, we present further clarifying information. We agree that the follow-up of the DLCST (and the 2 other European trials) is currently insufficient to assess the effect on mortality and the level of overdiagnosis. However, for mortality and cancer incidence, the follow-up in the screening and control groups was equal. As our status paper after 5 annual screening rounds stated, “the latest follow-up for both groups was set as end of screening, 31 March 2010” (2). © 2014 American College of Physicians 211
Downloaded From: http://annals.org/ by a Penn State University Hershey User on 04/16/2015
Letters Allocation in the DLCST was described for the first time in our article that reported on the prevalence round, which stated, “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” (3). Later, in our article that included all 5 screening rounds, we explained, “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)” (2). We would have been happy to clarify any matter about allocation concealment if Humphrey and colleagues had contacted us. The participants in the DLCST were randomly assigned by a centrally held, computer-generated list (random permuted blocks of 10 participants). Allocation concealment was ensured because the computer application did not release the randomization code until a participant had been recruited into the trial, which occurred after eligibility was checked and informed consent was provided. During the recruitment period (October 2004 to March 2006), the investigators involved in recruitment were unaware that the randomized list contained random permuted blocks and thus could not guess the next allocation in the sequence. John Brodersen, MD, GP, PhD University of Copenhagen Copenhagen, Denmark
tain magnitude. We do not believe that the Mayo Lung Project provides a valid estimate of overdiagnosis for many reasons, most of which we outlined in our report (1) and the prior review (2). More research in this important area is needed. We rated the quality of the DLCST as moderate. Limitations that we identified included a lack of description of allocation concealment, as Drs. Brodersen, Dirksen, and Pedersen note. They state that patients were randomly assigned at their first visit. Allocation concealment was not described, only that patients were randomly assigned in block permutation form (3). In general, we rely on information in publications to evaluate trial quality. Furthermore, Saghir and associates note unequal follow-up in the DLCST when they state, “Information on lung cancer in the control group is not as up to date as in the screening group” (4). As we state in our review, we strongly agree that more research in psychosocial outcomes will be important to aid individual decision making for persons considering LDCT screening for lung cancer. Please also note that we do not make recommendations about screening. These are made by the U.S. Preventive Services Task Force based on the systematic review that we prepare. Linda L. Humphrey, MD, MPH Mark Deffebach, MD Portland Veterans Affairs Medical Center Portland, Oregon
Asger Dirksen, MD, DrMSci Gentofte University Hospital Copenhagen, Denmark
Miranda Pappas, MA Bernadette Zakher, MBBS Oregon Health & Science University Portland, Oregon
Jesper Holst Pedersen, MD, DrMSci Rigshospitalet Copenhagen, Denmark
Christopher G. Slatore, MD, MS Portland Veterans Affairs Medical Center Portland, Oregon
Potential Conflicts of Interest: None disclosed. Forms can be viewed at
Potential Conflicts of Interest: Disclosures can be viewed at www .acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽M13-1080.
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽L13-1113.
References References 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;159:411-20. [PMID: 23897166] 2. 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;67:296-301. [PMID: 22286927] 3. Pedersen JH, Ashraf H, Dirksen A, Bach K, Hansen H, Toennesen P, et al. The Danish randomized lung cancer CT screening trial—overall design and results of the prevalence round. J Thorac Oncol. 2009;4:608-14. [PMID: 19357536]
IN RESPONSE: As we noted in our article and the associated system-
atic review, overdiagnosis is a risk of lung cancer screening of uncer-
1. Humphrey L, Deffebach M, Pappas M, Baumann C, Artis K, Mitchell JP, et al, eds. Screening for Lung Cancer: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation. Report no. 13-05188-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2013. 2. Humphrey LL, Teutsch S, Johnson M; U. S. Preventive Services Task Force. Lung cancer screening with sputum cytologic examination, chest radiography, and computed tomography: an update for the U.S. Preventive Services Task Force. Ann Intern Med. 2004;140:740-53. [PMID: 15126259] 3. Pedersen JH, Ashraf H, Dirksen A, Bach K, Hansen H, Toennesen P, et al. The Danish randomized lung cancer CT screening trial—overall design and results of the prevalence round. J Thorac Oncol. 2009;4:608-14. [PMID: 19357536] 4. 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;67:296-301. [PMID: 22286927]
212 4 February 2014 Annals of Internal Medicine Volume 160 • Number 3
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www.annals.org
Annals of Internal Medicine COMMENTS
AND
RESPONSES
Screening for Lung Cancer With Low-Dose Computed Tomography TO THE EDITOR: Humphrey and colleagues (1) recommend 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. Given the lack of evidence about overdiagnosis, psychosocial consequences, and cost-effectiveness of this screening, we cannot understand how there is “high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial” (2). There is considerable uncertainty about the extent of overdiagnosis with LDCT screening. We think that plausible estimates can be obtained from the NLST (National Lung Screening Trial), which is a trial of LDCT versus chest radiography, and from 2 trials of screening with chest radiography. The LDCT group of the NLST had an excess of 119 cases of lung cancer compared with the chest radiography group (approximately 4 more cases of lung cancer per 1000 participants) (3). No evidence of overdiagnosis was available at 6-year follow-up in the PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial within the subgroup of participants who met the eligibility criteria of the NLST (4). Nevertheless, in the Mayo Lung Project, lung cancer screening with chest radiography was associated with approximately 10 overdiagnosed cases of cancer per 1000 participants (5). Thus, the reduction of 3 deaths from lung cancer per 1000 participants found in the NLST needs to be balanced against the plausible estimates of overdiagnosis, which range from 4 per 1000 participants (the NLST and PLCO Cancer Screening Trial estimate) to 14 per 1000 participants (the NLST and Mayo Lung Project estimate). If psychosocial consequences of cancer screening are to be measured, questionnaires with high content validity and adequate psychometric properties are needed. In a qualitative study, none of the interviewees reported pathologic levels of anxiety and depression that needed therapeutic or pharmaceutical treatment (6). The use of anxiolytic or antidepressant medication might therefore be an insufficient surrogate outcome for psychosocial consequences of LDCT screening. So far, randomized, controlled trials on LDCT screening have not provided adequate evidence about the measurement qualities and properties of the questionnaires that were used. Therefore, the results of these surveys are questionable. In the DLCST (Danish Lung Cancer Screening Trial), an instrument has been developed using qualitative group interviews and item-response theory modelling: the Consequences of Screening in Lung Cancer questionnaire (6). This tool has been used throughout the DLCST. In this trial, we found that participation in lung cancer screening had negative psychosocial consequences for the apparently healthy participants 1 year after randomization. In another study (7), we revealed substantial sociodemographic and psychosocial participation bias in the DLCST that has probably underestimated the negative psychosocial consequences in Hestbech and colleagues’ study (8). We hope that the European randomized, controlled trials will be able to directly estimate the degree of overdiagnosis of LDCT
screening. Furthermore, in the DLCST, we are working on data on costs and psychosocial consequences and hope to report our main results soon. In addition, cost-effectiveness can be analyzed only if evidence about all relevant benefits and harms exists. Without highquality evidence about overdiagnosis, psychosocial consequences, and cost-effectiveness, we believe that any recommendation about LDCT screening is premature. John Brodersen, MD, GP, PhD Jakob Fraes Rasmussen, MD Bruno Heleno, MD, GP University of Copenhagen Copenhagen, Denmark Potential Conflicts of Interest: None disclosed. Forms can be viewed at
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽L13-1112. References 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;159:411-20. [PMID: 23897166] 2. Moyer VA; U.S. Preventive Services Task Force. Screening for Lung Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2013. [PMID: 24378917] [Epub ahead of print] 3. Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, et al; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409. [PMID: 21714641] 4. Oken MM, Hocking WG, Kvale PA, Andriole GL, Buys SS, Church TR, et al; PLCO Project Team. Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial. JAMA. 2011;306: 1865-73. [PMID: 22031728] 5. 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;92:1308-16. [PMID: 10944552] 6. Brodersen J, Thorsen H, Kreiner S. Consequences of screening in lung cancer: development and dimensionality of a questionnaire. Value Health. 2010;13:601-12. [PMID: 20345552] 7. 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;2:e000663. [PMID: 22382119] 8. Hestbech MS, Siersma V, Dirksen A, Pedersen JH, Brodersen J. Participation bias in a randomised trial of screening for lung cancer. Lung Cancer. 2011;73:325-31. [PMID: 21324544]
TO THE EDITOR: In their review, Humphrey and colleagues (1) stated that follow-up was insufficient and unequal to evaluate the degree of overdiagnosis in 3 European randomized, controlled trials and that the allocation in the DLCST was unclear. As representatives of that study, we present further clarifying information. We agree that the follow-up of the DLCST (and the 2 other European trials) is currently insufficient to assess the effect on mortality and the level of overdiagnosis. However, for mortality and cancer incidence, the follow-up in the screening and control groups was equal. As our status paper after 5 annual screening rounds stated, “the latest follow-up for both groups was set as end of screening, 31 March 2010” (2). © 2014 American College of Physicians 211
Downloaded From: http://annals.org/ by a Penn State University Hershey User on 04/16/2015
Letters Allocation in the DLCST was described for the first time in our article that reported on the prevalence round, which stated, “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” (3). Later, in our article that included all 5 screening rounds, we explained, “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)” (2). We would have been happy to clarify any matter about allocation concealment if Humphrey and colleagues had contacted us. The participants in the DLCST were randomly assigned by a centrally held, computer-generated list (random permuted blocks of 10 participants). Allocation concealment was ensured because the computer application did not release the randomization code until a participant had been recruited into the trial, which occurred after eligibility was checked and informed consent was provided. During the recruitment period (October 2004 to March 2006), the investigators involved in recruitment were unaware that the randomized list contained random permuted blocks and thus could not guess the next allocation in the sequence. John Brodersen, MD, GP, PhD University of Copenhagen Copenhagen, Denmark
tain magnitude. We do not believe that the Mayo Lung Project provides a valid estimate of overdiagnosis for many reasons, most of which we outlined in our report (1) and the prior review (2). More research in this important area is needed. We rated the quality of the DLCST as moderate. Limitations that we identified included a lack of description of allocation concealment, as Drs. Brodersen, Dirksen, and Pedersen note. They state that patients were randomly assigned at their first visit. Allocation concealment was not described, only that patients were randomly assigned in block permutation form (3). In general, we rely on information in publications to evaluate trial quality. Furthermore, Saghir and associates note unequal follow-up in the DLCST when they state, “Information on lung cancer in the control group is not as up to date as in the screening group” (4). As we state in our review, we strongly agree that more research in psychosocial outcomes will be important to aid individual decision making for persons considering LDCT screening for lung cancer. Please also note that we do not make recommendations about screening. These are made by the U.S. Preventive Services Task Force based on the systematic review that we prepare. Linda L. Humphrey, MD, MPH Mark Deffebach, MD Portland Veterans Affairs Medical Center Portland, Oregon
Asger Dirksen, MD, DrMSci Gentofte University Hospital Copenhagen, Denmark
Miranda Pappas, MA Bernadette Zakher, MBBS Oregon Health & Science University Portland, Oregon
Jesper Holst Pedersen, MD, DrMSci Rigshospitalet Copenhagen, Denmark
Christopher G. Slatore, MD, MS Portland Veterans Affairs Medical Center Portland, Oregon
Potential Conflicts of Interest: None disclosed. Forms can be viewed at
Potential Conflicts of Interest: Disclosures can be viewed at www .acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽M13-1080.
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽L13-1113.
References References 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;159:411-20. [PMID: 23897166] 2. 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;67:296-301. [PMID: 22286927] 3. Pedersen JH, Ashraf H, Dirksen A, Bach K, Hansen H, Toennesen P, et al. The Danish randomized lung cancer CT screening trial—overall design and results of the prevalence round. J Thorac Oncol. 2009;4:608-14. [PMID: 19357536]
IN RESPONSE: As we noted in our article and the associated system-
atic review, overdiagnosis is a risk of lung cancer screening of uncer-
1. Humphrey L, Deffebach M, Pappas M, Baumann C, Artis K, Mitchell JP, et al, eds. Screening for Lung Cancer: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation. Report no. 13-05188-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2013. 2. Humphrey LL, Teutsch S, Johnson M; U. S. Preventive Services Task Force. Lung cancer screening with sputum cytologic examination, chest radiography, and computed tomography: an update for the U.S. Preventive Services Task Force. Ann Intern Med. 2004;140:740-53. [PMID: 15126259] 3. Pedersen JH, Ashraf H, Dirksen A, Bach K, Hansen H, Toennesen P, et al. The Danish randomized lung cancer CT screening trial—overall design and results of the prevalence round. J Thorac Oncol. 2009;4:608-14. [PMID: 19357536] 4. 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;67:296-301. [PMID: 22286927]
212 4 February 2014 Annals of Internal Medicine Volume 160 • Number 3
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