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Figure.  Lung Cancer Incidence in the Danish Lung Cancer Screening Trial
Lung Cancer Incidence in the Danish Lung Cancer Screening Trial
1.
Pedersen  JH, Ashraf  H, Dirksen  A,  et al.  The Danish randomized lung cancer CT screening trial: overall design and results of the prevalence round.  J Thorac Oncol. 2009;4(5):608-614. doi:10.1097/JTO.0b013e3181a0d98fPubMedGoogle ScholarCrossref
2.
Saghir  Z, Dirksen  A, Ashraf  H,  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. doi:10.1136/thoraxjnl-2011-200736PubMedGoogle ScholarCrossref
3.
Wille  MMW, 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. 2016;193(5):542-551. doi:10.1164/rccm.201505-1040OCPubMedGoogle ScholarCrossref
4.
Welch  HG, Black  WC.  Overdiagnosis in cancer.  J Natl Cancer Inst. 2010;102(9):605-613. doi:10.1093/jnci/djq099PubMedGoogle ScholarCrossref
5.
Patz  EF  Jr, Pinsky  P, Gatsonis  C,  et al; NLST Overdiagnosis Manuscript Writing Team.  Overdiagnosis in low-dose computed tomography screening for lung cancer.  JAMA Intern Med. 2014;174(2):269-274. doi:10.1001/jamainternmed.2013.12738PubMedGoogle ScholarCrossref
6.
Paci  E, Puliti  D, Lopes Pegna  A,  et al.  Mortality, survival, and incidence rates in the ITALUNG randomised lung cancer screening trial.  Thorax. 2017;72(9):825-831. doi:10.1136/thoraxjnl-2016-209825Google ScholarCrossref
1 Comment for this article
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We can learn from the breast cancer experience
Stephen Hunt, MTR, MD, PhD | University of Pennsylvnia
We can learn a lot from our prior experience with breast cancer. There is no doubt that screening will save lives. But like everything else in life, it comes at some cost. That cost is not only the cost of screening, but also the cost of overdiagnosis. In breast cancer, this estimate is 15-35%, depending on which estimate you choose to believe. What that means is, 15-30% of people diagnosed with breast cancer would never have had that cancer affect their life trajectory. They would have died of heart disease, stroke, accident, or some other of a plethora of ways to die. In the absence of being able to separate the "indolent" from the "killers", which  can never be done completely as we cannot predict which folks will die of the other causes, we screen on regardless of the overdiagnosis rate. On the other hand, it is incumbent on us to inform the patient of the risk of the procedure, both in terms of the screening itself, as well as the subsequent biopsies, unnecessary chemotherapy, radiation, ablation or surgical resection. As someone who biopsies and ablates these cancers every day, I have had my fair share of patients who have had serious complications from the procedures, including death. That is the price of screening. Let us not kid ourselves otherwise. Despite all of those real and known risks of screening, screening will save lives. What I predict, just as occurred in breast cancer, is the rise in lung cancer diagnoses will spur a shift in treatment away from more invasive treatments such as lobectomy and resection, and toward more minimally invasive treatment modalities such as percutaneous ablation and radiation. In breast cancer, the switch came from mastectomy to the majority of patients today receiving lumpectomy and radiation instead, with adjuvant chemotherapy for the high risk patient subset. Mastectomy is now reserved for advanced cases or more aggressive subtypes (BRCA, etc...). The same will hold true for lung cancer. Already, many of the patient's whose lung cancers I ablate, whether in their lung, in their liver, in their adrenal, in their kidney or in their bone, are patients who have already received surgery and chemotherapy and radiation, and still have recurred. Ablation will come to be the first line therapy it deserves to be, as it offers the chance for a cure at far less morbidity and risk. 

CONFLICT OF INTEREST: None Reported
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Research Letter
Less Is More
October 2018

Estimation of Overdiagnosis of Lung Cancer in Low-Dose Computed Tomography Screening: A Secondary Analysis of the Danish Lung Cancer Screening Trial

Author Affiliations
  • 1The Research Unit for General Practice, Section of General Practice, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
  • 2Chronic Diseases Research Centre, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, Lisbon, Portugal
  • 3Primary Healthcare Research Unit, Region Zealand, Denmark
JAMA Intern Med. 2018;178(10):1420-1422. doi:10.1001/jamainternmed.2018.3056

There is uncertainty about the extent of overdiagnosis in lung cancer screening with computed tomography (CT). The National Lung Cancer Screening Trial (NLST) estimated that 18.5% of the cancers detected by CT are overdiagnosed, whereas the Italian Lung Cancer Screening Trial (ITALUNG) found no evidence of overdiagnosis. This study aimed to estimate overdiagnosis of lung cancer by screening CT in the Danish Lung Cancer Screening Trial (DLCST).

Methods

This was an unplanned, post hoc analysis of the DLCST (NCT00496977).1-3 In brief, 4104 current or former smokers (≥20 pack-years; former smokers must have quit <10 years before enrollment) aged 50 to 70 years were randomized (1:1) to 5 annual low-dose CT screenings or no screening. The absolute difference in the cumulative incidence of lung cancer in the screened and control groups was assessed 5 years after the last screening round. Overdiagnosis was calculated as the ratio between this difference and the cumulative incidence of screen-detected cancers.4 Bootstrapping (4999 repetitions) was used to estimate the 95% CI. Participants and practitioners could not be masked to the intervention. Cancer status and chest CT use was documented from national registries. Patients were enrolled from October 1, 2004, to March 31, 2006, and the present analysis was performed on follow-up until April 7, 2015. Participant consent was not obtained, but the presented data are deidentified. Statistical analyses were performed using R, version 3.3.1 (R Foundation for Statistical Computing). The DLCST has been approved by the Danish Scientific Ethics Committee and the Danish Data Protection Agency.

Results

A total of 4104 current or former smokers (mean [SD] age, 57.3 [4.8] years; 55.3% male) participated in the study. Participants were comparable at baseline, adherence to screening was high, and there were few losses to follow-up.1,2 From randomization until the end of follow-up, 416 participants (20.3%) in the control group had at least 1 off-protocol chest CT: 152 participants (7.4%; 357 scans) during the trial period and 264 participants (12.9%; 807 scans) during the follow-up period. In the screened group, 338 participants (16.5%; 955 scans) had at least 1 chest CT performed during the follow-up period.

The annual lung cancer incidence rate from randomization until the end of follow-up is presented in Figure, A. At the end of follow-up, 96 participants were diagnosed with lung cancer in the screened group (64 cancers were detected by screening) vs 53 participants in the control group. There was a 2.10–percentage point (95% CI, 1.0-3.2 percentage points) increase in the absolute risk of lung cancer with low-dose CT (Figure, B). Overdiagnosis was estimated at 67.2% (95% CI, 37.1%-95.4%) of the cancers detected by screening CT.

Discussion

The estimate of overdiagnosis in the DLCST (67.2%) was different from the estimate in the NLST (18.5%; 95% CI, 5.4%-30.6%),5 and there was no overdiagnosis in the ITALUNG.6 The contamination of the control group was low: 7.4% until the end of screening and 20.3% at 5-year follow-up.

All estimates of overdiagnosis were calculated with similar methods and duration of follow-up. The most extreme estimates were found in the ITALUNG and the DLCST, which shared similar eligibility criteria and study design.1,6 Thus, the differences among the trials’ results are not adequately explained by differences in participants, interventions, or comparators.

Limitations

The main limitation of the study is the possibility of higher baseline risk of lung cancer in the screened group of the DLCST. There are 2 findings that suggest this. First, in post hoc baseline comparisons, the screened group had a 3.1–percentage point higher rate of heavy smokers and a 1–percentage point lower mean ratio of forced expiratory volume in 1 second to forced vital capacity compared with the control group.3 Second, the annual lung cancer incidence in the screened group was persistently higher. After screening stops, it takes time for the cancers that were undetectable in the last screening round to grow large enough to cause symptoms. During this time, the annual cancer incidence should be lower in the formerly screened group compared with the control group.

Conclusions

The estimate of overdiagnosis in the DLCST was larger than what has been previously reported,5,6 but the screened group could have started with a higher baseline risk of lung cancer. However, the small differences in heavy smokers and ratio of forced expiratory volume in 1 second to forced vital capacity cannot explain the 67% overdiagnosis rate. Practice should not be changed immediately; however, it is crucial that the remaining trials report their estimates of overdiagnosis because this is a critical outcome for screening participants.

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Article Information

Accepted for Publication: May 7, 2018.

Corresponding Author: Bruno Heleno, MD, PhD, Chronic Diseases Research Centre, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056 Lisbon, Portugal (bruno.heleno@nms.unl.pt).

Published Online: August 13, 2018. doi:10.1001/jamainternmed.2018.3056

Author Contributions: Dr Heleno had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Heleno.

Critical revision of the manuscript for important intellectual content: Siersma, Brodersen.

Statistical analysis: Heleno, Siersma.

Obtained funding: Brodersen.

Administrative, technical, or material support: Brodersen.

Supervision: Siersma, Brodersen.

Conflict of Interest Disclosures: None reported.

Additional Contributions: Mathilde Marie Winkler Wille, MD, PhD, Department of Respiratory Medicine, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark, and Department of Imaging, Nordsjallands Hospital, Hillerod, Denmark, contributed with the DLCST extended follow-up data acquisition and preparation and received no financial compensation. Franciska Dis Brodersen, BA, The Research Unit for General Practice, Section of General Practice, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, contributed with data acquisition and received financial compensation for her work.

References
1.
Pedersen  JH, Ashraf  H, Dirksen  A,  et al.  The Danish randomized lung cancer CT screening trial: overall design and results of the prevalence round.  J Thorac Oncol. 2009;4(5):608-614. doi:10.1097/JTO.0b013e3181a0d98fPubMedGoogle ScholarCrossref
2.
Saghir  Z, Dirksen  A, Ashraf  H,  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. doi:10.1136/thoraxjnl-2011-200736PubMedGoogle ScholarCrossref
3.
Wille  MMW, 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. 2016;193(5):542-551. doi:10.1164/rccm.201505-1040OCPubMedGoogle ScholarCrossref
4.
Welch  HG, Black  WC.  Overdiagnosis in cancer.  J Natl Cancer Inst. 2010;102(9):605-613. doi:10.1093/jnci/djq099PubMedGoogle ScholarCrossref
5.
Patz  EF  Jr, Pinsky  P, Gatsonis  C,  et al; NLST Overdiagnosis Manuscript Writing Team.  Overdiagnosis in low-dose computed tomography screening for lung cancer.  JAMA Intern Med. 2014;174(2):269-274. doi:10.1001/jamainternmed.2013.12738PubMedGoogle ScholarCrossref
6.
Paci  E, Puliti  D, Lopes Pegna  A,  et al.  Mortality, survival, and incidence rates in the ITALUNG randomised lung cancer screening trial.  Thorax. 2017;72(9):825-831. doi:10.1136/thoraxjnl-2016-209825Google ScholarCrossref
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