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11 September 2013

Low-dose computed tomography screening for lung cancer: results of the first screening round

Abstract

Evaluation of: National Lung Screening Trial Research Team, Church TR, Black WC, Aberle DR et al. Results of initial low-dose computed tomographic screening for lung cancer. N. Engl. J. Med. 368, 1980–1991 (2013). In 2011, the US NLST trial demonstrated that mortality from lung cancer can be reduced by using low-dose computed tomography (LDCT) screening rather than chest x-ray (CXR) screening. This paper from the US NLST research team focuses on the results of the initial round of LDCT for lung cancer. A total of 53,439 participants were included and randomly assigned to LDCT screening (n = 26,715) or CXR screening (n = 26,724). In total, 27.3% of the participants in the LDCT group and 9.2% in the CXR group had a positive screening result. As a result, 3.8% (LDCT group) and 5.7% (CXR group) of these subjects were diagnosed with lung cancer. The sensitivity (93.8%) and specificity (73.4%) for lung cancer were higher for LDCT compared with CXR screening; 73.5 and 91.3%, respectively.
In 2013, lung cancer is estimated to become the second most frequently diagnosed cancer and the most lethal cancer in both males and females [1]. Typically, lung cancer patients are diagnosed at an advanced disease stage and their survival remains poor [1]. Several lung cancer screening trials have been conducted to investigate whether early detection can reduce lung cancer-specific mortality [2–6]. In 2011, the US NLST trial demonstrated a 20% mortality reduction using low-dose computed tomography (LDCT) screening compared with chest x-ray (CXR) screening [7]. Nowadays, several prominent medical associations have recommended implementation of LDCT screening for high-risk subjects [8,9,101,102].

Methods & results

In the current paper, the NLST research team presents results of the initial screening round: screening test characteristics, diagnostic evaluation and treatment of all lung cancers diagnosed by screening or during the 1-year interval to the next screening round [10].
Asymptomatic 55–74-year-old men and women, who smoked ≥30 pack-years and were still smoking or had quit <15 years ago, met the inclusion criteria and were randomized to annual screening for 3 years using either LDCT or CXR [2,11].
LDCT screenings were performed using multidetector helical scanners of four or more channels. CXR screenings were performed using single-view postero–anterior chest radiographs obtained by conventional film or digital radiographic systems [2]. Screening images were interpreted at the screening site, without computer-assisted diagnosis [2]. LDCT screenings were classified as positive if any noncalcified nodule with a maximum axial diameter of ≥4 mm was detected. CXR screenings were classified positive if any noncalcified nodule or pulmonary mass was detected [10].
In total, 53,439 individuals were included in the trial, 52,344 (97.9%) underwent baseline screening; 98.5% in the LDCT group and 97.4% in the CXR group. The baseline screening was positive for 7191 of the 26,309 (27.3%) participants in the LDCT group and for 2387 of the 26,035 (9.2%) participants in the CXR group. Only 270 (3.8%) of individuals had lung cancer in the LDCT group, and 136 (5.7%) in the CXR group. Lung cancer was diagnosed within 1 year after a negative screening result in 18 (0.09%) participants in the LDCT group and in 49 (0.21%) of those in the CXR. Overall, a greater number of lung cancers were diagnosed in the LDCT group (1.1%) compared with in the CXR group (0.7%).
In the LDCT group, the predictive value of a positive and a negative screening result were 3.8% (95% CI: 3.4–4.3) and 99.9% (95% CI: 99.86–99.94), respectively, and the sensitivity and specificity were 93.8% (95% CI: 90.6–96.3) and 73.4% (95% CI: 2.8–73.9), respectively. In the CXR group, the predictive value was 5.8% (95% CI: 4.9–6.9) for positive screening result and 99.8% (95% CI: 99.7–99.8) for a negative result. The sensitivity was 73.5% (95% CI: 67.2–79.8) and the specificity was 91.3% (95% CI: 91.0–91.6).
Diagnostic procedures for positive screenings were performed in 90.4% of the participants in the LDCT group and in 92.7% of those in the CXR group. The majority underwent supplementary imaging studies; 81.1% in the LDCT group and 85.6% in the CXR group. A minority underwent percutaneous cytologic analysis or biopsies and bronchoscopies; 2.2 and 4.3%, in the LDCT group, respectively, and in 3.5 and 4.6% in the CXR group, respectively. Surgical procedures were performed in 4.2% (LDCT group) and 5.2% (CXR group) of patients.
Invasive diagnostic procedures for false-positive screenings included: transthoracic biopsies in 0.6% of patients in both study groups and surgical procedures in 1.3% of patients in the LDCT group and 1.1% in the CXR group. Overall, 2.2% of subjects in the LDCT group and 1.9% in the CXR group underwent an invasive diagnostic procedure for a benign nodule. This is 0.56% (in the LDCT group) and 0.16% (in the CXR group) of all screened subjects.
Furthermore, the disease stage distribution of screen-detected lung cancers was more favorable compared with incidentally detected lung cancers in both groups. In total, 48.9% of the LDCT-detected lung cancers and 30.1% (n = 40) of the CRX-detected cancers were diagnosed at disease stage IA. Diagnosis at an advanced disease stage (IIIB and IV) occurred in 23.3% of the LDCT-detected cancers and in 30.8% of the CXR-detected cancers. Furthermore, 44.0% of the LDCT-detected lung cancers were adenocarcinoma compared with 39.0% of the CXR-detected cancers. In total, 14.2% of the LDCT-detected lung cancers were bronchoalveolar carcinomas, which constituted 5.9% of the CXR-detected cancers. Small-cell lung cancers were not often diagnosed by either LDCT screening (5.6%) or CXR screening (11.0%).
Finally, 96.6 and 96.8% of the participants with lung cancer in the LDCT group and the CXR group, respectively, received treatment. In the LDCT group, treatment included surgery more often (69.2%) than in the CXR group (58.9%).

Discussion

In the current paper, the results of the first screening round of the NLST are presented. The results of the first round of the second largest randomized lung cancer computed tomography (CT) screening trial, the Dutch–Belgian NELSON trial, were published previously. An overview of the design of the two trials is presented in Table 1. Both trials have a 1-year interval after the first screening round, but the participants of the NLST were older and had smoked more than the participants in the NELSON trial (Table 1).
In both trials, adherence to baseline screening was high: 97.9% in the NLST and 95.5% in the NELSON trial [12]. Substantially more participants had a positive screening in the NLST (27.3%) than in the NELSON trial (2.6%) [12]. Of these positive screening results, 3.8% (NLST) and 35.5% (NELSON) were actually lung cancer; a true positive screening result [12]. The sensitivity for LDCT screening in the NLST was 93.8% and the specificity was 73.4%, compared with a sensitivity of 94.6% and a specificity of 98.3% in the NELSON trial [3]. The high sensitivity and moderate specificity of the NLST protocol results from the assessment of nodule size using diameter measurements and low thresholds for a positive screening (Table 1). As a result, many additional diagnostic procedures were performed for individuals without lung cancer, which bears the risk of ionizing radiation and complications, causes psychological distress and is costly. The volumetry-based protocol of the NELSON trial with more stringent referral criteria yielded the same sensitivity and a higher specificity [3,13].
The majority of the subjects with a positive LDCT screening underwent chest CT (73.3%) and a minority underwent (combined CT-) PET examinations (8.2%). In the NELSON trial, both procedures were usually performed, in addition to bronchoscopy, which was performed in only 4.3% of the screen-positive patients in the NLST. Clearly, the follow-up for positive screenings was not the same in the two trials, which may result from the difference in lung cancer probability (3.8 vs 35.5%). Fewer invasive procedures for benign nodules (0.6% of all screened individuals) were performed in the NLST than in the NELSON trial (0.9%) [12]. Suspicious nodules detected in the NLST were followed for a longer period using CT examinations before proceeding to invasive procedures. Unfortunately, no information is provided on the number of imaging procedures per person, time to diagnosis and the cumulative radiation dose.
The disease stage distribution of the LDCT-detected lung cancers was less favorable in the NLST than in the first round of the NELSON trial. In the NELSON trial 59.5% of the participants were diagnosed at disease stage IA and 12.2% at stage IIIB or IV [14]. In both trials adenocarcinoma was the dominant histological subtype (47.3% in the NELSON trial). Remarkably, more bronchoalveolar carcinomas (NELSON 2.7%) and more small-cell carcinomas (NELSON 1.4%) were detected in the NLST.
Finally, the NLST reported no significant difference in lung cancer treatment between the two groups. However, when comparing treatment that included surgery (probably curative treatment) between the groups, the difference was statistically significant (69.2% in the LDCT group vs 58.9% in the CXR group; χ2 test: p = 0.02).

Conclusion

The New England Journal of Medicine paper of the NLST research team, which proved the principle that lung cancer mortality can be reduced significantly by using LDCT examinations as a screening test, was a landmark paper [7]. The current New England Journal of Medicine paper of the NLST provides additional information on the first screening round, but will probably not have such an impact [11]. Test characteristics were not published previously, but the incidence, characteristics and treatment of lung cancers were published in 2011 for all three screening rounds combined. Nevertheless, the subjects diagnosed in the first round through LDCT screening benefited from an earlier diagnosis and treatment. A comparison of the results with a nonscreening group, such as the control arm of the NELSON trial, is required to quantify any shift in cancer stage or treatment.

Future perspective

As researchers of the NELSON trial, we were excited and encouraged by the significant mortality reduction demonstrated in the NLST in 2011. European lung cancer screening trials are getting close to their anticipated follow-up time. For the implementation of LDCT, in Europe, it will be essential to determine whether these trials confirm the substantial lung cancer mortality reduction as seen in the NLST, as well as the cost–effectiveness and the weighing of harms and benefits of LDCT screening.
Future studies need to determine optimal target populations and screening algorithms. Lung cancer risk prediction models and biomarkers may be important tools in these studies. Furthermore, the implementation of screening will require more knowledge on the organization of care, patient safety and patient preferences. To achieve this, experiences from the implementation of other cancer screening programs may be useful and possibilities for collaborations should be explored.
Table 1.  Overview of the US NLST and NELSON lung cancer screening trials.
FactorsUS NLST [2]NELSON lung screening trial [13]
Screening designLow-dose CT vs chest x-rayLow-dose CT vs no screening
Screening rounds (n)34
Length of screening interval (years)11, 2 and 2.5
Year of initiation20022003
Enrolled participants (n)53,43915,822
Definitions of screening results:
– Positive result
– Negative result

Maximal axial diameter ≥4 mm
Maximal axial diameter <4 mm

Volume >500 mm3 or volume 50–500 mm3 and VDT <400 days
Volume <50 mm3
Entry criteria:
– Age (years)
– Smoking status
– Smoking cessation
– Smoking history

55–75
Current and former smokers
<15 years ago
≥30 pack-years

50–75
Current and former smokers
<10 years ago
≥15 per day for 25 years or ≥10 per day for 30 years
The presented definitions only concern noncalcified pulmonary nodules. Subjects with calcified nodules or without nodules have a negative screening result.
CT: Computed tomography; VDT: Volume doubling time.
Executive summary
▪ Lung cancer mortality can be reduced by using low-dose computed tomography screening.
▪ The initial low-dose computed tomography screening of the US NLST trial yielded 27.3% positive screening results, and demonstrated a sensitivity of 93.8% and specificity of 73.4%.
▪ It is essential for the implementation of low-dose computed tomography screening to confirm the cost–effectiveness in another trial and to optimize the screening strategy to reduce the associated harms.

Financial & competing interests disclosure

The authors are researchers of the NELSON trial, which is supported by Zorg Onderzoek Nederland-Medische Wetenschappen (ZonMw; 22000130), KWF Kankerbestrijding (EMCR 2007-3857) and Stichting Centraal Fonds Reserves van Voormalig Vrijwillige Ziekenfondsverzekeringen (RvvZ). Roche diagnostics provided a grant for the performance of proteomics research. Siemens Germany provided four digital workstations and LungCARE for the performance of 3D measurements. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

References

1.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J. Clin. 63(1),11–30 (2013).
2.
National Lung Screening Trial Research Team, Aberle DR, Berg CD, Black WC et al. The National Lung Screening Trial: overview and study design. Radiology 258(1),243–253 (2011).
▪ Design and screening algorithm of the US NLST trial.
3.
van Klaveren RJ, Oudkerk M, Prokop M et al. Management of lung nodules detected by volume CT scanning. N. Engl. J. Med. 361(23),2221–2229 (2009).
▪▪ Results of the first two screening rounds of the NELSON trial.
4.
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 67(4),296–301 (2012).
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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),308–315 (2012).
7.
Aberle DR, Adams AM, Berg CD et al.; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med. 365(5),395–409 (2011).
▪▪ A total of 20% mortality reduction was demonstrated by using low-dose computed tomography screening compared with chest radiography screening.
8.
Wender R, Fontham ET, Barrera E Jr et al. American Cancer Society lung cancer screening guidelines. CA Cancer J. Clin. 63(2),107–117 (2013).
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Detterbeck FC, Mazzone PJ, Naidich DP, Bach PB. Screening for lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143(Suppl. 5),e78S–e92S (2013).
▪▪ Most recent American College of Chest Physicians guidelines on lung cancer screening.
10.
National Lung Screening Trial Research Team, Church TR, Black WC, Aberle DR et al. Results of initial low-dose computed tomographic screening for lung cancer. N. Engl. J. Med. 368(21),1980–1991 (2013).
▪▪ Results of the first screening round of the US NLST trial.
11.
National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD et al. Baseline characteristics of participants in the randomized national lung screening trial. J. Natl Cancer Inst. 102(23),1771–1779 (2010).
12.
Horeweg N, van der Aalst CM, Vliegenthart R et al. Volumetric computer tomography screening for lung cancer: three rounds of the NELSON trial. Eur. Respir. J. doi:10.1183/09031936.00197712 (2013) (Epub ahead of print).
▪ Screening metrics of the first three screening rounds of the NELSON trial.
13.
Xu DM, Gietema H, De Koning H et al. Nodule management protocol of the NELSON randomised lung cancer screening trial. Lung Cancer 54(2),177–184 (2006).
▪ Design and screening algorithm of the NELSON trial.
14.
Horeweg N, van der Aalst CM, Thunnissen E et al. Characteristics of lung cancers detected by computer tomography screening in the randomized NELSON trial. Am. J. Respir. Crit. Care Med. 187(8),848–854 (2013).
▪ Characteristics of the lung cancers detected in the first three screening rounds of the NELSON trial.

▪ Websites

101.
American Lung Association. Guidance on CT lung cancer screening (2012). www.lung.org/about-us/our-impact/top-stories/guidance-on-ct-lung-cancer.html (Accessed 24 June 2013)
102.
National Comprehensive Cancer Network. Lung cancer screening guideline (2012). www.nccn.org/professionals/physician_gls/f_guidelines.asp#lung_screening (Accessed 24 June 2013)

Information & Authors

Information

Published In

History

Published online: 11 September 2013

Keywords:

  1. early detection of cancer
  2. histology
  3. lung neoplasms
  4. neoplasm staging
  5. predictive value of tests
  6. tomography
  7. x-ray computed tomography

Authors

Affiliations

Nanda Horeweg* [email protected]
Department of Pulmonology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands
1Department of Public Health, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands. [email protected]
Kristiaan Nackaerts
Department of Pulmonary Medicine, University Hospital Gasthuisberg, Herestaat 49, 3000 Leuven, Belgium
Matthijs Oudkerk
4Department of Radiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Center for Medical Imaging – North East Netherlands, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
Harry J de Koning
Department of Public Health, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands

Notes

*
* Author for correspondence

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Low-dose computed tomography screening for lung cancer: results of the first screening round. (2013) Journal of Comparative Effectiveness Research. DOI: 10.2217/cer.13.57

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