Which population group would potentially most benefit from CT screening for lung cancer?

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Note: This question was open for public comment from 19 August 2016 to 3 October 2016. This content is not part of the public consultation from 3-30 July 2017 and is therefore not open for comment.


Evidence - Population group most benefiting from CT screening

Although these guidelines do not currently recommend CT screening for lung cancer in Australia, it is possible this recommendation may change in future as more Australian-specific data is generated. The aim of this question is therefore to consider, should screening become recommended, which population stands to gain most from screening?

It is worth considering the definition of screening at this point. According to The Australian Population Based Screening Framework, population-based screening is where “a test is offered systematically to all individuals in the defined target group within a framework of agreed policy, protocols, quality management, monitoring and evaluation. A population-based screening program is an organised integrated process where all activities along the screening pathway are planned, coordinated, monitored and evaluated through a quality improvement framework. All of these activities must be resourced adequately to ensure benefits are maximised”.[1] In addition it is required that a screening program “offers more benefit than harm to the target population”.[1] On the other hand, opportunistic case-finding occurs when a test is offered to an individual without symptoms of the disease when they present to a health care practitioner for reasons unrelated to that disease.

CT screening carries potential benefit and potential harm. Although some individuals may find great comfort in knowing they have a negative screening CT scan, and others may be motivated to quit smoking on the basis of a positive CT scan, arguably the only individuals who will benefit from screening are those who harbour early-stage, curable lung cancer. All other participants are at risk of the harms of screening without any benefit. Harms include detriments to health-related quality of life, exposure to medical radiation, decreased motivation to quit smoking with negative scan results, exposure to invasive diagnostic procedures for benign lesions and even risk of death. This variable risk benefit ratio was illustrated in post hoc analysis of the NLST participants.[2] When stratified into quintiles of lung cancer risk, the ratio of false positive screening results (risk) to CT-prevented lung-cancer death (benefit) improved from 1648:1 in the lowest risk quintile to 65:1 in the highest risk quintile. Thus individuals at low risk of lung cancer are unlikely to gain any benefit from screening (i.e. early detection of occult lung cancer) but will be exposed to the harms of screening.

Eligibility criteria for NLST were age 55-74 years, current or former smokers who had smoked ≥30 pack years (20 cigarettes per day for 1 year = 1 pack year). Former smokers had to have quit less than 15 years before study entry.[3] The European screening RCTs determined eligibility based on slightly different age and smoking criteria. They mostly found prevalence lung cancer rates similar or slightly lower than NLST (Table 1). DLCST[4], MILD[5] and DANTE[6] reported no mortality benefit but lacked statistical power. In addition, all three trials accepted fewer smoking pack year history than NLST (≥30 years). Furthermore, MILD and DLCST recruited younger participants (from age 49 and 50 respectively). The estimated 10 year lung cancer risk for former smokers meeting minimum inclusion criteria were 1% for DLSCT, and less than 1% for NELSON compared to 2% in NLST.[7] Thus a population risk at least equivalent to NLST is probably mandatory to obtain the population benefit. The lower risk profile from younger participants with lighter smoking histories is reflected in lower baseline lung cancer prevalence rates (Table 1).

Lung cancer risk factors other than older age and smoking history are well recognised in the literature and might be useful additions when determining risk. Post hoc analysis of several screening trials has shed light on risk: Analysis of NLST data found weak evidence of slightly improved mortality benefit in women[8] and increased mortality reduction in African Americans[9]. Regarding age, participants ≥65years of age had higher cancer prevalence but also a higher rate of false-positive screening results.[10] DLCST found risk of death from lung cancer was associated with older age, COPD diagnosis and heavier smoking history.[11] Multivariable risk estimation in NLST showed improved cost-effectiveness and increased mortality reduction in higher risk individuals[2][12] and was more efficient than NLST criteria improving sensitivity and decreasing false-positive rates.[13][14] The UKLS[15] which used multivariable risk assessment showed slightly higher rates of prevalent lung cancer compared to other trials suggesting a higher risk group had been successfully targeted (Table 1).

Despite this suggestive evidence, there are no primary data to support mortality reduction in individuals who fall outside NLST criteria.

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Evidence summary and recommendations

Evidence summary Level References
Men and women aged 55-74 with heavy smoking histories (at least 30 pack years, current or former smokers who had quit within the prior 15 years) had reduced lung cancer mortality in a large, high quality randomised lung cancer CT screening trial. II [3], [7], [16]
Evidence-based recommendationQuestion mark transparent.png Grade
CT scans for the early detection of lung cancer in asymptomatic individuals should only be considered in those at high risk of lung cancer and who meet the following minimum criteria: aged 55-74 with heavy smoking histories (at least 30 pack years, current or former smokers who have quit within the prior 15 years).*

*See the section on population-based CT screening for more information.Available evidence is insufficient to recommend populated based CT screening.

C



Practice pointQuestion mark transparent.png

Current evidence does not support population-based screening with CT scanning.

For the asymptomatic individual at high risk for lung cancer who is considering a CT scan to detect early lung cancer, it is recommended that they discuss any potential benefits against the potential harms of a low dose CT scan with their GP.

Benefits and harms of screening

Screening benefits

Smoking cessation

Participation in lung cancer screening may prompt smokers to try and quit. Alternatively a negative scan result may give false reassurance and reduce motivation to quit. The evidence is not compelling either way. No primary data were found in the search however two systematic reviews of screening have noted limited data showing no difference or mixed results either way.[7][16]

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Screening harms

Medical radiation

No studies were identified. Systematic reviews reported dose ranges from RCTs and cohort trials of between 0.61 to 1.50mSv and cumulative dose across 4 annual screens of 6 to 7mSv.[16] Bach estimated NLST cumulative dose was ~8mSv per participant over 3 years, including both screening and diagnostic examinations.[7] The immediate potential benefit of diagnosing early lung cancer in some participants has to be weighed against the postponed potential risk of radiation-induced cancer many years later.

Over-diagnosis

The rate of over-diagnosis is uncertain.[16][7] NLST estimated the rate as 18.5% (95% CI, 5.4%–30.6%).[17]

False-positive rate

Varying definitions of what constitutes a positive scan result and difference in reporting make comparisons between RCTs difficult. FPR tends to be higher in baseline rounds. Cumulative positive scan rates were highest in NLST with an average of 24% across all three rounds and a cumulative rate of 39%. Of the positive scans, 96.4% were false positive. Most positive scans were followed with further imaging tests.[3]

Risks of major complications and death

In NLST, the risk of death following diagnostic events (including imaging) for benign nodules was 4.1 per 10,000 screened.[7] The risks of major complications following diagnostic events (including imaging) for benign nodules was 4.5 per 10,000 screened.[7] In comparison, the number needed to screen to prevent one lung cancer death in NLST was 320 (~31 deaths avoided per 10,000 screened).[3]

Anxiety, quality of life

When screening large numbers of individuals, participant reported health related quality of life (HRQoL) is an important consideration; even small decrements in HRQoL may have important implications when applied across large populations. Three RCTs reported HRQoL using generic and specific measures. Generic questionnaires allows comparison across a range of health problems, treatments and screening programs, whereas screening-specific questionnaires may be more sensitive to the impact of screening which might not be captured by generic tools.

NLST found participants with True Positive scans had worse generic HRQoL outcomes at 1 and 6 months after the first screening scan, but those with False Positive Scans or Significant Incidental Findings were similar to participants with Negative Scans at both time points.[18] NELSON assessed generic HRQoL. There were some statistically, but not clinically significant changes in HRQoL up to 6 months after baseline CT. Participants with higher levels of anxiety reported more discomfort in connection with having to wait for the results of the CT scan.[19] After 2 years follow-up, there was no significant difference between the screen and control groups. Participants with an indeterminate baseline result reported a temporary increase in lung cancer-specific distress compared to participants with a negative baseline scan, but this was no longer apparent at 2 years follow-up and an indeterminate result at the second screening round had no impact on HRQoL.[20][21] DLCST used a validated screening-specific instrument. There were statistically significant adverse HRQoL effects across all screening rounds for screen and control groups which were differentially worse in the control group. These negative effects tended to persist. Although statistically significant, a minimal clinically important difference was not defined a priori.[22][23] Evidence suggests individuals undergoing screening are at risk of negative HRQoL effects. Those most at risk are individuals diagnosed with lung cancer and individuals with pre-existing higher levels of anxiety. Positive scans may cause temporary adverse effects on HRQoL.

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References

  1. 1.0 1.1 Australian Population Health Development Principle Committee Screening Subcommittee. Population Based Screening Framework. Canberra: Commonwealth of Australia; 2008 Available from: http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/Content/lung-cancer-screening.
  2. 2.0 2.1 Kovalchik SA, Tammemagi M, Berg CD, Caporaso NE, Riley TL, Korch M, et al. Targeting of low-dose CT screening according to the risk of lung-cancer death. N Engl J Med 2013 Jul 18;369(3):245-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23863051.
  3. 3.0 3.1 3.2 3.3 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 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21714641.
  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 Apr;67(4):296-301 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22286927.
  5. Pastorino U, Rossi M, Rosato V, Marchianò A, Sverzellati N, Morosi C, et al. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev 2012 May;21(3):308-15 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22465911.
  6. Infante M, Cavuto S, Lutman FR, Passera E, Chiarenza M, Chiesa G, 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 2015 Mar 11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25760561.
  7. 7.0 7.1 7.2 7.3 7.4 7.5 7.6 Bach PB, Mirkin JN, Oliver TK, Azzoli CG, Berry DA, Brawley OW, et al. Benefits and harms of CT screening for lung cancer: a systematic review. JAMA 2012 Jun 13;307(22):2418-29 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22610500.
  8. Pinsky PF, Church TR, Izmirlian G, Kramer BS. The National Lung Screening Trial: results stratified by demographics, smoking history, and lung cancer histology. Cancer 2013 Nov 15;119(22):3976-83 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24037918.
  9. Tanner NT, Gebregziabher M, Hughes Halbert C, Payne E, Egede LE, Silvestri GA. Racial Differences in Outcomes within the National Lung Screening Trial: Implications for Widespread Implementation. Am J Respir Crit Care Med 2015 Apr 30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25928649.
  10. Pinsky PF, Gierada DS, Hocking W, Patz Jr EF, Kramer BS. National Lung Screening Trial Findings by Age: Medicare-Eligible Versus Under-65 Population. Ann Intern Med 2014 Sep 9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25199624.
  11. Wille MM, Dirksen A, Ashraf H, Saghir Z, Bach KS, Brodersen J, et al. Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-risk Profiling. Am J Respir Crit Care Med 2015 Oct 20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26485620.
  12. Black WC, Gareen IF, Soneji SS, Sicks JD, Keeler EB, Aberle DR, et al. Cost-effectiveness of CT screening in the National Lung Screening Trial. N Engl J Med 2014 Nov 6;371(19):1793-802 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25372087.
  13. Tammemägi MC, Church TR, Hocking WG, Silvestri GA, Kvale PA, Riley TL, et al. Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts. PLoS Med 2014 Dec;11(12):e1001764 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25460915.
  14. Tammemägi MC, Katki HA, Hocking WG, Church TR, Caporaso N, Kvale PA, et al. Selection criteria for lung-cancer screening. N Engl J Med 2013 Feb 21;368(8):728-36 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23425165.
  15. Field JK, Duffy SW, Baldwin DR, Whynes DK, Devaraj A, Brain KE, et al. UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening. Thorax 2015 Dec 8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26645413.
  16. 16.0 16.1 16.2 16.3 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 US Preventive services task force recommendation. Ann Intern Med 2013 Sep 17;159(6):411-20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23897166.
  17. Patz EF Jr, Pinsky P, Gatsonis C, Sicks JD, Kramer BS, Tammemägi MC, et al. Overdiagnosis in low-dose computed tomography screening for lung cancer. JAMA Intern Med 2014 Feb 1;174(2):269-74 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24322569.
  18. Gareen IF, Duan F, Greco EM, Snyder BS, Boiselle PM, Park ER, et al. Impact of lung cancer screening results on participant health-related quality of life and state anxiety in the National Lung Screening Trial. Cancer 2014 Nov 1;120(21):3401-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25065710.
  19. van den Bergh KA, Essink-Bot ML, Bunge EM, Scholten ET, Prokop M, van Iersel CA, et al. Impact of computed tomography screening for lung cancer on participants in a randomized controlled trial (NELSON trial). Cancer 2008 Jul 15;113(2):396-404 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18484588.
  20. van den Bergh KA, Essink-Bot ML, Borsboom GJ, Scholten ET, van Klaveren RJ, de Koning HJ. Long-term effects of lung cancer computed tomography screening on health-related quality of life: the NELSON trial. Eur Respir J 2011 Jul;38(1):154-61 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21148229.
  21. van den Bergh KA, Essink-Bot ML, Borsboom GJ, Th Scholten E, Prokop M, de Koning HJ, et al. Short-term health-related quality of life consequences in a lung cancer CT screening trial (NELSON). Br J Cancer 2010 Jan 5;102(1):27-34 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19935789.
  22. 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(2):e000663 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22382119.
  23. Rasmussen JF, Siersma V, Pedersen JH, Brodersen J. Psychosocial consequences in the Danish randomised controlled lung cancer screening trial (DLCST). Lung Cancer 2014 Nov 20 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25433982.

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Appendices


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