Margaret McCartney: Why ask, if you ignore the answer?
BMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j1824 (Published 18 April 2017) Cite this as: BMJ 2017;357:j1824
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Many thanks for the opportunity to respond to the views of Margaret McCartney in ‘No Holds Barred’ [1].
The UK National Screening Committee opinion cited by McCartney, examining the role of low dose CT in lung cancer screening, is over 10 years old and has not been revised despite a significant body of international evidence in high ranking peer-reviewed journals. Contemporary assessment of the evidence base for lung cancer screening by US healthcare & policy makers led to the implementation of lung cancer screening in 2015, underpinned by extensive modelling & an actuarial cost-effectiveness analysis [2,3].
This evidence confirms for the first time that screening ever-smokers aged 55-74 years with low dose CT scans, compared with chest x-ray alone, reduces lung cancer mortality by at least 20% [4], and possibly by as much as 38% if smoking cessation is integrated into screening programmes [5].
This magnitude of benefit appears to be insufficient in some eyes to consider a change in Screening Committee policy for a number of purported reasons. Firstly, it has been suggested that we need to see further evidence of a mortality reduction in a non-US population. This is questionable: since the National Lung Screening Trial was published in 2011, no other randomised controlled trial has been initiated that is adequately powered to answer this question. Expert consensus at the 2016 International Association for the Study of Lung Cancer CT Screening Workshop did not envisage such a trial to ever be performed. Instead, it is argued we should wait for a meta-analysis of poorly powered European trials, that at best would migrate the evidence base from a lowly grade 1B to a cherubic grade 1A? This is perhaps not unreasonable if anyone could plausibly argue why we would expect the biology of screen detected smoking related lung cancer in ever smokers aged 55-74 to be different between the US and Europe? We are also reminded of the hazards such as false positives, overdiagnosis and radiation-induced lung cancers. Such harms have been considered less relevant in lung cancer screening in the modern era [6,7] and new data is adding to this appreciation.
In a recent issue of the British Medical Journal, Rampinelli et al reported their experience of LDCT screening using over 42,000 LDCT scans over 10 years and assessed the cumulative radiation exposure from CT and PET-CT scans and the lifetime attributable risk of cancer. They concluded that 1.5 lung cancers and 2.4 other major cancers were induced by 10 years of screening, corresponding to a risk of additional major cancer from screening of 0.05% [8].
The potential harm of overdiagnosis has been significantly over-estimated. A recent USPSTF modelling analysis estimated that LDCT screening can prevent approximately 3 lung cancer deaths per over-diagnosed case, comparing very favourably with prostate and breast where one death is prevented per 2 or 3 overdiagnosed cases [9]. In addition, we now recognise CT-pathology correlates of overdiagnosed lung cancers reflected in updated TNM and WHO classifications as ‘adenocarcinoma in-situ’ and ‘minimally invasive adenocarcinoma’, formerly ‘bronchoalveolar cell carcinoma’ [10]. These are readily recognised by LDCT scanning and can be identified and harms avoided. No other screening program possesses such a radiological marker. Of note, a recently reported LDCT screening trial from Italy showed no evidence of overdiagnosis over an adequate follow up period [11].
It is against this backdrop of a proven mortality reduction with LDCT screening and little evidence of screen related harms, and in the absence of a credible national voice to guide decision making, that we chose to devise a pragmatic, evidence-based, innovative solution to address the leading population health need in our locality while at the same time avoiding most of the harms of screening for lung cancer. This included a local lung health check, the use of a robust lung cancer risk prediction tool, and immediate community access to same-day low dose CT scanning. Positive scans were modified by the implementation of the NICE approved British Thoracic Society recommendations on the management of pulmonary nodules [12], together with important published observations from the Dutch-Belgian study of lung cancer screening (NELSON) that determined nodule size and morphology for positivity [13]. The pilot program was embedded within broader initiatives for tobacco control, and other early diagnosis initiatives that include rapid access to high quality diagnostics, increasing radical treatment rates and effective survivorship programmes that, as a whole, we expect will address the inequality that currently exists.
We asked a question of specialists from Public Health, Screening, Primary Care, Patient Advocacy, NHS Commissioning, Respiratory Medicine, Thoracic Surgery and Thoracic Oncology using decision theory [14] by designing a pilot program rooted in high quality randomised controlled evidence, and supplemented by additional evidence, clinical knowledge and expertise. The answer received was in stark contrast to the UK National Screening Committee; it was that targeted screening can effectively deliver significant health gains in line with the published literature which can be embedded within a broader lung cancer revolution, including a tough tobacco plan, across a Cancer Network. Prejudice and misinformation have not dampened an overwhelmingly positive reception from the international thoracic oncology community to this significant pilot, nor the appetite of other regions of the UK seeking to address lung cancer mortality for ever-smokers in a manner enshrined within the NHS Constitution. On current evidence [15], the views of the UK National Screening Committee lack credibility, and appear irrelevant to those asking ‘the question’. Our own evidence based conclusion is that the targeted screening of high-risk populations can save many lives, especially if linked to a radically re-energised stop-smoking initiative.
References
1. McCartney M. BMJ. 2017 Apr 18;357:j1824.
2. Pyenson BS, Henschke CI, Yankelevitz DF, Yip R, Dec E. Offering lung cancer screening to high-risk medicare beneficiaries saves lives and is cost-effective: an actuarial analysis. Am Health Drug Benefits. 2014 Aug;7(5):272-82.
3. Humphrey L, Deffebach M, Pappas M, et al. Screening for Lung Cancer: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Jul. (Evidence Syntheses, No. 105.)
4. National Lung Screening Trial Research Team., Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, Gareen IF, Gatsonis C, Marcus PM, Sicks JD.N Engl J Med. 2011 Aug 4;365(5):395-409
5. Tanner NT, Kanodra NM, Gebregziabher M, Payne E, Halbert CH, Warren GW, Egede LE, Silvestri GA. The Association between Smoking Abstinence and Mortality in the National Lung Screening Trial. Am J Respir Crit Care Med. 2016 Mar
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6. Frank L, Christodoulou E, Kazerooni EA. Radiation risk of lung cancer screening. Semin Respir Crit Care Med. 2013 Dec;34(6):738-47.
7. Mascalchi M, Mazzoni LN, Falchini M, Belli G, Picozzi G, Merlini V, Vella A,Diciotti S, Falaschi F, Lopes Pegna A, Paci E. Dose exposure in the ITALUNG trial of lung cancer screening with low-dose CT. Br J Radiol. 2012 Aug;85(1016):1134-9.
8. Rampinelli C, De Marco P, Origgi D, Maisonneuve P, Casiraghi M, Veronesi G, Spaggiari L, Bellomi M. Exposure to low dose computed tomography for lung cancer screening and risk of cancer: secondary analysis of trial data and risk-benefit analysis. BMJ. 2017 Feb 8;356:j347.
9. Independent UK Panel on Breast Cancer Screening.. The benefits and harms of breast cancer screening: an independent review. Lancet. 2012 Nov 17;380(9855):1778-86.
10. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JH, Beasley MB,Chirieac LR, Dacic S, Duhig E, Flieder DB, Geisinger K, Hirsch FR, Ishikawa Y,Kerr KM, Noguchi M, Pelosi G, Powell CA, Tsao MS, Wistuba I; WHO Panel.. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic,Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol.2015 Sep;10(9):1243-60.
11. Paci E, Puliti D, Lopes Pegna A, et al Mortality, survival and incidence rates in the ITALUNG randomised lung cancer screening trial Thorax Published Online First: 04 April 2017. doi: 10.1136/thoraxjnl-2016-209825
12. Callister ME, Baldwin DR, Akram AR, Barnard S, Cane P, Draffan J, Franks K,Gleeson F, Graham R, Malhotra P, Prokop M, Rodger K, Subesinghe M, Waller D,Woolhouse I; British Thoracic Society Pulmonary Nodule Guideline Development Group.; British Thoracic Society Standards of Care Committee.. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax. 2015 Aug;70 Suppl 2:ii1-ii54.
13. Horeweg N, van Rosmalen J, Heuvelmans MA, van der Aalst CM, Vliegenthart R, Scholten ET, ten Haaf K, Nackaerts K, Lammers JW, Weenink C, Groen HJ, van Ooijen P, de Jong PA, de Bock GH, Mali W, de Koning HJ, Oudkerk M. Lung cancer probability in patients with CT-detected pulmonary nodules: a prespecified analysis of data from the NELSON trial of low-dose CT screening. Lancet Oncol.2014 Nov;15(12):1332-41.
14. Threlfall AG, Meah S, Fischer AJ, Cookson R, Rutter H, Kelly MP. The appraisal of public health interventions: the use of theory. J Public Health (Oxf). 2015 Mar;37(1):166-71.
15. https://www.macmillan.org.uk/_images/lung-health-check-manchester-report...
Competing interests: No competing interests
Dr McCartney, in her provocative full-page article in the BMJ “Why ask, if you ignore the answer”, states that “The reason most countries have hesitated to introduce lung cancer screening is the eye-wateringly high false positive rate.” This is misleading and not consistent with international consensus statements[1, 2] that have been published since the US National Lung Cancer Screening Trial (NLST) reported a 20% reduction in lung cancer mortality rate and a 6.7% reduction is all-cause mortality rate at the end of 2010 (the study was stopped 1 year earlier than planned)[3]. Instead, the international statements on low radiation dose CT (LDCT) screening provide excellent analyses of the remaining issues for implementation, most of which now have evidence-based solutions[4, 5]. There is currently an NIHR Heath Technology Assessment underway that is due to report this year[6]. Previously, a report published by the UK National Screening Committee[7], prior to the results of NLST, recommended awaiting the results of the Dutch-Belgian trial, NELSON, even though this is a much smaller trial (NLST randomised 53,454, NELSON 15,822)[8]. NELSON has provided some excellent data that has helped to design screening programmes but mortality outcomes may not be available for some time.
There is a good deal of well-informed comment on the issue of false positive rate in LDCT screening that is available to better inform readers of the BMJ. Firstly, the false positive rate depends on how false positive is defined and there are two aspects of this:
i) In NLST a positive CT was defined as one with a non-calcified pulmonary nodule ≥4mm in maximum diameter. Since publication of NLST it has become clear that smaller nodules have a very low risk of malignancy and the NELSON trial has shown that nodules ≤5mm confer no extra risk above baseline risk of lung cancer[9]. They have further demonstrated that measuring the volume of nodules offers more precise prediction of malignancy both at baseline and on follow-up imaging. These findings have been used to develop pulmonary nodule guidelines that have a higher threshold for follow up[10]. In the context of annual CT screening the threshold of nodule size can be increased, as growth can be safely assessed at the next screening round. This has led to the suggestion that nodule size threshold can be increased as far as 8mm, although this is still a subject of debate[11, 12]. If a higher nodule threshold of 7mm was applied in NLST, the false positive rate in NLST becomes 11.8%, less than half that reported.
ii) Another important consideration in the definition of a false positive rate is related to how the “positive” is likely to affect the individual. Interval imaging for a nodule with a low probability of malignancy is associated with very little chance of harm as the radiation dose of LDCT is very low and no intravenous contrast is given. Psychological harm has been shown to be transient[13]. Furthermore, smoking cessation rates are above baseline so there is likely to be some benefit. It is very different matter for subjects who are referred to the lung cancer service for further work up where higher radiation imaging is recommended (PET-CT) and if necessary a minimally invasive procedure such as lung biopsy. Thus both NELSON and the United Kingdom Screen Trial (UKLS) made the distinction between indeterminate findings and positive findings on this patient-centred basis and UKLS quoted both a false positive rate (3.6%) and an interval imaging rate (23.6% for nodules that required an additional CT at 3 months)[14]. Thus, from the patient’s perspective, the important false positive rate is low and with skilled use of protocols harm can be minimised; UKLS achieved one of the lowest benign resection rates seen in any CT screening study (10%).
Dr McCartney is critical of the various CT screening pilots that are in progress in the UK. These have arisen in part because clinicians are convinced that CT screening for lung cancer is effective and are impatient to improve the mortality from lung cancer. However, these projects are providing important information that will help in designing future national screening programmes. Especially challenging is selecting the correct subjects and encouraging them to participate. Selection of subjects requires a more sophisticated approach than that necessary for breast and colorectal screening. Since publication of NLST, there have been further publications illustrating how ineffective CT screening is in the groups at lower risk of lung cancer[15]. The number of false positives per death prevented was 64 and 65 in the highest two risk quintiles but rose to 1648 in the lowest risk quintile. Lung cancer is also twice as common in people in the most deprived socioeconomic quintile compared with the least yet those in the more deprived groups are known to be less likely to participate in screening. The screening projects are providing evidence of effectiveness of approaches such as mobile CT scanners and general practitioner approaches with, so far, variable results. Many of these projects are part of the Accelerate Coordinate and Evaluate programme[16].
It is important for a detailed evaluation of the evidence for CT screening for lung cancer, which cannot simply consist of an analysis of effect on mortality, NLST has already show both a disease specific and all-cause mortality benefit despite screening many low risk people that may have had almost no benefit. What is needed is an analysis that takes into account all we have learned after NLST about refining CT screening to ensure maximum benefit and least harm. Managing false positives and interval imaging is just one important consideration.
1. Field JK, Oudkerk M, Pedersen JH, Duffy SW: Prospects for population screening and diagnosis of lung cancer. Lancet 2013, 382:732-741.
2. Field JK, Smith RA, Aberle DR, Oudkerk M, Baldwin DR, Yankelevitz D, Pedersen JH, Swanson SJ, Travis WD, Wisbuba, II, et al: International Association for the Study of Lung Cancer Computed Tomography Screening Workshop 2011 report. Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer 2012, 7:10-19.
3. National Lung Screening Trial Research T, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, Gareen IF, Gatsonis C, Marcus PM, Sicks JD: Reduced lung-cancer mortality with low-dose computed tomographic screening. New England Journal of Medicine 2011, 365:395-409.
4. Baldwin DR, Hansell DM, Duffy SW, Field JK: Lung cancer screening with low dose computed tomography. BMJ 2014, 348:g1970.
5. Field JK, Devaraj A, Duffy SW, Baldwin DR: CT screening for lung cancer: Is the evidence strong enough? Lung Cancer 2016, 91:29-35.
6. The clinical and cost effectiveness of lung cancer screening by low dose C.T [CRD42016048530]
7. The UK NSC recommendation on Lung cancer screening in adult cigarette smokers [https://legacyscreening.phe.org.uk/lungcancer]
8. Yousaf-Khan U, van der Aalst C, de Jong PA, Heuvelmans M, Scholten E, Lammers JW, van Ooijen P, Nackaerts K, Weenink C, Groen H, et al: Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval. Thorax 2017, 72:48-56.
9. Horeweg N, van Rosmalen J, Heuvelmans MA, van der Aalst CM, Vliegenthart R, Scholten ET, ten Haaf K, Nackaerts K, Lammers JW, Weenink C, et al: Lung cancer probability in patients with CT-detected pulmonary nodules: a prespecified analysis of data from the NELSON trial of low-dose CT screening. Lancet Oncol 2014, 15:1332-1341.
10. Callister ME, Baldwin DR, Akram AR, Barnard S, Cane P, Draffan J, Franks K, Gleeson F, Graham R, Malhotra P, et al: British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax 2015, 70 Suppl 2:ii1-ii54.
11. Henschke CI, Yip R, Yankelevitz DF, Smith JP, International Early Lung Cancer Action Program I: Definition of a positive test result in computed tomography screening for lung cancer: a cohort study. Annals of Internal Medicine 2013, 158:246-252.
12. Lam S MA, Tammemagi M: Computed Tomography for Lung Cancer: What is a Positive Screen? Ann Intern Med 2013, 158:289-290.
13. Brain K, Lifford KJ, Carter B, Burke O, McRonald F, Devaraj A, Hansell DM, Baldwin D, Duffy SW, Field JK: Long-term psychosocial outcomes of low-dose CT screening: results of the UK Lung Cancer Screening randomised controlled trial. Thorax 2016, 71:996-1005.
14. Field JK, Duffy SW, Baldwin DR, Whynes DK, Devaraj A, Brain KE, Eisen T, Gosney J, Green BA, Holemans JA, 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 2016, 71:161-170.
15. Kovalchik SA, Tammemagi M, Berg CD, Caporaso NE, Riley TL, Korch M, Silvestri GA, Chaturvedi AK, Katki HA: Targeting of low-dose CT screening according to the risk of lung-cancer death. N Engl J Med 2013, 369:245-254.
16. Accelerate Coordinate Evaluate (ACE) Programme [http://www.cancerresearchuk.org/health-professional/early-diagnosis-acti...
Competing interests: No competing interests
Re: Margaret McCartney: Why ask, if you ignore the answer?
False positive breast cancer results after 10 years of mammography screening range from 33%-50% of women. [1][2][3][4][5][8][9]
All consequent overdiagnosis anxiety, depression, suicides, attempted suicides, risky behaviours, injuries, biopsies, mastectomies, irradiation, chemotherapies, lymphadenectomies, morbidity, mortality should be considered as iatrogenic, and calculated in National medical error statistics.
Thus, up to 50% of the population of mammographically screened women can be jeopardized by medical errors.
Nipple secretion cytology tests and targeted endoscopic biopsies are also used for breast cancer screening.
Even attempting to obtain combinations of first and second opinion on breast cancer pathology slides from expert pathologists with a high volume of diagnostic work, results in mistakes in 10.9% to 18.0% of patients. [6]
In a recent analysis of all available studies, cancer screening has never been shown to “save lives”. [7]
Unnecessary breast surgery is much more common than most people think.
Conclusions of the recent Swiss Medical Board report for abolishing mammographic screening are towards the right direction. [10]
References
[1] http://www.cochrane.org/CD001877/BREASTCA_screening-for-breast-cancer-wi...
[2] http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61216-1/fulltext
[3] http://www.bmj.com/content/339/bmj.b2587
[4] http://www.cancer.gov/types/breast/hp/breast-screening-pdq
[5] https://www.youtube.com/watch?v=8A9xuLmUHcQ
[6] http://www.bmj.com/content/353/bmj.i3069
[7] http://www.bmj.com/content/352/bmj.h6080
[8] http://jamanetwork.com/journals/jama/fullarticle/2040228
[9] http://annals.org/aim/article/2596394/breast-cancer-screening-denmark-co...
[10] http://www.nejm.org/doi/full/10.1056/NEJMp1401875
Competing interests: No competing interests