Lung cancer screening using low-dose computed tomography for high risk populations: Investigating effectiveness and screening program implementation considerations: An Evidence Check rapid review brokered by the Sax Institute (www.saxinstitute.org.au) for the Cancer Institute NSW
Authors: Rankin Nicole , McGregor Deborah , Donnelly Candice , Van Dort Bethany , De Abreu Lourenco Richard , Cust Anne , Stone Emily 
Published: October 2022

Background Lung cancer is the number one cause of cancer death worldwide.(1) It is the fifth most commonly diagnosed cancer in Australia (12,741 cases diagnosed in 2018) and the leading cause of cancer death.(2) The number of years of potential life lost to lung cancer in Australia is estimated to be 58,450, similar to that of colorectal and breast cancer combined.(3) While tobacco control strategies are most effective for disease prevention in the general population, early detection via low dose computed tomography (LDCT) screening in high-risk populations is a viable option for detecting asymptomatic disease in current (13%) and former (24%) Australian smokers.(4) The purpose of this Evidence Check review is to identify and analyse existing and emerging evidence for LDCT lung cancer screening in high-risk individuals to guide future program and policy planning. Evidence Check questions This review aimed to address the following questions: 1.	What is the evidence for the effectiveness of lung cancer screening for higher-risk individuals? 2.	What is the evidence of potential harms from lung cancer screening for higher-risk individuals? 3.	What are the main components of recent major lung cancer screening programs or trials? 4.	What is the cost-effectiveness of lung cancer screening programs (include studies of cost–utility)? Summary of methods The authors searched the peer-reviewed literature across three databases (MEDLINE, PsycINFO and Embase) for existing systematic reviews and original studies published between 1 January 2009 and 8 August 2019. Fifteen systematic reviews (of which 8 were contemporary) and 64 original publications met the inclusion criteria set across the four questions. Key findings Question 1: What is the evidence for the effectiveness of lung cancer screening for higher-risk individuals? There is sufficient evidence from systematic reviews and meta-analyses of combined (pooled) data from screening trials (of high-risk individuals) to indicate that LDCT examination is clinically effective in reducing lung cancer mortality. In 2011, the landmark National Lung Cancer Screening Trial (NLST, a large-scale randomised controlled trial [RCT] conducted in the US) reported a 20% (95% CI 6.8% – 26.7%; P=0.004) relative reduction in mortality among long-term heavy smokers over three rounds of annual screening. High-risk eligibility criteria was defined as people aged 55–74 years with a smoking history of ≥30 pack-years (years in which a smoker has consumed 20-plus cigarettes each day) and, for former smokers, ≥30 pack-years and have quit within the past 15 years.(5) All-cause mortality was reduced by 6.7% (95% CI, 1.2% – 13.6%; P=0.02). Initial data from the second landmark RCT, the NEderlands-Leuvens Longkanker Screenings ONderzoek (known as the NELSON trial), have found an even greater reduction of 26% (95% CI, 9% – 41%) in lung cancer mortality, with full trial results yet to be published.(6, 7) Pooled analyses, including several smaller-scale European LDCT screening trials insufficiently powered in their own right, collectively demonstrate a statistically significant reduction in lung cancer mortality (RR 0.82, 95% CI 0.73–0.91).(8) Despite the reduction in all-cause mortality found in the NLST, pooled analyses of seven trials found no statistically significant difference in all-cause mortality (RR 0.95, 95% CI 0.90–1.00).(8) However, cancer-specific mortality is currently the most relevant outcome in cancer screening trials. These seven trials demonstrated a significantly greater proportion of early stage cancers in LDCT groups compared with controls (RR 2.08, 95% CI 1.43–3.03). Thus, when considering results across mortality outcomes and early stage cancers diagnosed, LDCT screening is considered to be clinically effective. Question 2: What is the evidence of potential harms from lung cancer screening for higher-risk individuals? The harms of LDCT lung cancer screening include false positive tests and the consequences of unnecessary invasive follow-up procedures for conditions that are eventually diagnosed as benign. While LDCT screening leads to an increased frequency of invasive procedures, it does not result in greater mortality soon after an invasive procedure (in trial settings when compared with the control arm).(8) Overdiagnosis, exposure to radiation, psychological distress and an impact on quality of life are other known harms. Systematic review evidence indicates the benefits of LDCT screening are likely to outweigh the harms. The potential harms are likely to be reduced as refinements are made to LDCT screening protocols through: i) the application of risk predication models (e.g. the PLCOm2012), which enable a more accurate selection of the high-risk population through the use of specific criteria (beyond age and smoking history); ii) the use of nodule management algorithms (e.g. Lung-RADS, PanCan), which assist in the diagnostic evaluation of screen-detected nodules and cancers (e.g. more precise volumetric assessment of nodules); and, iii) more judicious selection of patients for invasive procedures. Recent evidence suggests a positive LDCT result may transiently increase psychological distress but does not have long-term adverse effects on psychological distress or health-related quality of life (HRQoL). With regards to smoking cessation, there is no evidence to suggest screening participation invokes a false sense of assurance in smokers, nor a reduction in motivation to quit. The NELSON and Danish trials found no difference in smoking cessation rates between LDCT screening and control groups. Higher net cessation rates, compared with general population, suggest those who participate in screening trials may already be motivated to quit. Question 3: What are the main components of recent major lung cancer screening programs or trials? There are no systematic reviews that capture the main components of recent major lung cancer screening trials and programs. We extracted evidence from original studies and clinical guidance documents and organised this into key groups to form a concise set of components for potential implementation of a national lung cancer screening program in Australia: 1.	Identifying the high-risk population: recruitment, eligibility, selection and referral 2.	Educating the public, people at high risk and healthcare providers; this includes creating awareness of lung cancer, the benefits and harms of LDCT screening, and shared decision-making 3.	Components necessary for health services to deliver a screening program: a.	Planning phase: e.g. human resources to coordinate the program, electronic data systems that integrate medical records information and link to an established national registry b.	Implementation phase: e.g. human and technological resources required to conduct LDCT examinations, interpretation of reports and communication of results to participants c.	Monitoring and evaluation phase: e.g. monitoring outcomes across patients, radiological reporting, compliance with established standards and a quality assurance program 4.	Data reporting and research, e.g. audit and feedback to multidisciplinary teams, reporting outcomes to enhance international research into LDCT screening 5.	Incorporation of smoking cessation interventions, e.g. specific programs designed for LDCT screening or referral to existing community or hospital-based services that deliver cessation interventions. Most original studies are single-institution evaluations that contain descriptive data about the processes required to establish and implement a high-risk population-based screening program. Across all studies there is a consistent message as to the challenges and complexities of establishing LDCT screening programs to attract people at high risk who will receive the greatest benefits from participation. With regards to smoking cessation, evidence from one systematic review indicates the optimal strategy for incorporating smoking cessation interventions into a LDCT screening program is unclear. There is widespread agreement that LDCT screening attendance presents a ‘teachable moment’ for cessation advice, especially among those people who receive a positive scan result. Smoking cessation is an area of significant research investment; for instance, eight US-based clinical trials are now underway that aim to address how best to design and deliver cessation programs within large-scale LDCT screening programs.(9) Question 4: What is the cost-effectiveness of lung cancer screening programs (include studies of cost–utility)? Assessing the value or cost-effectiveness of LDCT screening involves a complex interplay of factors including data on effectiveness and costs, and institutional context. A key input is data about the effectiveness of potential and current screening programs with respect to case detection, and the likely outcomes of treating those cases sooner (in the presence of LDCT screening) as opposed to later (in the absence of LDCT screening). Evidence about the cost-effectiveness of LDCT screening programs has been summarised in two systematic reviews. We identified a further 13 studies—five modelling studies, one discrete choice experiment and seven articles—that used a variety of methods to assess cost-effectiveness. Three modelling studies indicated LDCT screening was cost-effective in the settings of the US and Europe. Two studies—one from Australia and one from New Zealand—reported LDCT screening would not be cost-effective using NLST-like protocols. We anticipate that, following the full publication of the NELSON trial, cost-effectiveness studies will likely be updated with new data that reduce uncertainty about factors that influence modelling outcomes, including the findings of indeterminate nodules. Gaps in the evidence There is a large and accessible body of evidence as to the effectiveness (Q1) and harms (Q2) of LDCT screening for lung cancer. Nevertheless, there are significant gaps in the evidence about the program components that are required to implement an effective LDCT screening program (Q3). Questions about LDCT screening acceptability and feasibility were not explicitly included in the scope. However, as the evidence is based primarily on US programs and UK pilot studies, the relevance to the local setting requires careful consideration. The Queensland Lung Cancer Screening Study provides feasibility data about clinical aspects of LDCT screening but little about program design. The International Lung Screening Trial is still in the recruitment phase and findings are not yet available for inclusion in this Evidence Check. The Australian Population Based Screening Framework was developed to “inform decision-makers on the key issues to be considered when assessing potential screening programs in Australia”.(10) As the Framework is specific to population-based, rather than high-risk, screening programs, there is a lack of clarity about transferability of criteria. However, the Framework criteria do stipulate that a screening program must be acceptable to “important subgroups such as target participants who are from culturally and linguistically diverse backgrounds, Aboriginal and Torres Strait Islander people, people from disadvantaged groups and people with a disability”.(10) An extensive search of the literature highlighted that there is very little information about the acceptability of LDCT screening to these population groups in Australia. Yet they are part of the high-risk population.(10) There are also considerable gaps in the evidence about the cost-effectiveness of LDCT screening in different settings, including Australia. The evidence base in this area is rapidly evolving and is likely to include new data from the NELSON trial and incorporate data about the costs of targeted- and immuno-therapies as these treatments become more widely available in Australia.