Lung cancer screening with low dose computed tomography (LDCT): looking back and moving forward.

Low-dose computed tomography (CT) screening was shown to reduce lung cancer-specific mortality in a large randomized trial of a high-risk population. The decision to pursue CT screening for lung cancer is a timely question raised by individuals at risk of lung cancer and by their health care practitioners. To discuss the evidence for use of chest x-rays and low-dose CT in screening for lung cancer; to describe potential benefits, harms, and uncertainties of CT screening; and to review current guidelines for CT screening. MEDLINE and the Cochrane Library were searched from 1984 to 2012. Additional citations were obtained from lists of references from select research and review articles on this topic. Evidence was graded using the American Hospital Association level of evidence guidelines. Low-dose CT screening has been associated with a 20% reduction in lung cancer mortality in a large randomized controlled trial (National Lung Screening Trial [NLST]) of a high-risk population. Mortality data have not yet been reported for 5 other randomized controlled trials, and the sample sizes were too small to detect a meaningful difference in 2 other completed trials. A major risk of CT screening is a high false-positive rate, with associated risks and costs associated with follow-up CT scans and the potential for more invasive diagnostic procedures. Published guidelines for screening indicate a consensus that screening may be indicated for individuals who meet entry criteria for the NLST, but some guidelines expand their recommendations for screening beyond these criteria. Individuals at high risk of lung cancer who meet the criteria for CT screening in published guidelines should participate in an informed and shared decision-making process by discussing the potential benefits, harms, and uncertainties of screening with their physicians.

Lung cancer is the leading cause of cancer-related deaths in Europe, with low survival rates primarily due to late-stage diagnosis. Early detection can significantly improve survival rates, but lung cancer screening is not currently implemented in Italy. Many countries have implemented lung cancer screening programs for high-risk populations, with studies showing a reduction in mortality. This review aimed to identify key areas for establishing a lung cancer screening program in Italy. A literature search was conducted in October 2022, using the PubMed and Scopus databases. Items of interest included updated evidence, approaches used in other countries, enrollment and eligibility criteria, models, cost-effectiveness studies, and smoking cessation programs. A literature search yielded 61 scientific papers, highlighting the effectiveness of low-dose computed tomography (LDCT) screening in reducing mortality among high-risk populations. The National Lung Screening Trial (NLST) in the United States demonstrated a 20% reduction in lung cancer mortality with LDCT, and other trials confirmed its potential to reduce mortality by up to 39% and detect early-stage cancers. However, false-positive results and associated harm were concerns. Economic evaluations generally supported the cost-effectiveness of LDCT screening, especially when combined with smoking cessation interventions for individuals aged 55 to 75 with a significant smoking history. Implementing a screening program in Italy requires the careful consideration of optimal strategies, population selection, result management, and the integration of smoking cessation. Resource limitations and tailored interventions for subpopulations with low-risk perception and non-adherence rates should be addressed with multidisciplinary expertise.

Rationale: Current eligibility criteria for lung cancer (LC) screening are derived from randomized controlled trials and largely based on age and smoking history. However, the individualized benefits of screening are highly variable and may be affected by the presence of coexisting comorbid disease, including diabetes mellitus (DM). Objectives: This study examines differences in screening outcomes for those with or without DM. Methods: This was a secondary analysis of 53,452 high-risk subjects from the National Lung Screening Trial and compared outcomes after screening with computed tomography (CT) or chest radiography according to DM status. Models of LC mortality were derived after adjustment, and LC rate ratios (per 1,000 person-years), including 95% confidence intervals (95% CIs), were examined according to screening arm and DM status. Results: Compared with those without DM, subjects with DM (n = 5,174; 9.7%) had twofold greater baseline prevalence of cardiovascular comorbidity (P < 0.0001), twofold greater non-LC mortality (P < 0.0001), and greater LC lethality (P = 0.02), with more later-stage lung cancer (P = 0.04). We found comparable stage shift and surgical rates favoring the CT arm in both DM and non-DM subgroups, but LC mortality was higher in the CT arm for subjects with DM (2.2% vs. 2.1%), whereas for subjects without DM, it was lower (1.6% vs. 2.0%). However, the unadjusted P value for the interaction between DM status and screening arm was not significant (P = 0.28). In a competing-risk proportional hazards model for LC mortality adjusted for relevant risk factors, the non-DM group had a significant estimated screening benefit (hazard ratio, 0.82; 95% CI, 0.72, 0.94; P = 0.003), whereas the DM group did not (hazard ratio, 1.03; 95% CI, 0.71, 1.50; P = 0.88). However, the interaction between DM status and screening arm was again not significant (P = 0.27), indicating no overall screening difference according to DM status. Conclusions: Those reporting DM experienced more advanced LC, greater LC lethality, and greater non-LC mortality, whereas the benefits of CT-based screening remain unclear. Limitations from underpowering, lack of DM severity data, and older treatment approaches may have contributed to inconclusive results, and larger studies are warranted to better examine the effects of comorbid DM on current LC screening outcomes.

Lung cancer is the most common cause of cancer death in the world, with most patients having a dismal prognosis. As many as 40 % of lung cancers are diagnosed in stage IV, with current 5-year survival rates well below 20 %. Conventional chest radiography has been historically derided as a valid screening tool for this dreaded disease. A recent National Cancer Institute-sponsored study known as the Prostate, Lung, Colorectal, and Ovarian cancer screening trial found no benefit from such screening in patients at risk. In recent years, low-dose computed tomography (LDCT) of the chest has emerged as a promising screening tool. Recent evidence from the National Lung Screening Trial (NLST) demonstrated a 20 % reduction in mortality from lung cancer in patients undergoing three rounds of LDCT screening. Opponents of lung cancer screening favor its limited use in the setting of well-designed trials claiming excessive false-positive findings, overdiagnosis, and morbidity and mortality associated with invasive testing. That notwithstanding, leading medical societies such as ASCO and ATS have positioned themselves recently in favor of screening subjects meeting the NLST criteria.

The National Lung Screening Trial (NLST) demonstrated that screening with low-dose computed tomography (LDCT) is associated with a 20% reduction in lung cancer mortality. One potential limitation of LDCT screening is overdiagnosis of slow growing and indolent cancers. In this study, peritumoral and intratumoral radiomics was used to identify a vulnerable subset of lung patients associated with poor survival outcomes. Incident lung cancer patients from the NLST were split into training and test cohorts and an external cohort of non-screen detected adenocarcinomas was used for further validation. After removing redundant and non-reproducible radiomics features, backward elimination analyses identified a single model which was subjected to Classification and Regression Tree to stratify patients into three risk-groups based on two radiomics features (NGTDM Busyness and Statistical Root Mean Square [RMS]). The final model was validated in the test cohort and the cohort of non-screen detected adenocarcinomas. Using a radio-genomics dataset, Statistical RMS was significantly associated with FOXF2 gene by both correlation and two-group analyses. Our rigorous approach generated a novel radiomics model that identified a vulnerable high-risk group of early stage patients associated with poor outcomes. These patients may require aggressive follow-up and/or adjuvant therapy to mitigate their poor outcomes.

Implementing lung cancer screening: the US experience

Low dose computed tomography (LDCT) is a viable screening tool for early lung cancer detection and mortality reduction. In practice, the success of any lung cancer screening programme will depend on successful identification of individuals at high risk in order to maximise the benefit-harm ratio. Risk prediction models incorporating multiple risk factors have been recognised as a method of identifying individuals at high risk of developing lung cancer. Identification of individuals at high risk will facilitate early diagnosis, reduce overall costs and also improve the current poor survival from lung cancer. This review summarises the current methods utilised in identifying high risk cohorts for lung cancer as proposed by the Liverpool Lung Project (LLP) risk model, Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial risk models and the prediction model for lung cancer death using quintiles. In addition, the cost-effectiveness of CT screening and future perspective for selecting high risk individuals is discussed.

Smokers with low socioeconomic status (SES) are at a higher risk for developing and dying from lung cancer due to limited access to health care services and higher smoking prevalence. In 2011, the National Lung Screening Trial (NLST) found that in patients at high risk for developing lung cancer, lung cancer screening with low-dose helical computed tomography (LDCT) resulted in a 20% reduction in mortality from lung cancer. Current smokers who undergo annual LDCT screening and quit smoking derive the greatest reduction in lung cancer mortality. Thus, providing both LDCT screening and tobacco dependence treatment to current smokers can dramatically reduce smoking-related morbidity and mortality. In this report, we summarize the Society for Research on Nicotine and Tobacco (SRNT) and the Association for the Treatment of Tobacco Use and Dependence (ATTUD) guidelines on integrating smoking cessation interventions into lung cancer screening programs. We discuss barriers, potential solutions, and ongoing research efforts on how to implement tobacco treatment within LDCT screening, particularly as it pertains to low SES populations.

BackgroundThe National Lung Screening Trial (NLST) demonstrated that annual screening with low dose CT in high-risk population was associated with reduction in lung cancer mortality. Nonetheless, the leading cause of mortality in the study was from cardiovascular diseases.PurposeTo determine whether the used machine learning automatic algorithms assessing coronary calcium score (CCS), level of liver steatosis and emphysema percentage in the lungs are good predictors of cardiovascular disease (CVD) mortality and incidence when applied on low dose CT scans.Materials and methodsThree fully automated machine learning algorithms were used to assess CCS, level of liver steatosis and emphysema percentage in the lung. The algorithms were used on low-dose computed tomography scans acquired from 12,332 participants in NLST.ResultsIn a multivariate analysis, association between the three algorithm scores and CVD mortality have shown an OR of 1.72 (p = 0.003), 2.62 (p < 0.0001) for CCS scores of 101–400 and above 400 respectively, and an OR of 1.12 (p = 0.044) for level of liver steatosis. Similar results were shown for the incidence of CVD, OR of 1.96 (p < 0.0001), 4.94 (p < 0.0001) for CCS scores of 101–400 and above 400 respectively. Also, emphysema percentage demonstrated an OR of 0.89 (p < 0.0001). Similar results are shown for univariate analyses of the algorithms.ConclusionThe three automated machine learning algorithms could help physicians to assess the incidence and risk of CVD mortality in this specific population. Application of these algorithms to existing LDCT scans can provide valuable health care information and assist in future research.

Unexpected Observations on Tumor Size and Survival in Stage IA Non-small Cell Lung Cancer

Low-dose computed tomography (LDCT) screening is effective in reducing lung cancer mortality in smokers; however, the evidence in nonsmokers is scarce. This study aimed to evaluate the participant rate and effectiveness of one-off LDCT screening for lung cancer among smokers and nonsmokers. A population-based prospective cohort study was performed to enroll participants aged between 40 and 74 years from 2013 to 2019 from 4 cities in Zhejiang Province, China. Participants who were evaluated as having a high risk of lung cancer from an established risk score model were recommended to undergo LDCT screening. Follow-up outcomes were retrieved on June 30, 2020. The uptake rate of LDCT screening for evaluated high-risk participants and the detection rate of early-stage lung cancer (stage 0-I) were calculated. The lung cancer incidence, lung cancer mortality, and all-cause mortality were compared between the screened and nonscreened groups. At baseline, 62.56% (18,818/30,079) of smokers and 6% (5483/91,455) of nonsmokers were identified as high risk (P<.001), of whom 41.9% (7885/18,818) and 66.31% (3636/5483) underwent LDCT screening (P<.001), respectively. After a median follow-up of 5.1 years, 1100 lung cancer cases and 456 all-cause death cases (116 lung cancer death cases) were traced. The proportion of early-stage lung cancer among smokers was 60.3% (173/287), which was lower than the proportion of 80.3% (476/593) among nonsmokers (P<.001). Among smokers, a higher proportion was found in the screened group (72/106, 67.9%) than the nonscreened group (56/114, 49.1%; P=.005), whereas no significance was found (42/44, 96% vs 10/12, 83%; P=.20) among nonsmokers. Compared with participants who were not screened, LDCT screening in smokers significantly increased lung cancer incidence (hazard ratio [HR] 1.39, 95% CI 1.09-1.76; P=.007) but reduced lung cancer mortality (HR 0.52, 95% CI 0.28-0.96; P=.04) and all-cause mortality (HR 0.47, 95% CI 0.32-0.69; P<.001). Among nonsmokers, no significant results were found for lung cancer incidence (P=.06), all-cause mortality (P=.89), and lung cancer mortality (P=.17). LDCT screening effectively reduces lung cancer and all-cause mortality among high-risk smokers. Further efforts to define high-risk populations and explore adequate lung cancer screening modalities for nonsmokers are needed.

The purpose of this article is to review clinical computed tomography (CT) lung screening program elements essential to safely and effectively manage the millions of Americans at high risk for lung cancer expected to enroll in lung cancer screening programs over the next 3 to 5 years. To optimize the potential net benefit of CT lung screening and facilitate medical audits benchmarked to national quality standards, radiologists should interpret these examinations using a validated structured reporting system such as Lung-RADS. Patient and physician educational outreach should be enacted to support an informed and shared decision-making process without creating barriers to screening access. Programs must integrate smoking cessation interventions to maximize the clinical efficacy and cost-effectiveness of screening. At an institutional level, budgets should account for the necessary expense of hiring and/or training qualified support staff and equipping them with information technology resources adequate to enroll and track patients accurately over decades of future screening evaluation. At a national level, planning should begin on ways to accommodate the upcoming increased demand for physician services in fields critical to the success of CT lung screening such as diagnostic radiology and thoracic surgery. Institutions with programs that follow these specifications will be well equipped to meet the significant oncoming demand for CT lung screening services and bestow clinical benefits on their patients equal to or beyond what was observed in the National Lung Screening Trial.

COMPUTED TOMOGRAPHY (CT) SCANNING, WHICH WAS introduced for imaging the head in 1972 and became widely available for imaging the rest of the body by the early 1980s, has revolutionized the practice of medicine and surgery. This technology, for which the Nobel Prize was awarded in 1979, has been used to diagnose and guide the management of diseases affecting every part of the body, improving quality of life and saving countless lives. Two articles in this issue of JAMA, however, point out the complexities involved in deciding whether to extend the use of CT scanning from diagnosis to screening and in determining whether the current use of CT scanning is appropriate or excessive. As the value of CT scanning as a diagnostic tool became clear, it was natural to consider a potential role for this technology to screen for subclinical disease amenable to early intervention. The potential benefits of such screening must, of course, be weighed against the risks and costs. The risk that the ionizing radiation exposure from medical diagnostic tests will cause cancer appears to be small but not zero. Ionizing radiation causes DNA double-strand breaks that are repaired imperfectly, potentially leading to mutations and consequent cancers. An analysis of data from 15 countries has led to the estimate that from 0.6% to 3.2% of cancer diagnosed to age 75 years may be attributable to diagnostic x-rays, including CT scans, although these calculations involved assumptions subject to considerable uncertainty. Another risk of screening is the occurrence of falsepositive findings that may lead to adverse psychological effects on patients as well as physical harm caused by diagnostic procedures undertaken to investigate the findings. Moreover, CT scans are expensive, as are the diagnostic procedures performed to evaluate abnormalities detected. In this issue of JAMA, Bach and colleagues report the results of their systematic review of randomized clinical trials (RCTs) and cohort studies addressing the benefits and risks of screening for early-stage lung cancer using low-dose CT (LDCT) scans. The authors focus on lung cancer–specific and all-cause mortality outcomes in RCTs, avoiding the mistaken inferences that can result from lead-time bias, lengthbiased sampling, and overdiagnosis with other outcomes and designs. Their review yielded only 3 RCTs from which valid inferences can be drawn concerning the effect of LDCT screening for lung cancer among current or former smokers aged 50 years or older. Of these 3 studies, the National Cancer Institute’s National Lung Screening Trial (NLST) was by far the largest and most persuasive, driving the authors’ conclusion that lung cancer mortality is reduced by LDCT screening of adults meeting the NLST entry criteria: age 55 to 74 years, current or former smokers, 30 or more pack-years, and still smoking or having done so within the past 15 years. The good news of a mortality benefit is tempered by some of the specifics. In the NLST, the number needed to screen to prevent 1 lung cancer death was 320 persons undergoing 3 annual LDCTs. Across all studies reviewed, the average rate of detecting nodules per round of screening was 20%, and more than 90% of these nodules turned out to be benign, leading to substantial follow-up testing including invasive procedures. Combining screening and follow-up diagnostic scans, the estimated mean 3-year radiation exposure of NLST participants in the screening group was 8 mSv, which Bach et al estimate would cause 1 cancer death per 2500 persons screened, although this death would likely occur many years later. The heterogeneity in nodule detection rate both among NLST sites and among the other studies reviewed by Bach et al, and the inconsistent mortality results of the 2 smaller RCTs, add a measure of uncertainty to the estimated benefit that would be obtained from broad application of LDCT screening. Nevertheless, the estimates of the benefits and risks of LDCT screening for lung cancer derived from the NLST are the best information currently available. The American College of Chest Physicians, the American Society of Clinical Oncology, and the American Thoracic Society have endorsed an evidence-based practice guideline, included as an online appendix to the article by Bach et al, rec-

Informing Patient Surveillance for the Growing Number of Survivors of Lung Cancer

Lung cancer screening with low-dose CT in Europe: strength and weakness of diverse independent screening trials