Clinical Question: 

A 67 year old patient with past medical history of DM, HTN, and HLD presented to the family medicine clinic for a routine gynecologic evaluation. Upon further questioning, she revealed a history of lung cancer that was diagnosed by her primary care doctor, via a low-dose CT scan to screen for malignancy. She was referred due to her 20 pack year smoking history. I wanted to explore the utility of low dose CT scanning in diagnosing lung cancer, decreasing mortality, and its potential harms. 

PICO Question:

Does the use of low-dose computed tomography scans as a method of screening reduce the mortality and morbidity of lung cancer, as compared to no screening? 

P	I	C	O
Adults	Lung cancer screening	No screening	Smoking cessation
Smokers	Low dose CT scan	Chest X-ray	Reduced mortality
Asymptomatic adults

Database Search:

Pubmed

Search Criteria: low dose ct screening for lung cancer

Filters: free full text, last 10 years, clinical trial, meta-analysis, RCT, systematic review

Results: 76

Science Direct

Search Criteria: low dose CT scanning AND lung cancer 

Filters: 2014-2024, review articles, English

Results: 2,191

Cochrane

Search Criteria:  lung cancer screening with low dose ct scan

Filters: 2014-2024, review articles

Results: 1

Search Strategy: I noticed that this search criteria did not yield as many results on PubMed as my usual PICO searches. Many articles were European articles, which I excluded in my final choices. I read through the titles and a few of the abstracts on the first three pages of each search engine (except for Cochrane which only yielded one result). I focused on trying to find articles with high levels of evidence and most recent findings. I also wanted to pick articles that examined the potential harms of low-dose CT scanning, as CT scans expose individuals to radiation.

Articles Chosen (4 or more) for Inclusion (please copy and paste the abstract with link):

Article 1: 

Hoffman RM, Atallah RP, Struble RD, Badgett RG. Lung Cancer Screening with Low-Dose CT: a Meta-Analysis. J Gen Intern Med. 2020;35(10):3015-3025. doi:10.1007/s11606-020-05951-7

Why I chose this article: This article answers my PICO question exactly and is an American article with a high level of evidence, as it is a meta-analysis. It also discussed the differences between the impact of screening on males and females, along with the potential harms of screening. 

Abstract

Background

Randomized controlled trials have evaluated the efficacy of low-dose CT (LDCT) lung cancer screening on lung cancer (LC) outcomes.

Objective

Meta-analyze LDCT lung cancer screening trials.

Methods

We identified studies by searching PubMed, Google Scholar, the Cochrane Registry, ClinicalTrials.gov, and reference lists from retrieved publications. We abstracted data on study design features, stage I LC diagnoses, LC and overall mortality, false positive results, harm from invasive diagnostic procedures, overdiagnosis, and significant incidental findings. We assessed study quality using the Cochrane risk-of-bias tool. We used random-effects models to calculate relative risks and assessed effect modulators with subgroup analyses and meta-regression.

Results

We identified 9 studies that enrolled 96,559 subjects. The risk of bias across studies was judged to be low. Overall, LDCT screening significantly increased the detection of stage I LC, RR = 2.93 (95% CI, 2.16–3.98), I2 = 19%, and reduced LC mortality, RR = 0.84 (95% CI, 0.75–0.93), I2 = 0%. The number needed to screen to prevent an LC death was 265. Women had a lower risk of LC death (RR = 0.69, 95% CI, 0.40–1.21) than men (RR = 0.86, 95% CI, 0.66–1.13), p value for interaction = 0.11. LDCT screening did not reduce overall mortality, RR = 0.96 (95% CI, 0.91–1.01), I2 = 0%. The pooled false positive rate was 8% (95% CI, 4–18); subjects with false positive results had < 1 in 1000 risk of major complications following invasive diagnostic procedures. The most valid estimates for overdiagnosis and significant incidental findings were 8.9% and 7.5%, respectively.

Discussion

LDCT screening significantly reduced LC mortality, though not overall mortality, with women appearing to benefit more than men. The estimated risks for false positive results, screening complications, overdiagnosis, and incidental findings were low. Long-term survival data were available only for North American and European studies limiting generalizability.

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Article 2:

Slatore CG, Baumann C, Pappas M, Humphrey LL. Smoking behaviors among patients receiving computed tomography for lung cancer screening. Systematic review in support of the U.S. preventive services task force. Ann Am Thorac Soc. 2014;11(4):619-627. doi:10.1513/AnnalsATS.201312-460OC

Why I chose this article: This article extends on the topic of my PICO question and is an American article with a high level of evidence, as it is a systematic review. I liked this article because it evaluated the impact of low-dose CT scanning, particularly whether it would alter smoking behavior or increase smoking abstinence rates. This would subsequently decrease lung cancer incidence and mortality. 

Abstract

Rationale: 

Lung cancer screening using low-dose computed tomography (LDCT) is now widely recommended for adults who are current or former heavy smokers. It is important to evaluate the impact of screening on smoking abstinence rates. 

Objective:

Among current and former smokers eligible for lung cancer screening, we sought to determine the consequence of screening with LDCT, as well as subsequent results, on smoking cessation and relapse rates. 

Evidence Review: 

We searched the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth quarter, 2012), MEDLINE (2000 to May 31, 2013), reference lists of papers, and Scopus for relevant English-language studies and systematic reviews. To evaluate the effect of LDCT screening on smoking abstinence, we included only randomized controlled trials (RCTs) involving asymptomatic adults. To evaluate the association of particular results and/or recommendations from a screening CT with smoking behaviors, we included results from RCTs as well as cohort studies. 

Measurements and Main Results: 

A total of 8,215 abstracts were reviewed. Three publications from two European RCTs and five publications from three cohort studies conducted in the United States met inclusion criteria. The process of LDCT lung cancer screening did not influence smoking behaviors. LDCT recipients with results concerning for lung cancer had higher abstinence rates than those with scans without such findings. This association may have a dose–response relationship in terms of the number of abnormal CT scans as well as the seriousness of the finding. 

Conclusions: 

Limited evidence suggests LDCT lung cancer screening itself does not influence smoking behaviors, but positive results are associated with increased abstinence. As lung cancer screening is implemented in the general population, it is very important to evaluate its association with smoking behaviors to maximize its potential as a teachable moment to encourage long term abstinence. Clinicians should consider tailoring LDCT result communication to emphasize the importance of smoking abstinence.

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Article 3:

Jonas DE, Reuland DS, Reddy SM, et al. Screening for Lung Cancer With Low-Dose Computed Tomography: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2021;325(10):971-987. doi:10.1001/jama.2021.0377

Why I chose this article: This article answers my PICO question exactly as it examines the utility of low dose CT scans on lung cancer incidence, mortality, and the harms of it. It is an American article with a high level of evidence, as it is a systematic review. I liked this article because it evaluated the potential harms of low-dose CT scanning, whether through radiation exposure or even psychosocial harms due to incidental findings and unnecessary procedures. 

Abstract

Importance: Lung cancer is the leading cause of cancer-related death in the US.

Objective: To review the evidence on screening for lung cancer with low-dose computed tomography (LDCT) to inform the US Preventive Services Task Force (USPSTF).

Data sources: MEDLINE, Cochrane Library, and trial registries through May 2019; references; experts; and literature surveillance through November 20, 2020.

Study selection: English-language studies of screening with LDCT, accuracy of LDCT, risk prediction models, or treatment for early-stage lung cancer.

Data extraction and synthesis: Dual review of abstracts, full-text articles, and study quality; qualitative synthesis of findings. Data were not pooled because of heterogeneity of populations and screening protocols.

Main outcomes and measures: Lung cancer incidence, lung cancer mortality, all-cause mortality, test accuracy, and harms.

Results: This review included 223 publications. Seven randomized clinical trials (RCTs) (N = 86 486) evaluated lung cancer screening with LDCT; the National Lung Screening Trial (NLST, N = 53 454) and Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON, N = 15 792) were the largest RCTs. Participants were more likely to benefit than the US screening-eligible population (eg, based on life expectancy). The NLST found a reduction in lung cancer mortality (incidence rate ratio [IRR], 0.85 [95% CI, 0.75-0.96]; number needed to screen [NNS] to prevent 1 lung cancer death, 323 over 6.5 years of follow-up) with 3 rounds of annual LDCT screening compared with chest radiograph for high-risk current and former smokers aged 55 to 74 years. NELSON found a reduction in lung cancer mortality (IRR, 0.75 [95% CI, 0.61-0.90]; NNS to prevent 1 lung cancer death of 130 over 10 years of follow-up) with 4 rounds of LDCT screening with increasing intervals compared with no screening for high-risk current and former smokers aged 50 to 74 years. Harms of screening included radiation-induced cancer, false-positive results leading to unnecessary tests and invasive procedures, overdiagnosis, incidental findings, and increases in distress. For every 1000 persons screened in the NLST, false-positive results led to 17 invasive procedures (number needed to harm, 59) and fewer than 1 person having a major complication. Overdiagnosis estimates varied greatly (0%-67% chance that a lung cancer was overdiagnosed). Incidental findings were common, and estimates varied widely (4.4%-40.7% of persons screened).

Conclusions and relevance: Screening high-risk persons with LDCT can reduce lung cancer mortality but also causes false-positive results leading to unnecessary tests and invasive procedures, overdiagnosis, incidental findings, increases in distress, and, rarely, radiation-induced cancers. Most studies reviewed did not use current nodule evaluation protocols, which might reduce false-positive results and invasive procedures for false-positive results.

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Article 4:

Patz EF Jr, Greco E, Gatsonis C, Pinsky P, Kramer BS, Aberle DR. Lung cancer incidence and mortality in National Lung Screening Trial participants who underwent low-dose CT prevalence screening: a retrospective cohort analysis of a randomised, multicentere, diagnostic screening trial. Lancet Oncol. 2016;17(5):590-599. doi:10.1016/S1470-2045(15)00621-X

Why I chose this article: This article answers my PICO question as it examines the utility of low dose CT scans on lung cancer incidence, mortality, after an initial negative prevalence screen. It is an article with a patient population recruited from US medical centers. I liked this article because it evaluated the potential harms of low-dose CT scanning, and explored whether it was necessary to have subsequent CT scan screenings in high-risk individuals. 

Abstract

Background: 

Annual low-dose CT screening for lung cancer has been recommended for high-risk individuals, but the necessity of yearly low-dose CT in all eligible individuals is uncertain. This study examined rates of lung cancer in National Lung Screening Trial (NLST) participants who had a negative prevalence (initial) low-dose CT screen to explore whether less frequent screening could be justified in some lower-risk subpopulations.

Methods: 

We did a retrospective cohort analysis of data from the NLST, a randomized, multicenter screening trial comparing three annual low-dose CT assessments with three annual chest radiographs for the early detection of lung cancer in high-risk, eligible individuals (aged 55-74 years with at least a 30 pack-year history of cigarette smoking, and, if a former smoker, had quit within the past 15 years), recruited from US medical centers between Aug 5, 2002, and April 26, 2004. Participants were followed up for up to 5 years after their last annual screen. For the purposes of this analysis, our cohort consisted of all NLST participants who had received a low-dose CT prevalence (T0) screen. We determined the frequency, stage, histology, study year of diagnosis, and incidence of lung cancer, as well as overall and lung cancer-specific mortality, and whether lung cancers were detected as a result of screening or within 1 year of a negative screen. We also estimated the effect on mortality if the first annual (T1) screen in participants with a negative T0 screen had not been done. The NLST is registered with ClinicalTrials.gov, number NCT00047385.

Findings: 

Our cohort consisted of 26 231 participants assigned to the low-dose CT screening group who had undergone their T0 screen. The 19 066 participants with a negative T0 screen had a lower incidence of lung cancer than did all 26 231 T0-screened participants (371·88 [95% CI 337·97-408·26] per 100 000 person-years vs 661·23 [622·07-702·21]) and had lower lung cancer-related mortality (185·82 [95% CI 162·17-211·93] per 100 000 person-years vs 277·20 [252·28-303·90]). The yield of lung cancer at the T1 screen among participants with a negative T0 screen was 0·34% (62 screen-detected cancers out of 18 121 screened participants), compared with a yield at the T0 screen among all T0-screened participants of 1·0% (267 of 26 231). We estimated that if the T1 screen had not been done in the T0 negative group, at most, an additional 28 participants in the T0 negative group would have died from lung cancer (a rise in mortality from 185·82 [95% CI 162·17-211·93] per 100 000 person-years to 212·14 [186·80-239·96]) over the course of the trial.

Interpretation: 

Participants with a negative low-dose CT prevalence screen had a lower incidence of lung cancer and lung cancer-specific mortality than did all participants who underwent a prevalence screen. Because overly frequent screening has associated harms, increasing the interval between screens in participants with a negative low-dose CT prevalence screen might be warranted.

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc)	Outcome(s) studied	Key Findings	Limitations and Biases
Richard M. Hoffman, MD, MPH;  Rami P. Atallah, MD; Roger D. Struble, MD; Robert G. Badgett, MD(2020)	Meta-analysis	– Searched on PubMed, Google Scholar, the Cochrane Registry, ClinicalTrials.gov, and reference lists from retrieved publications- Identified 9 studies with 96,559 subjects	– Primary outcomes: lung cancer specific mortality and overall mortality- Secondary outcomes: diagnosis of early stage (stage I) lung cancer and harms from screening	– LDCT screening is associated with a significant reduction of lung cancer mortality though not overall mortality. – Lung cancer screening with LDCT was associated with a significantly increased likelihood of detecting stage I lung cancer. – Lung cancer screening with LDCT significantly reduced the risk of dying from lung cancer.- Women appeared more likely to benefit from screening than men.	– Long-term mortality data were only available for studies in North America and Europe so they were not able to generalize the results based on screening of only older, high-risk current and former smokers- Socioeconomic status, genetics, tobacco use, and resource availability plays a role in lung cancer incidence and mortality. Therefore, the results may not be applicable to community practice.
Christopher G. Slatore; Christina Baumann; Miranda Pappas; Linda L. Humphrey (2014)	Systematic Review	– Searched on Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews, MEDLINE, reference lists of papers, Scopus.- Included RCTs and cohort studies of LDCT screening involving asymptomatic adults to evaluate the effect of CT screening on smoking abstinence. – A total of 8,215 abstracts were reviewed and three publications from two RCTs, five publications from three cohort studies were used.	– Primary outcome: self reported smoking behavior and impact of LDCT screening on smoking abstinence – Secondary outcome: biochemical validation	– The process of low dose CT scan screening for lung cancer did not influence smoking behaviors. However, those who had results concerning for lung cancer demonstrated higher abstinence rates in comparison to those with benign results. – Therefore, it was concluded that low dose CT scanning does not significantly impact smoking behaviors but increases abstinence in affected populations.	– They did not evaluate cost-effectiveness because the USPSTF does not consider financial obligations in its decisions. – Results may be biased because characteristics associated with the results of the CT scan are associated with abstinence. It should be evaluated whether it is the findings themselves that increase abstinence or if it is the communication strategies regarding the findings of the low dose CT scan that result in the abstinence.
Daniel E Jonas; Daniel S Reuland; Shivani M Reddy; Max Nagle; Stephen D Clark; Rachel Palmieri Weber; Chineme Enyioha; Teri L Malo; Alison T Brenner; Charli Armstrong; Manny Coker-Schwimmer; Jennifer Cook Middleton; Christiane Voisin; Russell P Harris (2021)	Systematic Review	– A total of 223 publications were included. – Two investigators reviewed titles, abstracts, and full-text articles to determine eligibility using prespecified criteria. Eligible outcomes included estimated screen-preventable lung cancer deaths or all-cause mortality, estimated screening effectiveness (ex: number needed to screen) and estimated screening harms.	– Outcomes: incidence of lung cancer, lung cancer related mortality, all-cause mortality, test accuracy and harms associated with screening for lung cancer with LDCT	– Screening high-risk adults with low dose CT scans can reduce lung cancer mortality, but contributes to false-positive results leading to unnecessary tests and invasive procedures, overdiagnosis, incidental findings, increases in distress.- There was a significant reduction in lung cancer mortality with three rounds of annual LDCT screening compared with chest radiography.- Abnormal CT scan findings increased smoking cessation and continued abstinence, however normal results did not change smoking behavior.	– This review excluded non English language articles and studies with smaller sample sizes, potentially overlooking valuable insights into the harms of screening. – Some studies lacked accuracy metrics, requiring the calculation of values from reported data, leading to potential uncertainty and variability in the results.
Edward F Patz, Jr, Erin Greco, Constantine Gatsonis, Paul Pinsky, Barnett S Kramer, and Denise R Aberle (2016).	A retrospective cohort analysis of a randomized, multicenter, diagnostic screening trial	– There were 26, 231 eligible participants in the analysis- Comparing three annual low-dose CT assessments with three annual chest radiographs for the early detection of lung cancer in high-risk, eligible individuals (aged 55–74 years with at least a 30 pack-year history of cigarette smoking, and, if a former smoker, had quit within the past 15 years), recruited from US medical centers.- Participants were followed up for up to 5 years after their last annual screen.	– Primary objective: determine if low-dose CT screening is warranted in all patients and to explore whether less frequent screening is justified in some lower risk populations.	– Findings suggest that individuals with a negative prevalence screen have a substantially decreased risk of lung cancer compared with those with a positive prevalence screen, and that annual screens might not be warranted in this group.- The incidence and mortality of lung cancer over the course of the trial was significantly less in the group with an initially negative screen than in those with a positive initial screen and significantly less than in all low-dose CT-screened participants combined.	– Further validation with data from larger screened populations and various screening programs is necessary to avoid overfitting and ensure global applicability. – The study did not directly assess the effectiveness of biennial or longer interval screening.

Conclusion(s):

Article 1: The article concludes that LDCT screening significantly increases the likelihood of detecting stage I lung cancer and reduces the risk of lung cancer mortality by 16%. The evidence supports the effectiveness of LDCT screening, particularly in diagnosing early-stage cancer. The article highlights potential gender differences in the effectiveness of LDCT screening, with women benefiting more than men.

Article 2: The article concludes that while the process of LDCT lung cancer screening itself doesn’t seem to affect smoking behaviors, individuals who receive LDCT results indicating potential lung cancer have higher rates of smoking cessation. This association may be influenced by the number and seriousness of abnormal CT findings, implying a potential dose-response relationship. 

Article 3: The article reviewed using LDCT scans to screen for lung cancer in the US. It found that while LDCT screening can reduce lung cancer deaths, it also comes with risks such as false alarms and unnecessary procedures. Additionally, they concluded that abnormal CT scan findings increased smoking cessation and continued abstinence, but normal results did not alter smoking behavior. 

Article 4: The article discussed the effectiveness and challenges of using low-dose CT scans for lung cancer screening. It was found that individuals with a negative prevalence screen had a decreased risk of lung cancer compared with those with a positive prevalence screen, suggesting that annual screening after a negative initial scan might not be necessary for all patients with low risk factors. 

Overarching Conclusion: 

The overarching conclusion from these articles is that LDCT screening for lung cancer has shown effectiveness in detecting early-stage cancer and reducing lung cancer mortality, particularly in high-risk populations such as older smokers. However, LDCT screening also presents challenges and risks, including false alarms, unnecessary procedures, and overdiagnosis. Abnormal LDCT findings can prompt smoking cessation, but further research is needed to understand the impact on smoking behaviors, especially in cases of normal results. Tailoring screening schedules using risk prediction models may help optimize the balance of benefits and risks. Overall, implementing responsible screening programs requires careful consideration of the evidence, weighing the benefits against the potential harms and costs.

Clinical Bottom Line:

Weight of the evidence 

This paper analyzes four articles, and weighs them in the following order: Article 1, Article 3, Article 2, Article 4. 

Article 1 is a meta analysis that examined 9 studies with nearly 100,000 subjects. It is a very recent article from 2020. They assessed for a low risk of bias across all studies using the Cochrane Risk of Bias tool. Additionally, the primary outcomes were lung-cancer specific mortality and overall mortality. They examined harms for screening using LDCT. One weakness of this article is that it includes only data from North American and European studies, which limit the application of results to the general population. It also fails to consider other socioeconomic factors that may contribute to lung cancer incidence and mortality rates around the world. 

Article 3 is a systematic review for the USPSTF, including 223 publications. Nearly all of the articles assessed the benefits and accuracy of screening, as well as the harms of screening, work ups, and surveillance of nodules. One weakness of this article is that they excluded non-English language articles and studies with small sample size to focus on the best evidence, however some of these smaller studies reported on the harms of screening. Additionally, some studies did not report accuracy metrics, so values were calculated from the study data which can introduce uncertainty. 

Article 2 evaluated smoking behavior as it relates to LDCT screening for lung cancer, which subsequently would decrease mortality and morbidity of lung cancer. This article included only RCTs involving asymptomatic adults to evaluate LDCT screening on smoking abstinence. One weakness of this article is that it did not adjust for important confounders, such as whether particular CT findings were associated with abstinence, or whether it was the communication strategies. Additionally, this study did not include an evaluation of costs as the USPSTF does not weigh financial considerations. However, with respect to lung cancer screening, driving up healthcare costs is of concern. 

Lastly, Article 4 is a retrospective cohort analysis of data from randomized, multicenter screening trials with high-risk individuals. This is an older article from 2016. One weakness of this article is that the cohort consisted of 26,231 participants which is a relatively smaller sample size compared to Article 1. Evidence from larger populations would be required for worldwide applicability. Additionally, this article did not examine the effectiveness of screening at longer intervals, even though it concluded that there may not be a need for continuous annual screening for high risk individuals with a negative prevalence screen. 

Magnitude of any effects

All the articles were largely unanimous in their conclusions that low dose CT scans are effective in reducing morbidity and mortality in lung cancer. Two articles also examined the effects of positive CT scan findings on smoking cessation and abstinence. Therefore, the research demonstrates a high magnitude of effect. 

Clinical significance 

Based on the results of these four articles, I think low dose CT scans are of great utility for patients with considerable smoking history and risk factors, so they should undergo screening for early detection of lung cancer. Smoking cessation and early detection are paramount in improving quality of life and prolonging life in cases of lung cancer. Further research can be conducted to clarify the interval for which patients should undergo subsequent scans after an initial negative screen. Unfortunately, the risks associated with lung cancer screening include false-positives, other invasive procedures, and psychosocial harms. Therefore, further research can be conducted that incorporates current nodule evaluation protocols to reduce false-positive results and invasive procedures for these results.