Lung Cancer Screening (PDQ®)–Health Professional Version

Evidence of Benefit Associated With Screening

Evidence of No Benefit Associated With Screening

Screening by Low-Dose Computed Tomography

There have been intensive efforts to improve lung cancer screening with newer technologies, including low-dose computed tomography (LDCT).[1,2] LDCT was shown to be more sensitive than chest radiography. In the Early Lung Cancer Action Project (ELCAP),[2] LDCT detected almost six times as many stage I lung cancers as chest radiography, and most of these tumors were no larger than 1 cm in diameter.

A systematic analysis [3] summarized 13 observational studies of LDCT, which included 60 to 5,201 participants and were conducted between 1993 and 2004. Some Japanese studies included nonsmokers, but the other studies were limited to current and former smokers. Variability in detection of nodules—between 3% and 51%—may be attributed to several factors:

Overall, lung cancer was diagnosed in 1.1% to 4.7% of screened participants; most of these diagnoses were early-stage disease.[3]

The National Lung Screening Trial (NLST) provided the first solid evidence that screening with LDCT can reduce lung cancer mortality risk in ever-smokers who have smoked 30 pack-years or longer and in former smokers who have quit within the past 15 years. The NLST included 33 centers across the United States. Eligible participants were between the ages of 55 years and 74 years at randomization, had a history of at least 30 pack-years of cigarette smoking, and, if former smokers, had quit within the past 15 years. A total of 53,454 individuals were enrolled; 26,722 participants were randomly assigned to receive screening with LDCT, and 26,732 participants were randomly assigned to receive screening with chest x-ray. Any noncalcified nodule found with LDCT that measured at least 4 mm in any diameter and any noncalcified nodule or mass identified on x-ray images were classified as positive. Radiologists, however, had the option of calling a final screen negative if a noncalcified nodule had been stable on the three screening exams. The LDCT group had a substantially higher rate of positive screening tests than did the radiography group (round 1, 27.3% vs. 9.2%; round 2, 27.9% vs. 6.2%; and round 3, 16.8% vs. 5.0%). Overall, 39.1% of participants in the LDCT group and 16.0% in the radiography group had at least one positive screening result. Of those who screened positive, the proportion with lung cancer (i.e., positive predictive value) was 3.6% in the LDCT group and 5.5% in the radiography group.[4]

In the LDCT group, 649 cancers were diagnosed after a positive screening test, 44 after a negative screening test, and 367 among participants who either missed the screening or received the diagnosis after the completion of the screening phase. In the radiography group, 279 cancers were diagnosed after a positive screening test, 137 after a negative screening test, and 525 among participants who either missed the screening or received the diagnosis after the completion of the screening phase. Three hundred fifty-six deaths from lung cancer occurred in the LDCT group, and 443 deaths from lung cancer occurred in the chest x-ray group; the relative reduction in the rate of death from lung cancer was 20% (95% confidence interval [CI], 6.8%–26.7%) with LDCT screening at a median duration of follow-up of 6.5 years.[4] An updated analysis showed that the estimated reduction in lung cancer mortality was 16% (95% CI, 5%–25%).[5] Overall, mortality was reduced by 6.7% (95% CI, 1.2%–13.6%). The number needed to screen with LDCT to prevent one death from lung cancer was 320.[4]

An extended follow-up analysis of the NLST reported mortality data after a median of 12.3 years of follow-up. The estimated number needed to screen with LDCT to prevent one lung cancer death was 303.[6]

Since the publication of the results of the NLST, more has been learned about who may benefit the most from screening for lung cancer using LDCT.[7-9] One group of investigators developed an individual risk model to assess who might benefit from screening. The model used additional factors not used as inclusion criteria in the NLST, such as a history of chronic obstructive pulmonary disease, personal or family history of lung cancer, and a more detailed smoking history. More individuals would have been eligible to be screened using the trial's criteria as opposed to the inclusion criteria of the NLST without missing patients with cancer.[8] A second group performed a reanalysis of the NLST data, calculated each patient’s risk of developing lung cancer, and estimated each patient's lung cancer mortality.[9] The investigators then divided the NLST participants into five groups on the basis of risk. The number needed to screen to avoid a lung cancer death in the low-risk group was 5,276; 161 screens were needed in the high-risk group to avoid a lung cancer death. Furthermore, the number of false-positive screens decreased from 1,648 in the lowest quintile of risk to 65 in the highest-risk group. The three highest quintiles of risk accounted for 88% of the mortality reduction from screening, whereas the lowest quintile accounted for only a 1% reduction in mortality. These studies illustrate possible improvements for determining the population of patients who may benefit the most from screening, potentially reducing the number of false positives and reducing the potential harm related to the adverse events associated with their evaluation. One other benefit of calculating individual risk is the ability to incorporate the findings into a shared decision-making process so that patients can decide whether to undergo screening.[9] However, a comparison of ten models used for predicting lung cancer or lung cancer mortality risk found that four of the models were well calibrated with reasonable discrimination, but none of these models were considered superior to the others for identifying lung cancer risk among individuals who had ever smoked. Additional work is needed to address modeling weaknesses.[10]

The NELSON trial (Nederlands–Leuvens Longkanker Screenings Onderzoek) conducted in Belgium and the Netherlands examined screening for lung cancer in smokers (13,195 men, 2,594 women, and 3 unknown) with CT, using a volume criterion for positivity.[11] Participants were recruited from population registries in the two countries based on responses to questionnaires about their smoking history and other data. Those who either smoked currently or had quit for fewer than 10 years and had smoked more than 15 cigarettes a day for over 25 years or more than 10 cigarettes a day for over 30 years were eligible. Those with serious comorbidities or previous cancers were excluded. All participants were randomly assigned equally to either usual care or an initial screen and three subsequent screens at intervals of 1, 2, and 2.5 years. The screening test was LDCT, which was retrospectively analyzed by supervised software to determine nodule segmentation and volume. After a minimum follow-up of 10 years, 90% of men assigned to screening complied with each opportunity on average, with a 2.1% rate of being referred for diagnosis. These men experienced a lung cancer incidence rate of 5.58 per 1,000 person-years and a lung cancer–specific mortality rate of 2.5 per 1,000 person-years, compared with 4.91 cases and 3.3 deaths per 1,000 person-years in men assigned to usual care. The mortality rate ratio for screening was 0.76 (95% CI, 0.61–0.94).[11]

Although the NELSON study used a usual-care arm instead of a chest x-ray arm, the results are consistent with the main NLST results discussed above, both in the impact on lung cancer mortality and in overdiagnosis. The mortality results were even more similar when the NELSON cohort was constrained to the NLST smoking eligibility subgroup. The two studies diverged in several ways, however. The NLST observed an all-cause mortality reduction consistent with the dominant effect of lung cancer on mortality among smokers. NELSON did not find such an effect. In addition, no healthy volunteer effect was observed in NELSON, while the NLST reported a substantial effect. However, these differences between the studies do not cast doubt on the main effect on lung cancer mortality but may invite further analyses to understand the inconsistencies better.

Other, smaller randomized clinical trials (RCTs) of LDCT that compare a nonscreening arm with LDCT are under way or are already completed in a number of countries.[12-18] These smaller trials are not powered to assess mortality as an endpoint, but there is an effort to combine the findings from these studies with the NELSON data, once the data are fully mature. These studies may also assess consistency with the NLST findings. In addition to the data gleaned from ongoing trials, data from the NLST, NELSON, and other completed trials are being analyzed to examine other important issues in lung cancer screening, including cost-effectiveness, quality of life, and whether screening would benefit individuals younger than those enrolled in the NLST and those with fewer than 30 pack-years of smoking exposure. Data from the U.S. Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial suggest that, in the absence of screening, the risk of lung cancer death for current smokers who have a smoking history of 20 to 29 pack-years is no different from that of former smokers who have quit within 15 years and have a smoking history of more than 30 pack-years (hazard ratio, 1.07; CI, 0.75–1.5).[19] Although the risk for the 20-to-29-pack-years current-smokers group is no different from that of the former-smokers group (for whom LDCT screening is recommended by the U.S. Preventive Services Task Force), the efficacy of screening is unknown in the 20-to-29-pack-years current-smokers group.[19]

[Note: A Guide has been developed to help patients and physicians assess the benefits and harms of LDCT screening for lung cancer.20]

Screening and Smoking Cessation

The target population for lung cancer screening has a high prevalence of current smokers compared with the general population. A lung cancer screening program could potentially impact the likelihood of smoking cessation, theoretically promoting cessation among those screened who have lung abnormalities detected on their screen. Conversely, screening could also be a deterrent to cessation among those with no evidence of lung abnormalities on their screen. The Danish Lung Cancer Screening Trial is a randomized trial that compared LDCT with no intervention among participants aged 50 to 70 years who had at least a 20 pack-year smoking history.[21] The proportion of participants who had quit smoking was monitored every year for 5 years of follow-up and remained virtually identical in the two groups from baseline (CT group and control group each had 23% ex-smokers) until the 5-year follow-up (43% ex-smokers in both groups). The comparison of these two randomized groups indicates that the CT screening program had zero net effect on the likelihood of smoking cessation.

Another report used data from the NLST to address the question of whether the screening result influenced the likelihood of smoking cessation.[22] The NLST compared CT with chest x-ray, and data from both arms were pooled to examine the impact of abnormal findings on the likelihood of smoking cessation. Compared with those who did not have abnormal findings, current smokers who had a screening examination that was suspicious for lung cancer (but was not lung cancer) were significantly more likely to have stopped smoking 1 year later. The associations with quitting smoking among those who had a major lung abnormality that was not suspicious for lung cancer, or those who had a minor abnormality, were weaker and not uniformly statistically significant.

A third study from the U.K. Lung Cancer Screening pilot trial of an LDCT scan found that screening was associated with a statistically significant increase in short- and long-term cessation, and this effect was greatest among those whose initial screening test was positive, warranting additional clinical investigation.[23]

The results of these studies suggest that the net impact of a CT program on smoking cessation varied,[21] but there appears to be a higher likelihood of smoking cessation among current smokers who have findings suspicious for lung cancer.[22] This is an important research area that needs to be clarified.

A meta-analysis that includes 85 RCTs published between 2010 and 2017 [24] concluded that electronic/Web-based, in-person counseling, and pharmacotherapy treatment interventions significantly increased the odds of successful smoking cessation among populations eligible for lung cancer screening.

Screening by Chest X-ray and/or Sputum Cytology

The question of lung cancer screening dates back to the 1950s, when rising lung cancer incidence and mortality rates indicated a need for intervention. In response to the emerging lung cancer problem, five studies of chest imaging, two of which were controlled, were undertaken during the 1950s and 1960s.[1-8] Two studies also included sputum cytology.[1-5] The results of these studies suggested no overall benefit of screening, although design limitations prevented the studies from providing definitive evidence.

In the early 1970s, the National Cancer Institute funded the Cooperative Early Lung Cancer Detection Program,[9] which was designed to assess the ability of screening with radiologic chest imaging and sputum cytology to reduce lung cancer mortality in male smokers. The program comprised three separate randomized controlled trials (RCTs), each enrolling about 10,000 male participants aged 45 years and older who smoked at least one pack of cigarettes a day in the previous year. One study was conducted at the Mayo Clinic,[10-12] one at Johns Hopkins University,[13-15] and one at Memorial Sloan-Kettering Cancer Center.[15-18] The Hopkins and Sloan-Kettering studies employed the same design: participants randomly assigned to the intervention arm received sputum cytology every 4 months and annual chest imaging, while participants randomly assigned to the control arm received annual chest imaging. Neither study observed a reduction in lung cancer mortality with screening.[15] The two studies were interpreted as showing no benefit of frequent sputum cytology when added to an annual regimen of chest x-ray.

The design of the Mayo Clinic study (known as the Mayo Lung Project, or MLP), was different. All potential participants were screened with chest imaging and sputum cytology, and those known or suspected to have lung cancer, as well as those in poor health, were excluded. Remaining participants were randomly assigned to either an intervention arm that received chest imaging and sputum cytology every 4 months for 6 years, or to a control arm that received a one-time recommendation at trial entry to receive the same tests on an annual basis. No reduction in lung cancer mortality was observed. The MLP was interpreted in the 1970s as showing no benefit of an intense screening regimen with chest x-ray and sputum cytology.

One RCT of lung cancer screening with chest imaging was conducted in Europe in the 1970s. This Czechoslovakian study began with a prevalence screen (chest imaging and sputum cytology) of 6,364 men aged 40 to 64 years who were current smokers with a lifetime consumption of at least 150,000 cigarettes.[19,20] All participants except the 18 diagnosed with lung cancer as a result of the prevalence screen were randomly assigned to either an intervention arm or a control arm. Participants in the intervention arm received semiannual screening for 3 years. Participants in the control arm received screening during the third year only. The investigators reported 19 lung cancer deaths in the intervention arm and 13 in the control arm. They concluded that frequent screening was not necessary.

By 1990, the medical community was still unsure about the relationship between screening with chest imaging (using traditional chest x-ray) and lung cancer mortality. Although previous studies showed no benefit, findings were not definitive because of a lack of statistical power. A multiphasic trial with ample statistical power, the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial,[21] began in 1992. PLCO enrolled 154,901 participants aged 55 to 74 years, including women (50%) and never-smokers (45%). One-half of the participants were randomly assigned to screening, and the other half of them were advised to receive their usual medical care. PLCO had 90% power to detect a 20% reduction in lung cancer mortality.

The lung component of PLCO addressed the question of whether annual single-view (posterior-anterior) chest x-ray was capable of reducing lung cancer mortality as compared with usual medical care. When the study began, all participants randomly assigned to screening were invited to receive a baseline and three annual chest x-ray screens, although the protocol ultimately was changed to screen never-smokers only three times. At 13 years of follow-up, 1,213 lung cancer deaths were observed in the intervention group, compared with 1,230 lung cancer deaths in the usual-care group (mortality relative risk, 0.99; 95% confidence interval, 0.87–1.22). Subanalyses suggested no differential effect by sex or smoking status.[21]

Given the abundance and consistency of evidence, as well as the lack of benefit observed in the PLCO trial, it is appropriate to conclude that lung cancer screening with chest x-ray and/or sputum cytology, regardless of sex or smoking status, does not reduce lung cancer mortality.

Screening by Low-Dose Computed Tomography

A systematic review of the benefits and harms of computed tomography (CT) screening for lung cancer summarized 21 studies with respect to various diagnostic outcomes, although not all studies reported on all outcomes.[2] The rate of diagnostic CT imaging after a reported nodule varied from 0% to 45% of all individuals who were screened. Positron emission tomography scanning was performed in 2.5% to 5.5% of individuals who were screened. The frequency of nonsurgical biopsies or procedures ranged from 0.7% to 4.4% of individuals who were screened, with the finding of a benign result on biopsy ranging from 6% to 79%. The rate of surgical resection for screen-detected nodules was between 0.9% and 5.6% of individuals who were screened; the proportion among these with a benign result ranged from 6% to 45%.

In the NLST, most major complications were related to invasive procedures and surgeries performed on patients diagnosed with lung cancer, with a major complication rate of 11.8%. The rates of complications from the NLST may not be generalizable to a community setting; participants in the NLST were younger, better educated, and less likely to be current smokers (therefore, healthier) than the population of smokers and former smokers in the general U.S. population who would be eligible for screening. Of note, 82% of the participants were enrolled at large academic medical centers, and 76% of the participants were enrolled at National Cancer Institute–designated cancer centers. However, diagnostic follow-up did not necessarily occur at the NLST screening centers and could have been carried out in community settings. This may account for the low complication rate and surgical mortality rate (1%) found in the NLST. These findings led the multisociety position paper to strongly recommend that screening be carried out at centers with the same patient-management resources as those in the NLST.[4]

A retrospective cohort study of community practices indirectly estimated the complication rates and downstream medical costs of invasive diagnostic procedures performed for lung abnormalities identified through lung cancer screening.[5] The observed complications rates of 22.2% (in patients aged 55–64 years) and 23.8% (in patients aged 65–77 years) were more than twice that reported in the NLST (8.5%–9.8%). The mean costs of managing complications ranged from $6,320 (minor complication) to $56,845 (major complication). These data suggest that the NLST, which was conducted in the context of a controlled clinical trial, may have underestimated the potential for adverse events and high downstream costs in the community setting. Study limitations include a lack of information about patient eligibility for lung cancer screening, the fact that the diagnostic procedures were not generally performed as follow-up to screening, and the extent to which complications were affected by poorer patient health and lower quality of care. Despite limitations, these results reinforce the need for the discussion about risks, benefits, and shared decision making.[5]

Screening by Chest X-ray and/or Sputum Cytology

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about lung cancer screening. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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The preferred citation for this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Lung Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lung/hp/lung-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389268]

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