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Abstract
The United States Preventive Services Task Force recommends lung cancer screening with low-dose computed tomography (LDCT) in adults of age 55 to 80 years who have a 30 pack-year smoking history and are currently smoking or have quit within the past 15 years. This recommendation is largely based on the findings of the National Lung Screening Trial. Both policy-level and clinical decision-making about LDCT screening must consider the potential benefits of screening (reduced mortality from lung cancer) and possible harms. Effective screening requires an appreciation that screening should be limited to individuals at high risk of death from lung cancer, and that the risk of harm related to false positive findings, overdiagnosis, and unnecessary invasive testing is real. A comprehensive understanding of these aspects of screening will inform appropriate implementation, with the objective that an evidence-based and systematic approach to screening will help to reduce the enormous mortality burden of lung cancer.
Lung cancer is the leading cause of cancer death worldwide. Global lung cancer incidence and mortality closely parallel each other, with an estimated 1.8 million new cases and 1.6 million deaths annually (1). This toll has been rising, particularly in developed high-income countries, where lung cancer is the third leading cause of death (2). In the United States, overall 5-year survival for lung cancer is currently 18%, in sharp contrast to breast, colon, and prostate cancers, for which 5-year survival rates are 90, 65, and nearly 100%, respectively (3). Although controversy continues to be generated about the effectiveness of screening interventions for these tumors, what is not arguable is that the majority of lung cancers are diagnosed at an advanced stage. For these patients, cure is unlikely, and few survive beyond 1–2 years. Only a minority of patients with lung cancer are diagnosed with localized disease; in the absence of screening, those diagnoses are typically made because of incidental discovery of asymptomatic lung cancers on imaging studies performed for other reasons.
In late 2013, the U.S. Preventive Services Task Force (USPSTF) revised its lung cancer screening recommendation to the following: “The USPSTF recommends annual screening for lung cancer with low-dose computed tomography in adults ages 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery” (4). The USPSTF revised recommendation is a dramatic change, and reflects the position supporting lung cancer screening by low-dose computed tomography (LDCT) endorsed by most, although not all, major medical society and advocacy group stakeholders (5). The purpose of this review is to briefly recap the evidence base relating to the potential benefit and harm of lung cancer screening by LDCT, discuss currently published lung cancer screening guidelines and statements, consider the role of lung cancer risk assessment, and anticipate barriers to the successful implementation of screening in the broader community.
In the 1960s and 1970s, several large studies were performed in the United States to evaluate the efficacy of chest radiography (CXR) in screening for lung cancer (6–9). Although these efforts were limited by the absence of a true control group that did not undergo screening, no mortality benefit was demonstrated by screening with CXR, a finding that was definitively confirmed in 2011 by the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (10). In the 1990s and 2000s, uncontrolled studies evaluating LDCT as a lung cancer screening intervention demonstrated that more cancers, and specifically more stage I cancers, could be identified by annual screening LDCT (11–14). However, mortality benefit could not be ascertained, and legitimate concern relating to overdiagnosis bias tempered enthusiasm (15).
The National Lung Screening Trial (NLST), published in 2011, is the largest of several randomized lung cancer screening studies evaluating LDCT in lung cancer screening performed around the world over the last decade or still ongoing (16). NLST enrolled 53,454 subjects ages 55–74 years, with a history at least 30 pack-years of smoking, and who were either currently smoking or had quit within the 15 years before study enrollment. Exclusion criteria included a prior history of lung cancer, chest CT performed within 18 months of enrollment, hemoptysis, and unexplained weight loss of greater than 15 pounds in the previous year. Participants were randomized to three annual screenings with either chest radiograph or LDCT. The primary end point was lung cancer mortality; the study had 90% power to detect a 20% decrease in mortality from lung cancer in the LDCT group as compared with the radiography group. In late 2010, the independent data and safety monitoring board terminated the study early, when it was determined that the primary end point had been met.
The conclusion of NLST was that screening for lung cancer by LDCT prevents some deaths from lung cancer in high-risk smokers and former smokers and specifically that the absolute risk of lung cancer death was reduced from 1.66 to 1.33%, or 3 fewer deaths per 1,000 in the LDCT group. A reduction in all-cause mortality was also observed, driven entirely by the decrease in lung cancer deaths.
A number of other randomized trials evaluating lung cancer screening by LDCT are completed or ongoing (17–24). All such trials performed screening in restricted time frames although it is unlikely that a limited duration screening strategy would be used in actual clinical practice. For example, in NLST, screening was performed over a period of 3 years—the initial baseline prevalence scan and two annual incidence scans, with subsequent follow-up over 6 years without screening.
Systematic reviews evaluating the evidence relating to the benefits and harms of LDCT screening, including both randomized and cohort studies, were performed by Bach and colleagues on behalf of the American Cancer Society (ACS), the American College of Chest Physicians (ACCP), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN), and by Humphrey and colleagues on behalf of the USPSTF (25, 26). Both reviews identified three randomized studies that were believed to provide evidence of reasonable quality on the effect of screening on lung cancer mortality: NLST, the Detection and Screening of Early Lung Cancer by Novel Imaging Technology and Molecular Essays (DANTE) trial, and the Danish Lung Cancer Screening Trial (DLCST) (16, 17, 19, 27). A fourth large study, the Nederlands-Leuven Longkanker Screenings Network (NELSON) trial, is currently ongoing in the Netherlands and Belgium (28).
Participant characteristics and lung cancer–related mortality in each of the arms in these trials are summarized in Table 1. NLST demonstrated a significant decrease in lung cancer mortality whereas DANTE and DLCST were inconclusive. There was no hint of a mortality benefit in either of the latter trials, but the wide confidence intervals do not exclude the possibility of substantial benefit or harm. Participants in DANTE and DLCST had less smoking exposure than in NLST; assuming this would result in a decreased risk of lung cancer compared with NLST, these studies would have had even less power to detect a mortality benefit.
| RCT | Subject Characteristics | LDCT Comparison | Number of Subjects Screened in LDCT Arm (Baseline) | Number of Annual Screens, Including Baseline | Mortality Events | Number Needed to Screen to Prevent One Lung Cancer Death | ||
|---|---|---|---|---|---|---|---|---|
| Number (%) | P Value | |||||||
| LDCT | Control | |||||||
| NLST | • Age: 55–74 yr | Chest radiography | 26,722 | 3 | 356 (1.3) | 443 (1.7) | 0.004 | 320 |
| • Men and women | ||||||||
| • ≥30 pack-years smoking | ||||||||
| • Currently smoking or had quit within 15 yr of enrollment | ||||||||
| • Multicenter | ||||||||
| DANTE | • Age: 60–75 yr | Chest radiography and sputum cytology at baseline | 1,276 | 5 | 20 (1.6) | 20 (1.7) | 0.83 | 954 |
| • Men only | ||||||||
| • ≥20 pack-years smoking | ||||||||
| • Currently smoking or had quit within 10 yr of enrollment | ||||||||
| • Single center | ||||||||
| DLCST | • Age: 50–70 yr | Usual care without LDCT | 2,052 | 5 | 15 (0.7) | 11 (0.5) | 0.06 | NR |
| • Men and women | ||||||||
| • ≥20 pack-years | ||||||||
| • Currently smoking or had quit after age 50 yr and within 10 yr of enrollment | ||||||||
| • Single center | ||||||||
| NELSON | • Age: 50–75 | Usual care without LDCT | Target 8,000 | Years 1, 2, 4, and 6.5 | NA | NA | NA | NA |
| • Men and women | ||||||||
| • ≥15 pack-years | ||||||||
| • Currently smoking or had quit within 10 yr of enrollment | ||||||||
| • Four screening sites | ||||||||
NLST and other randomized trials cannot address the impact of interventions beyond the scope of their study designs, including the effects of additional rounds of screening, benefits or harms beyond the study follow-up period, or outcomes related to different screening intervals or varying inclusion criteria. To address these limitations, and to inform the USPSTF recommendations, the Cancer Intervention and Surveillance Modeling Network (CISNET) was asked by the Agency for Healthcare Research and Quality to model the effect of LDCT screening in populations beyond the tight inclusion criteria of NLST (29). Five independent models were developed using individual-level data from NLST and the PLCO trial. The models estimated the effects of different screening intervals, ages at which to start and stop screening, and intensities of smoking. Five hundred and seventy-six different scenarios were considered, and estimates generated relating to benefit (defined as the percentage of cancers detected at stage I or II, percentage and absolute number of lung cancer deaths averted, and life-years gained) and harms (defined as number of CT screens per 100,000 persons, number of screenings plus follow-up imaging examinations, number of radiation-induced lung cancer deaths, and number of overdiagnosed cancers), and the number of screens that would be needed to avert one lung cancer death. Although there was considerable variation between models, eight scenarios were deemed most “efficient,” defined as preventing the greatest number of lung cancer deaths for the number of examinations required, and are outlined in Figure 1. The model that extended the age limit for screening to 80 years while maintaining the NLST smoking criteria was more efficient and resulted in the same number of screenings leading to more lung cancer deaths averted when compared with the NLST sample. Among these, the scenario that most closely approximated the NLST included individuals ages 55–80 years, who had smoked 30 pack-years, and were currently smoking or had quit within the 15 years before screening (A-55-80-30-15 in Figure 1). The models indicated that screening by LDCT in this population would result in a 14% lifetime lung cancer mortality reduction. The CISNET working group made clear that there is no single correct model. Broadening the criteria for screening and including a larger percentage of the population will result in more cancer deaths prevented, but at the cost of more screening scans per death averted. The models cannot determine which scenario is best, but the balance of benefits and harms was believed to be optimal in the population specified in the USPSTF recommendation.
Figure 1. Estimated lung cancer mortality reduction (as a percentage of total lung cancer mortality in the cohort) and life-years gained (averages of five models) from annual computed tomography (CT) screening, for programs with minimal eligibility age of 55 years and maximum of 80 years at various smoking eligibility cutoffs and National Lung Screening Trial (NLST) scenario (A-55-75-30-15). The average number of CT screening examinations (5 models) is shown on the x-axis. The graph plots the average number of CT screening examinations against the percentage reduction of lung cancer mortality (top) or life-years gained (bottom) for each screening scenario (vs. no screening) that was estimated for 100,000 individuals of the 1950 cohort followed from ages 45 to 90 years. Programs are labeled as follows: frequency–start age–stop age–minimum pack-years–maximum years since quitting smoking. The reductions in lung cancer mortality differ from the point estimate of the reduction reported at the 6.5-year follow-up in the NLST because only eligible persons are screened in this cohort analysis (dilution) and lifetime reduction in lung cancer mortality is modeled. The top panel shows the efficiency frontier for all models combined. The blue line indicates the screening efficiency frontier plot. The yellow symbol indicates the NLST. The red symbols indicate the model predictions of the effect on efficiency of expanding the smoking eligibility in the age range of 55 through 80 years beyond the criteria of the NLST. When the slope in the efficiency frontier plot levels off, the additional reductions in mortality per unit increase in use of CT screening examinations are small relative to the previous strategies. A = annual. Reproduced by permission from Reference 29.
[More] [Minimize]Despite the reduction in lung cancer–specific mortality demonstrated in NLST, generalizability to the broader U.S. population is uncertain for a number of reasons. First, the demographics of NLST participants are different from the estimated 8 million Americans who would meet NLST entry criteria. Overall, NLST participants were younger, healthier, more educated, and less likely to be current smokers (30). These differences reflect the “healthy volunteer effect” in screening trials, in which there is a self-selection of better educated, health-conscious persons with better access to medical care (31). Second, NLST participants were enrolled in urban, tertiary care hospitals with substantial lung cancer expertise, including multidisciplinary clinics and dedicated thoracic radiologists. Access to this expertise was probably important. The rate of identification of positive findings, typically small pulmonary nodules, averaged 24.2%/year, the vast majority of which were false positives (25). Although management of these positive findings was not mandated by a specific protocol, the number of subjects requiring invasive interventions was remarkably low. Whether this parsimony in invasive testing will be broadly generalizable is not certain. Concern has been raised that variation in community practice management of screen-detected solitary pulmonary nodules has the potential to lead to an increased number of invasive procedures, with inherent risk of harm. For example, in a study including more than 15,000 adults in 4 states, a 2-fold variation in the use of CT-guided lung biopsy for diagnosis of pulmonary nodules was observed. The rate of pneumothorax was 16%, with 6% requiring chest tube and 1% suffering a major hemorrhage (32). Third, although NLST allowed participants to choose their own site for evaluation of a screen-detected nodule, it is likely that many were managed at an NLST site. Eight-two percent of these sites were tertiary care centers and 76% had a National Cancer Institute designation; these settings typically have dedicated thoracic surgeons and perform high volumes of procedures, both of which are associated with better outcomes (33, 34). This may explain the superior surgical outcomes in NLST; surgical mortality in NLST subjects undergoing thoracic surgery was 1%, compared with the national average of 3–5% (34). Such differences emphasize the harm that could be incurred related to performing unnecessary procedures, or performing surgery in settings of limited institutional experience. These are real challenges, because access to specialty expertise in the broader community is not uniform. Geographic differences in care delivery patterns are well described, and patients may not be able or may not desire to travel distances to obtain tertiary care. If the number of invasive procedures performed and the surgical mortality risk are higher in the broader community than in NLST, the same benefit of lung cancer screening may not be realized.
CT imaging necessarily incurs radiation exposure, with radiation-related cancer being another source of potential harm. The typical effective radiation dose per LDCT is approximately 1.5 mSv. Radiation doses related to usual CT or positron emission tomography are higher; all may vary in practice (35, 36). The National Academy of Science Committee to Assess the Biological Effects of Ionizing Radiation (BEIR VII) consensus opinion is that the relation between low-dose radiation exposure and resulting health effects in occupational settings are linear with no threshold, and that radiation exposure is cumulative over a lifetime (37). The International Commission on Radiological Protection (ICRP) estimates that every exposure to the maximum-allowable occupational radiation dose of 50 mSv/year induces approximately 1 additional fatal cancer per year in every 500 people exposed (38). In NLST, participants received an average radiation exposure of 8 mSv over 3 years of screening, between screening and diagnostic examinations (25). Using prediction modeling and estimates of radiation harm from commissioned studies of medical imaging, Bach and colleagues estimated that approximately 1 radiation-associated cancer death would result per 2,500 people screened (25). Although this would be outweighed in the NLST population by benefit in lung cancer mortality reduction, the tradeoff would be less advantageous for younger persons or those at lower risk for developing lung cancer. Using assumptions of 2 mSv per LDCT, 8 mSv per standard CT, and Fleischner Society guidelines for duration of interval follow-up, a modeling study by McCunney and Li was done to estimate the potential worst case scenario for cumulative radiation exposure of a 55-year-old lung cancer screening participant with a new small nodule detected on LDCT requiring 2 years of radiographic follow-up (39). They assumed that three additional full-dose CT scans would be necessary with an added 24 mSv of radiation. The authors estimated that if a new nodule was detected every 2 years and monitored to conclude benignity, there would be the potential to receive a cumulative radiation exposure of 280 and 420 mSv over 20 and 30 years, respectively. This exceeds the exposure experienced by atomic bomb survivors, as well as occupational standards for nuclear industry workers, suggesting that long-term screening could independently increase the risk of lung cancer. It should be noted that the modeling did not take into account follow-up by LDCT scans or less frequent screen-detected nodules. It is important to recognize that technology to substantively decrease radiation exposure related to CT scanning while preserving imaging quality is already available; clinical application in the near future should reduce radiation exposure incurred in screening settings.
Psychological distress associated with a positive test result is another potential downside of screening. This is a particularly important issue given the high false positive rate of LDCT. Overall, 39.1% of participants in the NLST LDCT group had at least one positive screening test, with a false positive rate of 96.4% across the three rounds of screening (16). The potential for physical harm related to invasive testing has already been noted; the magnitude of psychological harm related to prolonged uncertainty and anxiety may be more difficult to measure (40–42). Although this area has not been extensively studied, research in breast and prostate cancer screening suggests that false positive screening test results may be associated with depression and a change in patient perception of overall health (43, 44).
Last, the potential for overdiagnosis should be considered with any screening test. Overdiagnosis is defined as the detection of a cancer that would not have otherwise become clinically significant; it is intrinsic to screening and is one of its downsides. Patients may undergo unnecessary diagnostic interventions and treatment, and incur morbidity, health care costs, and emotional burden for a finding that would have caused no limitation to duration or quality of life (45). That overdiagnosis exists with lung cancer screening is supported by older trials evaluating CXR as the screening intervention, in which long-term follow-up of excess cancers identified in the screened arms demonstrated no improvement in mortality (6, 46). An examination of overdiagnosis in NLST suggested that 1.38 cases of overdiagnosis would be found in the 320 participants needed to be screened to prevent 1 death (47). The model used for this study predicted that approximately 25% of nonminimally invasive adenocarcinomas would have lead times of at least 5 years. These results are similar to the 25% estimated risk of overdiagnosis in the Italian Continued Observation of Smoking Subjects (COSMOS) study, in which volume doubling time (VDT) was used as an indicator of overdiagnosis (48).
Table 2 outlines screening guidelines from several of the major stakeholder societies and organizations, with recommendations as to who should be screened. Of note, some of these guidelines provide recommendations for who should not be screened, as benefit in populations outside the NLST is not proven and may be outweighed by the harms described previously.
| Organization | Date of Statement or Guideline | Recommendations for Screening by LDCT | Comments |
|---|---|---|---|
| American Cancer Society (ACS) (52, 54) | 2013, 2014 | Clinicians with access to high-volume, high-quality lung cancer screening and treatment centers should initiate a discussion about lung cancer screening with patients meeting the NLST criteria and are otherwise in good health: | • Physicians should engage individuals to participate in effective decision-making: |
| • Ages 55–74 yr | • Individuals who value the opportunity to reduce their risk of dying of lung cancer and who are willing to accept the risks and costs associated with screening and the relatively high likelihood of the need for further tests, may opt to be screened | ||
| • Current or former smoker with ≥30 pack-year smoking history | • Individuals who place a greater value on avoiding testing that carries a high risk of false-positive results and a small risk of complications, and who understand and accept that they are at a much higher risk of death from lung cancer than from screening complications, may opt not to be screened | ||
| • If not currently smoking, must have quit within the past 15 yr | • When possible, screening should be performed in an organized screening program with expertise in screening and access to a multidisciplinary team with expertise in the evaluation, diagnosis, and treatment of abnormal lung findings | ||
| American College of Chest Physicians (ACCP) (53) | 2012, 2013 | Annual lung cancer screening should be offered over both annual screening with CXR or no screening to individuals who meet the following criteria, but only in settings that can deliver the comprehensive care provided to National Lung Screening Trial participants: | • Individuals who have severe comorbidities that would preclude curative treatment and/or limit life expectancy should not be screened |
| American Society of Clinical Oncology (ASCO) (57) | • Ages 55–74 yr | • Individuals should be counseled as to potential benefits and harms of screening | |
| Endorsed by the American Thoracic Society (ATS) | • Current or former smoker with ≥30 pack-year smoking history | • Individuals who are screened should be enrolled in a registry to capture data on follow-up testing, radiation exposure, patient experience, and smoking behavior | |
| • If not currently smoking, must have quit within the past 15 yr | • Screening should be conducted in centers similar to NLST centers, with multidisciplinary coordinated care | ||
| • Quality metrics should be developed to enhance benefits and minimize harms | |||
| • The most effective duration/frequency of screening is unknown | |||
| U.S. Preventive Services Task Force (USPSTF) (4) | 2013 | Annual screening for lung cancer by LDCT is recommended in asymptomatic individuals who meet the following criteria: | • Discontinue screening when the patient has not smoked for 15 yr |
| • Asymptomatic adults aged 55–80 yr | • Age, total cumulative exposure to tobacco smoke, and years since quitting smoking are the most important risk factors for lung cancer. Other risk factors include specific occupational exposures, radon exposure, family history, and history of pulmonary fibrosis or chronic obstructive pulmonary disease | ||
| • Current or former smoker with ≥30 pack-year smoking history | • The USPSTF has made recommendations on counseling and interventions to prevent tobacco use and tobacco-caused diseases | ||
| • If not currently smoking, must have quit within the past 15 yr | |||
| International Association for the Study of Lung Cancer (IASLC) (56) | 2013 | Screening for lung cancer by LDCT is recommended in high-risk populations defined as: | Screening may be a reasonable option in persons with a smoking history of ≤ 30 pack-years, but an explicit recommendation in favor of screening such persons cannot be made |
| • Asymptomatic adults aged 55–80 yr | |||
| • Current or former smoker with ≥30 pack-year smoking history | |||
| • If not currently smoking, must have quit within the past 15 yr | |||
| • Disease-free at the time of screening | |||
| American Association for Thoracic Surgery (AATS) (59) | 2012 | Three screening populations defined: | • Lung cancer screening and treatment of early-stage lung cancers should be done by qualified subspecialty teams included board-certified thoracic surgeons, thoracic radiologists, pulmonologists, and oncologists |
| Tier 1 (highest risk): Subjects for whom there are data from randomized prospective clinical trials (level 1 evidence) to recommend screening | • Lung cancer screening programs should support smoking cessation | ||
| • Annual screening by LDCT for patients ages 55–79 with ≥30 pack-year smoking history | • Screening should not be offered if treatment is impractical due to comorbidity or functional status regardless of age | ||
| Tier 2: Subjects for whom there are data from case–control or nonrandomized trials (level 2 evidence) or consensus opinion (level 3 evidence) to recommend screening | • Data collection to study outcomes that are important for the practice of evidence-based medicine | ||
| • Annual screening by LDCT until age 79 for lung cancer survivors who have completed 4 yr of surveillance without evidence of recurrence (level 3 evidence) | |||
| • Annual screening by LDCT beginning at age 50 for patients with ≥20 pack-year smoking history if additional comorbidities produce a cumulative 5% risk of developing lung cancer over the following 5 yr. Known risks: FEV1 ≤ 70%, environmental/occupational exposure, prior cancer/radiation therapy, genetic/family history (level 2 evidence) | |||
| National Comprehensive Cancer Network (NCCN) (58) | 2011, updated 2014 | Lung cancer screening is appropriate to consider for those high-risk patients who are potential candidates for definitive treatment | • NCCN category 1 recommendation: Based on high-level evidence (e.g., randomized controlled trial) and uniform consensus among panel members that the intervention is appropriate |
| Two screening populations defined: | • NCCN category 2A recommendation: Based on lower level evidence (e.g., nonrandomized studies, observational data, ongoing randomized trials) and uniform NCCN consensus that the intervention is appropriate | ||
| • Individuals age 55 to 74 yr with ≥30 pack-year history of smoking tobacco, currently smoking or, if former smoker, have quit within 15 yr (category 1 evidence) | • NCCN category 2B recommendation: Based on lower level evidence and NCCN consensus that the intervention is appropriate | ||
| • Annual screening recommended for 2 yr, and can be considered until the patient is no longer eligible for definitive treatment | • Institutions performing lung cancer screening should use a multidisciplinary approach that includes the specialties of thoracic radiology, pulmonary medicine, and thoracic surgery | ||
| • Individuals age ≥50 yr with ≥20 pack-year smoking history and one additional risk factor (category 2B evidence). These additional risk factors include the following: | • Chest X-ray is not recommended for lung cancer screening | ||
| • Personal cancer history: Survivors of lung cancer, lymphomas, cancers of the head and neck, or other smoking-related cancers, particularly patients who continue to smoke and were previously treated by chest irradiation or with alkylating agents | • Lung cancer screening should not be considered a substitute for smoking cessation | ||
| • Personal history of lung disease: COPD, pulmonary fibrosis | • The NCCN does not recommend screening for the following groups: | ||
| • Family history of lung cancer in a first-degree relative. Risk is greater in individuals with multiple affected family members or lung cancer diagnosed at a young age | • Moderate-risk individuals, defined as age ≥50 yr and with a ≥20 pack-year history of smoking tobacco or second-hand smoke exposure but no additional lung cancer risk factors | ||
| • Radon exposure (residential) | • Low-risk individuals, defined as age ≤ 50 yr and/or a smoking history of ≤ 20 pack-years | ||
| • Occupational carcinogen exposure (silica, cadmium, asbestos, arsenic, beryllium, chromium, diesel fumes, nickel, coal smoke, and soot) | |||
| American Lung Association (ALA) (55) | 2012 | Low-dose CT screening should be recommended for those people who meet NLST criteria: | In addition to the recommendation for low-dose CT screening for people meeting NLST criteria, the ALA lung cancer screening committee made the following recommendations: |
| • Current or former smokers, aged 55–74 yr | • The best way to prevent lung cancer caused by tobacco is to never start smoking, or to quit smoking | ||
| • A smoking history of at least 30 pack-years | • Individuals should not receive a chest X-ray for lung cancer screening | ||
| • No history of lung cancer | • Low-dose CT screening should not be recommended for everyone | ||
| • The ALA should develop public health materials describing the lung cancer screening process in order to assist patients in talking with their doctors. This educational portfolio should include information that explains and clarifies for the public: | |||
| • The difference between a screening process and a diagnostic test | |||
| • The benefits and risks and costs | |||
| • That not all lung cancers will be detected through use of low-dose CT scanning | |||
| • A call to action should be issued to hospitals and screening centers to: | |||
| • Establish ethical policies for advertising and promoting lung cancer CT screening services | |||
| • Develop educational materials to assist patients in having careful and thoughtful discussions between patients and their physicians regarding lung cancer screening | |||
| • Provide lung cancer screening services with access to multidisciplinary teams that can deliver the needed follow-up for evaluation of nodules | |||
| American Academy of Family Physicians (AAFP) (60) | 2014 | The evidence is insufficient to recommend for or against screening for lung cancer by LDCT | The AAFP expressed significant concern, basing such a recommendation on a single study |
The target population for current lung cancer screening guidelines of the ACS, ACCP, ASCO, and American Lung Association (ALA) mirrors the entry criteria for NLST (25, 49–52). These were endorsed by the American Thoracic Society (ATS) and also reflect the recommendations of the International Association for the Study of Lung Cancer (IASLC) (53). These organizations recommend that screening be offered to persons of age 55–74 years, who have at least 30 pack-years of smoking, are actively smoking or have quit within the previous 15 years, and have no other life-limiting comorbidities (50, 51, 54). The recommendations endorse including patients in the decision process of whether to undergo screening, conducting screening in centers with multidisciplinary care and comprehensive programs similar to NLST sites, developing a registry to capture data on follow-up testing, radiation exposure, patient experience, and smoking behavior, and developing quality metrics for screening programs.
The USPSTF recommendation differs from the ACS/ACCP/ASCO/ATS guidelines in extending the age of individuals eligible for screening to 80 years, based on the results of the CISNET models. The USPSTF draft version of its new recommendation was posted for public comment in mid-2013. As would be anticipated, comments spanned the breadth of opinion, from restricting screening to groups with risk higher than the average NLST participant, to expanding the eligibility criteria beyond those of NLST. Ultimately, the USPSTF made its recommendation after considering the explicit tradeoffs that were informed by the CISNET simulation models as described previously (29).
The recommendations from NCCN and the American Association for Thoracic Surgery (AATS) both extend recommendations for screening to individuals who would not meet NLST eligibility criteria (55, 56). NCCN identifies two high-risk populations who could or might be targeted for screening: (1) individuals who meet NLST eligibility criteria; and (2) individuals age ≥50 years with more than 20 pack-years of smoking and one additional lung cancer risk factor (occupational carcinogen exposure, residential radon exposure, personal cancer history, first-degree family history of cancer, personal history of chronic obstructive pulmonary disease [COPD] or pulmonary fibrosis). AATS recommends screening in three populations of patients at high risk for lung cancer, divided into two tiers of screening based on the level of supportive evidence.
The American Academy of Family Physicians (AAFP) currently does not endorse lung cancer screening. AAFP concluded that the evidence is insufficient to recommend for or against screening by LDCT (57). AAFP indicated that they had significant concern recommending screening based on only a single study, but acknowledged that a shared decision between patient and clinician should be made on the basis of the benefits and potential harms of screening.
Debate exists as to the duration of screening; although the duration of screening in NLST was only 3 years, lung cancer risk increases with age, and so most guidelines endorse continuing screening as long as the patient remains free from life-limiting comorbidities. The NELSON trial, which enrolled subjects with a minimum of 15 pack-years of smoking, may be able to address the issue of what threshold of smoking intensity is appropriate for screening (58). When eventually combined, NELSON and DLCST are anticipated to have 80% power to demonstrate lung cancer mortality reduction of at least 25% at 10 years after randomization; completion is anticipated in 2015–2016.
NLST used simple clinical parameters to identify a population at increased risk for lung cancer. Refined risk-based assessments may improve the net effectiveness of screening in two important ways. The first is identifying those at the highest levels of risk for developing lung cancer, who would benefit most from screening. The second is identifying those at lower levels of risk, to avoid interventions and complications related to evaluation of false positive screening results or overdiagnosed cancers.
A number of lung cancer risk assessment models have been developed and validated in large cohorts of patients enrolled in a variety of trials (59–62). One model was developed by Tammemagi and colleagues using data from the PLCO trial, and subsequently refined with data from NLST (62). This model, PLCOm2012, was marginally better able to predict who developed lung cancer in NLST than the entry criteria for the trial (63). It has been proposed that more refined risk assessment, which would include additional risk information beyond NLST entry criteria, could improve lung cancer screening selection, and in doing so increase efficiency and cost-effectiveness (63–67). This is supported by indirect calculations of variation in screening benefit that estimate a nearly 10-fold difference in the number of LDCT-prevented lung cancer deaths in NLST participants at highest risk of lung cancer mortality compared with those at lowest risk (65, 68, 69). Moreover, Kovalchik and colleagues demonstrated that, even within NLST, LDCT screening prevented far more lung cancer deaths among those at highest lung cancer mortality risk (68). Screening only those at highest risk would have eliminated a large number of false positive findings and would also have increased the efficiency of screening. The number needed to screen to prevent 1 lung cancer death in the highest quintile of risk was 161, compared with 5,276 in the lowest quintile of risk and 302 in NLST overall. These findings provide additional support for targeting screening on the basis of risk assessment.
Informed decision-making for lung cancer screening necessitates a balanced presentation of both potential benefit and harm. Individualized risk assessment is an important component of this process, as is the discussion of risk with the patient (70). Unfortunately, few physicians are formally trained in methods to promote effective risk communication with patients (71). In addition, competing demands of clinical practice limit what can be done in a brief visit, decreasing the chances that risk is adequately discussed. Risk assessment models such as the PLCOm2012 (www.brocku.ca/cancerpredictionresearch) have the potential to be used as decision support tools to help both high- and low-risk patients understand their individual risks for developing lung cancer, and to facilitate discussion with providers as to whether lung cancer screening by LDCT is warranted.
There is controversy concerning whether it is reasonable to offer screening by LDCT to individuals who do not meet NLST criteria, and in particular those who have not smoked at the intensity of the subjects of NLST but have additional lung cancer risk factors. When applying NLST findings to other groups who have lung cancer risk factors but who do not meet NLST enrollment criteria, it is important to remember that individuals with a lower risk of death than the average NLST participant are less likely to benefit and are probably at least as likely to be harmed. Unfortunately, it is unlikely that studies examining screening for most other at-risk groups will be performed, given the sheer magnitude of subjects required and the enormous cost.
There are some commonalities between all screening programs that can be extrapolated to lung cancer screening. First, it is critical to develop protocols for evaluating positive examinations that minimize the need for invasive testing. Second, overdiagnosed cancers are to be expected; identification of these cancers will not provide benefit but has the potential to cause harm. Although we do not yet have a practical means of knowing which cancers have very long VDTs, we do know that pure ground-glass opacities behave differently than do subsolid and solid nodules and may not require aggressive treatment, particularly in those patients who are high-risk surgical candidates. Third, barriers to screening a population for cancer must be accounted for if we hope to screen the population at risk. Among women eligible for breast mammography, factors most frequently identified as associated with not being screened include minority status, pain and embarrassment associated with mammography, low income and lack of health insurance, poor knowledge about breast cancer screening, lack of physician recommendation, lack of trust in hospitals and doctors, language barriers, and lack of transportation (72). In a study of attitudes toward lung cancer screening among smokers and nonsmokers, lower income and education status, lack of insurance, and poor knowledge about the benefit of the test were identified as barriers to screening (73). In addition, current smokers were less likely than nonsmokers to be interested in screening or to believe in its benefit. Because lung cancer screening will be undertaken in smokers, this is a new and unique barrier that must be overcome to reach the target at-risk group.
While it is laudable to consider smoking cessation as an essential component of lung cancer screening because of concerns that a negative screen might result in smoking recidivism, there are no data to support that lung cancer screening is the “teachable moment.” Moreover, quit rates have been reported as higher among those with positive as compared with negative screening results, suggesting that either a positive test may motivate patients to quit smoking or that a negative test may provide false reassurance (74, 75). The ongoing NELSON trial, which is the only randomized study investigating smoking cessation in the context of lung cancer screening, has demonstrated no evidence of smoking recidivism (76). Samples of smokers in the LDCT and control arm were evaluated at randomization and 2 years later. All participants regardless of intervention were more likely to quit smoking than the average population, suggesting either that lung cancer screening is a teachable moment, or that the highly selected study participants were more likely than average to quit. In either case, the absence of a significant difference found between groups suggests that a negative screen does not adversely impact smoking cessation.
Lung cancer screening by LDCT performed by a qualified program in the appropriate patient population should result in more benefit than harm. The ACCP and ATS issued a joint policy statement outlining the components of screening that should be a part of all lung cancer screening programs, supported by evidence-based reviews of lung cancer screening and supplemented by expert opinion (77). Nine essential components were identified. Policy statements developed for each component define the criteria by which high-quality lung cancer screening programs should be assessed. The nine components and their policy statements are outlined in Table 3.
| Component | Policy Statement |
|---|---|
| 1. Who is offered lung cancer screening | USPSTF recommendation: Screening for lung cancer by low-dose computed tomography (LDCT) in adults aged 55–80 yr who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 yr. Screening may not be appropriate for patients with substantial comorbid conditions, particularly those who are at the upper end of the screening age range |
| • Lung cancer screening programs should collect data on all enrolled subjects related to the risk of developing lung cancer | |
| 2. How often, and for how long, to screen | USPSTF recommendation: |
| • Annual screening until age 80 | |
| • Screening should be discontinued once a person has not smoked for 15 yr or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery | |
| 3. How the CT is performed | • A low-dose lung cancer screening CT should be performed on the basis of ACR-STR technical specifications |
| • A lung cancer screening program should collect data to ensure the mean radiation dose is in compliance with ACR-STR recommendations | |
| 4. Lung nodule identification | A lung cancer screening program should: |
| • Have a policy about the size and characteristics of a nodule to be used to label the test as positive | |
| • Collect data about the number, size, and characteristics of lung nodules from positive tests | |
| 5. Structured reporting | A lung cancer screening program should: |
| • Use a structured reporting system, such as Lung-RADS | |
| • Collect data about compliance with the use of the structured reporting system | |
| 6. Lung nodule management algorithms | A lung cancer screening program must: |
| • Include clinicians with expertise in the management of lung nodules and the treatment of lung cancer | |
| • Have developed lung nodule care pathways | |
| • Have the ability to characterize concerning nodules through PET imaging, nonsurgical and minimally invasive surgical approaches | |
| • Have an approach to communication with the ordering provider and/or patient | |
| • Have a means to track nodule management | |
| • Collect data related to the use of, and outcomes from, surveillance and diagnostic imaging, surgical and nonsurgical biopsies for the management of screen-detected lung nodules | |
| 7. Smoking cessation | A lung cancer screening program: |
| • Must be integrated with a smoking cessation program | |
| • Should collect data related to the smoking cessation interventions that are offered to active smokers enrolled in the screening program | |
| 8. Patient and provider education | A lung cancer screening program: |
| • Should educate providers so that they can adequately discuss the benefits and harms of screening with their patients | |
| • Should develop or use available standardized education materials to assist with the education of providers and patients | |
| • Is responsible for the oversight and supplementation of provider-based patient education | |
| 9. Data collection | • A lung cancer screening program must collect data on all enrolled patients related to the quality of the program, including those enrolled in registered clinical research trials. Data collection should include elements related to each of the other eight components of a lung cancer screening program (as above). In addition, data collection should include the outcomes of testing (complications, cancer diagnoses), and a description of the cancers diagnosed (histology, stage, treatment, survival) |
| • A review of the data and subsequent quality improvement plan should be performed at least annually | |
| • An annual summary of the data collected should be reported to an oversight body with the authority to credential the screening program. Standards set forth in the above policy statements should be used by the oversight body to judge areas of compliance and deficiency |
The logistical complexity of screening and follow-up emphasizes the need for a comprehensive programmatic approach to screening. Multisociety guidelines from ACCP, ASCO, and ATS recommend lung cancer screening for high-risk individuals with the caveat that it be offered in settings able to provide comprehensive care similar to that provided to NLST participants (25). The team should include primary care providers, pulmonologists, thoracic radiologists, thoracic surgeons, nurse navigators, and smoking cessation counselors. The ACCP/ATS policy statement on lung cancer screening outlines a number of criteria that define a high-quality screening program (Table 3). Many of these criteria may inform quality measurements for lung cancer screening in the future. The policy statement committee specifically identified two quality metrics that are immediately feasible and relevant: (1) Regarding the USPSTF recommendation on who should be offered lung cancer screening (component 1 in Table 3), the committee recommended that at least 90% of all screened subjects must match the USPSTF recommendation; and (2) regarding structured reporting of the results of the LDCT screen (component 5 in Table 3), the committee recommended that the selected reporting system, either Lung-RADS (78) or a structured reporting system with similar elements, be used for at least 90% of LDCT screen reports. Data from screening registries may also help to inform future process improvements.
Cost-effectiveness is another controversial aspect of implementing lung cancer screening on a national level. Estimates vary widely, ranging from $2,500 per quality-adjusted life-year (QALY) at the low end to $2,000,000 at the high end (79, 80). One study showed that screening was cost-effective only if it were coupled with smoking cessation ($75,000/QALY with cessation vs. $150,000 without) (81). That smoking cessation intervention should be offered as part of a comprehensive screening program seems appropriate, although data from the NELSON trial showed that those randomized to screening versus usual care had similar rates of abstinence at 1 year (76). Results from an analysis performed using data from NLST suggest screening in the overall group screening costs $81,000 per QALY. However, there were marked differences in women ($46,000/QALY) versus men ($147,000/QALY), in current smokers ($43,000/QALY) versus former smokers ($615,000/QALY), and in those at the highest two quintiles of risk of developing lung cancer ($32,000/QALY and $52,000/QALY) versus the three lowest quintiles of risk($169,000/QALY, $123,000/QALY, $269,000/QALY) (82). Screening becomes less cost-effective when LDCT cost rises, the number of follow-up scans performed increases, and surgical mortality from a nodule resection increases. Further, what is unknown at present is whether certain aspects of the NLST trial such as conservative follow-up of nodules and the low surgical mortality will translate into the community setting. If they do not, it is unlikely that screening will be cost-effective in these settings.
Successful lung cancer screening will help to control lung cancer. The tools we have to accomplish this are still limited. Although age and smoking history as the criteria for determining who should or should not be screened by LDCT were adequate for the purposes of NLST, more refined risk assessment may enable targeting of high-risk individuals more likely to benefit from screening, and better evaluative strategies have the potential to improve our identification of true and false positive results.
Moving forward, technology used for CT screening will continue to advance. This includes a further reduction in the radiation dose required for CT imaging as well as semiautomated volumetric software. Diameter and VDT were used in the NELSON trial to improve the test characteristics of screening LDCT (28). In NELSON, any noncalcified nodule with a solid component greater than 500 mm3 was considered a positive result. A nodule with volume 50–500 mm3 was considered indeterminate, and was reevaluated with a 3-month follow-up scan. The final result was considered positive if a VDT less than 400 days was observed. This aggressive nodule-evaluative strategy resulted in a positive rate of 2.6 and 1.8% in rounds 1 and 2 of screening, respectively, in comparison with the 26.4% positive rate across all rounds of screening in NLST. Volumetric measurements added to traditional nodule prediction models have been shown to improve the classification of malignancy from 60 to 88%, with combined performance characteristics demonstrating an improved area under the curve of 0.915 (83, 84). Multivariable prediction models have also been developed to assess the probability of cancer in pulmonary nodules identified by screening LDCT (84).
A number of novel tests and biomarkers have been developed with the potential to more accurately identify whom to screen by LDCT or to aid in determining the likelihood that a screen-detected nodule is malignant. Exhaled breath analysis is based on the concept that volatile organic compounds (VOCs) in exhaled breath reflect the body’s metabolic activity. The ability of trained dogs to distinguish patients with lung, colon, and breast cancer from normal control subjects with sensitivity and specificity above 90% is presumably based on detection of VOCs (85). Various technologies to measure VOCs are described, the most accurate of which are gas chromatography and mass spectrometry (GC-MS). Although GC-MS has been reported to have reasonable sensitivity for identifying lung cancer, expense and complexity make its application in the clinical setting difficult. Newer technologies, including colorimetry, ion mobility spectrometry, nanosensors, and electronic nose instruments, are being studied for analysis of VOC patterns (86, 87). Exhaled breath condensate is another test under development that analyzes nonvolatile compounds in breath captured in liquid phase. The condensate reflects the fluid layer from the airway epithelium, sampling lipid products, proteins, cytokines, DNA, and nitric oxide metabolites (88). Exhaled breath analyses are appealing in that they are noninvasive and can be performed repeatedly at minimal risk, but are currently limited by lack of standards for sampling exhaled breath, small study populations, and as yet limited validation in independent groups.
Identification of aberrations in the gene expression of airway epithelial cells is a promising area focusing on identifying current and former smokers at high risk for developing lung cancer. The principle of this approach is that genetic alterations induced by cigarette smoke persist even after smoking cessation. An 80-gene biomarker in airway epithelial cells to distinguish whether smokers with a clinical suspicion of lung cancer actually had cancer or not has been described (89). Validation in independent patient sets yielded a sensitivity and specificity of 80 and 84%, respectively. Thus far, these multigene biomarkers have been used to study airway epithelial cells obtained by bronchoscopy; similar examination of other cells in the respiratory tract or blood may be less invasive approaches, and are more readily applicable to a broad population. Serum circulating tumor antibodies, other proteins, and micro-RNA panels are being actively studied, with a broad range of sensitivities and specificities for both diagnosis and prognosis in lung cancer (90–92). Although these have not been examined as tools for lung cancer screening, there is clear potential for such serum biomarkers to enhance currently available clinical lung cancer risk assessment models (63, 84). In addition, these biomarkers may be useful in further distinguishing between aggressive and indolent cancers.
For the present, we are challenged with the task of applying lung cancer screening to individuals on the basis of clinical data such as age and smoking history. A personalized discussion of the assessment of balance of benefit and risk ideally should be held with each patient. Ultimately, more accurate clinical, biochemical, and molecular predictive tools will be developed to identify individual patients at highest risk of lung cancer, for whom screening is likely to be of most benefit. Application of such tools, development of novel approaches to quantifying risk, and a deeper understanding of the biological processes that contribute to the development of lung cancer will more precisely inform our selection of individuals who should be targeted for lung cancer screening by LDCT or other interventions.
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Author Contributions: L.T.T., N.T.T., M.K.G., and G.A.S. all contributed to the conception and design of this work; participated in writing, revising, and approving the manuscript; and are in agreement as to the integrity of the work and the contributions of all the authors.
CME will be available for this article at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201410-1777CI on November 4, 2014
Author disclosures are available with the text of this document at www.atsjournals.org.
