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Lung Cancer Screening Douglas Arenberg, MD1 1 Division of Pulmonary & Critical Care Medicine, Department of

Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan

Address for correspondence Douglas Arenberg, MD, Medical Director: Lung Cancer Screening Program, University of Michigan Medical School, 1150 W Medical Center Drive, 6301 MSRB III, Ann Arbor, MI 48109-5642 (e-mail: [email protected]).

Abstract

Keywords

► ► ► ► ►

screening CT scan lung nodule lung cancer mortality

The National Lung Screening Trial demonstrated that lung cancer screening with three annual low-dose computed tomographic scans has the potential to reduce lung cancer– specific mortality by 20% in an older population of heavy smokers. This was a great achievement by the National Lung Screening Trial (NLST) investigators, but this should be viewed as an important first step in an unfinished process. Many major questions remain about how to best realize this mortality reduction in a practical real-world context. Screening for lung cancer will be most effective if it is accompanied by continued research into risk modeling, patient communication strategies, and biomarkers. For clinicians establishing a program of lung cancer screening, we encourage this to be done in a responsible fashion, adhering to practices specified in the design of the NLST, and with careful attention given to proper management of screen-detected abnormalities and maintenance of screening registries.

In the 1970s the National Institutes of Health sponsored three large randomized trials of lung cancer screening that tested various combinations of plain chest radiography, with or without sputum cytology compared with usual care. None of the studies demonstrated a mortality benefit. These findings led the American Cancer Society and the U.S. Preventive Services Task force to recommend against the use of routine chest X-rays as a screening modality for lung cancer and that “those with signs or symptoms of lung cancer” were to see their doctor. In that context the rate of lung cancer deaths continued to rise to the point that lung cancer killed more people than the next four most common causes of cancer-related death combined. Numerous retrospective analyses, commentaries, and editorials were published debating the results and conclusions of these trials and the role (if any) of lung cancer screening. A confluence of events in the late 1990s led to the conception and design of randomized trials of low-dose computed tomographic (LDCT) scans as a screening tool for lung cancer. These included development of multidetector computed tomographic (CT) scanners, delivering improved images with lower doses of radiation, along with studies demonstrating the feasibility of screening smokers with low-dose, singlebreath-hold CT scans.

Issue Theme Lung Cancer; Guest Editor, M. Patricia Rivera, MD

The National Lung Screening Trial (NLST) was the largest of these trials, and it randomized 50,000 individuals at risk for lung cancer. The study began in 2002 and completed enrollment ahead of schedule in 2004. The lung cancer community watched and waited for the results, until November 2010, when the NLST was halted by the National Institutes of Health (NIH). The announcement came with the news that, in heavy (30 pack-years or more) current or former (within 15 years) smokers between the ages of 55 and 75, three annual LDCT screens reduced lung cancer–specific mortality from 309 to 247 deaths per 100,000 person-years (relative risk of 0.8).1 Since that time, many academic and private facilities have either begun to offer or are considering offering lung cancer screening with LDCT, despite the lack of incorporation of screening into clinical practice guidelines, or third party payer coverage. This article briefly reviews the evidence for screening and addresses how the benefits and harms can be viewed to give patients and providers the opportunity to make informed decisions about lung cancer screening.

Translating Efficacy into Effectiveness Clinical trials are necessary to determine the effectiveness of one treatment or test over another, and the results of the NLST

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DOI http://dx.doi.org/ 10.1055/s-0033-1358549. ISSN 1069-3424.

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Semin Respir Crit Care Med 2013;34:727–737.

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were robust, causing great excitement for the lung cancer community. But clinical trial data do not always translate into effective health care. To generalize the findings of a well done clinical trial, it is necessary to examine the details of how the study was conducted and whether the patients in the study resemble the patients in your exam room. Did the setting of the study have any role in the outcome of the study? If so, do the qualities of the study setting match your practice setting? For example, those initiating lung cancer screening programs must recognize the need for quality control in the specifications of CT imaging, the qualifications and expertise of the interpreting radiologists, and the standardized criteria for reporting abnormalities. These factors were prospectively determined and closely monitored in the conduct of the NLST,2 and the impact of these “behind the scenes” quality control measures in the effectiveness of LDCT screening should not be taken for granted. Furthermore, although the process of evaluating abnormal screening findings was not standardized in the setting of the NLST, all findings were generally followed up in centers where there is significant expertise in the management of incidental or screen-detected nodules, and staffed by multidisciplinary teams built around evidence-based care of patients with known or suspected lung cancer. It is a mistake to look at the data on screening in isolation from the setting in which these reductions in mortality were achieved. Anyone starting a lung cancer screening program should understand both the risks and the benefits of screening, including the false-positive rate and appropriate downstream diagnostic pathways. Most nodules discovered on screening CTs are benign, and the process should focus on obtaining proof that the nodule is benign with the least amount of cost and risk to the patient. In almost all instances this means careful reassurance of anxious patients, serial follow-up at intervals meaningful enough to determine if growth has occurred, but at intervals that preserve treatment options. In addition to the potential for physical harm and psychological distress, data yet to be published from the NLST will provide important insights into the costs associated with CT lung cancer screening, cost-effectiveness, quality of life, and impact on smoking status. It is necessary to recognize the enormous potential for harm when screening large populations for a condition that is very rare (less than 2% of those screened). This potential harm is measured not only in the costs associated with screening but also in the reductions in quality of life associated with protracted follow-up of benign lung nodules, the potential for invasive procedures for incidental findings, and of course the risks associated with biopsy and surgery. For these reasons I recommend screening be primarily conducted in centers with access to experienced multidisciplinary thoracic oncology teams with experience in management of incidental lung nodules. LDCT screening for lung cancer is not a single test performed in isolation. Screening must be considered as a process that has, at its core, the goal of preventing death from lung cancer. Consequently, it is impossible to overstate the importance of effective tobacco cessation efforts being built into any Seminars in Respiratory and Critical Care Medicine

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screening program. The following are some of the most important questions to consider in the context of screening: 1. Who should be screened? 2. How do we measure screening effectiveness among various populations of patients? 3. How do we communicate screening benefits and risks to patients? 4. What is the role of smoking cessation as part of a lung cancer screening program? 5. In what environment should screening take place and test results be managed? 6. How should CT examinations be performed and interpreted for screening? 7. What is the proper approach to subjects with an abnormal screen? 8. What is the proper approach to subjects with a negative screen? 9. What data should lung cancer screening programs collect? 10. What is the cost-effectiveness of lung cancer screening, and what variables have the greatest effect on the costs, benefits, and harms of screening?

Who Should Be Screened? Identifying individuals for whom LDCT screening can potentially be beneficial requires a quantifiable measure of lung cancer risk. The NLST investigators sought to enroll people at high risk for lung cancer while aiming to maximize the benefit of screening by reducing the factor of competing mortality in a higher age group. The trial set an enrollment age of 55 to 74 years, and 30 pack-years or more of either current or recent (within 15 years) tobacco use.1–3 The strictest interpretation of the results of this trial should lead to the conclusion that only current or recent former smokers meeting these criteria for tobacco use and age range should be considered for LDCT screening. Numerous studies have recognized that there is wide variation in lung cancer risk even among those who are smokers.4–7 Although we can easily identify smoking as a risk factor for lung cancer, it is more useful as an epidemiological tool than for predicting the risk of any one individual. The importance of identifying risk at an individual level is further underscored by a recent study published by NLST investigators in which they examined risk for lung cancer death among NLST participants in the control group, developing a multivariable regression model of clinical variables that predicted a 5-year risk of lung cancer death. They then determined whether the benefit of screening was distributed equally among quintiles of risk. As might be expected they found that subjects in the three highest quintiles of lung cancer mortality risk (60% of participants at highest risk for lung-cancer death) accounted for 88% of the screen-prevented lung-cancer deaths and for 64% of participants with false-positive results. The 20% of participants at lowest risk (quintile 1) accounted for only 1% of prevented lung-cancer deaths.8 If screening is offered on a more widespread basis, it will be more effective and more cost-effective when we can identify those whose history puts them at the highest risk for lung cancer mortality.

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Lung Cancer Screening Several models have evolved with the goal of being able to quantify an individual’s risk for developing lung cancer over a defined period of time. These models employ characteristics easily identified in demographic and medical history to identify and quantify risk for lung cancer4–6,9 (►Table 1). It is important to note that, although all of these models have

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internal validity and have to varying extents been validated on external populations, none have been used to prospectively identify those who might benefit from LDCT screening. This need for prospective validation and refinement of risk prediction models suggests a need to develop registries to track screened individuals and the downstream outcomes of LDCT

Model Bach et al

Variables used 4

Spitz et al6

Cassidy et al (Liverpool Lung Project)5

Tammemägi (Modified Prostate Lung Colon and Ovary Trial model [PLCOm])56

Age Gender Asbestos exposure Average cigarettes smoked per day • Smoking duration • Duration of abstinence • • • •

• Second-hand smoke • Dust • Prior respiratory diseasea • Smoking history (current, former, never) • Age at smoking cessation • Asbestos • Family history of tobacco-related malignancy • Age • Smoking duration • Prior diagnosis of pneumonia • Asbestos (occupational exposure) • Prior malignancy • Family history of lung cancer (none, prior to, and after age 60) • • • • • • • • • • •

Age Educational level Body mass Index Family history COPD (yes/no) Recent (within 3 years) chest X-ray Smoking history (current, former, and never) Pack-years Smoking duration Ethnicity Duration of abstinenceb

Accuracy/utility

Training set

External validation

Reported only on the variation in 10-year lung cancer risk among smokers

Carotene and Retinol Efficacy Trial (CARET) trial participants

Compared predicted and observed rates of cancer across deciles of risk

69% and 70% true positive rate in current and former smokers, respectively

1,851 patients, and 2,001 controls matched by age, gender, ethnicity, and smoking status (current, former, never); three fourths of subjects were used for training set

One fourth of the participants were used for validation of the training set data

AUC of 0.7

579 lung cancer cases and 1,157 age- and gender-matched controls

Subsequent validation by D’Amelio et al, Brit J Cancer 2010;103:423 in a cohort recruited in Boston, Massachusetts, area

AUC of 0.803 in the development dataset and 0.797 in the validation set

PLCO control group 77,456 smokers

44,223 PLCO intervention arm participants

AUC, area under the curve; PLCO, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. a Emphysema, Hay fever (protective), Dust exposure (only significant in smokers). b Only one of two models used this variable, and it did not strengthen predictive ability. Seminars in Respiratory and Critical Care Medicine

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Table 1 Examples of published models aimed at identifying individuals at greatest risk for lung cancer

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screening. Screening programs should develop and maintain registries with the goal of prospectively tracking the results of LDCT screening, just as pharmaceutical companies are required to develop postmarketing monitoring of newly developed drugs. These registries can be used to hold screening programs accountable for the results of screening and to promote quality control.10 In addition to clinical and demographic variables, it is likely that any future clinically useful risk model would eventually include molecular or genetic indicators of risk. These biomarkers of risk ideally would reflect the underlying biological predisposition to lung cancer susceptibility, and several have been published.11–14 It is unlikely that any single biomarker will supplant all others, and a model that includes genetic risk, molecular indicators of susceptibility, age, medical history, and tobacco use is expected to have the greatest predictive accuracy for lung cancer risk.15–17 The effectiveness of screening in any given individual could be benchmarked to the average risk for lung cancer among NLST participants, with any risk model that predicts risk at or greater than the level of risk observed in NLST potentially justifying extending screening to those individuals. Costeffectiveness analyses can be modeled to estimate cost per years of life gained in a given level of risk, further informing the decision whether to pursue screening or not.

How Do We Measure Screening Effectiveness among Various Populations of Patients? A useful way of comparing effectiveness of any medical test or drug is to determine the number of individuals on whom one would have to perform a given intervention to achieve a prespecified outcome. For screening this is referred to as the number needed to screen (NNS) to prevent one death.18 Calculating NNS requires that one look at the absolute risk of death in screened and unscreened populations and then take the inverse of the difference. For the NLST the risk of death from lung cancer in the LDCT and control populations was 1.4% and 1.7%, respectively, a difference of 0.3%. Thus to save one life requires screening
320 people. A comparison of other estimates of screening efficacy is listed in ►Table 2 with estimates (where available) of the costs per quality adjusted life-year ($/QALY). Stated another way, for every 1,000 persons screened for three annual LDCT scans,
3 lives will be saved. For comparison, with annual mammography in women, screening between 380 and 1,900 persons (depending upon age) for
10 years results in one life saved. By this measure, LDCT screening in high-risk individuals is a very effective intervention. The use of NNS as a measure of screening efficacy can also be helpful when considering whom to screen. A paper by Bach and Gould pointed out elegantly that data describing average

Table 2 Comparison of relative effectiveness of various cancer screening modalities Age

Screen frequency

Relative risk of cancer death (95% CI)

Baseline risk of cancer death

Number needed to screen

$/QALY (where data are available)

55–69

Every 2–7 years

0.80 (0.65–0.98)

0.4%

1,400

55–74

Annual  6 y

1.10 (0.80–1.50)

0.1%

N/A

Annual  2–9 y

0.85 (0.75–0.96)

0.3%

1900

$105,000a61

PROSTATE CANCER ERSPC (PSA)57 PLCO (PSA)

58

BREAST CANCER Mammography

59,60

39–49

Mammography

59,60

50–59

0.86 (0.75–0.99)

0.5%

1,300

$18,000–21,400b61

Mammography

59,60

60–69

0.68 (0.54–0.87)

0.8%

380

$18,000–21,400b61

COLON CANCER FOBT or FIT59

50

Annually for 9 years

0.77

808

Dominates versus no screen62

Flexible Sigmoidoscopy63

50

Every 5 years (with FOBT)

0.82

361

$105,000 2010 $US (vs FOBT)62

Colonoscopy

50

$67,300 (vs FOBT)62

LUNG CANCER CXR64 Low-dose CT (vs CXR)

1

55–74

Yearly  4 y

0.94 (0.81–1.10)

1.6%

N/A

55–74

Annual  3 y

0.80 (0.73–0.93)

1.7%

300

$72,800 (2008 $ U.S. compared with CXR)

CI, confidence interval; CT, computed tomography; CXR, chest X-ray; ERSPC, European Randomized Study on Screening for Prostate Cancer; FIT, fecal immunotesting; FOBT, fecal occult blood testing; PLCO, N/A, not applicable; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; QALY, quality adjusted life-year. a Cost for screening women between ages 40 and 49 every 18 months. b Year 2000 $U.S., for 50- to 69-year-olds assuming film mammography. Digital mammography is considerably more expensive per QALY, approaching $300,000 if used in all age groups, and about $84,000 when used only in younger age groups with denser breast tissue.

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risks and benefits from large studies accurately capture those risks and benefits for very few, if any one individual. While the number needed to screen for the entire NLST population was reported as 320, the average risk individual in the NLST (e.g., a 65-year-old with a 50 pack-year current tobacco history) had an NNS of 256, whereas for very low risk individuals (the authors used as an example a 40-year-old former smoker) the NNS was over 35,000 to prevent lung cancer death.19 When properly applied, the NNS statistic is therefore unique in that it can inform both public policy and individuals in the exam room.

How Do We Communicate Screening Benefits and Risks to Patients? In addition to relating absolute risks of lung cancer death as accurately as possible, there are other useful items that patients should consider when being offered lung cancer screening. At the very least, individuals seeking screening should be counseled not only on the benefit of lung cancer screening with CT with respect to reducing lung cancer mortality but also on the likelihood of a positive screen, the subsequent management of a positive screen, the possibility that a significant non-lung-cancer-related abnormality may be detected, and the implications of a negative screen. The risk of radiation exposure should also be acknowledged, especially when patients express concerns. The nature of screening and the implication of false-positive findings are difficult for many people to comprehend. Patients should be counseled on the notion that screening for lung cancer is not a “test” but rather a process, and one that carries measureable risks. The following are important elements that may come up in the discussion of screening. What does a “positive” CT screen mean? Lung nodules 4 mm and larger and without specific benign features (such as certain patterns of calcification or fat), are considered positive for the purposes of screening. The likelihood of a nodule being detected is dependent in part on the geographic location where the screened individual lives, the thickness of the CT slice reconstruction, and the experience of the radiologist. In NLST, only 4% of patients with a positive screen had lung cancer; put conversely, 96% of the abnormal findings were false-positives. In NLST, 27% of CT-screened individuals had an abnormal screen on the first screening CT examination, and 39% were abnormal after three rounds of screening. In other screening trials, most of which are single-arm screened cohorts, up to 50% of subjects had an abnormal first screening CT examination. In the Mayo Clinic single-arm cohort, after five annual CT screening examinations, at least one noncalcified lung nodule was found in 74% of participants.20 The majority of the abnormal screens are small lung nodules, 4 to 8 mm in size, for which the probability of lung cancer is very low, and proper management is additional low-dose nodule CT examinations. Nodules less than 4 mm are not considered a positive screen, and individuals with these findings should undergo no additional testing but continue to the next annual screening CT. Data from a nonrandomized screening trial indicated that simply increasing the threshold of “abnormal” from 4 mm up to 7 or 8 mm can significantly

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reduce the number of false-positive scares (by perhaps 50%) with only a 5% decrease in the number of cancers detected.21 This practice cannot yet be recommended unless larger studies confirm that a higher threshold for abnormal does not diminish screening efficacy. What happens if my screen is positive? Reassurance of patients with lung nodules is one of the most common tasks of the pulmonologist practicing in a lung nodule clinic. A detailed discussion of communicating information about nodules to patients is beyond the scope of this review, but interested readers are encouraged to read an excellent study by Wiener and colleagues in which the authors elicited patient preferences about “nodule discussions” with their doctors.22 In addition to citing the foregoing data that fewer than 4% of lung nodules found in NLST participants were cancer, there are other data that can be looked to for this reassurance. Although data from nonrandomized screening trials are of very limited value in defining the role of screening, there are useful findings that can be culled from such reports. In a report from one such study of 27,500 individuals who had a negative baseline screening CT, 5.3% of individuals (n ¼ 1,460) developed a new lung nodule on subsequent annual screens. Of these new nodules, only 5% (n ¼ 70) were lung cancer.23 I use these data to reassure both myself and patients with new indeterminate lung nodules of the safety of serial CT observation when the probability of cancer is very low. Further discussion of how to evaluate screendetected nodules follows (see What Is the Proper Approach to Patients with an Abnormal Screen?) If my screening CT is negative, do I need to come back for another one? Screening for lung cancer must be thought of as a process, not a single test. To achieve results comparable to a clinical trial one must duplicate all the features of the trial that have an impact on the outcome. In the NLST, adherence to screening was over 90%.1 Adherence is a major hurdle to translating efficacy to effectiveness in cancer screening and other public health initiatives.24 Subjects seeking screening for lung cancer should be able to articulate that the reason to be screened is to reduce their probability of dying from lung cancer, and that this is best achieved first and foremost through tobacco cessation, and then by LDCT screening, which takes three annual LDCTs to complete. Only those who adhere to the prescribed schedule of CT screening can expect to realize the reduced probability of lung cancer death. What is the likelihood that an invasive procedure will be required to evaluate an abnormal screen? Throughout the NLST, invasive procedures were performed in a very small number of individuals, and the incidence of at least one complication was 1.4% in CT-screened individuals. Among those who did not have cancer, less than 0.1% of the positive screening tests led to a major complication after an invasive procedure. For individuals with cancer, the rate of major complications resulting from an invasive procedure was 11.2%. Of the over 26,000 subjects in the CT arm of NLST, 16 participants, 10 of whom had lung cancer, died within 60 days after an invasive diagnostic procedure (< 0.03%).1 Put another way, there were 10 invasive procedures per life saved, but 640 imaging studies per life saved, most of which were CT Seminars in Respiratory and Critical Care Medicine

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examinations driven by the large number of small nodules detected. What if you find significant abnormalities other than lung cancer on a lung cancer screening CT? In a systematic review of incidental findings on lung cancer screening CT examinations, 14.2% of individuals (confidence interval 13.2–15.2%; n ¼ 4,531 participants) had clinically significant incidental findings requiring additional investigation.25 These abnormalities ranged from lung disease, such as pulmonary fibrosis or bronchiectasis, to aortic aneurysm, mediastinal tumors, and upper abdominal malignancies.26 In a recent study of more than 5,200 individuals undergoing annual lung cancer screening with CT, 0.5% were diagnosed with an unsuspected extrapulmonary malignancy, the majority of which were renal cell carcinomas (44%), followed by lymphoma (26%).27 What is the risk from radiation if I get screened? Most of our understanding of radiation-induced cancer comes from extrapolation of exposure-disease history from Japanese survivors of the atomic bomb. Assumptions about risk require that one accepts the notion that DNA repair capacity from a single large dose of radiation is the same as DNA repair after smaller doses. These assumptions are almost certainly flawed and are likely to lead to overestimates of risk. Nevertheless, widespread use of CT imaging, especially among those with other cancer risk factors, is likely to cause a real but very small number of additional cancers. Estimates of the size of this risk vary, but all are well under the number of additional lives that could be spared lung cancer mortality as a result of LDCT screening.28,29 Consequently, patients should be counseled that there is risk with any medical imaging that uses ionizing radiation, and all use of radiation should be actively limited to the lowest possible level. Newer software-based methods to further reduce the already low dose of screening CTs are being developed, and the imperative to reduce radiation dose should never be taken for granted.30 One of the major achievements of registries for coronary calcium screening CT scans was the robust reductions in radiation dose that were achieved simply by tracking this as an outcome measure in centers participating in the registry.31

What Is the Role of Smoking Cessation as Part of a Lung Cancer Screening Program? Both smoking reduction and smoking cessation reduce the risk of lung cancer.32,33 Because the purpose of a lung cancer screening program is to reduce the likelihood of dying from lung cancer, and this goal is most efficiently achieved through smoking cessation, this is an essential element of any lung cancer screening program. All patients seen in a screening setting should be offered counseling and pharmacotherapy options for smoking cessation. Effective smoking cessation requires that the smoker overcome the cravings and other symptoms of nicotine addiction, as well as the deeply ingrained habit. Picking up and lighting a cigarette are as natural and automatic a behavior for most smokers as walking and breathing. These are the features of the smoking cessation that require conscious thought and active effort to overcome. Smokers are often able to navigate the 3 or so weeks of nicotine withdrawal but fall victim to the habitual and automatic nature of picking up and lighting a cigarette.34 Tobacco cessation products are generally effective at reducing nicotine withdrawal symptoms but less effective at interrupting habitual behavior. Bupropion and varenicline may be more effective in part because they disrupt the neural pathways involved in habitual maintenance.35–37 Follow-up phone calls to encourage continued abstinence after physician visits may also be effective.38 ►Table 3 lists a suggested hierarchy of pharmacological agents that help with smoking cessation, and it is worth noting that the same terms used to describe asthma medications, controller and breakthrough or rescue, can be used conceptually to assist in developing plans for tobacco cessation.

In What Environment Should Screening Take Place and Test Results Be Managed? Screening in general is one of many critical roles played by primary care physicians. This is true, for example, for hyperlipidemia, diabetes, hypertension, domestic violence, and breast, colon, and prostate cancers. Therefore, it is natural to assume that the responsibility for lung cancer screening, if and when this becomes an accepted screening test, will fall to

Table 3 Suggested pharmacological regimens for treating nicotine dependence based on severity of addiction. Mild

Moderate

Severe

Very severe

Controller

Controller

Controller(s)

Multiple controllers

Nicotine patch or bupropion-sustained release or varenicline

Nicotine patch or bupropion-SR

Nicotine patch and/ or bupropion-SR

Nicotine patch and/ or bupropion-SR

Or reliever meds

And/or reliever meds

And/or reliever meds

And/or multiple reliever meds

NNS, NI, NG, NL,a as needed

NNS, NI, NG, NL,a as needed

NNS, NI, NG, NL,a as needed

NNS, NI, NG, NL,a as needed

Or controller

Or controller(s)

Or

Varenicline, alone

Varenicline and/ or bupropion-SR

Varenicline and/or bupropion-SR

NNS, nicotine nasal spray; NI, nicotine (oral) inhaler; NG, nicotine gum; NL, nicotine lozenge. a Reliever medications (“rescue for breakthrough cravings”). When tobacco dependence is controlled (patient is not smoking AND not suffering from nicotine withdrawal symptoms), one can gradually reduce medications one at a time and monitor to maintain abstinence. Seminars in Respiratory and Critical Care Medicine

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primary care providers as well. This is likely to be the most efficient way to bring at-risk patients into contact with CT for lung cancer screening and may ultimately be possible with well-defined guidelines for managing positive screening test results. However, there are important differences between current cancer screening strategies and lung cancer screening. First, the rate of false-positives for lung cancer screening is higher than that for breast, colon, or prostate cancer screening,39 necessitating further testing in a high percentage of patients. This further testing should take place within a multidisciplinary group with experience detecting lung cancer in incidental lung nodules. As noted by the authors of the study, the low incidence of complications from investigation of screen-detected abnormalities in the NLST may not be achievable if the follow-up is done outside of high-volume centers.1 For example, one of the most important factors determining the success of screening will be the surgical mortality after lung cancer resection. This was much lower in the NLST than has been reported previously in the general U. S. population (1% vs 4%).1,40 Second, because screening for lung cancer should only be offered to high-risk individuals and not to the general population, considerable emphasis must be placed on identifying individuals at high risk for lung cancer, particularly those meeting the age and smoking criteria used in NLST. As described earlier, estimating risk is not a standardized or precise practice, even in highly specialized tertiary care research centers.4–6,9 These caveats are not meant to steer the responsibility for lung cancer screening away from well-qualified primary care providers. Rather, the purpose of emphasizing these differences is to suggest that the responsibility of those specializing in lung cancer diagnosis is to (1) develop and provide educational tools to assess risk, (2) disseminate guidelines for managing abnormal CT screening results to primary care physicians, and (3) serve as consultants for managing abnormal findings suggestive of malignancy, especially when additional interventions (e.g., positron emission tomographic scan, biopsy, or surgical resection) may be needed.

How Should CT Scans Be Performed and Interpreted for Screening? CT examinations for lung cancer screening are not the same as routine chest CTs performed for other purposes. Among the most important differences is radiation exposure and slice thickness. NLST used a low-radiation exposure protocol. Although the term low-dose has no standardized definition, the NLST specified technical scan parameters that resulted in a radiation exposure of
1.5 milliSievert (mSv) after LDCT. By comparison a conventional chest CT carries exposure of
5 to 8 mSv. Slice thickness should be 3 mm or smaller, with overlapping reconstructions at 50% of the slice thickness. This allows for improved detection and characterization of nodules, which is particularly important for nodule volume calculations and computer-aided diagnosis. Thicker slices are not appropriate for lung cancer screening. CT scans should always be compared with prior exams directly, and not simply to prior radiologist reports. For each indeterminate nodule, the size, shape, morphology, and lobar/segmental

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location should be reported. The series and slice number should be explicitly recorded in the report to facilitate comparison on future examinations. CT reports should include standard guidelines for further evaluation of positive test results, as developed by multidisciplinary groups, such as the Fleischer Society.41,42 Looking to the future, as techniques are developed for standard, reproducible volume measurement of lung nodules, nodule management may be determined by volume and not simply diameter. For example, investigators in the Dutch– Belgian randomized lung cancer screening trial (NederlandsLeuvens Longkanker Screenings Onderzoek; [NELSON trial]) recommended short-term follow-up for indeterminate nodules based on a volume of 50 to 500 mm3 (or
4–10 mm in diameter), and a repeat CT examination was obtained 3 months later to assess doubling time.43 If the lesion had a volume-doubling time of less than 400 days, subjects were referred to a chest physician for workup and diagnosis.43

What Is the Proper Approach to Patients with an Abnormal Screen? It is important to follow published guidelines on the management of small pulmonary nodules, and, although in-depth discussion of the management of screen-detected nodules is not practical in this review, one must always be aware that the evaluation of nodules starts first and foremost with an estimate of the pretest probability of cancer.44 Numerous prediction models exist for this purpose,45–47 but I have always relied on an older model developed at a time when most nodules were detected by chest X-ray.46 This model has been applied widely and successfully and uses six easily identifiable variables: three clinical variables (age, cancer history, and tobacco history) and thee nodule characteristics (diameter, upper/ lower lobe location, and edge characteristics). With the purpose of screening being to detect lung cancer at an early, asymptomatic, and ideally curable stage, one strategy is to approach abnormal findings with the notion that they are lung cancer until proven otherwise. This may sound extreme in light of data from the NLST (and, coincidentally, in other nonrandomized trials as well23), showing that only
4% of screen-detected abnormalities are cancer. It becomes less extreme when recognizing that the urgency with which “proof of benignity” is pursued, varies from person to person and from nodule to nodule. There are essentially three ways to prove a nodule is benign: 1. The nodule has a benign pattern of calcium, fat, or morphology that suggests an arteriovenous malformation. 2. The nodule exhibits benign biological behavior on serial follow-up low radiation exposure CT examinations for at least 2 years.44 3. The nodule is surgically removed and there is histological confirmation. The higher the pretest probability of malignancy in a nodule, the greater the degree of certainty that is required to prove it is benign. The vast majority of screen-detected nodules require only serial radiographic follow-up, usually with one extra CT done at a 4- to 6-month interval. Biopsy Seminars in Respiratory and Critical Care Medicine

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should be reserved for nodules with an intermediate pretest probability and not just to assuage patient anxiety. Although a biopsy (transbronchial or CT-guided) uncommonly provides a definitively benign result, when a “benign” diagnosis such as granuloma or organizing pneumonia is made, this is usually not a license to ignore the nodule. Some degree of follow-up to exclude a falsely negative biopsy result is to ensure resolution or lack of growth. Patients with nodules highly suspicious for cancer who are at very high risk for resection can be referred for tissue biopsy so that all treatment options (surgery, radiotherapy) can be discussed appropriately. Similarly, when an indeterminate nodule is large enough to be characterized on positron emission tomography (PET), generally when it is 8 mm or larger, a CT-PET scan should be performed.44 A negative PET is not license to cease evaluation of the nodule, but to follow the nodule using low-dose CT. Biopsy offers very little benefit and considerable risk in an otherwise healthy individual who has a nodule highly likely to be malignant (e.g., based on size, patient age, and nodule characteristics46). These patients should be referred for surgical resection.44,48 When approaching a patient with a nodule of low probability for lung cancer, the Fleischner Society Guidelines41 have performed very well for both patients and physicians in detecting malignancy while minimizing the number of CT scans required to reach proof of benignity. I strongly recommend adhering to these guidelines when selecting the interval of follow-up CT scans on indeterminate pulmonary nodules.41,42 It is clear that the “2-year rule” for radiological follow-up is not always sufficient to establish a benign etiology, particularly for pure ground-glass and mixed solid-ground-glass nodules, which carry a higher likelihood of malignancy than purely solid nodules but which can remain indolent for many years. One point that should be stressed again is that the management of patients with pulmonary nodules is best performed within the context of a multidisciplinary team consisting of radiologists, nuclear medicine specialists, surgeons, pulmonologists, and cancer specialists, all of whom preferably have a significant proportion of their practice focused on the management of patients with known or suspected lung cancer.40,49 Radiologists practicing in teaching hospitals or in a practice with at least one fellowship-trained thoracic radiologist are more likely to be aware of and follow the Fleischner Society guidelines than other radiologists.50

What Is the Proper Approach to Patients with a Negative Screen? Many feared that normal screening results would result in lesser rates of tobacco cessation, and that patients would not return for follow-up screens. Neither of these fears appeared to have been realized in the NLST.1 Patients with normal screening results should be reminded that screening for lung cancer is a process over time, not a single test, and that the mortality benefit of screening seen in NLST was achieved by yearly CT scans for 3 years. There are currently no data to support screening beyond 3 years, but extrapolating results of the NLST suggest that continued screens beyond three annual scans may yield greater Seminars in Respiratory and Critical Care Medicine

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mortality benefit than the 20% reduction in lung cancer–specific mortality observed in this trial.1,51 Further data and projected modeling of mortality as well as cost-effectiveness analyses from published screening studies will likely inform the decision as to whether to screen beyond three annual CT scans.

What Data Should Lung Cancer Screening Programs Collect? Establishing a lung cancer screening program in the current health care environment should come with a responsibility to establish a registry and standardized database of screened subjects, a biospecimen repository (where this is feasible) to facilitate development and/or validation of biomarkers, and a commitment to working in multidisciplinary groups to develop and/or prospectively validate a model that measures risk at the individual level. Suggested variables for registries include the lung cancer risk factors of screened individuals (with benchmarking using published models of risk such as those in ►Table 1), the results of the screen, the parameters of the CT scan (dose, slice thickness), the presence of any abnormal findings, the downstream testing done to investigate those findings, and complications resulting from screendetected abnormalities. We should not miss the opportunities presented by screening programs to conduct important research in improving the outcomes of screening and improving health care delivery in general. There are many lessons we should heed from past examples of mass implementation of cancer screening. One such lesson is the importance of radiological quality control as now legislated for mammography screening programs for breast cancer. A second area where past research has resulted in improvements in patient care is in colonoscopy screening for colorectal cancer. The sizable task of demonstrating a reduction in cancer-specific mortality with a screening modality does not necessarily lead to widespread adoption of screening behavior by those at risk. In the field of colorectal cancer, investigators specializing in health communications have taught us that patients process information on disease risk and screening benefits very differently from specialists, who differ still more from primary care physicians.52–54 It is also very likely that these beliefs will vary by socioeconomic, ethnic, and racial factors. Because the risk for lung cancer also varies over these same characteristics, successfully providing effective screening services to those at risk will necessitate that we characterize how screening behaviors vary by these social and genetic differences. If we can develop studies to define how laypersons understand their risk for lung cancer, and how these beliefs will affect their acceptance of lung cancer screening, we can more effectively direct screening resources at those most likely to benefit. Some investigators have anticipated this, and older studies done in populations at risk for lung cancer have shown concerning findings in that those most at risk for lung cancer may be among those least likely to accept screening.55 These studies predated the NLST findings that demonstrated the effectiveness of LDCT screening for lung cancer, and we will need further work in this area to understand whether these preferences persist in the current climate. Furthermore, if

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those most at risk for lung cancer are least likely to adhere to recommendations for screening, we should support studies to inform how we communicate risks of cancer and benefits of screening.

What Is the Cost-Effectiveness of Lung Cancer Screening and What Variables Have the Greatest Effect on the Costs, Benefits, and Harms of Screening? Most data on screening costs and cost-effectiveness are based upon models employing retrospectively collected data. Over the years prior to the publication of the NLST results, there were a variety of studies that attempted to model the potential costeffectiveness of lung cancer screening. This was a difficult task without evidence that there was any clinical efficacy in lung cancer screening, and each study employed a series of assumptions that would be expected to impact the results of the analysis. One of the major strengths of the NLST study design was the prospective inclusion of a substudy designed to determine the cost per quality adjusted life-year ($/QALY), or costeffectiveness, of lung cancer screening. These data (unpublished at the time of this writing) were announced on June 24, 2013m at a joint meeting of the National Cancer Advisory Board and the NCI Board of Scientific Advisors (http://videocast.nih.gov/live. asp?live¼12906&bhcp¼1 accessed June 25, 2013). The $/QALY for three rounds of LDCT screening in high-risk smokers enrolled in NLST was $72,916—in line with other screening tests in practice today, including mammography (see ►Table 2). Each cost-effectiveness study is based on some assumptions, and the effect of these assumptions is modeled in a sensitivity analysis once the base cost analysis is complete. During this public presentation, the major uncertainties in the NLST analysis suggested that, to the degree the assumptions were incorrect, the calculations of $/QALY were likely an overestimate. Selected variables that would improve the cost-effectiveness of LDCT screening for lung cancer included underestimating the efficacy of plain chest X-ray as a screening modality (unlikely) and additional “catch-up” cases in the control group (cases that were not detected in the control group that would eventually develop during longer follow-up. The model used assumed no further catch-up), decreasing cost of LDCT, and fewer follow-up studies done for indeterminate nodules. Conversely, variables that could significantly increase the $/QALY were identified as well, and most were simply the opposite of the variables that would decrease costs. One very important variable that could markedly increase the $/QALY (decrease cost-effectiveness) of LDCT screening is implementing screening a population with lower risk for lung cancer than that of the NLST-screened population. Such a practice would rapidly render screening as very ineffective from a cost standpoint. Physicians, patient advocates, public health authorities, and policy makers will be looking to the peer-reviewed publication of these data when making decisions regarding coverage of LDCT screening as a benefit in health care insurance.

Conclusion In summary, while the NLST findings represent a watershed moment in the effort to reduce lung cancer mortality, they

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represent more of a new beginning than an end point. Lung cancer screening with three annual CT scans using a low-dose protocol has the potential to reduce lung cancer–specific mortality by 20% in a population of older heavy smokers. The importance of this achievement by the NLST investigators cannot be overstated, but this should be viewed as an important first step, not a final destination. Many major questions remain about how to best realize this mortality reduction in a practical real-world context. Screening for lung cancer can and should be done, but it will be most effective if it is accompanied by continued research into risk modeling, patient communication, biomarkers along the full spectrum from molecular predictors of risk, to diagnostic and prognostic biomarkers as well. For clinicians seeking to establish a program of lung cancer screening, we encourage this to be done in a responsible fashion, adhering to practices specified in the design of the NLST, and with as much attention given to proper management of screen-detected abnormalities as is given to the initial screening process. As a final note, on July 30, 2013, the U.S. Preventive Services Task Force (USPSTF) issued a draft recommendation, seeking public comment on their conclusion that “Based on the available evidence, the Task Force recommends screening people who are at high risk for lung cancer with annual lowdose CT scans.” This is the first such recommendation for lung cancer screening from the USPSTF and will likely lead to this being adopted on a limited basis. The USPSTF statement also emphasized that screening is not a substitute for rigorous tobacco cessation initiatives.

Acknowledgments The author thanks Dr. Jeffery Horowitz for critical review of this manuscript.

Conflicts of Interest/Disclosure None

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